Author Archives: author

Summary About Health Education and Strategies on HIV Prevention Among Adolescents in Schools

1 Reply

DOI: 10.31038/IJNM.2025611

 
 

When analyzing the general vulnerability of the population, we realize that sexual transmission is among the most well-known forms of contagion among adults from 1980 to the present day. Some data from UNAIDS (the joint United Nations program on HIV/AIDS) indicate that there were around 37.7 million people worldwide living with HIV in 2020, of which 36 million were adults and 1.7 million were children (0-14 years old).

In Brazil, in addition to these statistics used as a basis for a study on the subject, some research was carried out by the Ministry of Health itself, which showed that AIDS is growing much more among young people (15-24 years old) than among adults in the last 11 years, confirming that everyone in the health area, specifically nurses, must be able to care for these young people and generate more consistent and comprehensive sexual health education for them. In Brazil, there is a very strong culture stemming from religion, where by simply talking about sex education, parents and guardians judge health professionals as influencing their children to engage in sexual acts, when in reality, we professionals only want to educate them, showing them how to prevent this disease and other events in their lives, such as an unwanted pregnancy. Another barrier found here in Brazil, due to religion, is that many parents and guardians do not talk to their children about sex education at home, leaving them with doubts and fear of talking to responsible adults. As a result, they look for answers on the internet, with friends of the same age, or even older, and end up not receiving all the prevention methods correctly.

In Brazil, we do not have nurses working in schools, as is the reality in many other countries.We believe that if a nurse were on standby in a school, which is where most of these young people (14-19) begin to have their first sexual contacts, we could educate them in a professional manner based on the prevention of sexually transmitted infections. Campaigns using youthful language would also make it much easier to share these prevention measures, thus allowing for easier and continuous communication to clear up any doubts that many people are unable to do at home.With these small changes and actions, the number of adolescents with HIV/AIDS would certainly decrease, as young people would have a safe space and source to talk about their sexual health without suffering prejudice from society or their own family.

Extreme Element Enrichment, According to the Lorentzian Distribution at the Transition of Supercritical to Critical and Under-Critical Melt or Fluids

1 Reply

DOI: 10.31038/GEMS.2024675

Abstract

We show the relationship between supercritical fluids or melts from mantle regions with the Variscan tin mineralization in the Ehrenfriedersdorf region in Central Erzgebirge, Germany. The formation of the primary tin mineralization and the granite pegmatites are immediately triggered or generated by such fluids, which by their load of high-pressure and high-temperature minerals such as diamond, lonsdaleite, graphite, and moissanite, as well as by the orthorhombic cassiterite (CaCl2-type) show clearly his origin. At least that means that the old ideas of the formation of the tin deposit Ehrenfriedersdorf (and others) need a critical reassess.

Keywords

Supercritical fluids, Pegmatites, Melt inclusions, Immiscibility, Extreme element enrichment, Lorentzian element distribution

Introduction

From the study of silicate melt inclusions, mostly in quartz, of evolved Variscan granites and pegmatites of the Erzgebirge region, Germany, we have found in both rock types melt inclusion which forms pseudo-binary solvus curves [1]. Both curves of granites and pegmatites in the coordinates of the water content of the silicate melt versus homogenization temperature are similar. The main difference between both rocks is the frequency of the relative water-rich melt inclusions. In granites, these inclusions are significantly rarer than in pegmatites; maybe the α-β-transition of quartz caused an influx of hydrothermal water and the destruction of melt inclusions by that. However, the solvus crests of both curves lie about in the same order of water concentration, slightly lower for the pegmatites. The temperature for the granite solvus is noticeably higher, ~760 vs. 700°C for pegmatites. Figures 1a and 1b show the solvus curves for granites (a) and pegmatites (b) in the coordinates of water content versus temperature. The asymmetry of the solvus curve for the pegmatites is striking and typically for most studied pegmatites [1]. Both solidus curves for granites and pegmatites suggest a relatively simple formation process. According to Vogel (1992) [2], the immiscibility process can proceed in different steps (with different composed droplets and matrix composition). Figures 6.18, 7.27, 7.28, and 7.29 in Vogel (1992) [2] show that impressive. Using hydrothermal diamond anvil cell (HDAC) experiments on synthetic pegmatite systems, such multi-stage immiscibility processes could be visually demonstrated (see also further below).

Figure 1: Solvus curves for the Variscan granites (a) and pegmatites (b) belonging to the Ehrenfriedersdorf region in central Erzgebirge, Germany. CP is the critical point.

By the rarity of melt inclusions in granites, we could, up to now, obtain no element distribution curves similar to the pegmatites for this rock. However, in some granite melt inclusions, there are also higher values of rare elements. Table 1 shows exemplary data for the Greifenstein granite near Ehrenfriedersdorf (Li, V, Zn, Rb, Nb, Cs, Ta) – see Borisova et al. 2012 [3].

Table 1: Enrichment of some elements in melt inclusions in quartz of the Greifenstein granite near Ehrenfriedersdorf, Central Erzgebirge, Germany. Clarke values according to Rösler and Lange (1975) [4].

Element

 Clarke for granitic rocks MI E2 in Greifenstein granite

Enrichment

Li

40

 4353 109
V 20 63.2

3.2

Zn

 40 905 22.6
Rb 200 3999

20

Nb

 20 1063 53
Cs 5 526

105

Ta

 3.5 488

139

The high concentration of trace elements in the accompanying granite (Greifenstein) makes it possible that the high concentration of trace elements in the granite and those of the pegmatites have a common source. The proof for that statement is the relicts of high- pressure and high-temperature minerals (diamond, lonsdaleite, moissanite, and others coming from mantle depths.

Sample Material and Methodology

Sample Materials

The used sample material is mentioned in the text and cited in the corresponding references. Generally, we used quartz crystals from pegmatites of the Variscan Ehrenfriedersdorf tin-tungsten deposit in the Central Erzgebirge/Germany. Most samples come from pegmatites of the Sauberg mine in the South of Ehrenfriedersdorf. A detailed description is in Hösel (1994) – [5-7]. Thermometrische data on fluid inclusions are in Thomas 1982 – [8]. Studies on melt inclusions in pegmatite, mainly from the Ehrenfriedersdorf mining district, are being stimulated by Thomas (2024a) [9].

Methodology

Details for the preparation (homogenization and analyses of the melt inclusions) of the used samples are in numerous publications of the first author [8,10-13], Thomas and his coauthors [1,14-17]. For homogenization of the melt inclusions, we generally used the conventional rapid hydrothermal quenching technique at 100, 300, and 500 MPa [15] as well as the cold-seal pressure vessel homogenization technique, using CO2 (± Ar) up to temperatures, starting at 500°C, to 800°C. For the chemical analysis (main and trace elements) of the melt inclusions, we used different micro-techniques [3,14,15,18,19].

Raman Spectroscopy

From 1993, the first author used a Dilor XY Laser RamanTriple 800mm spectrometer, and starting in 2005, the Jobin-Yvon LabRam HR800 spectrometer (grading: 1,800 g/mm) equipped with an Olympus optical microscope. We used the intern 633 nm and the 325, 488, and 514 nm excitation of a Coherent Ar+ laser Model Innova 70-3, and for the UV excitation (325 nm), the 35 mW HeCd-laser. After 2022, we performed all microscopic and Raman spectroscopic studies with a petrographic polarization microscope with a rotating stage coupled with the EnSpectr Raman spectrometer R532 for reflection and transmission. The Raman spectra were recorded in the spectral range of 0–4000 cm-1 using an up to 50 mW single-mode 532 nm laser, an entrance aperture of 20 μm, a holographic grating of 1800 g/mm, and a spectral resolution ranging from 4–6 cm-1. Generally, we used an objective lens with a magnification of 100x – the Olympus long-distance LMPLFLN100x objective. The laser power on the sample is adjustable down to 0.02 mW. The Raman band positions were calibrated before and after each series of measurements using the Si band of a semiconductor-grade silicon single-crystal. The run-to-run repeatability of the line position (based on 20 measurements each) is ± 0.3 cm-1 for Si (520.4 ± 0.3 cm-1) and 0.4 cm-1 for diamond (1332.7 ± 0.4 cm-1 over the range of 80–2000 cm- 1). The FWHM = 4.26 ± 0.42 cm-1. FWHM is the Full-Width at Half Maximum. We also used a water-clear natural diamond crystal (Mining Academy Freiberg: 2453/37 from Brazil) as a diamond reference (for more information, see Thomas et al. 2022) [17].

Results

In the papers of Thomas et al. [1,20], we have shown the general results on melt inclusions in pegmatite quartz from different locations. The main results are the specific distribution of some trace and main elements, which show Gaussian or Lorentzian distributions with the water content of the pegmatite melt. The maximum of the Gaussian or Lorentzian distribution curves is mainly related to the solvus crest of the pseudo-binary melt-water system. A schematic picture shows Figure 2.

Figure 2: Schematic diagram of the solvus curve of melt-H2O systems (red) and the Lorentzian distribution of some trace and main elements (green) according to Thomas and Rericha (2024) [21]. CP is the critical point of the pseudo-binary solvus curve. Water content, temperature, and concentration are in reduced coordinates (see Guggenheim 1945) [22].

That is typical for pegmatites primarily associated with the Variscan tin-specialized granite Erzgebirge. In the case of different species of an element (e.g., phosphate or borate of Be), the maxima of molecule species are distinct. Figure 3 shows such a case for the relationship of water versus Be concentration for some pegmatites of the Ehrenfriedersdorf tin deposit.

Figure 3: Distribution of Be (in ppm) in some melt inclusions in pegmatite quartz from Ehrenfriedersdorf. The sum curve (grey) results from the overlapping of two Lorentzian components caused by different Be-complexes in the melt inclusions: Peak 1 (red) for beryllonite [NaBePO4], and peak 2 (blue) for hambergite [Be2BO3(OH,F)] as daughter phases in the melt inclusions.

In Figure 3, the center of peak 1 is at 25.5 (%(g/g)) H2O, the height of the Lorentzian curve is at 12840 ppm Be, and the center of peak 2 is at 31.0 (%(g/g)) H2O and 4280 ppm Be. The highest Be value measured in a melt inclusion was 71500 ppm Be (from a large daughter crystal hambergite in a melt inclusion. Such runaway data destroy the nearby ideal Lorentzian into a pseudo-Lorentzian curve. Such runaway data are not only related to Be. We have found such a relationship, for example, for Sn and B, too (Figure 4).

Figure 4: Tin distribution in the pegmatite system Ehrenfriedersdorf (Sauberg mine). The Lorentzian maximum corresponds to about 0.6 (% (mol/mol)) SnO2. The up to now found maximal value corresponds to 1.39 (% (mol/mol)) SnO2, probably as Sn2+.

Figure 4 shows the Lorentzian plot of Sn (in ppm) versus the H2O concentration for water-rich melt inclusions in pegmatite quartz from Ehrenfriedersdorf: Area 54207, Center 25.8 (% (g/g) H2O, width 5.2 (% (g/g)) H2O, offset 547 ppm Sn, height 6606 ppm Sn. With cooling, there is also a change in the tin speciation, starting from the critical point in the direction of lower water concentration, an increase of Sn4+, and in the direction of higher water concentration, the Sn2+ bearing species increase, indicated by the arrows. Studies also show that not only species (cations and anions) are separated during the formation of the immiscibility curve, but also isotopes. At this place, we must remember that obviously, a lot of tin, in the case of Ehrenfriedersdorf, is supplied by the supercritical fluid or melt, solved in these phases or suspended as orthorhombic high-pressure and high-temperature cassiterite [21-24].

Figure 5 shows the B content of melt inclusions from pegmatite quartz, which plots a nice solvus curve. More details are given by Thomas (2002) [25]. The point over the solvus crest (CP) – 16.0 % B2O3 (= 28.42 % H3BO3) – represents an early value beyond the bulk equilibrium conditions. Similar runaway concentration data for elements (over the solvus crest) are not rare. A typical case describes Borisova et al. (2012) [3] for the extreme enrichment of zinc (75,258 ppm) and wolfram (4617 ppm) and further elements in two adjoining pegmatite inclusions. Figures 1 and 5 show pseudo-binary solvus curves. They represent equilibrium conditions obtained from homogenization experiments up to 760°C. The runaway data in Figures 3, 4, and 5 represent data trapped at higher temperatures and pressures. These are single points (melt inclusions) representing higher temperatures because, at conditions of the critical point of the solvus, the solubility of elements at higher temperatures must also be significantly higher. If they would form another complete solvus curve, more points around the critical temperature would be found. If we plot the B-concentration versus the temperature of melt inclusions from the Erzgebirge region, we obtain the following graph (Figure 6).

Figure 5: Boron versus water concentration in conjugate type-A (green) and type-B melt inclusions (blue) in the Ehrenfriedersdorf pegmatite quartz. Both points portray a solvus curve (melt-water system). CP is the critical point.

The plot (Figure 6) shows that the solvus curves represent the magmatic equilibrium end state and that the beginning of the evolution is at significantly higher temperatures (supercritical state) and under non-equilibrium conditions. Up to a temperature of about 500°C, the points represent the hydrothermal state, and from 500°C upwards start the pegmatitic and magmatic stages.

Figure 6: Correlation between B2O3 concentration in pegmatite melt inclusions and the homogenization temperature, mainly for the Ehrenfriedersdorf tin deposit (simplified, without standard deviations for B2O3 and T). The pegmatite and the magmatic stages end at about 500°C. Lower temperatures are typically for hydrothermal mineralizations.

Discussion

The origin of this type of element distribution is up to now unknown. Further studies have shown that the samples that show such exceptional element distribution contain minerals like diamond, lonsdaleite, moissanite, and orthorhombic cassiterite transported as solid aggregates, which are totally foreign to the parageneses in a more crustal region see Thomas et al. 2023) [26]. We interpret these as remnants of minerals coming from high-pressure and high-temperature areas – from the Earth’s mantle. Besides these solid aggregates suspended in the supercritical fluid or melt, the supercritical medium contains a lot of chemical ions. The content of solid and solved load depends on the way in which the supercritical phase moves from the mantle to the crust, which varies from place to place. If older ore deposits in the mantle by subduction are present, the origin of ore-forming elements or their more substantial enrichment is explainable. The processes of element enrichment at the transition from supercritical to critical and under-critical states and high temperatures are not well understood. Because the elements and compounds are in the melt inclusions, there are a lot of different processes working more or less simultaneously for the enrichment of elements. To obtain an idea of the complexity of pegmatite-forming processes, look at Figures 7 and 8.

Figure 7: HDAC experiment on a synthetic pegmatite melt (740°C). All bubble-like bodies are melt droplets (see insert). The large bubble contains smaller ones with different compositions. The white field is an aqueous pegmatite phase. The gasket diameter is 400 µm (according to unpublished data by Veksler et al. 2002) [25].

From the experiences obtained in the last 55 years on the Variscan tin-tungsten deposit Ehrenfriedersdorf and the related pegmatites, the following generalizations are possible:

  1. Quartz crystals start to grow and trap droplets of the surrounding (quasi-supercritical) fluid.
  2. At high temperatures, the trapping of rare elements (B, Be, Cs, Sn) depends only on the water content level, which the solvus crest determines – that is, outside the system equilibrium.
  3. With further cooling, the incorporation of rare elements, according to the Lorentzian distribution,
  4. Further growth of the quartz crystals is related to forming a thin semipermeable quartz film closing the trapped inclusion from the surrounding, which locks up the trapped droplet.
  5. Diffusion exchange between inclusion and surrounding via that semipermeable film, which increases in thickness up to the end of diffusion.
  6. The increasing thickness of the semipermeable film determines the change in the molecules passing this barrier, too.
  7. At the same time, a liquid boundary layer forms around the growing quartz crystal. In this boundary layer, the concentration of SiO2 is strongly reduced, and other elements are very enriched.
  8. Maybe microcrystals of different minerals grow in this boundary layer via Ostwald ripening and are trapped together with droplets into the growing quartz crystal.
  9. Multi-step immiscibility at falling temperatures leads to a heterogenic enrichment and distribution of some elements and compounds that are trapped at different temperatures.
  10. The micro-crystals growing in the boundary layer also receive the ions from the bulk fluid reservoir.
  11. The high diffusivity and low viscosity favor the Ostwald ripening, beginning at the transition from supercritical to critical and under critical stages.
  12. According to HDAC experiments, we know that immiscibility processes down to the microscale work during the whole crystallization of quartz and the connected trapping process of
  13. At high temperatures, the forming and trapping of rare compounds, g., beryllonite and hambergite, is energetically preferred because the solubility of beryllium is also very high in supercritical fluids.
  14. If the temperature falls under 500-400°C, an extremely fast crystallization starts.

Figure 8: HDAC experiment on a synthetic pegmatite melt (up to 900°C, now at room temperature). All bubble-like grey globules are at room-temperature glass (the former melt 2 is suspended in matrix glass – melt1). The fluid inclusion in the lower photomicrograph, produced by a rapid-quench cold-seal pressure vessel experiment (900°C, 0.2 GPa) contains a vapor bubble (dark) and an H3BO3 crystal (white) in a boric acid-rich solution (see Veksler et al. 2002 [25]). The bulk H3BO3 concentration is about 8.6 [%(g/g)].

Let’s consider the results and the generalization of the complex processes related to the formation of granite pegmatites, probably triggered by supercritical fluids coming from mantle depths. We see that the old ideas of the formation of the tin deposit Ehrenfriedersdorf (and others) need a critical reassess.

Acknowledgment

We thank many colleagues very much who have supported the work on pegmatites in the last 55 years (O Leeder, J D Webster, R Bodnar, W Heinrich, P Davidson, I Veksler, E Badanina, and many others).

References

  1. Thomas R, Davidson P, Appel K (2019) The enhanced element enrichment in the supercritical states of granite-pegmatite systems. Acta Geochim 38: 335-349.
  2. Vogel W (1992) Springer. Pg: 548.
  3. Borisova AY, Thomas R, Salvi F, Candaudap F, Lanzanova A, et al. (2012) Tin and associated metal and metalloid geochemistry by femtosecond LA-ICP-QMS microanalysis of pegmatite-leucogranite melt and fluid inclusions: new evidence for melt-melt-fluid Mineralogical Magazine 76: 91-113.
  4. Rösler JH, Lange H (1975) Geochemische Leipzig. Pg: 675.
  5. Hösel G (1994) Das Zinnerz-Lagerstättengsebiet Ehrenfriedersdorf/Erzgebirge (1994). Freiberg. Pg: 195.
  6. Schröcke H (1954) Zur Paragenese erzgebirgischer Zinnlagerstätten. Neues Jahrbuch Mineralogie, Abhandlungen 87: 33-109.
  7. Schütze H, Stiehl G,Wetzel K, Beuge P, Haberlandt R, et al. (1983) Isotopen- und elementgeochemische sowie radiogeochronologische Aussagen zur Herkunft des Ehrenfriedersdorfer Granites. – Ableitung erster Modellvorstellungen. ZFI- Mitteilungen Leipzig 76: 232-254.
  8. Thomas R (1982) Ergebnisse der thermobarometrischen Untersuchungen an Flüssigkeitseinschlüssen in Mineralen der postmagmatischen Zinn-Wolfram- Mineralisation des Erzgebirges. Freiberger Forschungshefte C370, Pg: 85.
  9. Thomas R (2024a) Vom Schmelzeinschluss zum superkritischen Fluid – Ergebnisse und Folgen der Befahrung der Grube Sauberg bei Ehrenfriedersdorf. Veröffentlichungen Museum für Naturkunde Chemnitz 47: 59-66.
  10. Thomas R (2000) Determination of water contents of granite melt inclusions by confocal laser Ramanan microprobe American Mineralogist 85: 868- 872.
  11. Thomas R (2002) Determination of the H3BO3 concentration in fluid and melt inclusions in granite pegmatites by laser Raman microprobe spectroscopy. American mineralogist 87: 56-68.
  12. Thomas R, Klemm W (1997) Microthermometric study of silicate melt inclusions in Variscan granites from SE Germany: Volatile contents and entrapment conditions. Journal of Petrology 38: 1753-1765.
  13. Thomas R, Webster JD (2000) Strong tin enrichment in a pegmatite-forming Mineralium Deposita 35: 570-582.
  14. Thomas R, Förster, H-J, Rickers K, Webster JD (2005) Formation of extremely F-rich hydrous melt fractions and hydrothermal fluids during differentiation of highly evolved tin-granite magmas: a melt/fluid inclusion study. Contrib Mineral Petrol 148: 582-601.
  15. Thomas R, Davidson P, Rhede D, Leh M (2009) The miarolitic pegmatites from the Königshain: a contribution to understanding the genesis of Contribution to Mineralogy and Petrology 157: 505-523.
  16. Thomas R, Webster JD, Davidson R (2011) Be-daughter minerals in fluid and melt inclusions: Implications for the enrichment of Be in granite-pegmatite systems Contrib Mineral Petrol 161: 483-495.
  17. Thomas R, Davidson P, Rericha A, Recknagel U (2022a) Water-rich coesite in prismatine-granulite from Waldheim/Saxony. Veröffentlichungen Naturkunde Museum Chemnitz 45: 67-80.
  18. Rickers K, Thomas R, Heinrich W (2004) Trace element analysis of individual synthetic and natural fluid inclusions with synchrotron radiation XFR using Monte Carlo simulation for European Journal of Mineralogy. 16: 23-35.
  19. Rickers K, Thomas R, Heinrich W (2006) The chemical evolution of a water-, B- and F-rich granite-pegmatite system related to a Sn-W mineralization: a melt/fluid inclusion study. Mineralium Deposita. 41: 229-245.
  20. Thomas R, Davidson P, Rericha A, Voznyak, DK (2022b) Water-rich melt inclusions as “frozen” samples of the supercritical state in granites and pegmatites reveal extreme element enrichment resulting under non-equilibrium conditions. Mineralogical Journal (Ukraine). 44: 3-15.
  21. Thomas R, Rericha A (2024) Meaning of supercritical fluids in pegmatite formation and critical-element Geology, Earth and Marine Sciences. 6: 1-5.
  22. Guggenheim EA (1945) The principle of corresponding The journal of chemical physics. 13: 253-261.
  23. Thomas R (2024b) The CaCl2-to-rutile phase transition in SnO2 from high to low pressure in Geology, Earth and Marine Sciences. 6: 1-4.
  24. Thomas R (2024c) Rhomboedric cassiterite as inclusions in tetragonal cassiterite from Slavkovský les – North Bohemia (Czech Republic). Geology, Earth and Marine Sciences. 6: 1-6.
  25. Veksler IV, Thomas , Schmidt C (2002) Experimental evidence of three coexisting immiscible fluids in synthetic granitic pegmatite. American Mineralogist. 87: 775-779.
  26. Thomas R, Davidson R, Rericha A, Recknagel U (2023) Ultra-high pressure mineral inclusions in crustal rocks: Evidence for a novel trans-crustal transport mechanism. Geosciences. 94: 1-3.

Long COVID: A Diagnostic Methodology (An Observational Study)

1 Reply

DOI: 10.31038/JCRM.2025811

Abstract

Importance: Long COVID has been defined as a chronic medical condition that occurs after a SARS-CoV-2 infection and is present for at least three months [1-3]. Long COVID includes a wide range of symptoms or conditions that may improve, worsen or to be ongoing, per criteria published by the Centers for Disease Control and Prevention. However, criteria confirming the diagnosis has yet to be developed. Several others have, though, identified a clinical overlap between Long COVID and fibromyalgia [4-10]. Their theories, however, lacked any objective documentation for the existence of fibromyalgia and therefore, the use of a well-established diagnostic fibromyalgia blood test was the basis for analyzing a cohort of patients with Long COVID.

Objective: To determine whether Long COVID infections could be objectively diagnosed via a blood test based upon the shared and proven characteristics between Long COVID and fibromyalgia.

Design, setting and participants: This cohort study recruited individuals who historically were diagnosed to have Long COVID based upon evidence of a past COVID-19 infection and related persistent symptoms. None of the individuals had experienced previous similar symptoms prior to the onset of their COVID-19 infection. Each individual had only experienced a single COVID-19 infection.

We recruited test-positive SARS-CoV-2 patients who had no chronic medical complaints prior to the onset of this infection and who post-SARS-CoV-2 had at least a 6 month history of chronic medical complaints, the nature of which have been recognized as common manifestations which define a Long COVID medical status. Those manifestations also classically define what afflicts fibromyalgia patients. The latter relationship has been recognized by multiple other researchers. These patient volunteers underwent blood testing for established immune system biomarkers which document and confirm the diagnosis of fibromyalgia.

Main outcomes and measures: A total patient population of 21 individuals was recruited. An analysis via blood testing looking for established criteria for the diagnosis of fibromyalgia which included peripheral blood mononuclear cell related deficiencies regarding the chemokines and cytokines of MIP- 1alpha, MIP-1beta, IL-6 and IL-8 of all of the patients documented that 18 now had evidence of these fibromyalgia diagnostic criteria.

Results: Clinical data regarding 21 volunteers was obtained to confirm their development of a SARS-CoV-2 infection. They were individually interviewed and they completed related health questionnaires. All volunteers had evidence of a positive COVID-19 test score. All of the volunteers denied having a pre-existing background of similar symptoms. The volunteers were 13 females and 8 males. The symptoms reported were: Headaches (78%), Brain Fog (72%), Fatigue (67%), Depression/Anxiety (61%), Joint/Muscle Pain (50%), Sleep Disturbance (50%), Dizziness (44%).

Conclusions and relevance: A percentage of individuals who contract a COVID-19 infection will develop a “Long Haul” residual set of symptoms which they did not previously experience. These symptoms mirror a medical disease termed fibromyalgia, which is actually an immune deficiency medical disorder. Consequently, a recognized, peer-reviewed, highly sensitive and highly specific diagnostic fibromyalgia blood test was performed on these 21 Post COVID-19 infection individuals. Of this group, 18 (86%) tested positive for fibromyalgia. Therefore, a potential explanation for their persistent symptoms was objectively indentified and a potential origin of fibromyalgia was detected and linked to a Corona virus(es).

Introduction

The Sars-CoV-2 virus (COVID-19) induced a worldwide pandemic commencing in 2019. Though its primary manifestations concerned the human respiratory tract, significant and major immune system effects were also identified. A percentage of these patients went on to experience residual and persistent symptoms and rarely had there been a pre-existing nature of those medical complaints. According to the CDC Household Pulse Survey, those with these Long Haul traits can amount to 20% of those who developed a confirmed COVID-19 infection. The major symptoms the latter group reported included neurologic (brain fog, headaches, sleep problems, dizziness, depression or anxiety), fatigue, and joint or muscle pain. These symptoms are also classical manifestations of the medical disease known as fibromyalgia. However, no etiology of fibromyalgia has ever been identified, though estimates of the incidence of this medical condition are estimated to range as high as 6% of the population. Further, fibromyalgia has been reported in the medical literature for decades and long before the Corona virus of Sars-CoV-2 was known to exist.

We therefore decided to explore a potential set of relationships between Long Haul Post-COVID-19 patients and fibromyalgia patients. To do so, we relied on a peer-reviewed, highly sensitive and highly specific blood test which was developed by the Department of Pathology at the University of Illinois College of Medicine at Chicago. This test has been commercialized under the names of the FM/a® Test, the 100SURE Test and the BSURE Test.

We recruited a cohort of 21 Long Haul patients and they were screened not only for evidence of a previous COVID-19 infection but to also confirm the residual medical complaints they were experiencing. Our goals included whether there was an objective manner to document their persistent symptoms, to learn whether there could be a link to fibromyalgia and to explore the possible role of a human Corona virus in the origin of fibromyalgia.

Methods

Via multi-media, patients who had objective evidence of a previous COVID-19 infection and were experiencing the characteristics of Long Haul COVID in the Chicago, IL area were recruited. They were screened in-person to confirm that they met the latter criteria and were documented to have never had such symptoms on a prior basis. After receiving informed consents (UIC IRB), a total of 21 patient volunteers were identified. All then underwent the FM/a® Test diagnostic blood test to determine whether they had proof of fibromyalgia. The FM/a® test determines whether there are specific deficits in the chemokines and cytokines of MIP-1alpha, MIP-1beta, IL-6 and IL-8 [11,12]. All participants additionally were personally interviewed and they individually completed related health questionnaires.

Results

The volunteers were asked via their self-reporting questionnaires whether they were experiencing not merely established Long Haul COVID-19 symptoms but also whether they had any chronic or pre-existing medical complaints. All were over the age of 18. They consisted of 13 females and 8 males. All had persistent symptoms for 180 days or longer. The questionnaires listed these symptoms:

  • Chronic Fatigue
  • Brain Fog
  • Anxiety/Nervousness Feeling Depressed
  • Trouble Concentrating
  • Headaches
  • Restless Legs
  • Poor Sleep
  • Muscle/Joint Pain
  • Leg Cramps
  • Numbness
  • Ringing of the ears
  • Dizziness
  • They reported symptoms of:
  • Headaches 78%
  • Brain Fog 72%
  • Fatigue 67%
  • Depression or Anxiety 61%
  • Joint/Muscle Pain 50%
  • Poor Sleep 50%
  • Dizziness 44%
  • Regarding the FM/a® Test results, 18/21 (86%) of the patients had a positive test score for fibromyalgia.

Discussion

Since the advent of the SARS-CoV-2 (COVID-19) pandemic, a significant percentage of these post-infectious patients have gone on to experience residual persistent symptoms. An objective source for these symptoms has avoided to be discovered. However, the classic post-COVID-19 (Long Haul) symptoms are essentially identical to those which have been attributed to the medical disease that has been labeled as fibromyalgia. Yet, the medical condition of fibromyalgia has been reported and diagnosed for many decades and long before COVID-19 infections were known to occur in humans.

We had particular interest in not merely potentially objectively identifying a basis for the persistence of the symptoms in Long Haul COVID-19 patients. We also desired to investigate if there was a source for why there was the development of fibromyalgia. We used multi-media sources to attract Long Haul COVID-19 patients whom we could document had experienced a COVID-19 infection, were willing to be personally interviewed, would complete related medical questionnaires and would also submit to undergo an established, highly sensitive and highly specific diagnostic blood test for fibromyalgia. While we secured such a cohort of volunteers, the number who were willing to meet all of these criteria proved limited.

Nevertheless, the findings were significant. Of the volunteers, 86% tested positive for fibromyalgia and for the related immune system deficiencies concerning the peripheral blood mononuclear reductions of the chemokine and cytokine proteins of MIP-1 alpha, MIP-1 beta, IL-6 and IL-8.

The origins of fibromyalgia have been debated for years. They have included hypothetical pathways stemming from trauma, emotional affiictions, post-surgical complications and chemical sensitivities among others. However, the only objective criteria that have ever been proven to exist in fibromyalgia is documentation that these individuals suffer with immune system deficiencies and in particular, an inability of their peripheral blood mononuclear cells to produce normal quantities of two chemokines, MIP-1 alpha, MIP-1 beta and two cytokines, IL-6 and IL-8.

Clearly, the extremely high percentage of Long Haul COVID-19 volunteers who tested positive for fibromyalgia far exceeds anything coincidental, circumstantial or fortuitous.

There are seven known human Corona viruses. Their role in being the leading origin of upper respiratory tract infections has been well- established.

Viruses can elicit epigenetic changes. According to recently published whole exome analyses, documentation of unique DNA pathways have been authenticated to occur in 100% of fibromyalgia/ FM/a® test positive patients and in 0% of healthy, matched control patients [13].

It is our hope and desire to promote further investigations of Long Haul COVID-19 patients in sufficient quantity to verify the findings our initial investigation have detected and confirmed.

References

  1. Long COVID Basics; CDC COVID-19; July 11, 2024.
  2. Thaweethai T, Jolley S, Karlson EW, Levitan EB, Levy B, et al. (2023) Development of a Definition of Postacute Sequelae of SARS-CoV-2 JAMA 29: 1934-1946. [crossref]
  3. Roth A, Pan SC, Jonas W (2021) Addressing the Long COVID Crisis: Integrative Health and Long Global Advances in Health and Medicine [crossref]
  4. Goldenberg D (2024) How to Understand the Overlap of Long COVID, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, Fibromyalgia and Irritable Bowel Seminars in Arthritis and Rheumatism 152455. [crossref]
  5. Mariette X (2023) Long COVID: A New Word for Naming Fibromyalgia. BMJ Journals 83: 12-14. [crossref]
  6. Claw D, Calabrese L (2024) Rheumatology and Long COVID: Lessons from the Study of Fibromyalgia. Ann Rheum Dis 82: 136-138. [crossref]
  7. Akel A, Almanasyeh B, Abo Kobaa A, Aljabali A, Al-Abadleh A, et al. (2023) A Cross- Sectional Study of Fibromyalgia and Post-Acute COVID-19 Syndrome: Could There be a Relationship. Cureus 1-13. [crossref]
  8. Martinez-Lavin M, Miguel-Alvarez A (2023) Hypothetical Framework for Post- COVID-19 Condition Based on a Fibromyalgia Pathogenetic Model. Clin Rheumatol 42: 3167-3171. [crossref]
  9. Ursini F, Ciaffi J, Mancarella L, Lisi L, Brusi V, et (2021) Fibromyalgia: A New Facet of the Post-COVID-19 Syndrome Spectrum? Results from a Web-Based Survey. RMD Open. [crossref]
  10. Hackshaw K, Yao S, Bao H, de Lamo Castellvi S, Aziz R, et al. (2023) Metabolic Fingerprinting for the Diagnosis of Clinically Similar Long COVID and Fibromyalgia Using a Portable FT-MIR Spectroscopic Combined with Chemometrics. Biomedicine 11: 2704. [crossref]
  11. Behm, F, Gavin, I, Karpenko O, Lindgren V, Gaitonde S, et al. (2021) Unique Immunologic Patterns in Fibromyalgia. BMC Clinical Pathology 1-7. [crossref]
  12. Wallace D, Gavin I, Karpenko O, Barkhordar F, Gillis BS (2015) Cytokine and Chemokine Profiles in Fibromyalgia, Rheumatoid Arthritis and Systemic Lupus Erythematosus: A Potentially Useful Tool in Differential Diagnosis. Rheumatology International 35: 991-996. [crossref]
  13. Mohapatra G, Dachet F, Coleman LJ, Gillis B, Behm FG (2024) Identification of Unique Genomic Signatures in Patients with Fibromyalgia and Chronic Pain. Nature- Scientific Reports 2024. [crossref]

Pyricularia Blast Disease Associated to the Wheat Production Losses in the Lowland Tropics of Santa Cruz, Bolivia

Leave a reply

DOI: 10.31038/MIP.2024522

Abstract

Cultivation of wheat (Triticum aestivum L.) in the lowlands (270 meters above sea level) tropics of Santa Cruz department is a strategic rotation crop and is the most important bread wheat producing region in Bolivia. However, phytosanitary limitations such as fungal diseases are a problem current. Pyricularia disease of wheat, registered in 1996 in this region, is one of the main limitations. Damage to production has been recurring in recent years and, according to reports, can cause severe reductions in production. Research objectives were: i. Identification of Pyricularia fungus from symptoms at the base of the spike rachis; ii. Estimate the incidence of Pyricularia disease, and, iv, Yield estimate (t.ha-1). One m2 was collected samples (with three repetitions) from three localities in the integrated north, Okinawa 1, Okinawa2, and Cuatroañadas, from the same municipalities and Warnes and Nuflo de Chavez provinces, respectively samples were taken to the plant pathology laboratory and processed for the Pyricularia fungus identification, symptomatology description, incidence and yield estimation. Results show that Pyricularia disease is caused by the fungus Pyricularia oryzae, in the field, it occurs with different levels of incidence and severity, being the highest in the localities of Okinawa 1 (57%) and Okinawa 2 (25.8%). Obtained yields show that, being affected by the disease, they are acceptable averages for the region. Correlation analysis it, under the relative humidity conditions of the 2023 winter crop, reaching 60% severity, the disease can cause drastic losses in wheat production.

Keywords

Yield losses, Mitosporic fungi, Intensity disease

Introduction

In the lowlands tropics of Santa Cruz department, the cultivation of wheat (Triticum aestivum L.) began to expand between 1985-1990 (INE, 2024). According to official statistics, since 1984, it has grown from 6,400 hectares to 120,000 to 140,000 hectares in 2022 [1]. Inter-Andean Cochabamba valleys were the main suppliers, in ’80 years, of semi-dwarf wheat varieties seeds such as “Chane and Saguayo” varieties for the east of Santa Cruz [2]. Subsequently, the lowland region of Santa Cruz began a self-sufficiency of improved wheat seeds supported by the Tropical Agriculture Research Center (CIAT), the Association of Oilseed and Wheat Producers (ANAPO), and private companies. Until then, the main diseases causing wheat production losses in the inter-Andean valleys (2000-3000 meters above sea level) of Bolivia and globally were considered traditional diseases, such as stem rust (Puccinia graminis tritici), leaf rust (Puccinia triticina) and stripe rust (Puccinia striiformis), Septoria leaf and glume spots (Septoria tritici and Septoria nodorum) and spot blotch (Cochlibolus sp.). On the other hand, for the eastern. Santa Cruz region, it was considered that they could be the same due to the “introduction” cultivation condition. However, later, in 1996, Barea and Toledo, it was reported by Santa Cruz Department of Bolivia as Pyricularia wheat blast disease [3]. So, this report helped guide subsequent phytosanitary research for wheat. At present, Pyricularia blast wheat is a generalized and important disease in wheat production in the Santa Cruz lowland tropics.

Wheat blast disease was first discovered in the state of Paraná, Brazil in 1985 (Igarashi et al., 1986), Since then, has become a major disease across central and southern Brazil and is now well established in tropical regions of South America [4]. At present wheat blast disease is not restricted to the tropical and sub-tropical regions of South America (north-eastern Argentina, lowlands of Bolivia, central and south-central Brazil, and Paraguay) only [3,5,6]. According to Metha (2014), the grain yield losses caused by Pyricularia blast can vary from very low to almost 100 % and the highest losses occur when the fungus attacks the rachis at the base of the spike affecting total or partial grain filling depending upon the time of infection. In Bolivia, in 1996, infections of wheat blast resulted in a loss of almost 80 % of the production, in 1997, the disease was devastating in the early seeded fields, causing a 100% loss [3]. The highest losses occur when the fungus attacks the rachis at the base of the spike thereby limiting the development of the grains and killing the spike completely [4]. Actually, after more than 27 years since the Pyricularia blast disease emerged, new varieties with genetic resistance, new management strategies, and new technologies have been introduced, but, the disease continues are cause losses in production. Research objectives were: i) Symptoms Description, ii) Incidence of Pyricularia disease estimation, and, iii) Yield estimation (t.ha-1).

Material and Methods

In August 2023, wheat sampling was carried out in commercial production plots in the harvest phase (‘Motacu’ variety) in two winter (April-August) wheat-producing municipalities in the lowlands Santa Cruz department. Localities were: Okinawa 1 (262 meters above sea level, 20K 510442 and UTM 8091262) and Okinawa 2 (271 meters above sea level, 20K 517888 and UTM 8085843), in the Okinawa municipality, Warnes Province and Cuatro Cañadas locality (267 meters above sea level, 20k 531485 and UTM 809). 8189) of the same name municipality, Ñuflo de Chávez Province, department of Santa Cruz (Figure 1). Sampling consisted of taking One m2 with three repetitions per plot completely at random. Each sample was cut manually with a sickle at the height of the stem base, was identified, and transferred for processing to the laboratory. Each sample was evaluated independently for incidence of disease according to Campbell and Madden (2011) [% Incidenced (Total diseased plants/total number plants*100)] and severity disease was estimated following an arbitrary criterion consisting into two categories: mild (Figure 2B, C), and high severity (Figure 2D, E). The evaluation was carried out on each stem by the stem for each sample under a stereomicroscope, checking from the base to the top of the spike rachis. Causal agent identification was carried out by mounting in lactophenol solution on the symptom and sign based. Conidiophores and conidia were observed according to the Ellis (1976) criteria, and the yield estimation manually threshing and weighing carried out was.

Figure 1: Wheat sampling areas location, in the north of the Santa Cruz department, Warnes and Ñuflo de Chavez Provinces. Bolivia. Map elaboration: CISTEL. Engineering department. FCAyP, UMSS. Cochabamba, Bolivia.

Results and Discussion

Characteristic symptom of Pyricularia disease, in the field, is a dark brown to blackish spot present at the rachis or base (Figure 2A) and its whitish color spike (Figure 2A, B). Under the stereoscope observed, the severity of disease degrees at the spike base and different spine parts are differentiated (Figure 2B, C, D, E). In the mildest severity degrees (Figure 2B, C), the disease is very little visible to the naked eye; On the other hand, in the more intense coloration degrees, the typical symptoms are evident (Figure 2D, E). At all severity degrees conidia and conidiophores of Pyricularia mass powdery are formed (Figure 2A). Conidiophores are mononematous, slender, strait, geniculate toward the ápex, brown, smooth. Conidiogenous cells are polyblastic, and integrated. Conidia solitary, dry, simple, obpyriform, ob clavate, pale olivaceous brown, smooth, 1-3 septate, hilum protuberant (Figure 2F, G, H) according description to of Pyricularia oryzae [7].

Figure 2: Symptom, sign and causal agent of Pyricularia blast wheat. A: fungus attacks the rachis; B: at the base of the spike at different phenological stage; C: Mild severity; D: High severity; E; Mass Pyricularia conidia; F-G: cell conidiogenuous; H: Conidiophore and conidia of Pyricularia oryzae tipically inserted. Motacu Variety. Santa Cruz, Bolivia. Year 2023.

Pyricularia disease was recorded in the three locations sampling, in different degrees incidence and severity (Figure 3A). Okinawa1 is recorded as the highest incidence (71%), and Cuatro Canadas sector 34% and Okinawa 2 (35%) (Figure 3A). Incidence of severity is highest in Cuatro cañadas locality (27%) followed by Okinawa1 (13.8%) and Okinawa2 (9.5%). With higher grain yields were Okinawa2 (1.9 t.ha-1) then Okinawa1 (1.7 t.ha-1) and Cuatroañadas (1.3 t.ha-1) (Figure 3B). According to INE (2023) and ANAPO (2022), wheat yield average for Santa Cruz is 1.5 txha-1. The yields of the present study are slightly higher than the averages reported by them. However, this could be explained because the data are departmental averages (INE and ANAPO) and, on the other hand, results are on specific localities (Cuatro Cañadas, Okinawa2, and Okinawa1).

Figure 3: A: Incidence and severity of Pyricularia wheat; B: Yield (txha-1) of wheat in different localities of the northern of Santa Cruz, Bolivia; C: Correlation analysis; D: Relative humidity of Okinawa 1 locality; E-F: April-September Tempeature variation, 2023. https://es.weatherspark.com/m/28522/8/Tiempo–promedioen–agosto–en–Okinawa–N%C3%BAmero–Uno–Bolivia#Figures–Temperature. Santa Cruz, Bolivia. Year: winter crop, 2023.

The first severe infections of wheat blast in Bolivia were observed in the lowland Santa Cruz region in 1996 and resulted in the loss of almost 80% of the production (Barea & Toledo 1996). But, yield to this year (1996) was 1.36 t.ha-1 (ANAPO 1996). According to Metha (2014), the grain yield losses caused by Pyricularia blast can vary from very low to almost 100 % and the highest losses occur when the fungus attacks the rachis at the base of the spike affecting total or partial grain filling depending upon the time of infection. A negative correlation is observed for severity vs yield, under the conditions of the present winter 2023 growing season, in Santa Cruz, it can be predicted that reaching a 60% disease severity loss could be drastic or up to 100% (Figure 3C).

According to climate data, relative humidity for Okinawa 1 (Figure 3D), apparently the optimal months for disease development could have occurred between May to June months (70-90% RH) (flowering and spike phenological stage), and fruiting between July and part of August month (grain filling and maturation phenology stage) (Figure 3D). In this same period, May to July, the temperature ranged between 26 to 28 oC (Figure 3E-F). Wheat Blast (WB) caused by the ascomycetes fungus Magnaporthe oryzae pathotype triticum (MoT) is one of the devastating diseases in the warm and humid growing region (Xinyao He et al. 2022) [5]. According to Perello et al. (2020) [8], indicate that climatic conditions are frequent rainy periods, temperatures ranging from 21°C to 27°C, cloudy days, and high relative humidity as most favorable for the occurrence of blast epidemics.

In conclusion, Pyricularia disease affects wheat production in the lowland tropics of Santa Cruz, Bolivia, and is caused by the fungus Pyricularia oryzae, in the field, it occurs with different levels of incidence and severity, being the highest in the localities of Okinawa 1 (57%) and Okinawa 2 (25.8%). Yields show that, being affected by the disease, they are acceptable averages for the region. Correlation analysis it, under the relative humidity conditions of the 2023 winter crop, reaching 60% severity, the disease can cause drastic losses in wheat production [9,10].

Acknowledgments

The authors thank the cooperation to Syngenta Crop Protection S.A. Santa Cruz, Bolivia, for his cooperation in collecting samples of wheat from locations of the department of Santa Cruz. To the Agronomist Jr. Juan Daniel Vargas, temporary intern, for his help in several field activities, and also to the producers of the sampled locations.

Funding

This study was funded by its institutional funds, the UMSS project.

References

  1. INE (2024) https://www.ine.gob.bo/index.php/estadisticas-economicas/agropecuaria/agriculturacuadros-estadisticos/ (January 21, 2024)
  2. CESAT (1985) Technical report. Centro de Estudios y Servicios a la Producción Triguera. Cochabamba, Bolivia. 25.
  3. Kohli MM, Mehta YR, Guzmán L, Viedma LD, Cubilla LE (2011) Pyricularia blast-a threat to wheat cultivation. Czech J Genet Plant Breed 47: S00-S04.
  4. Ceresini PC, Vanina Lilián Castroagudín, ávil a Rodrigues F, Ríos JA, Aucque-pérez CE, (2019) Review Wheat Blast: from its origins in South America to its emergence as a global threat. Molecular Plant Pathology 20: 155-172.
  5. Xinyao He, Navin C, Gahtyari, Chandan Roy, Abdelfattah A Dababat, Gurcharn Singh Brar, et al. (2022) Chapter 9, Globally Important Non-rust Diseases of Wheat. Pp: 143-158. In: M. P. Reynolds, H.-J. Braun (eds.), Wheat Improvement. Food Security in a Changing Climate. 658 p.
  6. Metha YR (2014) Chapter 3 Spike Diseases Caused by Fungi. Pp: 65-97. In: Wheat Diseases and Their Management. Springer International Publishing Switzerland 253.
  7. Ellis MB (1971) Dematiaceous Hyphomycetes. Commonwealth Mycological Institute. Kew, Surrey, England 218.
  8. Perelló AE, Consolo V, Martínez I (2020) Chapter 6 Ecology and Epidemiology of Wheat Blast. pp: 105-130. In: Wheat Blast (Eds. Sudheer Kumar, Prem Lal Kashyap, and Gyanendra Pratap Singh). CRC Press Taylor & Francis Group, Boca Raton London New York. 197 p.
  9. Campbell CL, Madden LV (1990) Introduction to Plant Disease Epidemiology. John Wiley & Sons, New York.
  10. Okinawa 1 (2023) https://es.weatherspark.com/m/28522/8/Tiempo-promedio-en-agosto-enOkinawa-N%C3%BAmero-Uno-Bolivia#Figures-Temperature (noviembre 14, 2023).

Hybrid Closed-loop Systems for the Treatment of Type 1 Diabetes: Narrative Review

Leave a reply

DOI: 10.31038/EDMJ.2025913

Abstract

Introduction/Objective: The scope of this review is a critical appraisal of the efficacy and safety of regulatory authorities-approved, commercially available Hybrid Closed-Loop Systems compared to conventional treatments in individuals with Type 1 diabetes

Methods: Medline and Embase databases were searched for Randomized Controlled Trials (RCT), meta-analyses of RCTs and Real-World studies using the terms hybrid closed-loop systems, automated insulin delivery systems and artificial pancreas.

Results: Limited data from Randomized Controlled Trials and meta-analyses and growing evidence from real-world use support the superiority of Hybrid Closed-Loop Systems in improving all the Ambulatory Glucose Profile metrics compared to Sensor Augmented Pumps or Multiple Daily Injections with Continuous Glucose Monitoring.

Conclusion: Commercially available Hybrid Closed-Loop Systems are effective in reducing HbA1c, increasing Time In Range and decreasing time in the hypoglycemic range in individuals with Type 1 diabetes.

Keywords

Hybrid closed-loop systems, Artificial pancreas, Type 1 diabetes, Hypoglycemia, Time in range, Severe hypoglycemia, Diabetic ketoacidosis

Introduction

Despite progress in the treatment of Type 1 Diabetes (T1D), less than one third of patients achieve optimal glycemic control [1,2]. Emerging technologies by means of newer insulin pumps, more reliable glucose sensors and efficient control algorithms drive a paradigm shift in the treatment of diabetes. Hybrid Closed-Loop Systems (HCLS), or else Automated Insulin Delivery (AID) systems represent the most advanced currently available treatment for T1D. These systems integrate data from Continuous Glucose Monitoring (CGM), a control algorithm and an insulin pump into an automated glucose-responsive subcutaneous insulin infusion. Mimicking basal endogenous insulin production, HCLS automatically modify insulin infusion rates during fasting state thus eliminating patients’ involvement with the self-management of diabetes to prandial boluses that are still given manually through a user-initiated procedure [3]. Three main classes of control algorithms are currently used to determine the insulin infusion rates in HCLS: Model Predictive Control (MPC) uses inputs such as Insulin to Carbohydrates Ratio (ICR), Active Insulin Time (AIT), glucose target and insulin sensitivity to build and update an individually customized algorithm. The Proportional-Integral-Derivative (PID) algorithm modifies insulin infusion rates in response to glucose increments (proportional component), difference from preset glycemic target (integral component), and the rate of glucose fluctuation (derivative component). Finally, Fuzzy logic algorithms combining elements of the other two mimic the decision-making of diabetes clinicians based on the current state of the user and accommodating day-to-day variations [4]. Fully closed-loop systems that require no user intervention are under investigation.This narrative review investigates the efficacy and safety of the commercially available HCLS. Medline and Embase databases were searched for Randomized Controlled Trials (RCT), meta-analyses of RCTs and Real-World studies published up to 31.01.2024 using the terms hybrid closed-loop systems, automated insulin delivery systems and artificial pancreas. The psychosocial impact and the cost effectiveness of HCLS are beyond the aims of this review.

Commercially Available Regulatory Authorities Approved HCLS

The Medtronic 670G was the first HCLS cleared by the U.S. Food and Drug Administration (FDA) and the Conformitè Européenne (CE) for ages above 7 years [5]. It was initially upgraded to the 770G (FDA approved, licensed for age 2 and above) and finally to the 780G (CE marked, licensed for age 7-80 years). Also known as the Advanced Hybrid Closed Loop (AHCL), the 780G incorporates Bluetooth connectivity and remote software updates. In addition, 780G automatically deliver correction boluses while maintenance in auto mode is substantially increased compared to 670G [6]. Medtronic’s PID algorithm is installed in the pump. Initiation of the auto-mode requires Insulin to Creatinine Ratio (ICR), Active Insulin Time (AIT) and glucose target. Two glucose sensors are compatible with the 780G: Guardian 3 lasts up to 7 days and requires at least 2 calibrations per day ,while the recently launched Guardian 4 requires no calibrations.

CamAPS FX (CamDiab, Cambridge, UK) is a HCLS using a MPC algorithm embedded into an Android smartphone. Both Dexcom G6 glucose sensors which last for 10 days and require no calibration and Libre 3 CGM devices are compatible with the algorithm. Insulin infusion is mediated by Dana RS, Dana I or YpsoPump insulin pumps. CamAPS FX is, for the time being, the only HCLS licensed by CE for use from 1 year upwards and in pregnancy [7,8]. It is also the HCLS where both rapid and ultra-rapid insulin analogues have been tested in clinical studies. In addition, CamAPS FX allows for multiple glucose targets to be set at different times.

Control IQ HCLS combines the Tandem t: slim X2 insulin pump with a MPC algorithm incorporated, the Dexcom G6 glucose sensor, and the Control-IQ technology. It is approved by both FDA and CE for use in ages 6 and above, but not during pregnancy. Augmented by total daily insulin dose and a preset basal program the Control-IQ algorithm predicts glucose value thirty minutes in advance adapting insulin infusion rate to achieve a preset glucose target which can be differentiated during nighttime and before announced exercise [6].

The Insulet Omnipod 5 combines a patch insulin pump, operated by a wireless handheld device with the Dexcom G6 CGM. It is the first tubeless HCLS cleared by FDA and CE marked for T1D patients aged 2 years or older. It is not approved for use during pregnancy. The adaptive MPC algorithm installed in the Omnipod 5 pump and Omnipod 5 application is initiated using total daily insulin dose and delivers insulin micro-boluses every 5min [9].

The Diabeloop Generation 1 (DBLG1) HCLS is a combination of Kaleido patch pump or Roche Accu-check pump, with Dexcom G6 glucose sensor, and a command module running the system’s MPC algorithm. It has received the CE mark for use in adults with T1D and is available in some countries in Europe [3]. A partly differentiated version of DBLG1, the Diabeloop for Highly Unstable Type 1Diabetes (DBLHU) has been recently approved in Europe for use by individuals with unstable diabetes [10].

Data from RCTs

The efficacy and safety of HCLS have been tested in a limited number of RCTs. In most of these crossover trials the number of participants was small, and the duration of intervention did not exceed six months.

Mc Auley et al. compared 670G HCLS to conventional treatment with Multiple Daily Injections (MDI) or insulin pump in adults with T1D. After 6 months intervention HbA1c was lower (-0.4%; -4mmol/mol, p<0.0001) and Time In Range (TIR) 70-180mg/dl; 3.9-10mmol/l was 15% higher (p<0.0001) with HCLS [11]. In a 4-week periods, crossover study, in AID naïve patients with T1D aged 7-80 years Collyns at al. compared 780G or Advanced Hybrid Closed-Loop System (AHCL) to therapy with Sensor Augmented Pump (SAP) with a Predictive Low Glucose Suspend (PLGS) algorithm. At the end of the study TIR was higher with AHCL (70.4% ± 8.1% vs. 57.9% ± 11.7%) by 12.5% ± 8.5% (p< 0.001), The improvement in TIR was even greater overnight (18.8 ± 12.9%, p<0.001) and in adolescents and young adults group (14-21 years) (14.4%±8.4%). During AHCL therapy, time with glucose <70 mg/dL,3.9mmol/l significantly decreased from 3.1%±2.1% to 2.1% ± 1.4% (p= 0.034) [12]. In the ADAPT study, 82 adults with T1D were randomly assigned to AHCL treatment or continuation of the conventional treatment with MDI combined with CGM. At 6 months, mean HbA1c decreased by 1.54%, from 9.0% to 7.32%, in the AHCL group and by 0.20%, from 9.07% to 8.91%, in the MDI plus CGM (between AHCL and MDI mean difference −1.42%, 95% CI −1.74% to −1.10%, p<0.0001) [13]. In a small, 12-week periods, crossover study 780G was superior to 670G in reducing HbA1c (mean difference -0.2%, p=0.03) and in increasing TIR (4%, p<0.0001) with no difference in hypoglycemia [14].

The CamAPS FX HCLS has been tested in a broad population of patients with T1D from children 1 year old, to elderly individuals and pregnant women. Tauschmann et al compared HCLS to treatment with SAP with the threshold suspend and PLGS features inactivated in individuals with T1D from the age of 6 years. After 12 weeks intervention, HbA1c was significantly lower (mean difference 0.36%, 95% CI 0.19% to 0.53%, p<0.0001) and TIR was significantly higher (65%± 8% vs 54%± 9%, mean difference 10.8%, 95% CI: 8.2% to 13.5%, p<0.0001) with HCLS compared to SAP. The time with glucose values within the ranges of hypoglycemia (<70mg/dl;3.9mmol/l) and hyperglycemia (>180mg/dl;10.0mmol/l) was also significantly reduced by -0.83%, 95% CI -1.40% to -0.16%, p=0.0013 and -10.3%, 95% CI -13.2% to -7.5%, p<0.0001, respectively with HCLS treatment compared to SAP. Severe adverse events were restricted to one episode of Diabetic Ketoacidosis (DKA) due to infusion set occlusion in the HCLS group, while no episodes of severe hypoglycemia were reported with either treatment Adverse events were numerically more in the HCLS group (13 vs 3) [15]. In another randomized crossover study adults previously treated with an insulin pump were assigned to HCLS therapy or continuation of insulin pump treatment for periods lasting 4 weeks. Compared to conventional insulin pump treatment, HCLS increased TIR by 10.5 percentage points;95% CI 7.6% to 13.4%, p<0.0001 and reduced time in the hypoglycemia range <3.5 mmol/L and <2.8 mmol/L by 65% and 76%,respectively (p<0.0001 for both comparisons), without increasing the risk of severe hypoglycemia or DKA [16]. Similarly, Thabit et al. reported decrease in HbA1c (mean difference −0.3%; 95% CI −0.5% to −0.1%, p=0.002) and 11% increase in TIR (95% CI, 8.1% to 13.8%) in adults treated with HCLS compared to SAP therapy [17]. In another multicenter, crossover trial,74 children 1 to 7 years old with T1D previously on insulin pump were randomized to receive HCLS or SAP treatment for two 16-week periods. During the closed-loop treatment TIR increased by 8.7 percentage points (95% CI, 7.4% to 9.9%, p<0.001) and HbA1c decreased by 0.4 percentage points (95% CI, −0.5% to −0.3%), while time spent in hypoglycemia was similar with the two treatments (p =0.74). One episode of severe hypoglycemia occurred during treatment with HCLS [18]. The efficacy and safety of CamAPS FX HCLS was also tested in16 pregnant women with T1D and gestational age 8-24 weeks randomized to receive closed-loop treatment or therapy with SAP without the option of PLGS. HbA1c, TIR and Time in Hyperglycemia>140mg/dl were comparable between HCLS and SAP. However, the incidence of hypoglycemia (median number of episodes over 28 days treatment: 8 vs 12, p=0.04) as well as the time with glucose values below 63mg/dl (1.6% vs 2.7%, p=0.02) and below 50mg/dl (0.24% vs 0.47%, p=0.03) favoured treatment with HCLS. Nocturnal hypoglycaemia (23: 00-07: 00 h) was also lower with HCLS treatment (1.1% vs 2.7%; p=0.008) [19]. Finally, in a randomized crossover trial 37 patients≥60 years old were enrolled to receive treatment with CamAPS FX HCLS or SAP therapy. After two 16-week periods, individuals assigned to HCLS treatment achieved significantly higher TIR (79.9% vs 71.4% p<0.0001). Severe hypoglycemia occurred twice during SAP period [20].

Four RCTs investigated the performance of the Control-IQ HCLS in a broad population of individuals with T1D. In a 6-month, multicenter trial,168 patients, at least 14 years old, with T1D were randomized to therapy with HCLS, or SAP. At the end of intervention the results for all the prespecified endpoints favoured treatment with HCLS. The TIR 70-180mg/dl increased by 11% (95%CI, 9% to 14%, p<0.001) with concomitant decrease in time with glucose below 70mg/dl by 0.88% (95% CI, −1.19% to −0.57%, p<0.001) and in HbA1c by 0.33% (95% CI, −0.53% to −0.13%, p = 0.001). Treatment with HCLS was safe with no episodes of severe hypoglycemia and one episode of DKA [21]. In another 16-week, multicenter trial, 101 young children between 6 and 13 year-old with T1D were randomized to treatment with HCLS or SAP. Compared to SAP, HCLS treatment increased the TIR 70-180mg/dl by 11% (95% CI, 7% to 14%, p<0.001) adding 2.6 hours of euglycemia per day, with no episodes of DKA or severe hypoglycemia [22]. Recently, in a trial lasting 13 weeks, 102 children with T1D between 2 and 6-year-old were randomized to receive treatment with HCLS or conventional treatment with either an insulin pump or MDI plus a CGM. HCLS treatment resulted in an increase in TIR 70-180mg/dl by 12.4% (95% CI, 9.5% to 15.3%, p<0.001) adding about 3 hours of euglycemia per day. HbA1c and time with glucose values below 70 mg/dl were comparable between the two interventions. Two episodes of severe hypoglycemia and one episode of DKA occurred during treatment with HCLS, while one case of severe hypoglycemia occurred during conventional treatment [23]. Finally, Control-IQ HCLS was compared with insulin pump and CGM treatment in 72 adults with impaired hypoglycemia perception defined as Clarke score >3 and/or history of severe hypoglycemia within the last 6 months. After 12 weeks intervention HCLS treatment resulted in significant reduction in time with glucose below 70mg/dl (TBR) by 23.7% (95% CI 24.8% to 22.6%, p < 0.001). In addition, TIR 70-180mg/dl increased by 8.6% (95% CI 5.2% to 12.1%, p < 0.001), and Time in hyperglycemia above 180mg/dl (TAR) decreased by 25% (95% CI 87.7% to 1.8%, p=0.004) [24].

The DBLG1 HCLS was compared to SAP in 63 adults withT1D and preserved hypoglycemia awareness. After 12-week periods interventions TIR 70-180mg/dl increased by 9.2% (95% CI 6.4% to 11.9%, p<0.0001) with HCLS compared to SAP treatment [25]. In another RCT, DBLG1 HCLS was compared to SAP in children aged 6-12. After 13 weeks, treatment with HCLS decreased time in the hypoglycemic range below 70mg/dl (2.04% with HCLS vs 7.06% with SAP, p<0.001), without episodes of severe hypoglycemia or DKA [26]. The DBLHU HCLS, derived from DBLG1, was tested in a randomized, controlled study that comprised 2 circles of N-of-1 trials in 5 adults with TID with severe glucose instability that could lead to eligibility for islet transplantation. Compared to SAP with PLGS feature activated, DBLHU treatment resulted in significantly higher TIR 70-180mg/dl (73.3%±1.7% vs 43.5%±1.7%, p<0.0001) and lower time with glucose<70mg/dl (0.9%±0.4% vs 3.7%±0.4%, p<0.0001) with no adverse events reported [10].

Data from Meta-analyses of RCTs

Six meta-analyses reported data from RCTs comparing intervention with a HCLS to other standard treatments for T1D such as MDI with Self-Monitoring of Blood Glucose (SMBG), flash or Continuous Glucose Monitoring, Continuous Subcutaneous Insulin Infusion (CSII), SAP and SAP with PLGS [27-32]. In all meta-analyses the intervention with HCLS was associated with significant increase in TIR 70-180mg/dl for sensor glucose. This increase ranged from 6.2% when HCLS was used during exercise to 17.9% when HCLS was compared to MDI with SMBG [29,30]. Time Below the Range of 70mg/dl (TBR) was significantly reduced by 1.09%, 1.49% and 2.45% in three meta-analyses remaining unchanged in the rest of them [27,31,32]. Similarly, a significant decrease in Time Above the Range of 180mg/dl (TAR) 8.5% and 8.9% was reported in two of the meta-analyses [27,31]. Overall, the existing meta-analyses comprising data from a wide range of patients and interventions in outpatient settings have shown the superiority of HCLS over conventional treatments in increasing time in euglycemia and reducing time in hypoglycemia in individuals with T1D.

Real-World Data

As commercial availability and affordability of HCLS increases, more and more people with T1D use technology for their treatment. However, reimbursement status, and socioeconomic criteria may still limit the access to advanced technology treatments to a large number of individuals with diabetes that could potentially benefit from it [1,33]. Evidence from real-world use of HCLS capture information from a broader patient population, such as those with bad glucose control and hypoglycemia unawareness, often under-represented in clinical trials. In addition, longer use of HCLS under real-life conditions may reveal adverse events and potential interactions with comorbidities that could not emerge during short-time intervention in a clinical trial.

Recently, Arunachalum et al. reported glycemic outcomes during real-world 670G HCLS use by a large cohort of 123,355 individuals with T1D in the United States. Compared with pre-670G initiation, HCLS users with a baseline Glucose Management Index (GMI) above 7% showed significant decrease in GMI from 7.3%± 0.6% to 7.1%± 0.5% (p <0 .001), in TBR<70 mg/dL, from 2.11%±2.4% to 2.07%± 2.25% (p = 0.002), and in TAR>180 mg/dL from 36.3%±15.7% to 29.8%±12.2% (p<0 .001), while TIR substantially increased from 61.5%± 15.1% to 68.1% ±11.9% (p <0.001). In users previously well-controlled with GMI<7%, TIR remained unchanged with HCLS treatment [34]. These results are in accordance with outcomes reported from numerous previous real-world studies with the use of 670G [35-45].

Outcomes from real-world use of 780G AHCLS from 4,120 individuals with T1D were reported by Da Silva et al. Treatment with AHCLS resulted in multiple glycemic targets achievement in almost 80% of individuals, with mean GMI 6.8%±0.3%, TIR 70-180mg/dl 76.2%± 9.1%, TBR<70mg/dl 2.5%± 2.1%, and TAR >180mg/dl 21.3%±9.4%. Compared to the previous treatment (data available for 812 individuals) AHCLS further reduced GMI by 0.4% ± 0.4% (p = 0.005) and increased TIR by 12.1%±10.5% (p < 0.0001). Almost 75% of AHCLS users achieved both the glycemic targets of GMI <7.0% and TIR>70% [46]. In another real-world study, treatment with 780G resulted in significant improvement in all ambulatory glucose profile metrics with decrease in mean GMI from 7.9 ± 2.1% to 6.95 ± 0.58%, increase in TIR from 63.48 ± 10.14% to 81.54 ± 8.43%, and substantial decrease in time spent in the hyperglycemic (>180mg/dl) and in the hypoglycemic (<70mg/dl) range [47].

The performance of CamAPS FX HCLS was analyzed with real-world evidence from 1,805 users across different age groups and countries. TIR (70-180mg/dl, 3.9-10 mmol/L) ranged from 66.9±11.7% in children younger than 6 years to 81.8± 8.7% in elderly above 65 years with the mean TIR for all users being 72.6±11.5%. TBR (<70mg/dl, 3.9 mmol/L) was 2.3% while mean sensor glucose and GMI were 151±20mg/dl, 8.4± 1.1 mmol/L and 6.9%, respectively. Adherence to closed loop use was as high as 94.7% [48]. Ng et al. reported also significant improvement in HbA1c (pre-HCLS: 7.9±3.2%, 63±12mmol/mol, at 3 months: 7.3±3.0%, 56.6 ± 9.3mmil/mol, p=0.03), TIR (at baseline 50.5±17.4%, at 3 months 67.0± 14%,p=0.001), and TBR (at baseline 4.3±1.6%, at 3 months 2.8±1.4%,p=0.004) after 3-months real life use of CamAPS FX HCLS from a small cohort of individuals with T1D [49].

Results from real-world performance of Control-IQ HCLS were reported by Breton and Kovatchev analyzing retrospectively data from 9,451 individuals using the HCLS for at least 12 months. Median TIR 70–180 mg/dL increased from 63.6 % (IQR: 49.9%–75.6%) to 73.6% (IQR: 64.4%–81.8%) after 12 months use of Control-IQ technology remaining stable thereafter. Median TBR <70 mg/dL was 1% at baseline and did not change with HCLS treatment [50]. In the Control-IQ Observational (CLIO) study almost 3,000 individuals with T1D older than 6 years initiated treatment with theControl-IQ HCLS and were longitudinally observed in real-world focusing primarily on adverse events (AE) such as severe hypoglycemia and DKA. AEs were reported every month over a period of 12 months and were compared to data available from the participants in the T1D Exchange cohort. Rates of severe hypoglycemia were significantly lower than those expected from conventional treatment both for children (9.31 vs. 19.31 events/100 patient years, p< 0.01) and adults (9.77 vs. 29.49 events/100 patient years, p< 0.01). DKA incidence was also significantly lower in all HCLS users. AEs incidence was lower for all the range of baseline HbA1c and was independent to prior treatment. TIR 70–180mg/dL was 70.1% for adults, 61.2% for ages 6–13, 60.9% for ages14–17, and 67.3% overall. Less self-involvement in the management of diabetes was steadily reported by most of the users [51].

Real-world performance of DBLG1 HCLS was assessed in a small cohort of T1D individuals. After 6 months, HCLS therapy resulted in decrease in HbA1c from 7.9%, 63 mmol/mol, to 7.1%,54 mmol/mol (p<0.001), increase in TIR 70-180 mg/dL from 53% to 69.7% (p<0.0001), and decrease in TBR <70 mg/dl from 2.4% to 1.3% (p=0.03), without episodes of severe hypoglycemia or DKA [52]. In a retrospective observational study, real world use of Omnipod 5 HCLS from a cohort of 179 individuals with T1D resulted in reduction of HbA1c by a mean of -0.2±1.0%, p=0.005 [53].

Recently, Crabtree et al. reported data from 520 HCLS users with T1D followed-up for a median of 5.1 months after initiation of any of the available in England HCLS. Treatment with HCLS reduced HbA1c by 1.7%,18.1mmol/mol (95% CI 1.5%,16mmol/mol to 1.8%,19.6mmol/mol p < 0.0001), and increased TIR 70–180 mg/dl from 34.2% to 61.9% (p< 0.001). More users on HCLS treatment achieved optimal glycemic control defined as HbA1c≤7.5%,58 mmol/mol (from 0% at baseline to 39.4%, p < 0.0001) and TIR 70-180mg/dl≥70% with TBR 70mg/dl <4% (from 0.8 at baseline to 28.2%, p < 0.0001). Almost all participants reported improvement in the quality of their life with HCLS therapy [54].

Future Perspectives

Several other closed-loop systems, such as Tidepool Loop MPC algorithm, Inreda PID algorithm and the iLet bionic pancreas, are under clinical investigation, or at the final stage to receive approval by regulatory authorities [55]. Compared to other HCLS, iLet bionic pancreas allows for a qualitative approach to meal announcement defining a scheduled meal as usual, bigger or smaller than usual thus alleviating the burden of accurate carbohydrates counting [56]. Do-It-Yourself (DIY) Artificial Pancreas Systems are based on the combination of existing CGMs and pumps with open-source algorithms engineered mostly by individuals experienced in self-management of their diabetes and embedded within a smart device. While there are still concerns about safety, preliminary data demonstrate an efficacy comparable to that of licensed systems [57].

Dual Hormone (DH) artificial pancreas combines insulin with glucagon or pramlintide. Although DH systems seem to better mimic normal pancreatic function, results from clinical trials have not so far shown superiority over single hormone systems in outpatient settings [58,59]. New algorithms that incorporate more detailed data such as pulse rate, sweat, movements and step count in glucose management are under development and may be a step ahead to the fully closed-loop systems that require no intervention from the user [60,61]

Conclusions

Commercially available HCLS are effective in reducing HbA1c, increasing TIR and decreasing time spent in hypoglycemia in individuals with T1D. Although data from RCTs are limited for some of these systems, real-world data from thousands of current users confirm the efficacy and safety already established in the environment of clinical trials in a broad age population from early childhood to older adults. Areas that need further investigation include the use of HCLS in pregnancy and during exercise as well as the management of meals. Technology can alleviate much of the daily burden of people with T1D. However, the cost of HCLS and the existing reimbursement disparities may discourage many people with T1D and suboptimal glycemic control from using technology, contributing to socioeconomics and geographical inequities in the treatment of T1D.

Disclosures and Declarations

All the authors declare no conflict of interest for this review. There was no funding for this work. Konstantinos Kitsios had the idea for the article, performed the literature search and wrote the initial draft. Christina-Maria Trakatelli and Maria Sarigianni participated in literature search and revised the work. All the authors vouch for the accuracy of the data presented in this review and approve the submission.

References

  1. Foster NC, Beck RW, Miller KM, et al. State of Type 1 diabetes management and outcomes from the T1D Exchange in 2016-2018. Diabetes Technol Ther 2019. [crossref]
  2. NHS Digital. National Diabetes Audit 2017-18. Report 1: Care processes and treatment targets, full report2019, England and Wales,13th June 2019. Leeds: NHS Digital; 2019.
  3. Boughton CK, Hovorka R. New closed-loop insulin systems. Diabetologia 2021. [crossref]
  4. Youssef JE, Castle J, Ward WK. A review of closed-loop algorithms for glycemic control in the treatment of type 1 diabetes. Algorithms 2009
  5. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed-loop insulin delivery system in patients with type 1 diabetes. JAMA. 2016. [crossref]
  6. Sherwood JS, Russell SJ, Putman MS. New and emerging technologies in type 1 diabetes. Endocrinol Metab Clin N Am. 2020. [crossref]
  7. Ware J, Allen JM, Boughton CK, et al. Randomized trial of closed-loop control in very young children with type 1 diabetes. N Engl J Med. 2022. [crossref]
  8. Stewart ZA, Wilinska ME, Hartnell S, et al. Day-and-night closed-loop insulin delivery in a broad population of pregnant women with type 1 diabetes: a randomized controlled crossover trial. Diabetes Care. 2018. [crossref]
  9. Cobry EC, Berget C, Messer LH, Forlenza GP. Review of the Omnipod 5 automated glucose control system powered by Horizon TM for the treatment of type 1 diabetes. Ther Deliv. 2020. [crossref]
  10. Benhamou PY, Lablanche S, Vambergue A, Doron M, Franc S, Charpentier G. Patients with highly unstable type 1 diabetes eligible for islet transplantation can be managed with a closed-loop insulin delivery system: a series of N-of-1 randomized controlled trials. Diabetes Obes Metab. 2021. [crossref]
  11. McAuley SA, Lee MH, Paldus B, et al. Six months of hybrid closed-loop versus manual insulin delivery with fingerprick blood glucose monitoring in adults with type 1 diabetes: a randomized, controlled trial. Diabetes Care. 2020. [crossref]
  12. Collyns O, Meier R, Betts Z, et al 199-OR: Improved Glycemic Outcomes with Medtronic Minimed Advanced Hybrid Closed-Loop Delivery: Results from a Randomized Crossover Trial Comparing Automated Insulin Delivery with Predictive Low Glucose Suspend in People with Type 1 Diabetes. Diabetes 2020. [crossref]
  13. Choudhary P, Kolassa R, Keuthage W, et al. Advanced hybrid closed loop therapy versus conventional treatment in adults with type 1 diabetes (ADAPT): a randomised controlled study. Lancet Diabetes Endocrinol. 2022;10(10): 720-731. [crossref]
  14. Bergenstal RM, Nimri R, Beck RW, et al A comparison of two hybrid closed-loop systems in adolescents and young adults with type 1 diabetes (FLAIR): a multicentre, randomised, crossover trial. The Lancet 2021. [crossref]
  15. Tauschmann M, Thabit H, Bally L, et al. Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial. 2018. [crossref]
  16. Bally L, Thabit H, Kojzar H, et al. Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study. Lancet Diabetes Endocrinol 2017. [crossref]
  17. Thabit H, Tauschmann M, Allen JM, et al (2015) Home Use of an Artificial Beta Cell in Type 1 Diabetes. New Engl J Med 2015. [crossref]
  18. Ware J, Allen JM, Boughton CK, et al. Randomized trial of closed-loop control in very young children with type 1 diabetes. N Engl J Med. 2022. [crossref]
  19. Stewart ZA, Wilinska ME, Hartnell S, et al. Day-and-night closed-loop insulin delivery in a broad population of pregnant women with type 1 diabetes: a randomized controlled crossover trial. Diabetes Care. 2018. [crossref]
  20. Boughton CK, Hartnell S, Thabit H, et al. Hybrid closed-loop glucose control compared with sensor augmented pump therapy in older adults with type 1 diabetes: an open-label multicentre, multinational, randomised, crossover study. Lancet Healthy Longev. 2022. [crossref]
  21. Brow SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, et al. Six-month randomized, multicenter trial of closed-loop control in type 1 diabetes. N Engl J Med 2019. [crossref]
  22. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L, Forlenza G, Cengiz E, et al. A randomized trial of closed-loop control in children with type 1 diabetes. N Engl J Med 2020. [crossref]
  23. Wadwa PR, Reed ZW, Buckingham BA, DeBoer MD, Ekhlaspour L, Forlenza GP. Trial of hybrid-closed-loop control in young children with type 1 diabetes. N Engl J Med 2023. [crossref]
  24. Renard E, Joubert M, Villard O, Dreves B, Reznik Y, Farret A, et al. Safety and Efficacy of Sustained Automated Insulin Delivery Compared With Sensor and Pump Therapy in Adults With Type 1 Diabetes at High Risk for Hypoglycemia: A Randomized Controlled Trial. Diabetes Care 2023. [crossref]
  25. Benhamou PY, Franc S, Reznik Y, et al. Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial. Lancet Digit Health 2019. [crossref]
  26. Kariyawasam D, Morin C, Casteels K, et al. Hybrid closed-loop insulin delivery versus sensor-augmented pump therapy in children aged 6–12 years: a randomised, controlled, cross-over, non-inferiority trial. Lancet Digit Health 2022. [crossref]
  27. Jiao X, Shen Y, Chen Y. Better TIR, HbA1c, and less hypoglycemia in closed-loop insulin system in patients with type 1 diabetes: a meta-analysis. BMJ Open Diabetes Res Care. 2022. [crossref]
  28. Fang Z, Liu M, Tao J, Li C, Zou F, Zhang W. Efficacy and safety of closed-loop insulin delivery versus sensor-augmented pump in the treatment of adults with type 1 diabetes: a systematic review and meta-analysis of randomized-controlled trials. J Endocrinol Invest. 2022. [crossref]
  29. Eckstein ML, Weilguni B, Tauschmann M, et al. Time in range for closed-loop systems versus standard of care during physical exercise in people with type 1 diabetes: a systematic review and meta- analysis. J Clin Med. 2021. [crossref]
  30. Pease A, Lo C, Earnest A, Kiriakova V, Liew D, Zoungas S. Time in range for multiple technologies in type 1 diabetes: a systematic review and network meta-analysis. Diabetes Care. 2020. [crossref]
  31. Bekiari E, Kitsios K, Thabit H, et al. Artificial pancreas treatment for outpatients with type 1 diabetes: systematic review and meta- analysis. 2018. [crossref]
  32. Weisman A, Bai JW, Cardinez M, Kramer CK, Perkins BA. Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomized controlled trials. Lancet Diabetes Endocrinol. 2017. [crossref]
  33. Rytter K, Madsen KP, Andersen HU, et al. Insulin pump treatment in adults with type 1 diabetes in the capital region of Denmark: design and cohort characteristics of the steno tech survey. Diabetes Ther. 2022. [crossref]
  34. Arunachalum S, Velado K, Vigersky RA, Cordero TL. Glucemic outcomes during real-world hybrid closed-loop system use by individuals with type 1 diabetes in the United States. J Diabetes Sci Technol 2023. [crossref]
  35. Petrovski G, al Khalaf F, Campbell J, Umer F, Almajaly D, Hamdan M, Hussain K One-year experience of hybrid closed-loop system in children and adolescents with type 1 diabetes previously treated with multiple DAILY injections: drivers to successful outcomes. Acta Diabetol 2020. [crossref]
  36. Salehi P, Roberts AJ, Kim GJ. Efficacy and safety of real-life usage of MiniMed 670G automode in children with type 1 diabetes less than 7 years old. Diabetes Technol Ther 2019. [crossref]
  37. Stone MP, Agrawal P, Chen X, Liu M, Shin J, Cordero TL, Kaufman FR Retrospective analysis of 3-month real-world glucose data after the minimed 670G system commercial launch. Diabetes Technol Ther 2018. [crossref]
  38. Beato-Víbora PI, Gallego-Gamero F, Lázaro-Martín L, Romero-Pérez M del M, Arroyo-Díez FJ. Prospective Analysis of the Impact of Commercialized Hybrid Closed-Loop System on Glycemic Control, Glycemic Variability, and Patient-Related Outcomes in Children and Adults: A Focus on Superiority over Predictive Low-Glucose Suspend Technology. Diabetes Technol Ther 2020. [crossref]
  39. Akturk HK, Giordano D, Champakanath A, Brackett S, Garg S, Snell-Bergeon J. Long-term real-life glycemic outcomes with a hybrid closed-loop system compared with sensor-augmented pump therapy in patients with type 1 diabetes. Diabetes Obes Metab 2020.[crossref]
  40. Usoh CO, Johnson CP, Speiser JL, Bundy R, Dharod A, Aloi JA. Real-World Efficacy of the Hybrid Closed-Loop System. J Diabetes Sci Technol 2021. [crossref]
  41. Lal RA, Basina M, Maahs DM, Hood K, Buckingham B, Wilson DM. One year clinical experience of the first commercial hybrid closed-loop system. Diabetes Care 2019. [crossref]
  42. Lepore G, Scaranna C, Corsi A, Dodesini AR, Trevisan R. Switching from Suspend-Before-Low Insulin Pump Technology to a Hybrid Closed-Loop System Improves Glucose Control and Reduces Glucose Variability: A Retrospective Observational Case-Control Study. Diabetes Technol Ther 2020. [crossref]
  43. Faulds ER, Zappe J, Dungan KM. Real-world implications of hybrid close loop (HCl) insulin delivery system. Endocrine Practice 2019.
  44. Berget C, Messer LH, Vigers T, Frohnert BI, Pyle L, Wadwa RP, Driscoll KA, Forlenza GP. Six months of hybrid closed loop in the real-world: An evaluation of children and young adults using the 670G system. Pediatr Diabetes 2020.
  45. Duffus SH, Ta’ani Z al, Slaughter JC, Niswender KD, Gregory JM. Increased proportion of time in hybrid closed-loop “Auto Mode” is associated with improved glycaemic control for adolescent and young patients with adult type 1 diabetes using the MiniMed 670G insulin pump. Diabetes Obes Metab 2020. [crossref]
  46. Silva J da, Lepore G, Battelino T, Arrieta A, Castañeda J, Grossman B, Shin J, Cohen O Real-World Performance of the MiniMedTM 780G System: First Report of Outcomes from 4120 Users. Diabetes Technol Ther 2022. [crossref]
  47. Elbarbary NS, Ismail EAR. MiniMed 780G™ advanced hybrid closed-loop system performance in Egyptian patients with type 1 diabetes across different age groups: evidence from real-world users. Diabetology & Metabolic Syndrome (2023)[crossref]
  48. Alwan H, Wilinska ME, Ruan Y, DaSilva J, Hovorka R. Real-world evidence analysis of a hybrid closed-loop system. J Diabetes Sci Technol 2023. [crossref]
  49. Ng SM, Katkat N, Day H, Hubbard R, Quinn M, Finnigan L. Real‐world prospective observational single‐centre study: Hybrid closed loop improves HbA1c, time‐in‐range and quality of life for children, young people and their carers. Diabetic Medicine 2022.
  50. Breton MD, Kovatchev BP. One Year Real-World Use of the Control-IQ Advanced Hybrid Closed-Loop Technology. Diabetes Technol Ther 2021.
  51. Graham R, Mueller L, Manning M, Habif S, Messer LH, Pinsker J, Aronoff-Spencer E. Real-World use of Control-IQ Technology is associated with a lower rate of severe hypoglycemia and Diabetic Ketoacidosis than historical data: Results of the Control-IQ Observational (CLIO) Prospective Study. Diabetes Technol Ther 2024. [crossref]
  52. Amadou C, Franc S, Benhamou P-Y, Lablanche S, Huneker E, Charpentier G, Penfornis A. Diabeloop DBLG1 Closed-Loop System enables patients with Type 1 Diabetes to significantly improve their glycemic control in real-life situations without serious adverse events: 6-month follow-up. Diabetes Care 2021. [crossref]
  53. Brown RE, Vienneau T, Aronson R. Canadian Real‐World Outcomes of Omnipod Initiation in People with Type 1 Diabetes (COPPER study): Evidence from the LMC Diabetes Registry. Diabetic Medicine 2021. [crossref]
  54. Crabtree TSJ, Griffin TP, Yap YW, Narendran P, Gallen G, Furlong N, et al. Hybrid Closed-Loop Therapy in adults with Type 1 Diabetes and above-target HbA1c: A real-world observational study. Diabetes Care 2023. [crossref]
  55. Nwokolo M, Hovorka R. The Artificial Pancreas and Type 1 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 2023. [crossref]
  56. Bionic Pancreas Research Group; Russell SJ, Beck RW, et al. Multicenter, randomized trial of a bionic pancreas in type 1 diabetes. N Engl J Med. 2022.
  57. Burnside MJ, Lewis DM, Crocket HR, et al. Open-Source automated insulin delivery in type 1 diabetes. N Engl J Med. 2022. [crossref]
  58. Zeng B, Jia H, Gao L, Yang Q, Yu K, Sun F. Dual-hormone artificial pancreas for glucose control in type 1 diabetes: A meta-analysis. Diabetes Obes Metab. 2022.
  59. Peacock S, Frizelle I, Hussain S. A systematic review of commercial hybrid closed-loop Automated Insulin Delivery Systems. Diabetes Ther 2023.
  60. Hettiarachi C, Daskalaki E, Desborough J, Nolan CJ, O’Neal D, Suominen H. Integrating multiple inputs into an artificial pancreas system: narrative literature review. JMIR Diabetes. 2022.
  61. Tsoukas MA, Majdpour D, Yale JF, et al. A fully artificial pancreas versus a hybrid artificial pancreas for type 1 diabetes: a single- centre, open-label, randomised controlled, crossover, non- inferiority trial. Lancet Digit Health. 2021.

Changes in Metabolic Markers During Ramadan Fasting According to the IDF-DAR Risk Score 2021 in Patients with Type 1 and Type 2 Diabetes: A Multicentre Study in Algeria

Leave a reply

DOI: 10.31038/EDMJ.2025912

Abstract

We aimed to assess changes in the metabolic markers of patients with diabetes between the pre-Ramadan and Ramadan periods according to the IDF-DAR risk stratification. We conducted a prospective observational study in 22 centres across Algeria. The IDF-DAR risk-stratification tool was used to categorize patients at the pre-Ramadan assessment.

A total of 1647 patients (1541 patients with type 2 diabetes and 106 patients with type 1 diabetes) were included. Of the 1324 patients who fasted, 42.1%, 26.9% and 31% were categorized as low-risk, moderate-risk and high-risk respectively. Hypoglycemia was more common in the high-risk (37.8%), compared with the moderate-risk (27.2%) and the low-risk (18.3%), p-value < 0.001. Compared with the pre-Ramadan period, during Ramadan glycemia increased by 33.6 ± 55.2 mg/dL in the low-risk category; 19.3 ± 60.6 mg/dL in the moderate-risk and 10.8 ± 70.9mg/dL in the high-risk category, while the mean reduction in HbA1c was significantly higher in the high-risk category (-0.4 ± 2.4%) compared with the moderate-risk (-0.3 ± 2.2%) and low (0.3 ± 1.9%) categories.

Conclusion: Markers of glycemic control between the pre-Ramadan and Ramadan fasting periods varied according to the IDF-DAR risk categories with less favourable changes observed in the low-risk category.

Keywords

Diabetes, Ramadan, Metabolic markers

Introduction

Fasting during Ramadan is an obligatory duty for Muslims as it is one of the five pillars of Islam. Ill people such as patients with diabetes are exempted from fasting. Diabetes is highly prevalent in the Middle East and North Africa where the majority of Muslims reside [1]. The highest prevalence of diabetes globally at 16.2% in 2021 was found in the Middle East and North Africa region. Of the 73 million people estimated to live with diabetes in Africa, 17 million were from North Africa [2]. Despite being exempted from fasting during Ramadan, many patients with diabetes choose to fast, sometimes against medical advice. Fasting during the month of Ramadan involves not eating or drinking anything from dawn to sunset. The duration of fasting depends on the period of the sacred month, and can range from 12 to 18 hours daily for 29 or 30 consecutive days. This prolonged fasting in patients with diabetes leads to an increased risk of adverse events such as hypoglycemia, hyperglycemia and hospitalizations [3]. This risk is higher in patients with type 1 diabetes who tend to be on multiple injections of insulin treatment and in patients with type 2 diabetes on certain medications [4]. In 2021, the International Diabetes Federation (IDF) in collaboration with Diabetes and Ramadan (DAR) international alliance suggested a risk score to minimize the risk of complications during fasting for patients with diabetes (IDF-DAR 2021 risk stratification tool) [5]. This risk stratification tool categorizes patients with diabetes into three risk categories based on their likelihood of safely fasting during Ramadan with recommendations about fasting: Low-risk individuals (score of 0–3) are considered safe to fast; moderate-risk (score of 3.5–6) may fast with caution, and high-risk individuals (score of >6) should not fast. Previous studies show that high risk patients according to the IDF DAR 2021 risk stratification are more likely to present with adverse events especially hypoglycemia during Ramadan fasting [6-8]. However, none of these studies reported on the changes in HbA1c a robust measure of glycemic control before and during Ramadan by IDF-DAR risk category. Moreover, it is unclear how the IDF-DAR 2021 guidelines are currently implemented in clinical settings by treating physicians and the patients’ responsiveness to risk-category-based recommendations for fasting during Ramadan. In this large prospective study in Algeria, we aimed to assess the changes in metabolic parameters (markers of glycemic control, cholesterol and triglycerides levels) before and during Ramadan according to the different IDF-DAR risk categories in patients with type 1 and type 2 diabetes.

Methods

Study Design and Participants

This was a prospective hospital-based observational study conducted in 2021 in 22 counties, Algeria. Participants were adults aged above 18 years with type 1 diabetes or type 2 diabetes regardless of whether they intended to fast during Ramadan. Patients with any severe disorder needing special care were not included. Patients with cancer or any other severe illness requiring specific follow-up were not included. Inclusion of participants in this study started 6 weeks before Ramadan and ended one week before the beginning of Ramadan. Recruitment of participants into this study and data collection was done by their treating physicians which included general practitioners trained in diabetes management, and specialists working in the public or private sector who had previously received training on patients’ education during Ramadan (training the trainers) been trained on pin the data collection.

Data for this study was collected using a pre-designed questionnaire administered using Google Forms in the pre-Ramadan and post-Ramadan periods.

Ethical Approval

Ethical approval for this study was obtained from Setif University ethical committee and all participants provided written informed consent before inclusion.

Pre-Ramadan Period

Patients were seen before Ramadan for a full assessment of their diabetes, complications and paraclinical check-up, as well as to receive therapeutic education focused on Ramadan in line with IDF-DAR recommendations (risk score, whether or not to fast, how to adapt their treatment, self-monitoring of blood glucose and how to stop fasting in the event of significant hyperglycemia or hypoglycemia). Specifically, data was collected on past medical history including type of diabetes and presence of comorbidities and current treatment, capacity of the patient to conduct Self-monitoring blood glucose (SMBG) and self-manage diabetes, experience during the previous Ramadan and all clinical and biological parameters included in the calculation of the risk score. This was used to categorize patients at the pre-Ramadan assessment into 3 categories of risk according to the IDF-DAR risk stratification tool: low-risk (score <3), moderate-risk (score 3.5–6) and high-risk (score >6). Anthropometric parameters and the most recent biochemical data available were also collected. A second visit was scheduled after Ramadan for data collection on the fasting experience, complications and biochemical results available.

Ramadan

During the Ramadan period which lasted 30 days, participants were contacted by phone by their treating physician to remind them about self-monitoring blood glucose and collect the recorded self-blood glucose monitoring (SBGM) results and data on the Ramadan fasting progress. Ramadan glycemia was obtained by calculating the mean of all glycemia recorded during the Ramadan fasting period.

Post Ramadan Period

In the post-Ramadan period, data was collected on aspects related to fasting or no fasting reasons for breaking fasting, fasting experience, self-reported adverse events, SMBG results noted during Ramadan, 2-months post-Ramadan HbA1c noted

Outcomes

Our primary outcome changes in HbA1c between the pre-Ramadan and post-Ramadan periods according to the IDF-DAR risk categories. Secondary outcomes were changes in glycemia, and lipid profile in the pre-Ramadan and post-Ramadan periods according to the IDF-DAR risk categories; and differences in the proportion of patients in the different risk categories who experienced adverse events.

Statistical Analyses

Statistical analyses were performed using Stata 15. Descriptive statistics are presented as means and standard deviations ± SD for continuous data (or median and [25th-75th percentile] for non-normally distributed continuous data) or numbers and percentages for categorical variables. We tested differences in means between the three risk categories using a one-way ANOVA (or differences in medians using the Kruskal Wallis test) and performed a Tukey’s post hoc test for comparing the possible group pairings, when the ANOVA test was significant. Differences in proportions were tested using the chi-squared test. We also compared differences in changes in the metabolic parameters between the pre-Ramadan and Ramadan periods and derived linear trends across the risk categories by fitting linear regressions and including the IDF-DAR risk categories as an ordinal variable. Throughout, a p-value < 0.05 was considered statistically significant

Results

Baseline Characteristics of Participants

Table 1 shows the descriptive characteristics of participants stratified by risk score according to the IDF-DAR 2021 risk stratification tool. Using the IDF-DAR risk criteria at the pre-Ramadan assessment, 675(41%) were categorized as low-risk (score <3), 437(26.5%) as moderate-risk (score 3.5–6) and 535(32.5%) as high-risk (score >6). Of the 1647 participants with mean age 57.8 ± 12.7 years, 57.3% were women. There was no difference in age and sex between participants in the different risk strata. The number of years of known diabetes and the proportion of smokers was lower in the low risk category compared with the moderate and high-risk categories. A total of 1012 patients were authorized to fast by their treating physicians of which 63.4% in the low-risk category, 28.1% in the moderate risk category and 8.5% in the high risk category. More patients in the low risk category self-reported intending to fast compared with the moderate and high-risk category.

Table 1: Socio-demographic characteristics of study population by risk score (n=1647).

Characteristics

 Low risk Moderate risk High risk

p-value
n (%)

675 (41)

 437 (26.5) 535 (32.5)

Age

 57.5 ± 10.02 58.7 ± 11.68 57.5 ± 16.1

0.207
SexFemale, n(%)

377 (55.9)

 257(58.8) 309(57.8) 0.598

Type 2 diabetes

 673(99.7) 425(97.3) 443(82.8)

< 0.001
Duration diabetes (years)

5[2-8]

 7[2-11] 8[4-13] 0.0001

Smoking

No

Yes

 648(96.0)

27(4.0)

 411(94.1)

26(6.0)

 487(91.0)

48(9.0)

  

0.002
Education level, n(%)NonePrimary

Middle

Secondary

University

156(23.1)

159(23.7)

113(16.7)

152(22.5)

95(14.1)

 127(29.1)102(23.3)

80(18.3)

81(18.5)

47(10.8)

 181(33.8)110(20.6)

83(15.5)

97(18.1)

64(12.0)

  

 

0.007
Marital statusSingleLives with family

06(0.9)

669(99.1)

 04(0.9)433(99.1) 16(3.0)519(97.0)

0.006
Profession, n(%)UnemployedCivil servant

Faculty staff

Retired

Others

348(51.6)

117 (17.4)

02(0.3)

170(25.2)

37(5.5)

 229(52.5)61(14.0)

03(0.7)

110(25.2)

33(7.6)

 301(57.2)58(11.0)

08(1.5)

125(23.8)

34(6.5)

  

 

 

0.01
Authorized to fast

642(95.1)

 284(64.1) 86(16.1)

< 0.001
Intention to fastWill not fastWill fast

Don’t know

07(1.04)

658(97.5)

10(1.5)

 44(10.1)365(83.5)

28(6.4)

 298(55.7)192(35.9)

45(8.4)

  

< 0.001

The clinical and biochemical characteristics of participants in the pre-Ramadan period are shown in Table 2. Last HbA1c and glycemia were lower in the low risk category compared with the moderate and high-risk categories. There was no difference in the cholesterol levels between the different strata.

Table 2: Clinical and biochemical characteristics of participants according to risk score (n=1647).

Characteristics

 Low riskn=675 Moderate riskn=437 High riskn=535

p-value

Weight (Kg)

79.8 ± 13.6

 81.1 ±15.7 78.4 ± 14.6 0.01

BMI (Kg/m2)

 29.2 ± 4.9 29.5 ± 5.5 28.6 ± 5.4

0.029
BMI categoriesUnder weightNormal weight

Overweight

Obese

10(0.61)

341(20.70)

683(41.47)

613(37.22)

 2(1.89)61(57.55)

27(25.47)

16(15.09)

 8(0.52)280(18.17)

656(42.57)

597(38.74)

  

 

< 0.001
Waist circumference (cm)

100.6 ± 12.1

 101.5 ± 14.0 99.1 ± 13.8

0.01
Systolic blood pressure (mmHg)

128.4 ± 13.7

 130.6 ± 15.4 129.3 ± 16.9 0.08

Diastolic blood pressure (mmHg)

 76.0 ± 8.7 76.3 ± 8.7 76.7 ± 9.5

0.32
Last HbA1c (%)

7.0 ± 1.1

 7.8 ± 1.8 8.2 ± 1.9 < 0.0001

Mean glycemia pré-ramadan (mg/dL)

 143.1 ± 32.9 157.2 ± 37.4 173.0 ± 48.9

< 0.0001
Number of days for glycemic measurement (days)37

14

30

90

392(58.1)

131(19.4)

58 (8.9)

51(7.3)

43(6.4)

 248(56.8)

104(23.8)

40(9.2)

28(6.4)

17(3.9)

 289(54.0)

122(22.8)

52(9.7)

40(7.5)

32(6.0)

  

 

 

0.45
GFR (ml/mn), n(%)≥9060-89

45-59

30-44

15-29

<15

350(51.9)

322(47.7)

03(0.4)

0

0

0

 209(47.8)202(46.2)

23(5.3)

03(0.7)

0

0

 207(38.7)180(33.6)

92(17.2)

41(7.7)

13(2.43)

2(0.37)

  

 

 

 

<0.001
Total cholesterol (mg/dL)

164.6 ± 40.0

 163.9 ± 40.7 161.6 ± 43.9 0.44

HDL cholesterol (mg/dL)

 42.3 ± 9.3 42.0 ± 8.9 42.0 ± 9.9

0.76
LDL cholesterol (mg/dL)

93.1 ± 31.2

 93.9 ± 32.2 93.7 ± 33.9 0.89

Triglycerides (mg/dL)

 144.3 ± 65.3 147.1 ± 69.3 146.6 ± 68.5

0.04

Fasting Practice and Complications

Of the 1647 participants included in this study, 1324 (80.4%) fasted (58.2% were women). Patients who fasted were significantly younger (57.5 ± 12.6 years) than patients who did not fast (59.2 ± 13.2 years), p-value = 0.026. There was no difference in sex or BMI between patients who fasted and those who did not fast. According to the IDF-DAR risk category, 42.1%, 26.9% and 31% of those who fasted were in the low, moderate and high-risk category respectively (Table 3).

Table 3: Factors related to fasting in those who fasted (n=1324).

Characteristics

 Low riskn=557 Moderate riskn=357 High riskn=410

p-value
n (%)
Authorized to fast

528(94.8)

 232(65.0) 77(18.8)

<0.001
Patient’s initial decisionWill not fastWill fast

Don’t know

 06(1.08)

543(97.5)

08(1.4)

 34(9.5)

301(84.3)

22(6.2)

 215(52.4)

161(39.3)

34(8.3)

  

 

< 0.001
Fasted against medical advice

29(5.2)

 125(35.0) 333(81.2)

< 0.001
Patient acted differently from initial decision

131(19.4)

 126(28.8) 291(54.4)

< 0.001
Reasons for fasting,n (%)Don’t know

Religious beliefs

Vertus du jeûne

Scared of stigmatisation

Don’t feel ill

Doctor authorized

Religious beliefs + other reasons

11(1.97)

155(27.8)

16(2.87)

1(0.18)

1(0.18)

05(0.90)

368 (66.1)

 07(1.96)

123(34.5)

09(2.5)

0

05(1.4)

1(0.28)

212(59.4)

 25(6.1)

117(28.6)

cfcfcc08(1.96)

01(0.06)

08(1.96)

0

251(61.4)

  

 

 

 

 

 

< 0.001
Fasted 30 days

346(62.1)

 229(64.2) 200(48.8) <0.001

Days fasted

 30[25-30] 30[25-30]

29[21-30]
Fasting broken

209(37.5)

 128(35.9) 217(52.9) <0.001

Reason for breaking fasting:

Hypoglycemia

Acute disease

Hypoglycemia and acute disease

Hyperglycemia

Other complications

 11(1.6)

08(1.2)

07(1.0)

0

183(27.1)

 16(3.7)

01(0.2)

02(0.5)

0

109(24.9)

31(5.8)

0

09(1.7)

0

177(33.1)

Hypoglycemia was defined as blood glucose < 70 mg/dL; Hyperglycemia was defined as blood glucose > 300 mg/dL Overall 487 (36.8%) of those who fasted were not authorised to fast by their treating physician. 81.2% of patients who were not authorized to fast were in the high risk category, compared with 35% in the moderate risk category and 5.2% in the low risk category (Table 3). Amongst those who fasted, 55.7% of those in the high-risk category had said they would not fast in the pre-Ramadan period compared with 10.1% in the moderate risk category and 1% in the low risk category (p-value < 0.001). 62.1%, 64.2% and 48.8% fasted for the full 30 days in the low risk, moderate and high-risk category respectively.

In addition, 43.4% of those with type 1 diabetes broke their fasting, compared with 33.0% of those with type 2 diabetes (p-value= 0.028). Regardless of the IDF-DAR risk category, 57.6% of the patients authorised to fast broke their fast compared with 37.0% of patients not authorised to fast (p-value = 0.02).

SMBG: Self-Monitoring Blood Glucose

The median number of time points recommended for self-monitoring blood glucose during Ramadan was significantly higher for the high risk category 4 [4,5] compared with the low risk category 3 [2-4] (Table 4). There was no difference in the median number of time points of SBGM done during Ramadan between the categories. Mean HbA1c (2 months after Ramadan) was lower in the low risk category compared with the high-risk category. The number of glycemic results between 0.70 and 1.80 g/L was higher in the moderate category compared with the high-risk category. There was no difference in the mean of glycemia during Ramadan between the categories. A lower proportion of patients in the low risk category (18.3%) reported any hypoglycemia compared with the moderate (27.2%) and high-risk category (37.8%), and severe hypoglycemia was reported by 10.2%, 19.1% and 25.9% in the low, moderate and high-risk category respectively. Hyperglycemia (> 3g/L) was also more prevalent in the high-risk category (48.8%) compared with the moderate (38.7%) and low risk category (35.0%). There was a difference between the categories in the how patients perceived their glycemia during Ramadan fasting. A higher proportion of patients in the high-risk category (52.9%) reported breaking their fast compared with the moderate (35.9%) and low risk (37.5%) categories (p-value < 0.001). The main reason for breaking fasting was hypoglycaemia. More patients in the low risk category reported following dietary advice, and having a good experience during Ramadan compared with those in the high-risk category (Table 5).

Table 4: Glycemic control and complications during Ramadan in those who fasted.

Characteristics

 Low riskn=557 Moderate riskn=357 High riskn=410

p-value
SMBG recommended

3[2-4]

 4[3-5] 4[4-5] < 0.001

SMBG done

 1.4[1-2.2] 1.5[1.1-2.3] 1.6[1.2-2.5]

0.07
HbA1c 2 months after Ramadan

7.3 ± 1.5

 7.5 ± 1.5 7.8 ± 1.7 < 0.001

Mean glycemia during Ramadan (mg/dL)

 175.8 ± 46.8 175.3 ± 46.7 182.2 ± 54.4

0.07
Number of glycemia between 0.70 and 1.80 g/L

23.4[16.8-35.1]

 24.9[18-37.8] 23.4[16.0-32.0]

0.006
Total number of glycemia during Ramadan

38[27-51]

 41[30-58] 40[30-58]

0.01
Total hypoglycemia

102(18.3)

 97(27.2) 155 (37.8) < 0.001

Symptomatic hypoglycemia

 87(15.6) 88(24.7) 152(37.1)

< 0.001
Documented hypoglycemia

118(21.2)

 79(22.1) 410(30.4) < 0.001

Severe hypoglycemia

 57(10.2) 68(19.1) 106(25.9)

< 0.001
Hyperglycemia > 3 g/L

195(35.0)

 138(38.7) 200(48.8)

< 0.001
Hospitalisation n(%)NoKetosis coma

COVID 19 infection

Infection

Hyperosmolar coma

Acute condition

Diabetic foot

Others

546(98.0)

02(0.36)

06(1.08)

02(0.36)

0

01(0.18)

0

0

 346(96.9)01(0.28)

07(1.96)

01(0.28)

0

0

02(0.56)

0

 385(94.1)03(0.73)

11(2.69)

02(0.49)

03(0.73)

0

04(0.98)

01(0.24)

  

 

 

 

 

 

0.115
Perception about glycemiaWithin normal rangeHigh

Too high

Don’t know

436(78.4)

81(14.6)

10(1.8)

29(5.2)

 269(75.4)62(17.4)

09(2.5)

17(4.8)

 290(70.7)78(19.0)

16(3.9)

26(6.3)

  

 

0.14

Table 5: Dietary adherence and experience during Ramadan according to the risk score (n=1324).

Characteristic

 Low riskn(%) Moderate riskn(%) High riskn(%)

p-value

Did you follow dietary adviceNoYes

Don’t know

84(15.1)

428(76.8)

45(8.1)

 63(17.7)268(75.1)

26(7.3)

 84(20.5)279(68.2)

46(11.3)

  

0.03
How many meals per day?23

4

539(96.8)

18(3.2)

0

 341(95.5)16(4.5)

0

 385(93.9)24(5.9)

1(0.2)

  

0.18
Family support in following dietary adviceNoYes

Don’t know

168(30.2)

360(64.6)

29(5.2)

 98(27.5)242(67.8)

17(4.8)

 150(36.6)234(57.1)

26(6.3)

  

0.035
Experience during RamadanGoodFair

Bad

Don’t know

447(80)

37(6.6)

45(8.1)

30(5.4)

 263(73.9)33(9.3)

41(11.5)

19(5.3)

 273(67.2)47(11.6)

59(14.5)

27(6.7)

  

 

0.001

Changes in Metabolic Parameters Before and During Ramadan

We also examined changes in metabolic parameters before and during Ramadan (Tables 6 and 7). Mean glycemia during Ramadan fasting was higher in the high-risk category than the low and moderate risk categories. Compared with the pre-Ramadan period mean glycemia was significantly higher during Ramadan fasting in all three categories. Being in the high-risk category was associated with a lower mean increase in glycemia (10.8 ± 70.9mg/dL) compared with the moderate (19.3 ± 60.6 mg/dL) and low risk (33.6 ± 55.2 mg/dL) categories, p-value for linear trend < 0.001. The mean reduction in HbA1c was significantly higher in the high-risk category (-0.4 ± 2.4%) compared with the moderate (-0.3 ± 2.2%) and low (0.3 ± 1.9%) risk categories. HDL cholesterol increased significantly in the high-risk category (1.7 ± 13.1 mg/dL) during Ramadan fasting compared with the pre-Ramadan period. Still, there was no evidence of a significant difference in the low and moderate categories. Total cholesterol and LDL cholesterol did not change during Ramadan compared with the pre-Ramadan period in any of the categories.

Table 6: Change in metabolic parameters before and after Ramadan in the different risk categories in those who fasted (n=1324).

Markers

 Pre-RamadanMean ± SD Post RamadanMean ± SD Mean difference95 % [CI]

p-value
Low risk
Glycemia (mg/dL)

142.1 ± 32.1

 175.8 ± 46.8 33.6 ± 55.2 < 0.0001

HbA1c (%)

 7.0 ± 1.1 7.3 ±1.5 0.3 ± 1.9

< 0.0001
Total cholesterol (mg/dL)

163.2 ± 39.0

 163.9 ± 46.2 0.7 ± 43.4 0.69

HDL cholesterol (mg/dL)

 42.2 ± 0.4 41.8 ± 10.0 -0.4 ± 12.3

0.42
LDL cholesterol (mg/dL)

92.2 ± 30.1

 97.8 ± 41.8 5.7 ± 40.9 0.001

Triglycerides (mg/dL)

 143.5 ± 64.4 142.1 ± 67.3 -1.5 ± 66.8

0.61
Moderate risk
Glycemia (mg/dL)

155.9 ± 38.2

 175.3 ± 46.7 19.3 ± 60.6 < 0.0001

HbA1c (%)

 7.8 ± 1.8 7.5 ± 1.5 -0.3 ± 2.2

0.003
Total cholesterol (mg/dL)

165.0 ± 40.8

 163.6 ± 46.9 -1.4 ± 45.2 0.56

HDL cholesterol (mg/dL)

 42.1 ± 8.7 40.8 ± 9.6 -1.4 ± 12.4

0.03
LDL cholesterol (mg/dL)

94.4 ± 32.1

 96.9 ± 39.6 2.5 ± 39.7 0.23

Triglycerides (mg/dL)

 148.3 ± 71.4 144.8 ± 68.0 -3.5 ± 69.9

0.34
High risk
Glycemia (mg/dL)

171.4 ± 48.3

 182 ± 54.4 10.8 ± 70.9 0.002

HbA1c (%)

 8.2 ± 1.9 7.8 ± 1.7 -0.4 ± 2.4

0.0008
Total cholesterol (mg/dL)

162.0 ± 45.8

 167.3 ± 51.4 5.3 ± 45.9

0.02
HDL cholesterol (mg/dL)

41.9 ± 9.9

 43.6 ± 11.9 1.7 ± 13.1

0.007
LDL cholesterol (mg/dL)

93.0 ± 2.1

 98.2 ± 42.1 5.2 ± 41.8

0.01
Triglycerides (mg/dL)

145.5 ± 64.6

 150.7 ± 67.0 5.2 ± 71.0

0.14

Table 7: Comparison of changes in metabolic parameters before and after Ramadan between the different risk categories (n=1324).

Markers

 Low riskMean difference (95% CI) Moderate riskMean difference (95% CI) High riskMean difference (95% CI)

p-value for linear trend
Glycemia (mg/dL)

33.7(29.1, 38.3)

 19.3(13.0, 25.7) 10.9(4.0, 17.8)

< 0.001
HbA1c (%)

0.3(0.2, 0.5)

 -0.3(-0.6, -0.1) -0.4(-0.6, -0.2)

 0.001
Total cholesterol (mg/dL)

0.7(-2.9, 4.4)

 -1.4(-6.1, 3.3) 5.3(0.8, 9.7)

0.12
HDL cholesterol (mg/dL)

-0.4(-1.4, 0.6)

 -1.4(-2.7, -0.1) 1.7(0.5, 3.0)

0.008
LDL cholesterol (mg/dL)

5.7(2.2, 9.1)

 2.5(-1.6, 6.6) 5.2(1.2, 9.3)

0.87
Triglycerides (mg/dL)

-1.5(-7.0, 4.1)

 -3.5(-10.8, 3.8) 5.2(-1.7, 12.1)

0.14

Discussion

In this prospective observational study including 1647 patients living with diabetes recruited from outpatient private and publics clinics in the public and private healthcare sectors in Algeria, we showed differences in metabolic parameters according to risk categories during the Ramadan fasting compared to the pre-Ramadan period. Specifically, we observed that changes in glycemic markers and cholesterol levels between the pre-Ramadan and Ramadan fasting periods varied by risk categories. Our study reinforces the importance of applying the risk score and of understanding the impact of fasting on biological parameters, notably glycaemic and lipid balance. Our study showed a higher proportion of smokers in the high-risk category compared with the low and moderate risks. The presence of a cardiovascular disease is one of the IDF-DAR criteria for severity and smoking is a major risk factor for CVD [9]. Therefore, the higher proportion of smokers in the high-risk category may be reflective of their CVD state. Our findings showed that there has been improvement in the application of the IDF-DAR recommendations for fasting according to the risk categories by the treating physicians. While our study shows that 16% of patients in the high-risk category were authorized to fast, this represents an improvement as our previous study in 2017 showed that up to 43.2% of the patients were authorized to fast [10]. Despite this, 36% of the patients in the high-risk category reported intending to fast. Ramadan fasting is of significant importance to many Muslims and although religious beliefs was the major reason reported in our study shows that there are other reasons why Muslims choose to fast beyond religious beliefs. However, in the low risk category, 642 patients were authorised to fast, but only 557 patients fasted, whereas up to 77% of patients in the high risk group fasted. In the two previous situations, our hypothesis is that these 2 changes may be linked to parameters not covered by the current score, which may overestimate or underestimate the risk score. We observed that patients in the high-risk category were more likely to break their fast compared with those in the low and moderate category and the leading factor associated with breaking fasting was hypoglycemia. This is consistent with previous studies showing that patients in the high-risk category are ~ 8 fold more likely to develop adverse events than those in the low risk category [6]. Overall, the proportions of patients in the high-risk category reporting hypoglycemic events (total, symptomatic or severe hypoglycaemia) were significantly higher in the high-risk category than the moderate and low risk category. However, about half of patients in the high-risk category were able to fast for the full 30 days. This suggests that the education provided to patients may have been effective with a high proportion of patients even in the high-risk category being able to fast safely and improve glycemic control. Patients in the high risk category presented with a poorer metabolic profile during Ramadan than the moderate and low risk categories. Specifically, glycemia, HbA1c, total and LDL cholesterol and triglycerides were higher in the high-risk category, than in the low and moderate risks categories. Also, mean changes between the Ramadan and pre-Ramadan periods were higher in the low risk categories than in the high and moderate risks. For instance, HbA1c significantly increased in the low risk categories, while it dropped in the moderate and high risk categories. Previous studies reporting the changes in metabolic parameters before and during Ramadan fasting show mixed results with some studies showing a better metabolic profile during Ramadan [11,12] than before Ramadan and others showing a worse metabolic profile or no difference [10-14]. However, these studies did not examine the metabolic changes according to risk levels. Therefore, it is possible that the beneficial effects observed during Ramadan were driven by the patients in the high-risk category whose metabolic baseline parameters tend to be very poor.

Strengths and Limitations

This is the largest prospective study to date in patients with diabetes comparing the metabolic parameters of patients before and during Ramadan fasting according to the IDF-DAR risk categories. Patients were recruited by probability sampling from many centres (both private and public healthcare sector) leading to high external validity. We did not record any lost-to-follow up as we used lessons learned from our previous study in this population to ensure high retention. We recorded 2 months post-Ramadan HbA1c a robust measure of glycemic control and compared it with the pre-Ramadan HbA1c. Despite these strengths, the main limitation of our study resides in the lack of a control arm. Therefore it is unclear whether the changes observed in the post Ramadan period are associated with Ramadan fasting, or the education provided or both. In addition, complications recorded in this study such as hypoglycemic events were self-reported which may be subject to recall bias and social desirability bias leading to misclassification. Lastly, post-Ramadan data collection happened by telephone call due to the COVID-19 pandemic.

Conclusion

In this study, we showed that metabolic control during Ramadan varied according to the IDF-DAR risk categories, with worse metabolic parameters during Ramadan in the high-risk category than in the moderate and low risks categories. However, mean changes in glycemia and HbA1c between the pre-Ramadan period and during Ramadan (2 months post-Ramadan for HbA1c) were less favourable in the low risk category compared with the moderate and high risk categories, suggesting that patients in the low risk category may also benefit from monitoring during Ramadan fasting. Still, a high proportion of patients in all 3 risk categories including the high-risk category were able to fast for all the 30 days suggesting that the education provided in the pre-Ramadan period may have been effective. Concerning the change of mind of patients authorized or not to fast, and according to their risk score, the work of pre-Ramadan education remains important, but it could be that revaluations or the addition of certain risk score parameters would provide some solutions.

Declarations of Interest

None

Funding

The authors declare not receiving funding for this study.

References

  1. Wormald B. The Future of World Religions: Population Growth Projections, 2010-2050. [Internet]. Pew Research Center. (2015)
  2. International Diabetes Federation. IDF Diabetes Atlas, 10th edn. Brussels, Belgium: 2021.
  3. Al-Arouj M, Assaad-Khalil S, Buse J, Fahdil I, Fahmy M, Hafez S, et al. (2010). Recommendations for Management of Diabetes During Ramadan. Diabetes Care. [crossref]
  4. Jemai C, Nouira M, Htira Y, Ali ZH, Ben Mami F (2024). Description of clinical profile, acute complications and glycemic control after Ramadan fasting in a Tunisian population of patients with diabetes. Human Nutrition & Metabolism.
  5. Hassanein M, Afandi B, Ahmedani MY, Alamoudi RM, Alawadi F, Bajaj HS, et al. (2022). Diabetes and Ramadan: Practical guidelines 2021. Diabetes Research and Clinical Practice. [crossref]
  6. Shamsi N, Naser J, Humaidan H, Al-Saweer A, Jaafar M, Abbas F, et al. Verification of 2021 IDF-DAR risk assessment tool for fasting Ramadan in patients with diabetes attending primary health care in The Kingdom of Bahrain: The DAR-BAH study. Diabetes Research and Clinical Practice. 2024. [crossref]
  7. Mohammed N, Buckley A, Siddiqui M, Al Ahmed S, Afandi B, Hassanein M, et al. Validation of the new IDF-DAR risk assessment tool for Ramadan fasting in patients with diabetes. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2023. [crossref]
  8. Kamrul-Hasan ABM, Alam MS, Kabir MdA, Chowdhury SR, Hannan MA, Chowdhury EUR, et al. Risk stratification using the 2021 IDF-DAR risk calculator and fasting experience of Bangladeshi subjects with type 2 diabetes in Ramadan: The DAR-BAN study. Journal of Clinical & Translational Endocrinology. 2023. [crossref]
  9. Banks E, Joshy G, Korda RJ, Stavreski B, Soga K, Egger S, et al. Tobacco smoking and risk of 36 cardiovascular disease subtypes: fatal and non-fatal outcomes in a large prospective Australian study. BMC Med. 2019. [crossref]
  10. Malek R, Hannat S, Nechadi A, Mekideche FZ, Kaabeche M. Diabetes and Ramadan: A multicenter study in Algerian population. Diabetes Res Clin Pract. 2019. [crossref]
  11. Elmajnoun HK, Faris ME, Abdelrahim DN, Haris PI, Abu-Median AB. Effects of Ramadan Fasting on Glycaemic Control Among Patients with Type 2 Diabetes: Systematic Review and Meta-analysis of Observational Studies. Diabetes Ther. 2023. [crossref]
  12. Hassanein M, Al Awadi FF, El Hadidy KES, Ali SS, Echtay A, Djaballah K, et al. The characteristics and pattern of care for the type 2 diabetes mellitus population in the MENA region during Ramadan: An international prospective study (DAR-MENA T2DM). Diabetes Res Clin Pract. 2019. [crossref]
  13. Al-barha NS, Aljaloud KS. The Effect of Ramadan Fasting on Body Composition and Metabolic Syndrome in Apparently Healthy Men. Am J Mens Health. 2018. [crossref]
  14. Chowdhury A, Khan H, Lasker SS, Chowdhury TA. Fasting outcomes in people with diabetes and chronic kidney disease in East London during Ramadan 2018: The East London diabetes in Ramadan survey. Diabetes Res Clin Pract. 2019. [crossref]

Experiences of Patients Living with Sjögren’s Syndrome: A Qualitative Meta-synthesis

Leave a reply

DOI: 10.31038/EDMJ.2025911

Abstract

Objective: To conduct a systematic review of the experiences of patients with Sjögren’s syndrome.

Methods: We performed a computerized search across PubMed, Web of Science, Embase, Cochrane Library, CINAHL, PsychINFO, Proquest, CNKI, CBM, Wanfang Data, and VIP databases to identify qualitative studies on the illness experiences of Sjögren’s syndrome patients from the inception of the libraries to September 2023. The JBI Critical Appraisal Tool for qualitative research in Australia was utilized to assess the quality of the included studies, and synthesis methods were employed to integrate the findings.

Results: Nine studies were included, yielding 32 findings that were categorized into 10 themes, culminating in 4 overarching outcomes: (1) prolonged and challenging diagnostic and treatment journeys; (2) significant daily life disruptions; (3) diverse coping styles and illness attitudes; (4) a pronounced need for, yet scarcity of, social support.

Conclusions: Sjögren’s syndrome patients endure profound physical and mental disturbances, leading to a markedly diminished quality of life. It is imperative for healthcare professionals to enhance symptom management and intervention, focus on assessing patients’ psychological well-being and coping mechanisms, and develop a comprehensive medical and social support system to ameliorate patients’ quality of life.

Keywords

Sjögren’s syndrome, Illness experience, Qualitative research, Meta-synthesis

Introduction

Sjögren’s syndrome (SS) is a chronic autoimmune disease hallmarked by dry mouth and eyes due to lymphocytic infiltration of the salivary and lacrimal glands, with primary clinical manifestations including xerostomia, fatigue, and musculoskeletal pain [1]. Predominantly affecting middle-aged and elderly women, the global incidence rate ranges from 0.04% to 4.80% [2]. SS is a protracted and relapsing condition; as it advances, symptoms can impact multiple bodily systems, severely compromising patients’ physical and mental health [3,4]. Amid the evolution of the bio-psycho-social medical model, the psychological well-being of patients with SS has become a focal point for researchers. Existing studies, while exploring the experiences and sentiments of SS patients, exhibit variations in racial, contextual, and methodological aspects, preventing a comprehensive understanding from a single study. This investigation employs a meta-integration approach to compile a more exhaustive qualitative evidence base reflecting the experiences of SS patients, aiming to inform clinical healthcare professionals and bolster the development of targeted interventions and measures.

Methods

The protocol was registered a priori with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023472699.

Search Strategy

PubMed, Web of Science, Embase, Cochrane Library, CINAHL, PsychINFO, Proquest, CNKI, CBM, Wanfang Data and VIP was searched for qualitative studies on the experience of SS from its inception to 30 September 2024, and the references of the included studies were searched manually. Search terms such as ‘Sjogren’s Syndrome/primary Sjogren’s syndrome/Sjogren’s syndrome/ Sicca Syndrome/Sicca exocrinopathy/SS/pSS; illness experience/ experience/feel*; qualitative research/qualitative research/qualitative study/participant observation/phenomenology/action research’ etc. The search strategy is illustrated with a PubMed example, see Figure 1.

Figure 1: Pubmed search strategy

Literature Inclusion and Exclusion Criteria

The inclusion criteria referred to the PICoS model [5,6]. (1) Population (P): patients diagnosed with SS (including primary Sjögren’s syndrome and Sjögren’s syndrome), age≥18 years old, gender is not limited; (2)Interest phenomenon (I): patients with SS since the disease since the real experience of the disease and feelings; (3) Context (Co): the life experiences of patients with SS during or after the diagnosis and treatment process; (4)Study design (S): qualitative research, including phenomenology, Grounded theory, ethnography and action research. Exclusion criteria: (1)duplicated published literature; (3)non-Chinese and English literature; (2)literature with no access to full text.

Literature Screening and Data Extraction

Literature screening and data extraction were carried out independently by 2 researchers (1st and 2nd authors), with a 3rd researcher (4th author) assisting in judgement when differences of opinion were encountered. The retrieved literature was imported into Endnote21, duplicates were eliminated, titles and abstracts were read for initial screening, and the full text was further read for re-screening to make a final decision on whether to include the literature. The information extracted mainly included the author, year of publication, country, subject of study, research method, phenomenon of interest and findings.

Evaluation of Literature Quality

The included literature was evaluated by 2 researchers using the JBI qualitative research quality assessment tool [7]. The tool consists of 10 items designed to assess the quality of qualitative research literature with different methods, including research methodology and conceptual depth of information. 2 researchers were assessed with ‘yes’, ‘no’, ‘not clear’were used to assess the quality of the literature, which was classified into 3 grades, A, B, and C. All criteria were assessed as grade A if they were met, grade B if they were partially met, and grade C if none of them were met. Only studies with grades A and B were included in this study and studies with grade C were excluded. Disagreements, if any, were resolved through independent judgement by a 3rd researcher.

Meta Integration Methodology

The pooled integration method from the Australian JBI Centre for Evidence-Based Healthcare was employed to synthesize the qualitative research literature under review [7,8]. Researchers, well-versed in evidence-based nursing and experienced with qualitative methodologies, meticulously examined the included literature. This process aimed to comprehend and elucidate the significance of each finding, consolidate them into categories, and ultimately amalgamate these into novel insights by dissecting the interconnections between categories.

Results

Literature Search Results

The results of the initial literature search were 588 articles, and 9 articles were included after screening and quality evaluation. The time range was from 2001 to 2020, including 1 article in Chinese and 8 articles in English. Research methods phenomenology 6 articles, descriptive research 2 articles, grounded theory 1 article. The literature screening process is shown in Figure 2.

Figure 2: Flow chart of literature screening

Basic Characteristics and Quality Evaluation of the Included Literature

The basic characteristics of the literature are shown in Table 1 and the quality evaluation is shown in Table 2.

Table 1: The basic characteristics of the included literature(n=9).

Author

 Year Country Participants Study design Location Aim

Themes
Nancy et al. [9]

2001

 America 10 patients Descriptive Research telephone interview To explore the lived experiences of people with SS and to uncover the coping strategies and attitudes of actual patients with SS Four themes: helping hindering hoping hurting
Rebecca J et al. [10]

2017

 The United Kingdom 20 patients Phenomenological Research Hospital outpatient departments or research institutes To investigate the experience of fatigue and related symptoms in patients with pSS Three themes: the physical experience of fatigue; ocular fatigue and fatigue related to ocular complaints; cognitive aspects of fatigue
Jemma L et al. [11]

2023

 The United Kingdom not mentioned Phenomenological Research Online Sites To qualitatively explore the conversations about sexual functioning that females with SS had on internet forums Four themes: the symptoms of SS and their impact on the sexual environment; the emotional responses that are commonly evoked in response to sexual difficulties; the strategies that users have implemented to manage sexual problems; and the impact that a partner’s behavior may have on the sexual environment.
Di Ying J et al. [12]

2016

 Singapore 10 patients Phenomenological Research Dental school conference room To provide clinicians with insight into how dry mouth can impact on the daily lives of Sjögren’s Syndrome patients Four themes: the journey to diagnosis; disease impact spectrum (of dry mouth amid other symptoms); interactions with healthcare professionals; and the positive coping process.
Angelika et al. [13]

2017

 Austria 20 patients Phenomenological Research Outpatient quiet room To explore perspectives and needs of patients with PSS that influence health related quality of life (HRQL) Three themes: Physical dimension; psychological & emotional challenges; social life & daily living
Gonzalo et al. [14]

2016

 Chile 12 patients Grounded Theory Hospital lighting and soundproofed private rooms To give an encompassing in-depth account of the life experiences of women with pSS and health-related behaviours, and to summarize these experiences in an integrated model. Three themes: illness experience, social interaction and psychological response
Peng et al. [15]

2023

 Taiwan, Province of China 14 patients Phenomenological Research Patient’s neighborhood fast food restaurant or hospital To explore the experiences of SS patients seeking care Four themes: annoying symptoms; difficulty in confirming a diagnosis; fear of medication side effects; confronting the disease
Anne et al. [16]

2014

 Norway 9 patients Phenomenological Research not mentioned To examine how fatigue may differ from ordinary tiredness in patients with primary Sjögren’s syndrome (SS) Two themes: a heavy, resistant body and ever- present lack of vitality; unpredictable and uncontrollable fluctuations in fatigue
Kerry et al. [17]

2020

 The United Kingdom 48 patients Descriptive Research Online Forum To explore the disease and treatment experiences of patients with pSS Three themes: Symptoms; Symptom Impacts; Patient Experiences with pSS Management

Note: 1 Was there a clear statement of the aims of the research? 2 Is a qualitative methodology appropriate? 3 Was the research design appropriate to address the aims of the research? 4 Was the recruitment strategy appropriate to the aims of the research? 5 Was the data collected in a way that addressed the research issue? 6 Has the relationship between researcher and participants been adequately considered? 7 Have ethical issues been taken into consideration? 8 Was the data analysis sufficiently rigorous? 9Is there a clear statement of findings? 10 How valuable is the research?

Table 2: Methodological quality evaluation of the included literature (n=9).

Publication

 1 2 3 4 5 6 7 8 9

10
Nancy et al. [9] Yes Yes No No Yes No Yes Yes Yes Yes
Rebecca J et al. [10] Yes Yes Yes Unclear Yes No Yes Yes Yes Yes
Jemma L et al. [11] Yes Yes Yes Unclear Yes No No Yes Yes Yes
Di Ying J et al. [12] Yes Yes Yes Yes Yes No Yes Yes Yes Yes
Angelika et al. [13] Yes Yes Yes No Yes No Yes Yes Yes Yes
Gonzalo et al. [14] Yes Yes Yes Yes Yes No Yes Yes Yes Yes
Peng et al. [15] Yes Yes Yes No Yes No Yes Yes Yes Yes
Anne et al. [16] Yes Yes Yes Unclear Yes No No Yes Yes Yes
Kerry et al. [17] Unclear Yes Yes Unclear Yes No No Yes Yes Yes

Results of Meta-integration

The researcher distilled a total of 32 findings by iteratively reading and analyzing the nine pieces of literature included, organizing and generalizing the similar findings into 10 new categories, and obtaining four integrative findings.

Integrating Outcome 1: A Long and Difficult Consultation Experience

Category 1: Long Time to Diagnosis of Disease

Patients often experience multiple visits to the doctor due to disease symptoms involving multiple systems throughout the body (‘These searches were complicated by the need for multiple diagnoses including fibromyalgia, Raynaud’s, RA, lupus, and chronic fatigue syndrome’[9] ‘Many respondents discussed their histories of multiple doctor visits both to general practitioners and to specialists’[9]), in which most patients received only specialist symptomatic management (‘the focus of the physician’s visit was on prescribing medication to bring symptomatic relief ’[15]), and the time to confirmation of the diagnosis was continually prolonged (‘after 5 years of symptoms and unsatisfying visits at different doctors, one doctor was on the right way’[13]) they questioned the professionalism of the doctors (‘the thing is do the general practitioners know about it ?’[12] ‘Every practitioner speaks differently, three speak three ways and no one can tell me what it really is’[15] ‘My doctor doesn’t believe I have SS’[9])

Category 2: Difficult Treatment Process

Due to a lack of knowledge about the disease, patients often felt overwhelmed (‘she didn’t always know what was enough importance to alert her doctor’[9], ‘I don’t know that I actually really need to know all just at this point in time’[12]), and showed concern about medications that bring about side effects and effectiveness (‘worried about the side effects from western medication’[15], ‘the various medications do not help much’[9]), and financial burdens that grew as the disease progressed (‘every year thousands of dollars to the dentist’[12], ‘my retirement and savings have been depleted’[16])

Integration Outcome 2: Severe Daily Life Distress

Category 3: Physical Symptoms Throughout the Body

The most common discomfort experienced by patients is dry mouth and eyes (‘my lips stick together and I can’t separate them’[14], ‘my eyes are dry it feels like sandpaper has been rubbed over them’[16] ‘a feeling of choking’[13]), limited dietary choices (‘I can’t eat dry food, I can’t swallow it’[13]) Some patients experience a gradual loss of their sense of taste (‘sometimes I can’t taste food, I also find myself losing my sense of taste and smell’[14]); pain accompanies the patient (‘limbs, everything hurts’[13]), and constant fatigue fills the daily routine (‘just peeling potatoes is exhausting!’[15], ‘I don’t even have the energy to talk’[16], ‘I can sleep for days at a time when the fatigue comes’[10]), and sleep is affected (‘When I sit up in bed, I can only sleep’[13], ‘When I turn around, I have a feeling of suffocation’[13])

Category 4: Intimate Relationships in Trouble

Disease manifestations of oral dryness and female vaginal dryness (‘I don’t realise that I’m only comfortable with kisses on the mouth’[11], ‘My vaginal dryness has gotten worse’[11]) affect the patient’s intimate relationship harmony(‘My husband and I have not had sex for over a year’[11] ‘My husband does not tolerate changes in our sex life’)[14]), patients’ libido declines, intimacy decreases, and they feel guilt and pain (‘It’s too painful’[11] ‘The guilt overwhelms me’[11])

Category 5: Negative Psychological Experiences

Patients often feel helpless and sad in the face of the disease (‘especially when you are tired, you feel low’ [9] ‘one time I broke down and burst into tears, which stressed me out a lot’ [9]) SS is a chronic disease for which there is no cure for it, and a variety of symptomatic medications such as immunological agents and other drugs are mostly used in the clinic. While taking medications, patients are concerned about their potential range of side effects (‘anti-inflammatories, paracetamol, codeine, you end up with more tablets’ [11] ‘too many side effects of western medication’ [15]), and some patients are annoyed with the status (‘a few people questioned what they were doing to deserve SS’ [11], ‘I’m getting very, very annoyed’ [10] ‘I’m getting very, very bad’ [10]). During the course of the disease, the functioning of multiple organ organs throughout the patient’s body is progressively affected, and the patient expresses his or her fears about the uncertainty of the future progression of the disease (‘The worst thing is not knowing what is going to happen’ [8] ‘Fear of organ failure and dialysis’ [8] ‘fear of incapacitation’ [8]) In understanding the incurable nature of the disease, coupled with the constant physical and mental distress, patients develop self-loathing (‘I hate myself, I hate this woman in pain’ [10]), they chose to reject the sympathy of others and tried to hide the condition (‘don’t want people to look at me differently or say ‘poor me’’ [8] ‘I don’t let anyone see it…I cover everything up’ [9])

Category 6: Social and Work Disorders

SS symptoms affect all systems throughout the body and cause many inconveniences to the patient during daily life and social interaction (‘I can’t read at night because my eyes are too sore and tired’ [9] ‘Driving is often limited due to fatigue and dry eyes’ [8] ‘My tongue gets stuck and I can’t express myself clearly’ [13] ‘I have a very limited life of shutting myself away and going to the hospital’ [13]), and was unable to perform previous work (‘I have noticed that I get tired faster in conversations’ [9] ‘Especially with computer work, patients find it challenging to have long conversations with clients’ [12] ‘My dryness is greatly affected my life, causing me to stop working and retire early’ [16])

Integrating Outcome 3: Very Different Coping Styles and Attitudes Towards Illness

Category 7: Positive Attitude and Coping

Patient maintains a positive outlook throughout the disease diagnosis and treatment process, believing that he or she will ultimately overcome the disease (‘I’ll be lucky if that’s all that’s knocked out of me’ [8] ‘I think in time I’ll get back to where I was before’ [13] ‘There are a lot of people who lie down and die, they sink because of health problems – not me!’ [13] ‘I’m trying to say come across it and accept it’ [15]) They actively use multiple resources around them to seek help to learn about the disease (‘learning how to understand and help themselves from multiple sources such as other patients, support groups, literature and computer searches’ [8]) while attempting to make lifestyle adjustments to accommodate the disease (‘Many respondents drank water more frequently and changed their eating patterns. Keeping their hands and feet as warm as possible and pacing themselves according to their activity and rest needs’[8] ‘Made a lateral move to work’ [8] ‘We tried all the backwash.’[10] ‘My water bottle is my best friend’ [10] ‘Making vaginal uterine trays, moisturisers or soaps to alleviate the dryness associated with dry syndrome’ [10]), and some patients try alternative medicine treatments (‘Started actively exploring complementary and alternative medicine and started seeing a nutritionist’ [11]) Some patients comfort their souls by being religious and helping each other (‘I also attend spiritual events and worship God, all we do is ask for human nature’ [13] ‘We would go to church, and when we were sick we would ask our brothers and sisters in the group to pray for me, and then there would be an outlet for our moods’[15] ‘Doing small feats of charity myself, exhorting people to be good, teaching while doing so, and contributing my skills during my lifetime’[15]), and in doing so, patients experienced positive physical and mental positive feedback (‘personal growth and development can be facilitated’ [8] ‘the research process itself is an altruistic act that positively affects their self-esteem’ [11])

Category 8: Negative Attitudes and Coping Styles

Conversely some patients maintained negative attitudes and chose to delay seeking treatment (‘She tried to deny her symptoms and sometimes let the bad signs and symptoms go on for too long before seeking help’ [8] ‘She tried not to think about anything and took it day by day. I didn’t cope with it properly and that was my way’ [8]).

Integration Outcome 4: Thirst for and Lack of Social Support

Category 9: Lack of Social Support

SS patients do not receive sufficient support from family (especially spouses) and friends (‘My husband is the worst problem because he doesn’t understand’ [8] ‘My husband is not supportive or helpful, and doesn’t tolerate changes in our sex life’ ‘There are no friends to talk to about dry syndrome’ [8]) and on the other hand, the help received by patients in peer support groups is not sufficiently represented (‘There is a marked negativity in the support group and a lack of shared responsibility for managing the group’ [8] ‘The support group did not support her as a leader and she found herself dragged down by the others’ [8])

Category 10: Desire for Social Support

Adequate support from close relationships brought great help to the patient (‘More than one person said that her best support came from her spouse’ [8] ‘My whole family knows about this and they all try to help me not to talk too much and to keep me calm’[13]) Meanwhile, during the visit, patients were eager to be able to communicate effectively with each other and with healthcare professionals to give them psychological support and comfort (‘It’s very important to be able to talk to the healthcare professionals, I know that at the moment they can’t do anything about it, it’s okay, but you’re listening to it, you’re not just folding it’ [11] ‘An understanding healthcare practitioner made a big impact’ [8])

Discussion

Focus on the Impact of SS Symptoms on Patients and Actively Take Appropriate Measures to Alleviate Them

Integration results reveal that Sjögren’s syndrome (SS) patients endure a spectrum of symptoms, including dry mouth and eyes, fatigue, and generalized pain, significantly impairing their quality of life. As dry eyes can progress to keratitis, patients may experience blurred vision, redness, and ocular discomfort. Reduced salivary gland secretion not only affects eating and swallowing but also speech and taste perception, potentially leading to halitosis, oral ulcers, and rampant caries, which disrupt daily eating and social interactions [17- 18]. Healthcare professionals should advise patients on maintaining oral and ocular hygiene, facilitate early screening and diagnosis, and intervene to enhance glandular secretion, thereby mitigating the symptoms’ impact on physical and mental well-being. Sleep quality is closely linked to quality of life; sleep disorders can affect daily life and may trigger immune and inflammatory responses, increasing the risk of autoimmune diseases [19]. Professionals should assess and address patients’ sleep issues promptly, employing personalized treatments. Cognitive-behavioral therapy has been shown to improve sleep quality in SS patients, and both exercise therapy and traditional Chinese medicine (TCM) offer safe and effective interventions for sleep disorders [20,21]. Sexual dysfunction, a significant aspect of physical and mental health, is prevalent among female SS patients, threatening intimacy and potentially inducing negative emotions such as embarrassment and helplessness. Studies indicate that the prevalence of sexual dysfunction in SS patients is twice that of the general population, with vaginal dryness, pain, and fatigue influencing sexual behavior [22]. Given the sensitive nature of this issue, few patients are willing to discuss it openly. Healthcare professionals should delve into patients’ experiences, bolster nurse-patient trust, and provide empathetic listening, respect, and support. Collaborating with gynecologists and psychologists can offer patients comprehensive professional and psychological assistance.

There is no cure for SS, hence treatment focuses on symptom relief, mitigating local and systemic damage, and enhancing quality of life [23]. The emphasis should be on early screening and diagnosis through collaborative efforts with multidisciplinary teams. In recent years, traditional Chinese medicine (TCM) and its techniques have gained traction in SS treatment, attributed to their efficacy in symptom improvement and lower incidence of toxic side effects [24,25]. Future clinical outcomes may be enhanced by integrating TCM with other therapeutic approaches. Additionally, patients can be empowered to adopt healthier lifestyles, thereby improving their quality of life, through comprehensive and personalized health education initiatives.

Focusing on Negative Emotions in SS Patients and Fostering Positive Coping Strategies

Integrative findings reveal that SS patients experience a spectrum of negative emotions, impacting their quality of life due to enduring clinical symptoms, daily life limitations, and compromised social functioning [27]. Research indicates that the prevalence of anxiety and depression among SS patients is markedly higher than in the general population, with rates of 33.8% and 36.9%, respectively [26]. Healthcare professionals must prioritize the emotional well-being of SS patients, delve into the origins of their negative emotions, and guide them towards effective emotional expression and coping mechanisms. Encouraging a realistic understanding of disease symptoms and bolstering confidence in treatment outcomes is crucial. Evidence supports the efficacy of positive thinking training therapy and narrative care in alleviating anxiety and depression, thereby enhancing life quality [28-30]. Tailored interventions for SS patients can strengthen nurse-patient rapport, mitigate negative emotional impacts, and promote a positive and stable mental state.

The study’s findings highlight the diverse coping strategies employed by SS patients, which are their cognitive and behavioral responses to the disease and its associated disruptions [31]. Effective coping strategies are crucial for alleviating symptoms, enhancing functional status, and improving quality of life [32,33]. Healthcare professionals should promptly assess these strategies and provide ongoing support to patients who utilize positive approaches. Additionally, professionals must delve into the challenges faced by patients with negative or avoidant coping mechanisms to foster better disease acceptance and develop constructive cognitive coping strategies. Family support is pivotal in bolstering patients’ confidence in treatment and in converting negative emotions and coping behaviors [34]. Engaging patients and their caregivers in treatment decisions is essential for increasing their investment in therapy. Continuity of care, including regular professional guidance, is vital for encouraging patients to actively engage in their disease management and to confront their condition with a positive attitude.

Constructing an Optimal Medical and Social Support System

The integration findings indicate that Sjögren’s syndrome (SS) can affect multiple bodily systems, prompting patients to seek treatment for their presenting symptoms. Without adequate disease knowledge and interdisciplinary collaboration in diagnosis and treatment, healthcare providers may fail to make accurate assessments, leading to delayed SS diagnoses. During consultations, patients often receive only symptomatic treatment, which falls short of addressing their comprehensive needs. Thus, medical staff must enhance their expertise and foster interdisciplinary collaboration to develop personalized diagnostic and treatment plans, as well as offer patients thorough, evidence-based education and guidance on SS [23]. Patient care continuity should also be a priority, leveraging ‘Internet + nursing services’, interdisciplinary nursing teams, and hospital-community- family collaborative frameworks to ensure precise and efficient patient management [35]. Additionally, family, peer, and social support are crucial for SS treatment. Patients require ample emotional support from families, and peer support groups should be professionalized and made more effective. Group composition should be carefully selected to foster constructive communication and sharing among patients, with ongoing monitoring to address their emotional and informational needs, and to implement timely adjustments and management strategies.

Conclusion

Using meta-integration methodology, this study thoroughly examined the illness experiences of patients with SS, revealing four key themes: the complexity and duration of diagnostic and treatment processes, substantial disruptions to daily life, a variety of coping styles and illness attitudes, and an evident gap in social support despite a high demand. Healthcare professionals are advised to implement personalized care strategies to mitigate patients’ distressing symptoms, address psychological well-being to foster positive outlooks, and engage in interdisciplinary collaboration to enhance diagnostic and therapeutic approaches.

Limitation

This study has certain limitations: it did not include studies that have not yet been published, introducing a degree of selective bias; and some of the included literature is relatively old, which may limit the applicability of the meta-integrated results and may not fully reflect the experiences of SS patients. This indirectly suggests that there is a current lack of attention to the psychological experiences of SS patients, which warrants further in-depth exploration in the future.

Acknowledgements

We would like to express our sincere gratitude to all those who contributed to this work. Your support and assistance have been invaluable throughout the research process.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

References

  1. Seror R, Nocturne G, Mariette X (2021) Current and future therapies for primary Sjögren syndrome. Nature Reviews. Rheumatology. [crossref]
  2. Cui Y, Li J, Li L, Zhao Q, Chen S, Xia L, Fu T, Ji J, Gu Z (2020) Prevalence, correlates, and impact of sleep disturbance in Chinese patients with primary Sjögren’s syndrome. International Journal of Rheumatic Diseases, 23(3): 367-373. [crossref]
  3. Zhang W, Li X M, Xu D, Liu D Z, Dong Y (2020) Recommendations of diagnosis and treatment of primary sjgren’s syndrome in china. Zhonghua nei ke za zhi. [Chinese journal of internal medicine], 59(4): 269-276. [crossref]
  4. Miyamoto, Samira T.Valim, ValeriaFisher, Benjamin A (2021) Health-related quality of life and costs in sjogren’s Rheumatology, 60(6) [crossref]
  5. Westerlund A, Kejs A M T, Beydogan H, Gairy K (2021) Primary Sjögren’s Syndrome: A Retrospective Cohort Study of Burden of Illness in Sweden. Rheumatology and Therapy. [crossref]
  6. Stern C, Jordan Z, McArthur A (2014) Developing the review question and inclusion The American Journal of Nursing. [crossref]
  7. The Joanna Briggs Critical appraisal checklist for qualitative research[EB/ OL].[2022-02-05].
  8. Lockwood C, Munn Z, Porritt K (2015) Qualitative research synthesis: methodological guidance for systematic reviewers utilizing meta-aggregation. International Journal of Evidence-based Healthcare. [crossref]
  9. Schoofs N (2001) Seeing the glass half full: living with Sjogren’s Journal of Professional Nursing: Official Journal of the American Association of Colleges of Nursing. [crossref]
  10. Stack R J, Southworth S, Fisher B A, Barone F, Buckley C D, Rauz S, Bowman S J (2017) A qualitative exploration of physical, mental and ocular fatigue in patients with primary Sjögren’s Syndrome. PloS One. [crossref]
  11. McCready J L, McCarty K, Deary V, Collins T L, Hackett K L (2023) A qualitative exploration of internet forum discussions surrounding female sexual function for individuals with Sjögren’s PloS One 18(9): e0291422.
  12. Ngo DYJ, Thomson WM, Nolan A, Ferguson S (2016) The lived experience of Sjögren’s BMC oral Health. [crossref]
  13. Lackner A, Ficjan A, Stradner MH, Hermann J, Unger J, Stamm T, Stummvoll G, Dür M, Graninger WB, Dejaco C (2017) It’s more than dryness and fatigue The patient perspective on health-related quality of life in Primary Sjögren’s Syndrome – A qualitative study. PloS One 12(2) e0172056. [crossref]
  14. Rojas-Alcayaga G, Herrera Ronda A, Espinoza Santander I, Bustos Reydet C, Ríos Erazo M, Wurmann P, Sabugo F, Geenen R (2016) Illness Experiences in Women with Oral Dryness as a Result of Sjögren’s Syndrome The Patient Point of View. Musculoskeletal Care 14(4): 233-242. [crossref]
  15. Chih-Yu P, Mei-Ping L, Pin-Hsuan L, Cheng-I Y, Huai-Ti H, Meng-Chen H, Li- Hung L (2023) Experiences of patients with Sjögren’s Syndrome in seeking medical Nursing Magazine 70(5): 36-43.
  16. Mengshoel AM, Norheim KB, Omdal R (2014) Primary Sjögren’s syndrome fatigue is an ever-present fluctuating and uncontrollable lack of energy. Arthritis Care & Research 66(8): 1227-1232. [crossref]
  17. Gairy K, Ruark K, Sinclair SM, Brandwood H, Nelsen L (2020) An Innovative Online Qualitative Study to Explore the Symptom Experience of Patients with Primary Sjögren’s Rheumatology and Therapy 7(3): 601-615. [crossref]
  18. Baer AN, Walitt B (2017) Sjögren Syndrome and Other Causes of Sicca in Older Clinics in Geriatric Medicine 33(1): 87-103. [crossref]
  19. Chung SW, Hur J, Ha YJ, Kang EH, Hyon JY, Lee HJ, Song YW, Lee YJ (2019) Impact of sleep quality on clinical features of primary Sjögren’s syndrome. The Korean Journal of Internal Medicine 34(5): 1154-1164. [crossref]
  20. Oláh C, Schwartz N, Denton C, Kardos Z, Putterman C, Szekanecz Z (2020) Cognitive dysfunction in autoimmune rheumatic diseases. Arthritis Research & Therapy 22(1) 78. [crossref]
  21. Chen HH, Lai JN, Yu MC, Chen CY, Hsieh YT, Hsu YF, Wei JC (2021) Traditional Chinese Medicine in Patients With Primary Sjogren’s Syndrome A Randomized Double-Blind Placebo-Controlled Clinical Trial. Frontiers in Medicine 8 744194. [crossref]
  22. Lp D, Aba G, Pa M et al. (2022) The effects of resistance training in patients with primary Sjögren’s Clinical Rheumatology 41(4) [crossref]
  23. H I, M I, O A et (2017) Are the women with Sjögren’s syndrome satisfied with their sexual activity?. Revista Brasileira de Reumatologia 57(3) [crossref]
  24. Liu H, Wang X, Liu W, He G, Liang X, Bian Y (2023) Effectiveness and Safety of Traditional Chinese Medicine in Treatment of Primary Sjögren’s Syndrome Patients A Meta-analysis. Combinatorial Chemistry & High Throughput Screening 26(14) 2554-2571. [crossref]
  25. Yen CM, Lin HC, Chen WS, Hsu CC, Liaw CC, Kung YY, Ma CP, Chen HY, Su YT, Chang CM (2024) Evaluation of traditional Chinese medicine tea bag TBDESJS in patients with Sjögren’s syndrome and dry eye syndrome A phase II pilot study. International Journal of Rheumatic Diseases 27(11) [crossref]
  26. Popescu A, Hickernell J, Paulson A, Aouhab Z (2024) Neurological and Psychiatric Clinical Manifestations of Sjögren Current Neurology and Neuroscience Reports 24(8): 293-301. [crossref]
  27. Cui Y, Xia L, Li L et (2018) Anxiety and depression in primary Sjögren’s syndrome A cross-sectional study. BMC Psychiatry 18(1): 131. [crossref]
  28. Liu Z, Dong Z, Liang X et (2017) Health-related quality of life and psychological status of women with primary Sjögren’s syndrome A cross-sectional study of 304 Chinese patients. Medicine 96(50) e9208. [crossref]
  29. Mao WJ, Chen WD, Cai WD, Jiang MJ, Du J, Guo JY (2024) Effects of virtual reality- based positive thinking training on negative emotions and fatigue in ovarian cancer patients undergoing chemotherapy. China Nursing Management 24(1): 29-34
  30. Lin Wan-Ting, Cai-Hong Lu, Zheng-Rong Wang, Huan Hong, Qiao-Rong Liu (2023) Effects of Focused Solution Brief Therapy Combined with Positive Thinking Training on Anxiety, Depression, and Quality of Life in Dry Eye Journal of Nursing 38(14): 72-76
  31. Zhao Jiao, Li Aixian, Feng Yuanyuan, Zhu Ying, Yuan Jiu-Lian, Xu Meng (2022) Effects of narrative care on anxiety, depression and well-being in hematopoietic stem cell transplantation patients. China Nursing Management.
  32. Folkman S (1984) Personal control and stress and coping processes A theoretical Journal of Personality and Social Psychology 46(4): 839-852.
  33. Líška D (2022) Exercise in the treatment of ankylosing Vnitrni Lekarstvi 68(E-1): 16-21. [crossref]
  34. Macfarlane TV, Abbood HM, Pathan E et al. (2018) Relationship between diet and ankylosing spondylitis A systematic European Journal of Rheumatology 5(1): 45-52. [crossref]
  35. Yang HL, Wang P, Hou WX, Luan XR (2016) Design and application of a hospital- community-family ternary linkage continuity of care platform. Chinese Journal of Nursing.

Ending the Mpox Endemic: Beyond Declaring a Public Health Emergency

1 Reply

DOI: 10.31038/IJVB.2025911

Abstract

The first recorded human case of the Monkeypox virus occurred in the Democratic Republic of the Congo in 1970. Over the past six decades, human Monkeypox has remained endemic in Western and Central Africa and emerged as a global public health threat since 2022 [1,2]. The Africa Centers for Disease Control and Prevention (Africa CDC) classified the escalating Mpox outbreak across 15 countries in the World Health Organization (WHO) African Region as a Public Health Emergency of Continental Security. In response, WHO Director-General Dr. Tedros Ghebreyesus declared a Public Health Emergency of International Concern (PHEIC) on 14 August 2024. This global outbreak has affected over 120 countries since 2022. Addressing this prolonged endemic requires global collaboration and concerted efforts. Given the similarities between smallpox and Mpox, valuable lessons can be drawn from the successful eradication of smallpox in 1980. The global vaccination model and eradication of smallpox in 1977 are compared with lessons from the ongoing Mpox endemic since 1970.

Keywords

Poxvirus vaccination, Monkeypox, Vaccine awareness, Vaccine inequity, Vaccine monopoly, Vaccine subsidy

The Global Vaccination Model and Eradication of Smallpox

The eradication of smallpox in 1980 was the result of a highly successful global vaccination campaign led by the World Health Organization (WHO). This effort demonstrated an unparalleled level of global collaboration among WHO, health agencies, epidemiologists, and international workers. The intensified smallpox eradication program successfully implemented six key components, which played a pivotal role in eradicating smallpox in Africa by 1977 [2]. As depicted in Figure 1, these components included international funding for the eradication program and collaboration efforts, vaccine production, technology transfer, vaccine donations, vaccine distribution, and vaccination mobilization.

Figure 1: Global Vaccination Model and Eradication of Smallpox in 1980.

International Funding for the Eradication Program and Collaboration

The intensified smallpox eradication program was funded by the WHO, the World Health Assembly, and endemic countries. The World Health Assembly mobilized member nations to commit resources, with two-thirds of the funding coming from donations. Maintaining the program over a decade depended on strong collaboration among eradication staff at WHO headquarters, supervisory personnel at national and provincial levels, and local health workers [2]. This multi-level global partnership and pooled resources were essential for the effective coordination of large-scale surveillance and containment initiatives [2,3].

Vaccine Production and Vaccine Technology Transfers

A key aspect of the vaccination efforts in the 1970s was the production of higher-quality freeze-dried vaccines and the large-scale manufacture of user-friendly bifurcated needles. Additionally, vaccine technology transfers enabled higher-risk countries to produce their freeze-dried vaccines and serve as suppliers [2].

Vaccine Donations

Many endemic countries, being developing nations, lacked sufficient health budgets to fund a smallpox eradication program. Vaccine donations played a crucial role, with the U.S. and Soviet Union leading as major contributors, providing over 450 million doses of vaccine. Other donor countries, including the U.K., France, Canada, and Cuba, also contributed vaccines, which were distributed by the WHO [2,4].

Vaccine Distribution and Vaccination Mobilization

Higher-quality freeze-dried vaccines, which were easier to store and administer, facilitated the mass distribution and mobilization of vaccines. This advancement supported universal childhood immunization programs and mass vaccination efforts, even in regions with underdeveloped health systems and significant logistical challenges. The global smallpox vaccination campaigns achieved remarkable success through targeted surveillance-containment strategies and robust collaboration among health personnel and surveillance officers [5].

Lessons from the Ongoing Mpox Endemic Since 1970

As discussed in the preceding section, the WHO played a pivotal role in the successful implementation of the global intensified smallpox eradication program by securing collaborative resources and driving mass vaccination efforts. Unfortunately, the strategies that proved effective in eradicating smallpox have not been adequately applied to combat Mpox. Since 1970, the Democratic Republic of Congo has experienced endemic Mpox cases. A WHO-sponsored global Mpox vaccination campaign remains largely absent due to significant barriers to vaccine access, despite the creation of the Mpox Strategic Preparedness, Readiness, and Response Plan (SPRP) [6,7]. As shown in Figure 2, six key components highlight the global disparities in Mpox vaccination efforts.

Figure 2: Lessons from the Ongoing Mpox Endemic Since 1970.

Lack of International Funds for the WHO and Africa CDC Plan

Although Mpox has persisted as an endemic issue in Western Africa for decades, international funding to combat this pandemic has been insufficient. As demonstrated by the global smallpox eradication campaign, international funding and collaborative efforts are critical for the success of the SPRP. The WHO should take a leading role in securing increased financial support from member nations to fund the WHO and Africa CDC Plan, complementing the U.S.’s pledge of at least $500 million [8].

Vaccine Monopoly and No Vaccine Technology Transfers

Compared to the AIDS and COVID-19 pandemic, Mpox endemic is experiencing more severe vaccine inequities due to the Mpox vaccine manufacturing monopoly [9]. The Danish Bavarian Nordic is the only Mpox vaccine manufacturer in the U.S. and the European Union. Deadweight loss occurs in a monopoly as its price is above the competitive price with an inefficient lower output. The significantly high price of the Mpox vaccine at $141 quoted by the WHO poses a high pricing barrier to low-income countries and poses challenges in securing millions of shots for Africa [10]. International agencies including UNICEF are trying to secure as many as 12 million doses for African countries by 2025 [10]. Africa’s vaccine manufacturing capacity remains limited, and the uncertainty surrounding future demand for vaccines in the region discourages vaccine technology transfers [10].

Pledged Vaccine Donations

High-income countries have secured the majority of available Mpox vaccine doses, leaving endemic African countries unable to afford vaccination for their populations due to high costs and limited supply. To effectively contain Mpox outbreaks in these regions, vaccine donations and subsidies for low-cost vaccines are crucial. More than 5.4 million vaccine doses have been pledged for the Mpox response, with 3 million doses committed by Japan and 2.34 million doses contributed by the U.S., Canada, EU Member States, the European Commission Health Emergency Preparedness and Response Authority, Gavi, the Vaccine Alliance, and Bavarian Nordic [11].

Limited Vaccine Distribution and Vaccination Mobilization

Significant barriers hinder Mpox vaccine distribution in African nations, including unaffordable pricing, limited supply, logistical challenges in storage and delivery, and the limited proximity of vaccination sites [12]. Socioeconomic and cultural factors further impede vaccination mobilization, such as mistrust of vaccines and cultural opposition [13,14]. At the community level, vaccine advocates and opinion leaders should work together to reduce stigma, raise awareness, and spread accurate vaccination information.

Conclusion

The successful eradication of smallpox was achieved through an unprecedented level of global collaboration, fully implementing the intensified smallpox eradication program. The WHO played a central role by mobilizing funding, coordinating targeted surveillance and containment efforts, and leading vaccination campaigns. Vaccine donations and technology transfers significantly expanded vaccine availability, while vaccines that were easy to store and administer facilitated mass immunization efforts. In contrast, the Mpox vaccine manufacturing monopoly is severely limiting access to vaccines in African countries hardest hit by the endemic. These nations also face infrastructural, logistical, economic, and cultural barriers. To address this, the WHO and Africa CDC must mobilize collaborative resources to bring the Mpox endemic under control. Bridging vaccine disparity gaps is critical, drawing lessons from past global health efforts [15]. Global coordinated actions are increasingly necessary to combat the rising threat of infectious disease outbreaks. High-income nations should support preventive measures in resource-poor countries by investing in healthcare infrastructure, water treatment, sanitation, waste management, and transportation systems.

References

  1. Abbara A, Rao B, Titanji B, Boum Y, Zumla A (2022) The monkeypox outbreak must amplify hidden voices in the global discourse. The Lancet. [crossref]
  2. Son BWK, Wambalaba OW, Wambalaba WF (2024) A Multi-pronged Approach to Addressing Global Poxviruses Vaccine Inequity: A Case of Monkeypox. In: Rezaei, N. (eds) Poxviruses. Advances in Experimental Medicine and Biology, vol 1451. Springer, Cham. [crossref]
  3. Henderson, D, Klepac P (2013) Lessons from the eradication of smallpox: an interview with D. A. Henderson. Philosophical Transactions of the Royal Society of London. Series B, Biological sciences 368(1623): 20130113. [crossref]
  4. Haynes J, Li C (2020) The US cooperated with the Soviets on smallpox – it should do the same with China on COVID-19 vaccine distribution.
  5. Henderson DA, Moss B. (1999) Public Health. In: Plotkin SA, Orenstein WA, editors. Vaccines. 3rd edition. Philadelphia: Saunders.
  6. WHO (2022) Monkeypox Strategic Preparedness, Readiness, and Response Plan (SPRP).
  7. Yang Z, Gray M, Winter L (2021) Why do poxviruses still matter? Cell Biosci 11, 96. [crossref]
  8. HHS (2024) Announces Mpox Vaccine Donations, Boosting Domestic and International Supply. [crossref]
  9. Hart R (2024) Mpox Vaccine Maker Bavarian Nordic Shares Soar Amid Concern Over Virus Outbreak. Forbes.
  10. Wass S, Kew J (2024) Higher price of mpox vaccine to pose key hurdle in Africa order talks. Business Standard.
  11. WHO (2024) Donors making a difference: United against mpox, swift and effective response in action.
  12. Molteni M, Branswell H, Joseph A, Mast J (2022) 10 key questions about monkeypox the world needs to answer.
  13. Lancet Editorial Board (2022) Monkeypox: a global wake-up call. [Editorial]. The Lancet 400: 337. [crossref]
  14. Son B, South-Winter C (2018) Human Behavior Impacts on Health Care. Journal of International & Interdisciplinary Business Research 5(8): 138-146.
  15. Son BWK (2023) A Multipronged Approach to Combat COVID-19: Lessons from Previous Pandemics for the Future. In: Rezaei, N. (eds) Integrated Science of Global Epidemics. Integrated Science, vol 14. Springer, Cham.

Commentary: Implications of Critical Periods in the Development of Autism

1 Reply

DOI: 10.31038/PSYJ.2025711

 

Autism spectrum disorder (ASD, or autism) is a collection of developmental disorders with an increasing diagnosis rate. The most recent data compiled by the CDC (Centers for Disease Control and Prevention [1]) show a prevalence of 2.76% of 8 year olds in the US as diagnosed autistic in 2020, compared with 1.47% in 2010 and 0.67% in 2000. A new report [2] provides some guidance on factors that may contribute which, in combination with other recent studies, gives direction on what can be done to help mitigate this rise.

The report reviews determining factors of folate and of inflammation in the development of autism and observes that there are multiple critical periods in ASD where these factors play essential roles.

Critical Periods

The concept of critical periods was first demonstrated in the visual system, showing that the absence of light during a key period in visual cortex development determined the ultimate pathways made in the visual cortex, and that even normal exposure to light following this critical period was insufficient for the pathways to develop if they had not had light stimulation during the critical period. Wiesel and Hubel named this a critical period in the visual cortex, earning them the Nobel Prize in physiology or medicine in 1981 for this central understanding of the development of key brain functions [3]. The report [2] assesses that autism has multiple critical periods, and lists factors involved in at least two of these critical periods. In so doing, they point to a means to potentially reduce the diagnosis rate of ASD possibly other neurodevelopmental disorders (ADHD in particular comes to mind due to several overlapping symptoms in focus and attention).

Folate and Autism

Several clinical trials have shown that in the autistic population, about 70% make an autoantibody to the folate receptor [4,5]. Production of this folate receptor autoantibody (FRAA) seems to be triggered by dairy products in someone’s diet [6] and results in a cerebral folate deficiency (CFD, or folate deficiency in the brain). If CFD is not corrected by dosing with natural folate (the form used is folinic acid, trade name leucovorin), or by removing the FRAA antigen (presumably by eliminating all dairy products from the diet), the ASD symptom of poor social communication firms up during the critical period, and even if correction is made later, neurotypical behavior cannot be fully restored and the ASD behavior is not abbreviated.Thus, a critical period is the need for natural folate (folate in its reduced form), and an abundance of synthetic folate (folate in its oxidized form) cannot help those with FRAA. Indeed, excess oxidized folate (folic acid) may be detrimental, as there is increasing evidence that unmetabolized folic acid (UMFA) can outcompete natural folate at the folate receptor, creating a CFD despite measured high plasma folate [7].

Oxidative Stress

Similarly, there is now abundant evidence that oxidative stress can alter neurotypical development, as documented [8] and postulated in that oxidative stress during critical periods in development will result in a decrease in microglial cells in the brain [2]. Microglia serve as part of the brain’s immune system, since the lymphocytes (B cells and T cells) cannot cross the blood brain barrier. These microglia scavenge and clean out discarded or unused cell structures during development, most specifically for ASD, they remove unused synapses during the process of synaptic pruning. Synaptic pruning follows neurogenesis, when there is a proliferation of neuronal birth and synaptic contacts made, with only the active synapses retained later to create neurotypical brain pathways. If the excess synapses are not pruned, the report contends this gives rise to the ASD symptom of inability to focus on a task as well as explains a possible neural mechanism for the documented extraordinary memory for detail seen in ASD. Thus, this reduction in synaptic pruning can explain the excellent memory but also the inability to focus on a task that is seen in autism.

What are the causes of oxidative stress in neurodevelopment? Oxidative stress can be caused by inflammation from infection, emotional stress, under nutrition or exposure to foreign compounds [8,9]. The foreign chemicals include the usual litany of pesticides and persistent compounds from the environment (such as “forever chemicals”) [10] as well as heavy metal ions such as lead exposure [11] but also include a number of pharmacological drugs. While drug side effects are often well established, their impact on a developing fetus or infant can often be overlooked. Thus, even well-tolerated psychopharmacological medicines may need to be reconsidered during pregnancy, putting them in a category perhaps similar to alcohol or caffeine, which are not typically discontinued during pregnancy and nursing due to the potential lasting impact of such depressants and stimulants on neurodevelopment.

In addition to these known agents of oxidative stress, we may need to add micro- and nanoplastics to the list, as these are reported to be embedded in every human organ, with documented effect on cardiovascular system, development and the microbiome, according to a report from the December 2024 hearing on health impacts of plastics held in Korea [12]. Indeed, this report reminds us that the microbiome is the essential processing zone for all nutrients, and alterations to someone’s microbiome can have broad impacts.

Reducing Damage

While the report also reveals the mechanism of oxidative stress in the development of ASD, it also reveals the ways to minimize its effect. Oxidative stress depletes microglia nutrients, particularly N-acetyl cysteine and taurine. Increasing the intake of these nutrients should limit the damage to the microglia and support neurotypical development. Significantly, these small molecule nutrients are present in many foods (especially fish and seafood) and these are no reports of adverse effects of using supplements to restore these nutrients during periods of oxidative stress. Similarly with folate, many foods (including legumes, leafy greens, eggs and citrus) have high levels of this vitamin, and there is also a prescription source of natural folate available in leucovorin. Leucovorin has successfully been used in the ASD clinical trials mentioned above, and there are decades of its use in cancer treatment, where it is used to replenish the vitamin B-9 that is depleted by certain chemotherapies, so it is known to have no adverse effects.

Intriguingly, a new preprint [13] shows extra folate during pregnancy can reduce the impact of metabolism disrupting chemicals on a child. Thus, folate may be quite central to two mechanisms of neurotypical development.

Vaccine Impact

An intriguing aspect that comes out of the 2024 report [2] gives credence to the continued concern of vaccines and autism. In previous decades (until the 1980s), the pertussis vaccine was made from whole cells, which could be very inflammatory in up to one percent of children receiving the vaccine, causing brain fever. Now that we have an understanding about critical periods in autism development, we can see that if this inflammation occurred during such a critical neurodevelopmental period, there may be a lasting effect that could increase the risk of ASD. The most common pertussis vaccine used now no longer uses whole cells, and this acellular version does not cause such inflammation. Also, the timing of the vaccine is adjusted now to minimize developmental impact. However, the lingering concern among some parent groups about this vaccine is linked to a reality that is has passed. Originally, the vaccine used, DPT (for diphtheria-pertussis-tetanus) was problematic for neurodevelopment of an estimated 3 children per million vaccinations, while the newer version, the DTaP (for diphtheria-tetanus-acellular pertussis, or Tdap which is used for booster vaccinations) does not have this detrimental effect. This should be comforting news for parents, as they can continue to protect their children from these deadly diseases while no longer raising the risk for such children to have a neurological disorder.

Conclusion

Critical periods help us understand neurotypical as well as autistic development. The knowledge that those at higher risk due to inflammation and/or the presence of FRAA can help mitigate these risks with functional or lifestyle medical actions of modifying diet to include more foods with folate and with N-acetyl cysteine or taurine, along with getting regular exercise. Indeed, this may be an optimal treatment for someone at higher risk of ASD, further supporting use of a Mediterranean diet, which provides these nutrients, and also benefits the microbiome. Given the overabundance of ultra-processed foods (UPF) in many contemporary diets, we may have chosen a side of increased neurological disorders with the convenience of these fast foods. A comparison of neurodegenerative disorders in matched communities with UPF diets compared with blue zone diets may help provide confirmation that the increasing ASD diagnoses may be in part due to dietary changes made by families in the past half century.

References

  1. https://www.cdc.gov/autism/data-research/index.html
  2. Ayoub G (2024) Neurodevelopment of autism: critical periods, stress and Cells. 13: 1-11. [crossref]
  3. Wiesel TN: Nobel NobelPrize.org.
  4. Frye RE, Slattery J, Delhey L, et al. (2016) Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Mol Psychiatry. 23: 247-256. [crossref]
  5. Renard E, Leheup B, Guéant-Rodriguez RM, Oussalah A, Quadros EV, et al. (2020) Folinic acid improves the score of Autism in the EFFET placebo-controlled randomized trial. Biochimie. 173: 57-61. [crossref]
  6. Ramaekers VT, Sequeira JM, Blau N, Quadros EV (2008) A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency Dev Med Child Neurol. 50: 346-352. [crossref]
  7. Akiyama T, Kuki I, Kim K, Yamamoto N, Yamada Y, et (2022) Folic acid inhibits 5-methyltetrahydrofolate transport across the blood–cerebrospinal fluid barrier: Clinical biochemical data from two cases. JIMD 63: 529-535. [crossref]
  8. Usui n, Kobayashi H, Shimada S (2023) Neuroinflammation and oxidative stress in the pathogenesis of autism spectrum disorder. In J Mol Sci. 24: 5487. [crossref]
  9. Ahmavaara K, Ayoub G (2024) Stress and folate impact neurodevelopmental J Health Care & Res 5: 1-6.
  10. Parenti M, Slupsky CM (2024) Disrupted prenatal metabolism may explain the etiology of suboptimal neurodevelopment: a focus on phthalates and micronutrients and their relationship to autism spectrum disorder. Adv Nutri. 15: 3-19. [crossref]
  11. McFarland 2024 https://doi.org/10.1111/jcpp.14072
  12. Moulun AG (2024) Quel impact des micro- et nano-plastiques sur la santé humaine? Medscape.
  13. India-Aldana S et al. (2024) Metabolism-Disrupting Chemical Mixtures during Pregnancy, Folic Acid Supplementation, and Liver Injury in Mother-Child Pairs. medRxiv. [crossref]

What is a Metallic Alloy in Reality?

Leave a reply

DOI: 10.31038/NAMS.2024733

Abstract

The article is a collection of ideas and experimental results that show that existing ideas about metallic alloys should go away to history of Metal Science. Here we present to the reader the results of experiments obtained as an example on four binary and two ternary alloys. Briefly, the main conclusions of the experiments are as follows: Interatomic chemical interactions exist in all metal alloys at temperature of both solid and liquid states. Chemical bonds in alloys have an amazing property to change their signs at a certain temperature (there is a phase transition “ordering – separation”). The reason for this transition is the electronic transition “ionic bond ↔ covalent bond”. The process of formation of new phases in binary alloys begins with the formation of solute clusters, in ternary alloys – with the formation of diffusion micro-pairs during the melting of the alloy. Such cardinal differences between the existing now notions about the nature of alloys and those revealed in this work should definitely lead to changes in the technology of heat treatment of alloys, to changes in the binary phase diagrams and to a change in the principles of creating new alloys.

Keywords

Introduction alloys, Chemical bonds, Transmission electron microscopy, Microstructure, Phase transition “ordering – separation”, Electron transition “ionic bond ↔ covalent bond”, Diffusion micro-pairs, Chemical bonds, Transmission electron microscopy, Microstructure; Phase transition “ordering – separation”, Electron transition “ionic bond ↔ covalent bond”

Introduction

Development of human civilization is inconceivable without progress in the advancement of its material base, in which metals and metal alloys play one of the leading roles. In recent years, we have observed significant changes for the better in the elaboration of new alloys. However, unfortunately, they achieved in a long, empirical way. This is because our ideas about the nature of alloys are still at the level of almost 100 years ago. This circumstance hinders progress in the development of new alloys and does not allow researching alloys in a necessary direction. The source of the existing now theory of alloys dates back to when researchers, studying the solubility of a salt in water with decreasing temperature, found that in time, salt crystals precipitate from the solution. They suggested whether the process of nucleation of particles of a new phase during the tempering of quenched metal alloys does not occur in the same way as during the isolation of salt crystals from a supersaturated aqueous solution. The idea turned out to be tempting, and since then, metal science has been living with the illusions of the past: a solid solution disordered after quenching becomes to supersaturated with a decrease in the heat treatment temperature, and particles of the excess phase precipitate. Only then, chemical bonds arise between the atoms of this phase. This means that not chemical interatomic bonds cause the formation of chemical compounds, but chemical compounds cause the occurrence of chemical interatomic bonds (!). Obviously, the comparison of the process of formation of a new phase during the tempering of a metal alloy and the process of precipitation of salt crystals with a decrease in the temperature of the water-salt solution is highly incorrect. However, this idea is so ingrained in our heads that even the discussion on this topic, held by the journal Acta Metallurgica in 1960-80 [1,2], ending in favor of existing ideas. This is not surprising, since in all universities of the world for many decades now, all professors have been presenting these ideas as an axiom that does not require proof.

The author of this article, starting his experimental work on the above topics, chose the direct method for studying the microstructure – TEM, and studied the microstructure of each alloy at all heat treatment temperatures (with an interval of about 200-300°C and, including in the liquid state). We hope that the reader already knows some of our papers or monography [3], where it is described what the “ordering-separation” phase transition is in binary alloys. This is a phase transition that occurs at a well-defined temperature, when, in the AxBy alloy, atoms A and atoms B, instead of mutual attraction experience mutual repulsing. This is not surprising if we consider alloys from the point of view of the structure of their electronic structure. As you know, in a pure metal between its atoms, takes place a 100% metallic bond. However, when atoms of another metal are added to one metal (i.e., when creating a binary alloy), a certain part of the metal bonds in the alloy are replaced by chemical ones, namely, ionic and/or covalent ones [4]. The ionic component of the chemical bond appears when, with a change in the alloy’s temperature, the B atoms become the nearest neighbors of the А atoms. Because of this instantaneous proximity, their valence orbitals localize the chemical compound AxBy form. The covalent component of a chemical bond forms when two atoms of the dissolved component B become the nearest neighbors. Because of this instant proximity, their valence orbitals hybridize, i.e. a cluster forms comprising these two atoms B. Thus, we understand how an ionic bond forms and how a covalent bond forms. However, it does not understand why, at the temperature characteristic of each alloy, these bonds pass one into the other, i.e., why an electronic transition “ionic bond ↔ covalent bond” occurs.

Materials and Methods

In this article, we will consider some binary alloys, for example, Ni75Mo25, Fe50Cr50 and Ni88Al12, as well as two ternary Ni65Mo20Cr15 and Ni53Mo35Al12 alloy, as examples. We smelted alloys from pure components in an induction furnace. We cut out specimens from them for research at different temperatures. After holding at any temperature, the specimens immediately cooled in water to fix the microstructure at this temperature. One of the specimens melted down and the contents of the crucible poured into water to study the microstructure of the liquid state. Foils cut out from all the blanks for study on a transmission electron microscope EM-125.

Results

Alloy Ni75Mo25. For those who had to deal with the problem of pouring liquid Ni-Mo alloys, it seemed surprising that its very low fluidity of that alloy even when it was overheated by 200°C above the solidus line. Now it becomes clear what we connect this with the phenomenon. The Figure 1a shows dark particles of molybdenum, which formed at the melting of the charge. This means that even at temperatures of the liquid state, the alloy under study has the tendency to phase separation. Indeed, we observe on the electron diffraction pattern a system of additional reflections {1 1½ 0} as four symmetrical pairs (Figure 1b). These reflections formed near each of the fundamental reflections {110} and {200}. Quenching of the same alloy from 1300̊°C, i.e. temperature, at which “a disordered solid solution” forms gives the same picture.

“a disordered solid solution” forms gives the same picture.

Figure 1a shows dark particles of molybdenum, which formed at the melting of the charge. This means that even at temperatures of the liquid state, the alloy under study has the tendency to phase separation. Indeed, we observe on the electron diffraction pattern a system of additional reflections {1 1½ 0} as four symmetrical pairs. These reflections formed near each of the fundamental reflections {110} and {200}. Quenching of the same alloy from 1300̊ C, i.e. temperature, at which “a disordered solid solution” forms gives the same picture. Exactly the same picture you can watch after quenching this alloy from 1300°C. This means that the type of microstructure of the alloy is determined not by its state of aggregation at such temperatures, but by completely different parameters. A further decrease in the alloy’s temperature by only 100°C dramatically changes the type of microstructure: instead of the structure formed because of a tendency to separation, a chemical compound Ni3Mo forms as long square-section laths (Figure 2a and 2b). This shows that in the temperature range of 1200-1300°C, the “ordering-separation” phase transition occurs in the alloy under study.

Comparing the microstructures shown in Figures 1 and 2, we see that there are two diametrically opposed types of interaction between dissimilar atoms: separation at high temperatures (liquid state), ordering at a temperature of 1000°C. It is even more interesting to observe the phase transition “Ordering – separation” in alloy Fe50Cr50, where it occurs twice with a change in the temperature of the alloy.

 

Figure 1: Alloy Ni75Mo25.Water quenching from liquid state: (a) microstructure (Mo-particles); (b) electron diffraction pattern.

Figure 2: Ni75Mo25 alloy. Quenching from 1000°С. Bright-field image of the microstructure (a); electron diffraction pattern (b).

Fe50Cr50 alloy (Figure 3). The author [3], investigating the microstructure of alloys of the iron-chromium system by TEM, discovered a surprising phenomenon, which consists in the fact that at a quite definite heating temperature of these alloys, the sign of the chemical interaction between iron and chromium atoms changes. At some temperatures (above 1150°C), repulsion is observed between these atoms (particles of atoms of pure chromium with the Al2 lattice are formed – Figure 3a), at other temperatures (600-830°C) – attraction (a ϭ-phase is formed – Figure 3b). At the boundary between these two regions, when the sign of the chemical interaction passes through zero, a solid solution was found in the alloys of the iron-chromium system, and electronic domains were found during two-stage heat treatment (Figure 3c). Such domains, arising during the “ordering-phase separation” transition, best observed when defocusing the electron microscopic image of the specimens. We consider electronic domains as some regions of the alloy, inside which the sign of the ordering energy has already changed, in comparison with the surrounding matrix, where it remains the same. Since the chemical interaction energies have opposite signs on both sides of the domain wall, the electron beam passing through the foil is deflected in opposite directions, which, upon defocusing, leads to a deficiency (light lines) or an excess (dark lines) of electrons. Thus, electronic domains, as well as magnetic and ferroelectric domains, are a reflection on a conventional photographic plate of a phase transition occurring at the level of changes in the electronic structure of the alloy.

In contrast to, where the formation of electronic domains was considered as a temporary, unstable state of the alloy (a state of transition from a tendency to phase separation to a tendency to ordering), it was shown in Ref. [3] at domains in Fe-Cr alloys under certain conditions can represent a stable state of the alloy. The existence in the alloy’s bulk of such a state (incomplete phase transition ordering-separation) prevents the formation of the σ-phase in the entire volume of the alloy; the σ-phase forms only in a thin surface layer, where, apparently, the surface plays the role of a catalyst for the “ordering-separation” transition process. A further decrease in temperature to 500°С again leads to the formation of particles (or, possibly, highly concentrated clusters) of chromium atoms, Figure 3e. At the boundary between the regions of the ϭ-phase and low-temperature separation, we again found electronic domains (Figure 3f). The formation of electronic domains on the line of the “ordering-phase separation” phase transition (Figure 3c and 3f) tells us it is the changes in the electronic structure that underlie the microstructural phase transition “ordering-phase separation”. Low-temperature domains occupy the entire volume of the alloy, and therefore it can expected that such a microstructure of the alloy will have certain specific properties, such as magnetic or ferroelectric.

Figure 3: Fe50Cr50 alloy. Microstructure. Water quenching from 1400°C. Inset: electron diffraction pattern (a); σ-phase taken from subsurface layer (b). High-temperature (c) and low-temperature (d) electron domains. Microstructure of low-temperature phase separation (e).

Ni88Al12 Alloy

Figure 4a shows the electron diffraction pattern (a) and the dark-field image of the microstructure (b) got from a satellite near the (020) reflection [5,6]. Such formation of clusters usually shows the ordering of a binary alloy at 1300°C into particles comprising one component each, i.e. about the positive deviation of the investigated alloy from Raoult’s law. With a further decrease in temperature (1200, 1000 and 700°C), the sign of the ordering energy changes to the opposite and the chemical compound Ni3Mo (L12) forms in the alloy (Figure 4). Thus, we can conclude that in the Ni88Al12 alloy the “ordering-separation” phase transition occurs in the temperature range of 1200-1300°C.

Figure 4: Ni88Al12 alloy. Quenching from a liquid state (tendency to separation) (a). Quenching from 1000°С: chemical compound Ni3Mo (L12). The electron diffraction pattern is in the Inset (b).

Alloys of Ni-Cr system

The phase transition “ordering-phase separation” in most of the binary systems studied by us occurs at a not quite definite heating temperature of the alloys (transition temperature). However, in alloys of the nickel-chromium system, a unique picture observed [7]. For example, in alloys with a chromium content of 32 wt.% and below at any heating temperature, there is only a tendency to phase separation since in the entire temperature range from 500 to 1500°C, clusters of chromium atoms are noticed in the microstructure of this alloy (Figure 5a and 5b). In alloys with a chromium content of 60 wt.% Cr and above at all temperatures is observed only a tendency toward ordering, since particles of the Cr2Ni compound are noticed in the microstructure (Figure 5c and 5d). In alloy Ni46Cr54, the composition of which is between concentrations from 32 to 60% Cr, with a change in the heating temperature of the alloy, the usual transition “ordering – phase separation” is observed at 1200°C (Figure 5e and 5f).

Figure 5: Alloys of the Ni-Cr system. (a) Ni68Cr32, water quenching from a liquid state. Absorption contrast. Cr-clusters; (b) Ni68Cr32, water quenching from 500°C; Absorption contrast. Cr-clusters; (c) Ni40Cr60 [9], water quenching from a liquid state. Ni2Cr particles. (d) Ni46Cr54, water quenching from a liquid state. Absorption contrast. Cr-clusters; (e) Ni46Cr54, water quenching from 1000°C. Ni2Cr particles [7].

As we see, we have investigated many other binary. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In addition, in each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any, but quite specific for each pair of atoms. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a so-called disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition the blurred “ordering -separation” one. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – separation” transition.

We have investigated many alloys. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition a blurred “ordering – separation” transition. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – phase separation” transition.

Ternary Alloys

Ternary Ni65Mo20Cr15 alloy [7]. Electron microscopic analysis shows that in different sites of the same foil quenched from the liquid state (1450°C) accumulations of only two types of precipitates of the second phase found. In the Ni/Mo diffusion pair, observed single-component particles of molybdenum atoms, in the Ni/Cr diffusion pair – two-component clusters chromium atoms. Since molybdenum is a refractory metal, the formation of particles of Mo atoms in the alloy under study occurs at the maximum temperature that reached in the melting zone of the furnace. Whereas formation of the Cr-clusters (Figures 5-7), observe a fully formed microstructure up to the temperature of 1300°C. In the Ni/Mo diffusion pair, below 1250°C, the tendency to phase separation is substituted for the tendency to ordering (the “ordering-separation” transition), and the particles of Mo atoms dissolve.

After quenching the alloy from 1550°C, clusters of chromium atoms observed in diffusion pairs Ni/Cr as concentration waves of absorption contrast, which emanate from a certain light-colored center in a thin foil, forming apparently, in the moment of contact of the liquid alloy with water (Figure 6).

Figure 6: Ni65Mo20Cr15 alloy [8]. Nucleation of the Ni/Cr diffusion pair. Water quenching from 1550°C. Absorption contrast.

Comparing the microstructures in Figures 6-8, we can conclude that with a decrease in the temperature from which the alloy quenched the microstructure of the Cr-clusters forms over the entire volume of the alloy.

Figure 7: Ni65Mo20Cr15 alloy [9]. Ni/Cr diffusion pair. Water quenching from 1450°C. Absorption contrast.

We investigated many other binary alloys. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In addition, in each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any, but quite specific for each pair of atoms. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a so-called disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition the blurred “ordering -separation” one. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – separation” transition.

We have investigated many alloys. It turned out that in almost every binary alloy there is a transition “ordering-phase separation”. In each alloy, this transition has its own characteristics, which manifested at the level of changes in the microstructure. In each alloy, we need to determine the temperature at which this transition occurs. The temperature can be any. For example, in the Co-30% Mo alloy, it is close to the solidus temperature. The regions of a disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition a blurred “ordering – separation” transition. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – phase separation” transition. Ternary Ni53Mo35Al12 alloy [8]. As is known from the electronic theory, in ternary alloys, as in binary ones, the chemical interatomic interaction is pair-wise [8]. Therefore, ternary Laves phases cannot form in a ternary alloy. We have shown that the ABC ternary alloy, while still in the liquid state divided into diffusion micro-pairs A/B, A/C, and B/C. Each diffusion micro-pair occupies its own microscopic area. All phases formed in ternary alloys comprised atoms of no more than two components [8].

In the Ni53Mo35Al12 alloy, this process has its own characteristics, since the aluminum and molybdenum atoms form the Mo3Al chemical compound, the melting point of which is about 2600°C. This means that the chemical bond between the Al and Mo atoms is very strong. Therefore, in Figure 8 we see the microstructure of solid Mo3Al particles in the investigated liquid alloy. This compound forms instantly in the process of melting the charge. The same microstructure as in Figure 1 retained in the alloy under study after its quenching from 1300°C. As was shown above, at a temperature of about 1200°С, the “ordering–separation” transition occurs in binary alloys of the Ni–Mo system [5]. This means that the chemical orientation of the Ni and Mo atoms relative to each other changes sharply at separation – ordering phase transition.

Figure 8: Ni65Mo20Cr15 alloy. Ni/Cr diffusion micro-pair. Water quenching from 1300°C. Absorption contrast.

Figure 10 shows the internal microstructure of a large solid Mo3Al particle in the liquid alloy under study. When the charge melted, this compound form instantly. As long as it exists, the Mo/Ni and Al/Ni diffusion pairs cannot form in the alloy. The alloy under study has the same microstructure. However, at a temperature of about 1200°C, when the “ordering-separation” phase transition should have occurred in diffusion Ni/Mo pairs, the microstructure of the studied alloy completely changes (Figure 9).

Figure 9: Ni53Mo35Al12 alloy [10]. Quenching from the liquid state. Light-field image. Accumulations of particles of the Mo3Al phase. Inset: Electron diffraction pattern (the zone axis is close to the direction <001>).

Figure 10: Ni53Mo35Al12 alloy. Quenching from the liquid state. Another bright-field image of the internal structure of a large Mo3Al particle (a). Electron diffraction pattern (b).

Figure 11: Alloy Ni53Mo35Al12. Quenching from 1000°С. Bright field images of the microstructure of diffusion micro-pairs Ni3Mo (a) and Ni3Al (L12).

The regions of a disordered solid solution located between the regions of phase separation and regions of ordering have not found in all systems where such a transition has occurred. In a number of alloys (for example, Ni-Co), the same image showed phase particles formed as a result of the appearance of a tendency to ordering in the alloy, and particles dissolving due to the disappearance of the tendency to phase separation in this alloy. We called such a transition a blurred “ordering – separation” transition. As a result of this “mixing of phases”, a disordered solid solution was not found even on the line of the “ordering – phase separation” transition.

When studying the Ni53Mo35Al12 alloy by TEM, we again encountered with the same fact that we discovered earlier in some other ternary alloys: in one region of the foil, we find one binary (or one-component) phase, in another region of the same foil, a completely different one. This immediately indicates that the alloy divided into certain sections that differ from each other in composition, i.e. into two different diffusion micro-pairs: Ni/Mo and Ni/Al.

In the Ni53Mo35Al12 alloy, this process has its own characteristics, since the aluminum and molybdenum atoms form the Mo3Al chemical compound, the melting point of which is about 2600°C. This means that the chemical bond between the Al and Mo atoms is very strong. Therefore, we see the microstructure of solid Mo3Al particles in the investigated liquid alloy. This compound forms instantly in the process of melting the charge. The same microstructure retained in the alloy under study after its quenching from 1300°C. As was shown above, at a temperature of about 1200°C, the “ordering–separation” transition occurs in binary alloys of the Ni–Mo system [5]. This means that the chemical orientation of the Ni and Mo atoms relative to each other changes sharply from separation to ordering.

Discussion

Our experimental detection of such transitions and their publication in the literature for during 20 years did not lead to any progress in the worldview of metallurgists, and, as a result, to the appearance of works by other authors on this topic. Although, thanks to our experiments, these changes simply suggested themselves, since their introduction would significantly improve the technological properties of all heat-treated parts and products made of metal alloys and more than halve the cost of their heat treatment [9]. It could happen in all the engineering plants in the world. Perhaps the complete lack of interest of metallurgists in these two transitions explained because, in this case, they would have to change their ideas about alloys and change your attitude towards binary phase diagrams [10]. However, it is difficult to make this step when the entire community of metallurgists thinks alternatively and university professors teach of students’ alternative.

Diffusion Micro-pairs

Usually, diffusion micro-pairs in multi-component alloys form during their smelting [11]. However, if a chemical compound’s melting point is higher than the alloy, we cannot fix these micro-pairs, and compounds will found first (for example, Mo3Al). If lower, then we will find the formation of chemical compounds takes place inside the diffusion micro-pairs.

Heat treatment of metal alloys “quenching + tempering (aging)” has known for a very long time and currently carried out at almost all machine-building plants in the world.

According to existing concepts, after quenching at high temperatures, a microstructure of a disordered solid solution forms in alloys. Subsequent tempering, carried out at a lower temperature, leads to the fact that the solid solution comprising quenching becomes “supersaturated” and “excess” phases are released from it (either by the spinodal mechanism or by the nucleation-growth mechanism).

In contrast to the existing theory of heat treatment, in alloys at all temperatures, there is a chemical interaction between similar (covalent bond) and dissimilar (ionic bond) atoms. Such an interaction exists both in the liquid and in the solid state of the alloy. This means that we can never get a disordered solid solution after quenching the alloy from high temperatures, even if we will quench from the liquid state. This also means that at each temperature forms own microstructure, which distinguished from any other microstructure by type or dispersity of precipitates. The final microstructure of an alloy is determined by the temperature of the final heat treatment, i.e. tempering. The heat treatment, such as quenching from region “disordered solid solutions”, does not affect the final microstructure of the alloy.

Because of this instantaneous proximity, their valence orbitals localized, i.e. the chemical compound AxBy forms. The covalent component of the chemical bond, which activated for the same reason, causes the two atoms of the dissolved component B to become the nearest neighbors. Because of this instantaneous proximity, their valence orbitals hybridize, i.e. a cluster forms comprising these two atoms B. However, our experimental detection of such transitions and their publication in the literature for over 20 years did not lead to any progress in the worldview of metallurgists, and, as a result, to the appearance of works by other authors on this topic. In addition, these changes simply suggested themselves, since their introduction would significantly improve the technological properties of all heat-treated parts and products made of metal alloys and more than halve the cost of their heat treatment. It could happen in all the engineering plants in the world. Perhaps the complete lack of interest of metallurgists in these two transitions explained because, in this case, they would have to change very many ideas about alloys. Moreover, it is difficult to take this step when the entire community of metallurgists thinks differently and university professors teach of students differently.

In the experimental part of the article, we presented the reader with the results of our studies of binary and ternary substitution alloys. The cardinal difference between our research (TEM) and those works (XRD) thanks to which the current theory of alloys built is immediately striking. Now that it has become clear to us that the X-ray method is not suitable for these purposes, and that those authors who used the TEM method in the discussion of 1960-80 were right, there is no doubt that our ideas about the existence of some disordered solid solution in alloys should go down in the history of alloy science. If this is really the case, then any quenching in water from any heating temperature of the alloy should lead to formation of the microstructure that formed in the alloy at this temperature. It has been known that almost every machine-building plant in the world uses “double” heat treatment of alloys – quenching from the region of a “disordered” solid solution + tempering at low temperatures. Select a few parts from the batch intended for quenching and simply do not make it.

Compare their microstructure and properties with those parts that have been as quenched. I should note that for the purity of the experiment, samples (or parts) that have quenched should cooled in water to fix the microstructure characteristic of your tempering temperature. Even if you are not strong in alloy theory, you will be able to deduce whether you need that quenching to get a “disordered solid solution” before tempering.

High-entropy Alloys

When a ternary alloy forms three diffusion micro-pairs at once, the uphill diffusion of atoms of each component will be on coming. As a result, the rate of formation of one or another diffusion pair will slow down significantly, and perhaps even drop to zero. Most likely, these streams separated either in time or in temperature. However, when many number of streams of different directions, they completely suppressed to each other. Therefore, the more components an alloy contains, the slower one or other diffusion micro-pairs will form in it. That is why in high-entropy alloys (HEA), which contain five or more components, diffusion micro-pairs do not form. By performing a straightforward calculation, it becomes apparent that formation 10 diffusion micro-pairs in 5-component alloy is possible only on paper. In reality, it is impossible. This is why long-distance diffusion is completely absent in HEA and diffusion micro-pairs do not form. This meant that chemical bonds between the atoms of the components cannot manifest themselves in these alloys and no chemical compounds can form in them. The question arises: whom needs such alloys that do not have the properties of alloys and microstructure of which represents randomly arranged different atoms (only sometimes -small solid solution regions).

In their properties and structure, they are more similar to metal ore. It turns out interesting with HEA. A person has invested considerable effort to receive pure metals from natural metal ore, only to produce a new synthetic metal ore from these metals later. Typically, diffusion micro-pairs in multicomponent alloys form during their smelting, when the crystal lattice of the alloy has not yet formed. In the solid state of the alloy, uphill diffusion of atoms of the dissolved component also occurs, but much more slowly. I am not maintaining, but it is hardly possible to expect that in the solid state in a ternary alloy, uphill diffusion of atoms of two components at once is possible. Most likely, either on time or on temperature separate these flows. However, with a large number of flows in different directions, they are completely suppress each other. Consequently, the more components an alloy contains, the lower the likelihood of the formation of certain diffusion micro-pairs and, consequently, particles of new phases of one or other type.

It should be noted that to obtain true alloys, one should avoid not only adding a large number of alloying components (usually more than two), but also adding a small amount of any component (usually 3% or less). With such alloying, one must proceed from the principle that the amount of the alloying component would been enough to form diffusion micro-pairs in the alloy, i.e. so that particles containing this component formed. Otherwise, such doping can considered as simple clogging of the crystal lattice with foreign atoms. Our understanding of this or that physical phenomenon always changes with time and usually corresponds to the level of experimental technique in the period under consideration. Let us recall the once fashionable classical theory of the “nucleation and growth” of a new phase, the theory of the “in situ” nucleation of special carbides in alloyed steels, and so on. Where are they now? They forgotten because their description of processes occurring in nature differs from reality. At the same time, there are theories and ideas with a different fate, which came to us from the past century, but are so deeply rooted in our minds that even now, when the experiment does not confirm them, we believe that they are an indisputable truth. For example, we cannot imagine equilibrium phase diagrams without solid solution regions at high temperatures, although a solid solution, from the point of view of thermodynamics, is not an equilibrium phase at any temperature. We cannot imagine the probability of decomposition of a quenched solid solution without its “supersaturation” in solutes, which occurs at a decrease of heat treatment temperature. We cannot imagine the heat treatment carried out to obtain a highly dispersed two-phase structure, which would not include the preliminary high-temperature quenching from the solid solution region, and so on.

The discovery of the ‘ordering-phase separation’ transition in alloys puts an end to these ideas. It becomes clear that the ideas about the nature of alloys that we acquired in our universities turn out to be largely outdated, as they based on experimental data obtained as far back as the mid-twentieth century and without the use of the method of TEM. From the above discussion, it follows that introduction of such a concept as the ‘ordering-phase separation’ transition into common use changes our previous understanding of the driving forces of the process of new phase formation. In addition, it becomes apparent that in order to change this situation a great number of experimental studies is to upgrade existing phase diagrams. The ‘ordering-phase separation’ transition, regarded as changes in the chemical interaction sign, is such a transition, in the process of which the ionic component of the chemical bond between the atoms, due to the electron-phonon interaction, replaced by the covalent component, or vice versa. All processes occurring in alloys during heat treatment and leading to a change in their properties considered from the point of view that the disordered solid solution is the initial phase in these processes, and the elastic forces arising between dissimilar atoms are the driving force. The experimental results presented in this monograph debunk this point of view and show that it is necessary to take the liquid state of the alloy as the initial phase, and interatomic chemical interactions as the driving force of all diffusion processes occurring in the condensed state of an alloy.

Cardinal Changes in Heat Treatment of Alloys

The detection of the ‘ordering-phase separation’ transition allowed for the conclusion that, at a certain temperature, the sign of the chemical interaction between dissimilar atoms can change. This means that it is only at the temperature of such a transition, when the energy of the interatomic chemical interaction is close to zero, which a disordered solid solution can form in the alloys. However, such a clearly pronounced change in the microstructure not observed in the alloys of all systems. In the alloys of some other systems, at a transition temperature one can see a mixture of microstructures of phase separation and ordering. It should also note that the microstructure of the solid solution could observed in alloys in which the energy of the interatomic chemical interaction is low at all temperatures. When any composition of the alloy is in a molten state, it subdivided into microscopic areas, each of which enriched with one alloying component or another (in other words, one or several types of diffusion pairs formed in it). Binary chemical compounds (tendency to ordering) or clusters (tendency to phase separation) can form inside these diffusion pairs. When the heat treatment temperature decreases, the average chemical composition of such diffusion pairs is always preserved, and at the same time the distribution of components inside the diffusion pairs themselves becomes more heterogeneous: chemical compounds (if their melting point is higher than the melting temperature of the alloy itself) or clusters similar to the corresponding binary alloys are formed. The driving force of such a partitioning process is the tendency of the similar atoms to form clusters in the solvent lattice or the tendency of dissimilar atoms to form a chemical compound.

The ‘ordering-phase separation’ transition, which at the microstructure level manifests itself as changing of the sign of energy of the chemical interaction between the atoms A and B, at the electronic level manifests itself in exactly the same way. It is a transition from the state when all pairs of valence electrons localized on atoms A and B and forming ionic bonds between atoms come out from this state. At the same time, some pairs of valence electrons, due to the electron-phonon interaction, are involved in the formation of hybridized orbitals between two B atoms (which leads to the formation of B clusters, i.e. phase separation). This means that the ‘ordering-phase separation’ transition in an alloy is a consequence of the electronic ‘covalent bond ↔ ionic bond’ transition. This article shows metallurgists should come to terms with the existence in nature of such a type of microstructure as diffusion micro-pairs and say goodbye to such a type of microstructure as a disordered solid solution. And the sooner they do this, the less effort and money will be spent all over the world on heat treatment of alloys (water-quenching “to get a disordered solid solution” will disappear), on the design of new and improvement of existing alloys. The phase diagrams of binary alloys will become more informative and truthful (because of the regions of non-existent disordered solid solutions will disappear). We will understand many of the mysteries of nature regarding metallic alloys that nature has hidden from us for many years. In the case, all of us, metallurgical scientists, will need to contribute to this work.

Conclusion

This article shows metallurgists should come to terms with the existence in nature of such a type of microstructure as diffusion micro-pairs and say goodbye to such a type of microstructure as a disordered solid solution. And the sooner they do this, the less effort and money will be spent all over the world on heat treatment of alloys (water-quenching “to get a disordered solid solution” will disappear), on the design of new and improvement of existing alloys. The phase diagrams of binary alloys will become more informative and truthful (because of the regions of non-existent disordered solid solutions will disappear). We will understand many of the mysteries of nature regarding metallic alloys that nature has hidden from us for many years. However, for this, all of us, alloy specialists, will need to contribute to this work.

References

  1. Nesbit LA (1981) Laughlin DE. Solid-state morphological instability of Ni4Mo precipitates. J Crystal Growth 51: 273-278.
  2. Van Tendeloo G, Amelinkx S (1985) De Fontaine D. On the nature of the “short-range order” in 1 ½ 0 alloys. Acta Crystallography.B41: 281-292.
  3. Ustinovshikov Yuri (2019) The ‘Ordering-Phase Separation’ Transition in Alloys. Cambridge Scholars Publishing.
  4. Ustinovshikov Y (2017) Changes in electronic structure of metallic alloys at the transition ‘ordering-phase separation’. J Alloys & Compounds 714: 476-483.
  5. Ustinovshikov Y, Shabanova I (2011) Phase transitions in alloys of the Ni-Mo system. Mat Chemic Phys 129: 975-980.
  6. Ustinovshikov Y (2012) Phase transition ‘ordering-phase separation’ in the Ni-12 at. % Al alloy. J Alloys & Compounds 528: 141-145.
  7. Ustinovshikov Y (2018) Multi-component alloys: Regularities in the formation of microstructures. J Alloys & Compounds. 735: 2298-2302.
  8. Ustinovshikov Y (2016) Formation of microstructures responsible for remarkable properties of the Ni- and Co-based super-alloys. Acta Mater 111: 66-74.
  9. Ustinovshikov Y (2014) A new paradigm for heat treatment of alloys. J Alloys & Compounds 614: 258-263
  10. Ustinovshikov Y (2017) Mapping of the transition ‘ordering-phase separation’ into phase diagrams. J Alloys & Compounds. 691: 713-720.
  11. Ustinovshikov Y (2014) Phase and structural transformation in the Ni65Mo20Cr15 alloy at changing the temperature of heat treatment. Journal of Alloys and Compounds 588: 470-473.