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Progress Research on Wnt/β-Catenin Signaling Pathway

2 Replies

DOI: 10.31038/IMROJ.20251011

Abstract

The Wnt/β-catenin signaling pathway is a key signal pathway. Its occurrence and development are closely related to biological mechanisms such as inflammation and angiogenesis. This article systematically elaborates on the current research progress of the Wnt/β-catenin signaling pathway from several aspects, including the activation process of the Wnt/β-catenin signaling pathway, the controllable disease spectrum, the research status in the field of cerebrovascular disease, typical receptors, agonists, inhibitors of the signaling pathway, research progress on inflammatory effects, and the crosstalk of the NF-κB signaling pathway. In order to provide a basis for subsequent studies on the correlation between diseases or drugs in this pathway.

Keywords

Wnt/β-catenin signaling pathway, Activation, Disease spectrum, Cerebral vascular disease, Inflammation, NF-κB

Wnt/β-Catenin Signaling Pathway Activation

The Wnt/β-catenin signaling pathway is a classic pathway in current disease research. It plays a very important role in regulating the normal development of embryos and participating in cell proliferation and differentiation. The typical Wnt/β-catenin signaling pathway is used in the signal transmission of the cdkey cell regulator, the β-catenin protein, which is mainly found in the cytoplasm, and its level determines the activation of the pathway. The mechanism of the β-catenin dependence is regulated by the cytoplasmitic complex, including the Gsk3β \ Axin \CK1/2 \PP2A\Apc factor etc. In the absence of the Wnt ligands signal, the β-catenin in the cytoplasm is phosphorylated by Gsk3β, which in turn is modified, which is eventually degraded, so that the β-catenin in the cytoplasm remains low level. In the case of the Wnt ligands signal, they combine with the transmembrane receptors, destroy destruction complex including GSK3β, inhibit Gsk3β activity, and lost its phosphorylation to β-catenin, thus result in the accumulation of unphosphorylated β-catenin in the cytoplasm and subsequent translocation to the nucleus, where it binds to various transcription factors. This promotes the transcription of the Wnt target gene in the downstream Wnt target of the Wnt signal transduction and vascular growth.

The Disease Spectrum of Wnt/β-Catenin Signaling Pathway and the Research Status of Cerebrovascular Disease

Wnt/β-Catenin Signaling Pathway Can Regulate the Spectrum of Diseases

The Wnt/β-catenin signaling pathway is now found to be associated with a variety of diseases. ① Neurological disease: [1]. In the study of the animal model of the mice Alzheimer’s disease, the mechanism of the memory and particle cells of mice may be improved by downregulating DKK1 to activate the Wnt/β-catenin pathway, which can improve the shortening and lack of cognition of neuronal dilatations. ② Hepatic disease: [2] In the study of non-alcoholic fatty liver disease, the multi-pathway analysis platform showed that the Wnt-signaling was a common biological pathway associated with non-alcoholic fatty liver disease and non-alcoholic fatty hepatitis. For the first time, the activation of the classic Wnt signal may be one of the main ways of the two diseases associated with gender type 2. ③ Renal disease: [3] Dong Xiangnan et al. found that long-chain non coding RNA-H19 mediates the fibrosis process from acute kidney injury to chronic kidney disease by regulating the miR-196a/Wnt/β-Catenin signaling pathway. ④ Tumor disease: The overactivation of β-catenin caused by mutations in APC, Axin, or β-catenin is a well-known cancer-related high-risk factor, such as colon cancer [4]. ⑤ Metabolic disease: [5-8] The imbalance of lrp6 has a strong correlation with coronary artery disease (CAD) and atherosclerosis. Through whole genome analysis of CAD patients, it was found that multiple residue mutations such as r473q in LRP6 are associated with the pathogenesis of CAD, which is determined by the levels of hyperglycemia, hyperlipidemia, and low- density lipoprotein in blood vessels [9]. The impaired activity of lrp6 is highly correlated with coronary heart disease, mainly through pdgf signaling transduction. Studies have found that miRNA-17-92 clusters targeting LRP6 can downregulate wnt/β-catenin signal transduction, and the lack of miRNA17-92 in endothelial cells can improve blood flow and atherosclerosis. ⑥ Inflammatory disease: [10]cytokines can regulate the Wnt/lrp6 signal. For example, the cell kinetic interferon or tumor necrosis factor, which is exposed in the state of inflammation for a long period of time, induces the expression of dkk1, inhibiting the transmission of Wnt/β-catenin signaling and increasing the incidence of intestinal inflammation [11]. Dendritic cells (DCs) – Specific knockout of LRP5/6 can promote the differentiation of effector T cells, inhibit the differentiation of regulatory T cells, thereby enhancing anti-tumor immunity and inhibiting tumor growth, both of which indicate that the fine regulation of LRP6 is crucial for appropriate immune responses. ⑦ skeletal muscle disease: [12] LRP5 mutations typically lead to decreased bone mass and osteoporosis, which is caused by downregulation of the Wnt/β-catenin signaling pathway. ⑧ Blood disease: [13] Hematopoietic stem cells are the best mammal stem cells. Many studies have shown that the Wnt signaling pathway is an important regulatory factor for hematopoietic stem cells and progenocytes. The hematopoietic stem cells themselves and the bone marrow microenvironment can produce Wnt protein. The above lists some of the diseases related to the Wnt/β-catenin signaling pathway that have been discovered. In addition, there are still many related diseases that need to be explored.

Research Status of Wnt/β-Catenin Signaling Pathway in the Field of Cerebrovascular Diseases

Animal experiments have found that miR-124 can affect neuronal apoptosis during cerebral infarction through the Wnt/β-catenin signaling pathway [14]. [15] Zhizhun et al. observed abnormal activation of Wnt signaling in ischemic stroke, accompanied by blood- brain barrier disruption, neuronal apoptosis, and neuroinflammatory symptoms in the central nervous system. Through cell experiments, it has been proposed that the Wnt/β-catenin signaling pathway can serve as a therapeutic target for ischemic stroke. [16] Satchakorn et al. found through animal experiments and motor function tests that after reperfusion injury, quercetin can significantly reduce the infarct size, blood-brain barrier leakage, and apoptotic cells after injury. The main mechanism involved is angiogenesis, and the Wnt/β-catenin signaling pathway may run through it. [17] Wenyong et al. pointed out that celastrol mediates the Wnt/β-catenin signaling pathway to alleviate cerebral ischemia-reperfusion injury in rats. [18] Donya et al. believe that the FoxO1 and Wnt/β-catenin signaling pathways are molecular targets for protecting against cerebral ischemia/reperfusion injury. [19] Other studies have shown that NPD1 inhibits excessive autophagy in cerebral ischemia-reperfusion injury by targeting the RNF146 and Wnt/β-catenin pathways; [20] Dexmedetomidine hydrochloride has a protective effect on the Wnt/β-catenin signaling pathway in cerebral ischemia-reperfusion injury; [21] The involvement of Wnt/β-catenin signaling pathway in cerebral vascular reperfusion injury may be related to the transforming growth factor β 1/Smad3 signaling pathway. The Wnt/β-catenin signaling pathway is closely related to the occurrence, development, and treatment of various cerebrovascular diseases, especially ischemic cerebral perfusion injury, which can serve as a new therapeutic target.

Wnt/β-Catenin Signaling Pathway Receptors, Agonists, and Inhibitors

Wnt signaling receptors [22] can bind to frizzled (fz) proteins, which are seven transmembrane receptors characterized by an extracellular cysteine rich N-terminal domain (crd). The current research results show that the surface expression of LRP5/6 receptors is a necessary condition for initiating Wnt signaling. The transmembrane tyrosine kinase receptor Derailed is also a Wnt signaling receptor.

The main agonists of the Wnt signaling pathway have been found to be Norrin, r-spondins, and others. Norrin [23] binds with high affinity to frizzled4 and activates typical signaling pathways in an LRP5/6-dependent manner. Other factors that activate the typical Wnt signaling pathway include r-spondins, which are proteins containing thrombin reactive protein. In previous studies [24], it was confirmed that r-spondin-2 is a Wnt agonist that can synergistically activate β-catenin with Wnt. Moreover, cell experiments have shown that r-spondins can physically interact with the extracellular regions of LRP6 and frizzled8, thereby activating Wnt signaling [25].

The main inhibitors of the Wnt signaling pathway have been found to be DKK, WISE, SFRPS, and WIFS. Secretory DKK protein inhibits Wnt signaling by directly binding to LRP5/6 [26]. The secretory Wnt inhibitor WISE also acts by binding to lrp [27], such as its member SOST [28,29]. The soluble frizzled related protein (SFRPS) is similar to the ligand binding crd domain of frizzled family Wnt receptors [30]. WIF protein is a secreted molecule that is similar to the extracellular portion of Derailed/ryk transmembrane Wnt receptors [31]. SFRPS and WIFS are considered to have the function of extracellular Wnt inhibitors [32,33].

There are many receptors, agonists, and inhibitors of Wnt that have been discovered, and here are only some typical proteins. With the continuous deepening of research, more and more protein targets will be discovered in the future.

Research Progress on the Inflammatory Effects of Wnt/ β-Catenin Signaling Pathway

The Wnt/β-catenin pathway has dual anti-inflammatory and pro- inflammatory effects. Its anti-inflammatory and pro-inflammatory effects vary with different conditions, and the regulatory mechanisms are also different. The anti-inflammatory effect of Wnt/β-catenin signaling pathway: On the one hand, studies have found that Wnt/β-catenin signaling can downregulate the production of pro- inflammatory cytokines such as IL-1 β and IL-6 when stimulated by lipopolysaccharides, cytokines, viruses, and bacteria [34-40]. The anti-inflammatory effect of β-catenin may be due to the induction of PI3K/Akt signaling transduction and the reduction of TLR4 driven inflammatory response in DCs. Liu Yongsheng et al. [41] found that in the process of atherosclerosis, PAR2 plays an anti-inflammatory role in ox-LDL treated macrophages through Dkk 1/Wnt/β-catenin signaling pathway.

There are also studies indicating that the deficiency of β-catenin leads to increased inflammatory response and disease onset [42]. The Wnt/β-catenin pathway not only has anti-inflammatory effects but also pro-inflammatory effects [43]. The β-catenin signal can induce inflammatory responses in liver cells, participate in direct transcriptional regulation, and activate the NF-κB pathway. This β-catenin signaling may indirectly promote tumor associated inflammatory responses by altering cellular components in the microenvironment. Another study also reported the positive effect of β-catenin on lipopolysaccharide induced production of pro- inflammatory cytokines in human bronchial epithelial cells [44].

Interference  Between  Wnt/β-Catenin  Signaling Pathway and NF-κB Signaling Pathway

The Wnt/β-catenin and NF-κB signaling pathways are two very important inflammatory signaling pathways. Numerous literature studies have confirmed the inhibition of inflammatory response by interfering with the Wnt/β-catenin or NF-κB pathways. Zhang Tao et al. [45] found through experiments that metformin reduces inflammation and cell apoptosis by activating the Wnt/β-catenin signaling pathway. Similarly, studies have found that curcumin can alleviate asthma symptoms and inflammatory responses by activating the Wnt/β-catenin signaling pathway[46]. Puerarin inhibits atherosclerotic inflammatory response in rabbits by inhibiting NF-κB signaling pathway[47]. In addition, many effective traditional Chinese medicine monomers have been experimentally proven to rely on the NF-κB signaling pathway to exert anti-inflammatory effects, such as gastrodin, quercetin, baicalin, and so on.

The crosstalk between Wnt/β-catenin and NF-κB signals is bidirectional, indicating that these two pathways regulate each other. In the hair follicle development model [48], members of the tumor necrosis factor-α family bind to their receptor EDAR to induce NF- κB nuclear translocation and activation in developing hair follicles. EDAR is a direct target of Wnt/β-catenin and can activate the Wnt/β- catenin signaling pathway. The literature suggests that the localization expression of Wnt10b/Wnt10a requires NF-κB signaling transduction, and Wnt10b is a direct transcriptional target gene of NF-κB. In addition, Wnt/β-catenin signaling antagonist DKK4 is a target gene of the EDAR/NF-κB pathway and can act as a negative feedback to limit β-catenin signaling transduction [49]. Other studies have found that high expression of β-catenin can block NF-κB-mediated cell apoptosis, while endotoxin induced NF-κB can promote β-catenin expression and β-catenin regulated cell proliferation [50]. Xi Yang et al. [51] revealed that esomeprazole can inhibit the activation of MAPK and Wnt/β-catenin induced by IL-1 β, as well as inhibit the process of p65 entering the nucleus from the cytoplasm induced by IL-1 β. The progression of rheumatoid arthritis model in rats can be delayed in vivo, providing new treatment ideas for clinical treatment of rheumatoid arthritis. Some studies have also found that curcumin can inhibit the inflammatory response of acute lung injury by suppressing the Wnt/β- catenin and NF-κB signaling pathways. Tang Bi et al. [52] found that Circ 0001434 RNA inhibits the inflammatory response of acute lung injury models by regulating miR-625-5p, NF-κB, and Wnt/β-catenin signaling pathways. Suo Tao et al. [53] found that MicroRNA-1246 inhibits acute lung injury induced lung inflammation and apoptosis by suppressing NF-κB and Wnt/β-catenin pathway activation.

In summary, Wnt/β-catenin and NF-κB signaling are mutually regulated in various cells and tissues, and play an important role in maintaining environmental balance within cells/tissues.

The cross regulation of Wnt/β-catenin and NF-κB also links inflammation and tumorigenesis, not only within cells but also between cells. Carcinogenic inflammation has been recognized as one of the biomarkers of cancer [54]. The positive regulation of Wnt/β- catenin by the NF-κB pathway in tumor models may contribute to tumor development. For example, in colon cancer models, activated NF-κB and β-catenin/Tcf4 act as transcriptional co activators, inducing a series of stem cell genes and subsequently promoting tumor cell growth [55]. In a gastric tumor model, macrophages activated by Helicobacter pylori infection induce NF-κB-mediated TNF-α production, thereby enhancing the oncogenic Wnt/β-catenin signaling pathway [56,57]. In addition to creating favorable tumor microenvironments composed of various pro-inflammatory cells, NF- κB mediated inflammation can enhance the tumorigenic potential of cancer cells by upregulating Wnt/β-catenin signaling. Therefore, NF- κB may be a therapeutic target for inflammation related cancers.

Author Contributions

HYZ: designed this work of review; TLW: performed the literature search of the databases; YL: wrote the manuscript of this paper; YW, QNY, and CCY: revised the manuscript; All authors approved the paper for publication.

Funding

This paper was supported by Major national projects(No. 2019ZX09201004-002-092) and Shanghai University of Traditional Chinese Medicine research project (No. Y2021085)

Acknowledgments

The authors gratefully acknowledge funding support.

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Cause of Extinction of Dinosaurs

2 Replies

DOI: 10.31038/GEMS.2025723

 

I would like to present here a substantially different view for the cause of extinction of dinosaurs for which, to start with, the cause of growth of the huge animals is vital to understand. The concept suggests that the Permian and Carboniferous era were marked by rich Gondwana coal deposits formed from glossopteris-rich forests of that era. These thick forests would cause extensive process of photosynthesis, thereby producing considerable amount of oxygen that would enrich the atmosphere. Hence it can be visualized that oxygen content of the atmosphere of Triassic period must have been very high compared to the earlier periods. In consequence it seems that the animals of the Triassic period roamed in an oxygen-rich environment where plenty of food was also available. The fossil records point out that animals of that period became huge in size, which can, therefore, reasonably be related to the oxygen-rich environment associated with availability of food of that period. However, during K-T boundary stage a contrasting situation prevailed when widespread volcanism occurred in various parts of the globe for which oxygen content of the atmosphere substantially reduced. This led large animals which required larger quantum of oxygen for sustenance to face selective extinction whereas smaller animals were not affected. Hence, it seems in the pertinent geological ages the following events took place (Table 1).

Table 1: Pertinent geological ages

Period

 Age (m. years) Main Event

Main Result
Cretaceous

65-130

 Igneous Activity Dinosaur Extinction
Jurassic

130-165

 Reign of Dinosaurs Dinosaur Supremacy
Triassic

165-230

 Oxygen-rich-Globe Growth-of-Dinosaurs
Permian

230-265

 Photosynthesis Oxygen Production
Carboniferous

265-355

 Photosynthesis Oxygen Production

Conclusion

I consider that cause of extinction of large sized animals of various types which also consist of birds, bipedal and quadrupedal animals of both herbivorous and carnivorous types, commonly termed as dinosaurs, was not due to impact of meteorites, but depletion of oxygen of the atmosphere. During the Triassic period oxygen content of the atmosphere was greatly enhanced owing to widespread photosynthesis of the glossopteris forests. In such a congenial oxygen-enriched environment with plenty of foods, the animals grew up to large size. However, due to the incidences of igneous activities that occurred during the Cretaceous period oxygen content of the atmosphere was significantly depleted when the large-sized animals that required more oxygen selectively faced extinction while the smaller animals remained unaffected.

Strong Isotope Fractionation Between 13C and 12C in the Supercritical Fluids Related to the Variscan Mineralizations in Erzgebirge, Slavkovský Les(Kaiserwald), and Lusatian Mountains, Germany, and the Czech Republic and Some Remarks on the Low-Pressure Formation of Diamond

2 Replies

DOI: 10.31038/GEMS.2025722

Abstract

The document shows strong isotope fractionation between 13C and 12C of diamonds transported and formed by supercritical fluids related to Variscan mineralizations in Germany and the Czech Republic at a crustal level. Furthermore, we give evidence that the formation of diamonds at low pressure and temperature at a crustal level is also possible. Beyond that, diamonds can form at the interface of metals and graphite crucibles by catalytic activation of methane at low pressure. On an exotic example, the growth of diamond during the Stockbarger growth of fluorite, we show that the range of diamond formation is vast in pressure and temperature.

Keywords

13C-rich diamond, Supercritical fluid, Strong isotope fractionation, Variscan mineralization, Extensive range of diamond formation

Introduction

According to Cartigny (2005) [1], the abundance for 12C is about 98.9%, and for 13C, 1.1% in natural diamonds formed in Earth’s mantle. Therefore, the ratios of both isotopes are expressed in parts per thousand relative to an internationally accepted standard. However, the finding of very high 13C values in natural diamonds is a novum and needs an acceptable interpretation (e.g., Thomas, 2025). The low 13C concentration of diamonds is more or less the same for the principal diamond types: peridotitic or P-type and eclogitic or E-type. That is also true for the strange diamonds carbonado and framesite [2]. Traditionally, the formation of diamonds is associated with extremely high pressures and temperatures deep in the Earth’s crust or upper mantle. However, in the last years, this canonical view has been challenged by recent data and interpretations that suggest metastable growth of diamonds in low-pressure environments [3]. Diamonds were found in various regions of the world embedded in geological structures that do not exhibit the typical conditions for diamond formation. For example, in recent years, diamonds have been discovered in the Brazilian state of Bahia in rock layers that have experienced only low pressure and moderate temperatures. These diamonds demonstrate that the rock environment can play a crucial role in stabilizing the diamond structure, even in the absence of the usual extreme conditions regarding pressure and temperature. Thomas et al. (2023a) [4] have shown that diamonds can transported fast via supercritical fluids from the mantle region into the crust. Such diamonds, mostly spherical with a very smooth surface, are entirely out of the formation place. However, further studies show unusual diamond and lonsdaleite crystals for which a high-pressure and high-temperature formation is at least unlikely [5] because some such crystals are on growth zones of fluorite from Zinnwald. Also, the occurrence of moissanite whiskers (together with nano-diamonds) in beryl crystals [6] speaks against the high-pressure and high- temperature formation. Melt inclusion studies [7] yield data for the pressure and temperature of about ≤ 3 kbar and ≤ 750°C. This data is very different from the classic results.

Recently, Gong et al. (2024) [8] have produced diamonds under normal pressure and high temperatures of about 1175°C in a metal bath in a graphite crucible under a low-pressure methane atmosphere. Together with our results and the results from Gong et al. (2024) [8] and Pujol-Solà et al. (2020) [3], there are obviously more possibilities for the formation of diamonds in nature and technique: (i) classic way at high pressure and high temperature, (ii) via high-pressure and high-temperature transport of diamonds via supercritical fluids into the moderate pressure and temperature range in the Earth’s crust (iii) direct formation at crustal conditions and (iv) formation at high temperature and very low pressure at technical processes (e.g., Gong et al. (2024) [8] and this work).

Sample Material and Methodology

Sample Material

A brief description of the sample material used and basic results is provided in a row of old and recent publications [4-7,9-13] and the references cited in them.

Here, we want to restrict ourselves to two different samples, which have not been described up to now; however, they give new views on the formation of diamonds under very different conditions.

The beryl-quartz sample (Figure 1) from Schlaggenwald (Slavkovský les) is from a small symmetric shaped vein (Mining Academy Freiberg, old archive material from an underground mine from the 1930s years) – see René (2018) [14] and Sejkora et al. (2006) [15].

Figure 1: Beryl-quartz sample from Schlagenwald (Slavkovský les). Brl: beryl, Qtz: quartz, Mol: molybdenite. Scale is in cm.

Synthetic fluorite (Figure 2) grown in graphite crucible after the Stockbarger method (in Jena, Germany) – see Leeder 1979 [16].

Figure 2: Synthetic water-clear and very pure fluorite grown by the Stockbarger method at atmospheric pressure.

Beryl Crystals from SLAVKOVSKÝ les (Kaiserwald)

The beryl-quartz sample contains the primary minerals beryl, quartz, and molybdenite, as well as many tiny graphite and moissanite crystals in beryl. The thickness of the small vein is about 7 cm. Genetically, the beryl crystals are earlier than the quartz. Beryl grows from the wall to the center of the vein (The sample looks like the beryl sample from the Sauberg mine near Ehrenfriedersdorf [6,10]. The graphite is characterized by nano-, micro-diamonds, and moissanite, which are obviously formed during the graphite crystallization.

Synthetic Fluorite Crystal, Grown After the Stockbarger Method

Sample 2, a water-clear fluorite aggregate, is a cropped piece from a larger one grown using the Stockbarger method (Figure 2). This sample contains a very small number of tiny spherical melt inclusions (~20µm in diameter) and has never dealt with diamonds for preparation.

Microscopy and Raman Spectroscopy

We performed all microscopic and Raman spectroscopic studies with a petrographic polarization Microscope (BX 43) with a rotating stage coupled with an EnSpectr RamMics M532 Raman spectrometer. Raman spectra were recorded in the spectral range of 0–4000 cm-1 using a 50 mW single mode 532 nm laser, an entrance aperture of 20 µm, a holographic grating of 1800 g/mm, and a spectral resolution of 4–6 cm-1. Depending on the grain size, we used microscope objectives with magnifications between 3.2× and 100×. For most measurements on diamonds, lonsdaleite, and moissanite, we used a long-distance LMPLFLN 100× objective from Olympus. The laser energy on the sample was continuously adjusted down to 0.02 mW. The position of the Raman bands was controlled before and after each series of measurements of the Si band, using a single crystal chip of semiconductor-grade silicon. The run-to-run repeatability of the line position (from 20 measurements each) was ± 0.3 cm-1 for Si (520.4 ± 0.3 cm-1) and 0.5 cm-1 for diamond (1332.3 ± 0.5 cm-1 over the range 0–2000 cm-1), respectively. For diamond reference, we used a water-clear natural diamond crystal from Brazil (Mining Academy Freiberg, No 2453/37). For azimuth-dependent measurements, we used a scaled rotating microscope stage. For the identification of the different mineral phases using Raman micro-spectroscopy, we used the data from Hurai et al. 2015 [17] and the RRUFF database (Lafuente et al. (2016) [18]. We also routinely determined the zero point of the Raman spectrometer to test the first-order band position of the diamonds. The position of the first-order Raman bands of the used diamond sprays 0.25 and 1 µm (Struers A/S, Pederstrupvej 84, DK-2750 Ballerup/Denmark) for polishing, measured with Raman spectrometer M532 (n = 10 diamond grains each):

DP-Spray 0.25 µm, 1332.1 ± 1.9 cm-1, FWHM = 65.7 ± 12.8 cm-1,

DP-Spray 1.0, µm, 1332.6 ± 0.7 cm-1, FWHM = 75.4 ± 4.4 cm-1.

FWHM is the Full-Width at Half Maximum.

Results

Slavkovský les (Kaiserwald)

The beryl sample from Slavkovský les is similar to the beryl samples from Ehrenfriedersdorf [10]. However, diamond and moissanite are significantly rarer. In some of the graphite needles, there are also calcite crystals that hint at the starting of a hydrothermal reworking.

Raman measurements on diamond and graphite of such graphite needles give the following values (see also Figures 3 and 4):

Diamond: 1326.8 ± 2.6 cm-1 and Graphite: 1570.0 ± 7.2 cm-1 (n = 18 each).

Figure 3: Graphite (Gr) crystals (arrows) at the rim of the graphite/carbon needle in beryl (Brl) and diamond cluster (D).

In contrast to the spherical diamond crystals, which came with the supercritical fluid from the mante region into the crust, the graphite needles crystallized together with beryl on the spot.

Figure 4: Raman spectrum of nano-diamond (1327.4 cm-1) in the graphite needle (Figure 3) shows the strong G-band of graphitic carbon (1565.3 cm-1).

Generalizing the Finding of Diamonds in a Crustal Level

During the Raman spectrometric study of different minerals (mostly beryl, cassiterite, fluorite, quartz, and topaz) in the Variscan tin-tungsten mineralizations of the Slavkovsky les and Erzgebirge as well as in quartz of quartz veins and granites in the Lusation Mountains we often found nano- and micro-diamonds. To avoid contamination by the preparation [19], the samples were carefully cleaned in an ultrasonic bath, and only diamond, lonsdaleite, and SiC grains that lay under the polished surface were generally used. Cropped pieces that have never seen diamonds for preparation are also suitable. Polishing with Al2O3 or a suspension of silica gel in an alkaline solution is an alternative, which we used in the case of cassiterites. In Figure 5, the results are plotted for diamonds and belonging graphite. Conspicuously, the measuring points often accumulate around 1330 cm-1 for diamonds and 1570 cm-1 for graphite. The most spherical diamonds, transported via supercritical fluids (as inclusions), belong to this group. Noteworthy are the trends A and B. Both trends show a decrease in the first-order Raman position of the diamond with a decline in the carbon band position. The diamonds of the B-trend are more strongly related to the 13C-rich graphite/carbon than trend A. Note, however, that the Raman band of pure 13C-graphite is at 1519 cm-1. The points under these values correspond to the D-band of carbon or can be attributed to vibrations of trans-polyacetylene molecules (see Zaitsev 2001) [20]. The small group of diamonds (point C) represents, according to Zaitsev (2001) [20], a low-temperature formation.

Figure 5: Correlation of the first-order diamond line with the belonging graphite band (475 points). A, B: show the correlations of diamond vs. graphite; C: diamond cluster, grown according to Zaitsev (2001) [20] at low temperatures (below 500°C).

Figure 6 shows the frequency distribution of the 13C content in diamonds (475 sample points) – calculated according to Enkovich et al. 2016 [21]. Such extreme isotope fractionation is remarkable (see Thomas 2025b) [22] and was, up to now, never found. An explanation is a strong isotope fractionation of CH4 or CO2 (12C/13C) in the supercritical fluid and the crystallization of the 13C-rich diamond from it in the crust. Because most 13C-rich diamonds are related to beryl crystals, another explanation should be discussed: Does beryllium, maybe as an intermediate and metastable salt-like carbide [23] at supercritical or near supercritical conditions, have a catalytic meaning for the crystallization of moissanite (often as whiskers) and also favor the formation of 13C-rich diamonds? We know that the solubility of BeO (bromelite) under near-critical conditions is extreme (see Figure 5 in Thomas and Davidson 2010) [24]. It is also essential here that 13C-rich diamonds were never used for sample preparation because the effort to produce such material is too considerable.

Figure 6: Frequency distribution of 13C in diamond, calculated according to Enkovich et al. 2016 [21].

Two bands dominate most diamonds in crustal rock: the diamond band ≤ 1332.7 cm-1 and the G-band of graphitic carbon around 1584 cm-1 (see Figure 5). However, there are a small number of diamonds that show no or only a very small G-band (Figure 7). That means that the shielding effect of graphitic and amorphous carbon (see Al- Tamimi et al. 2019) [25] usually surrounding the nano-diamonds does not work. That means that the diamonds without the characteristic G-band are micro-diamonds greater than 1 µm.

Figure 7: Raman spectrum of 13C-rich diamond in cassiterite (Sn-23) from Zinnwald [12]. The Raman band at 1527 cm-1 is the G band from the 13C-rich graphite [26].

Figure 8 gives the frequency distribution of diamonds without the graphite/carbon band, corresponding to about 30% of all measurements. Table 1 shows the Gaussian fitting results of Figure 8.

Figure 8: Frequency distribution of the Raman first-order diamond band for diamonds without a graphite band (n = 145 measurements).

Table 1: Gaussian fitting results of the data plotted in Figure 9 (R2 = 0.99344).

Peak

Area

Center

Width

Height

1

386.68

1333.7

5.42

56.88

2

226.11

1315.5

11.26

23.10

The difference between peaks 1 and 2 is significant. A classification of these diamonds as lonsdaleite, according to Shumilova et al. (2011) [27], is not convincing.

Some Remarks on the Low-Pressure Formation of Diamonds

We have shown that at least two different diamonds occur in Variscan minerals in the Earth’s crust: (i) diamonds transported via supercritical fluids from the mantle region into the crust (mostly very smooth spherical crystals) and (ii) diamonds (often together with moissanite) formed directly in the crust level under low pressure (~3 kbar, ≤ 750°C). The possibility of the formation at low pressure and temperature of nano-diamonds has also been shown, for example, by Pujol-Solà et al. (2020) [3] at the serpentinization of ocean lithosphere under strong reducing conditions (350°C and 1 kbar). However, see Yang et al. 2020 [28], which does not accept this interpretation.

The Formation of Diamonds at Low Pressure and High Temperatures in Technological Processes

The formation of diamonds is traditionally associated with extremely high pressures and temperatures deep in the Earth’s crust or upper mantle. These conditions are also necessary for the technique of transforming carbon atoms into the dense, crystalline structure of diamonds. However, recent research and discoveries have shown that diamonds can also form under less extreme conditions. These findings shed new light on the diverse processes of diamond formation and expand our understanding of geological activities. Gong et al. (2024) [8] have shown through laboratory experiments that diamonds can form under less extreme conditions than previously thought. In controlled experiments, these authors were able to synthesize diamonds at lower pressures and temperatures by using specific chemical catalysts. These experiments confirm that diamond formation is not exclusively dependent on high pressures and temperatures but can also be facilitated by chemical processes. We show here that the unforeseen (and overlooked) formation of diamonds is possible at high temperatures (~1418°C) and very low (~10-4 Torr) pressures during the Stockbarger growing of optical fluorite (CaF2) in a graphite crucible [29]. Figure 2 shows such a water- clear cropped piece of optical fluorite fragment, which contains very rare melt inclusions. These inclusions contain calcium carbide (CaC2), graphite, and tiny diamond crystals (see Figure 9).

Figure 9: Melt inclusion in fluorite. CaC2: calcium carbide, D: diamond, Gr: graphite.

Figure 10 shows a Raman spectrum of diamond and carbon in such inclusion in optical fluorite. The strong band at 1875 cm-1 in some Raman spectra is characteristically for CaC2 [30]. From 9 measurements, the mean for the first-order Raman band of the diamond is 1320 ± 13.7 cm-1. The FWHM = 31.9 ± 13.4 cm-1.

Figure 10: Raman spectrum of diamond in synthetic CaF2 characterized by the 1303.6 cm-1 band and the strong band at 1446 cm-1 corresponding to Zaizev (2001) [20] to nondiamond carbon phases.

Conclusion

The traditional view that diamonds can only form under extreme conditions deep in the Earth’s crust or upper mantle is being challenged by new evidence and research findings. The discovery of diamonds in geological structures with less extreme conditions, such as the Variscan mineralizations represented by them, and experimental evidence expands our understanding of diamond formation processes. These insights open new perspectives for the search for diamonds and the exploration of geological activity on Earth, as well as the technique of production of synthetic diamonds.

Acknowledgment

This paper is dedicated to Paul Davidson (Hobart/Tasmania) for his 20 years of productive cooperation with the first author.

References

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Effectiveness of Cosmetic Rhinoplasty on Psychosocial Outcomes and Quality of Life: An Experimental Study of Iranian Women

4 Replies

DOI: 10.31038/AWHC.2025814

Abstract

Despite increase in the number of cosmetic rhinoplasty between women worldwide, its different aspects remained unclear. This study explores the impact of cosmetic rhinoplasty on psychosocial outcomes and quality of life among Iranian women attending cosmetic surgery clinics in Tehran. Participants, aged 18 to 56 years, completed questionnaires one month before surgery and three months post-surgery. The sample of 235 women was randomly selected from two private clinics in central and northern Tehran, with the sample size determined using Cochran’s formula. Out of 400 eligible participants, 301 patients completed the pre-surgery questionnaires, and 240 returned the post-surgery questionnaires. Results indicated significant improvements in quality of life (t=6.91, p < 0.001, d=0.41) and self-esteem (t=4.57, p < 0.001, d=0.63) following rhinoplasty, though no significant changes were observed in physical or mental health. The study highlights the need to address psychological factors that may limit the positive outcomes of cosmetic surgery. These findings are valuable for healthcare providers, emphasizing the importance of comprehensive pre- and post-operative counselling to optimize patient outcomes.

Keywords

Cosmetic rhinoplasty, Quality of life, Psychosocial outcomes, Physical health, Self-esteem, Women

Introduction

Cosmetic surgery, also known as aesthetic surgery, involves elective procedures designed to improve an individual’s appearance. These procedures include liposuction, breast augmentation, rhinoplasty (nose surgery), blepharoplasty (eyelid surgery), and rhytidectomy (facelift). Rhinoplasty, in particular, has seen significant popularity in recent years, both globally and in Iran. In 2022, liposuction was the most commonly performed cosmetic surgery worldwide, followed by breast augmentation, eyelid surgery, and abdominoplasty (tummy tuck). Among non-surgical procedures, Botox injections, hyaluronic acid (dermal fillers), laser hair removal, and chemical peels are among the most common [1-6].

In Iran, approximately 320,000 cosmetic surgeries were conducted in 2022, with rhinoplasty being one of the most popular. The desire for physical enhancement is natural across all human societies, but it holds particular significance for women, who are often more concerned with their appearance compared to men. Many women use cosmetic surgery to improve their social status and reinforce their personal identity [4]. This trend has been amplified in modern societies where women feel pressure to meet stringent and sometimes unattainable beauty standards. The dominant culture’s validation of these standards contributes to increased anxiety regarding appearance, leading many women to undergo costly and potentially harmful procedures [7-10].

This study specifically focuses on cosmetic rhinoplasty, one of the most commonly performed cosmetic surgeries in Iran. Despite its popularity, there is a limited body of research examining the psychosocial outcomes and quality of life impacts following this procedure. While previous studies have shown that many patients experience dissatisfaction with body image, social pressures, and cultural influences related to beauty standards, little research has specifically focused on the impact of rhinoplasty on quality of life, physical health, social well-being, and self-esteem in Iranian women [11].

Iran’s unique cultural and social factors, such as the influence of media, societal pressures, and the importance of beauty in shaping personal identity, have contributed to an increasing demand for cosmetic procedures, particularly rhinoplasty. These factors necessitate an in-depth exploration of the psychological and psychosocial effects of such surgeries on Iranian women. Thus, this study aims to evaluate the effectiveness of cosmetic rhinoplasty on the quality of life, physical health, social well-being, and self-esteem of Iranian women. By examining these factors before and after surgery, this research will contribute valuable insights into how rhinoplasty impacts the lives of women, addressing both the benefits and potential drawbacks of such a popular cosmetic procedure [12].

Given the limited data on this subject in Iran, the findings from this study could help inform medical practitioners, policymakers, and counsellors, enabling them to provide more effective psychological support and guidance for individuals considering or recovering from cosmetic rhinoplasty.

Methodology

Participants and Procedures

This study employed a semi-experimental design [11] to investigate the psychosocial outcomes and quality of life following cosmetic surgery. The participants were women aged 18 to 56 years who visited cosmetic surgery clinics in Tehran, Iran. They completed questionnaires at two time points: one month before and up to three months after their cosmetic procedures. Exclusion criteria included individuals with alcohol or drug addiction, mental illnesses, congenital nasal deformities (e.g., polyps and nasal deviation), prior nasal trauma, cleft lip and nose, previous rhinoplasty or septoplasty, obsessive–compulsive disorder, or major depression. Participants provided informed consent before being included in the study. Randomized sampling was employed, with participants selected based on clinic visitation days.

Sampling was conducted in two stages to ensure geographic diversity. First, two private clinics in central and northern Tehran were randomly selected. Second, patients who had undergone cosmetic surgeries within the prior one to three months were randomly chosen. The sample size was determined using Cochran’s formula, resulting in 235 distributed questionnaires, accounting for potential incomplete or missing data.

Measures

Several standardized instruments were employed to assess the impact of cosmetic surgery on quality of life, psychological well-being, and social functioning. These included the Glasgow Benefit Inventory (GBI), measuring changes in physical, mental, and social health dimensions; the Rhinoplasty Outcomes Evaluation (ROE), assessing satisfaction with rhinoplasty; and the Deriford Appearance Scale (DAS59), evaluating appearance-related concerns and their influence on self-esteem. Reliability coefficients for these tools were 0.85, 0.80, and 0.88, respectively. Additionally, the main questionnaire gathered demographic data and included 29 questions addressing appearance awareness, social support, and physical health, rated on a five-point Likert scale [13,14].

Data Analysis

Data were analysed using SPSS software. Descriptive statistics, including relative frequency and means, were calculated, and paired-sample t-tests were performed to assess differences between pre- and post-surgery measures. Participants provided voluntary informed consent and were thoroughly briefed about the study’s purpose, procedures, potential risks, and their right to withdraw at any time without penalty. Confidentiality was ensured by anonymizing data and securely storing it with access restricted to the research team. Measures were implemented to minimize psychological or emotional discomfort, with participants encouraged to seek counselling if needed.

Results

The demographic characteristics of the subjects are included gender, age, education level, occupation, the number of cosmetic surgeries, and marital status shown in Table 1. The comparison of the studied variables before and after the aesthetic rhinoplasty in the subjects studied is shown in Table 2. The results of the t-tests indicate significant changes in some psychosocial indicators following cosmetic surgery. Participants reported a notable improvement in quality of life, with mean scores increasing from 3.16 (SD=0.86) before surgery to 3.52 (SD=0.89) after surgery, (t (239)=6.91, p < .001, d=0.41), reflecting a moderate positive effect. Additionally, a significant increase in self-esteem was observed, with mean scores rising from 3.24 (SD=0.67) to 3.41 (SD=0.76), (t (239)=4.57, p < .001, d=0.63), indicating a large effect size. Social well-being also showed slight improvement, with mean scores increasing from 3.09 (SD=0.49) to 3.16 (SD=0.51), (t (239)=2.34, p=.02, d=0.15), though the effect size was small.

Table 1: Demographic characteristics of female participants before and after cosmetic surgery.

Characteristic

 Before Surgery (n)

After Surgery (n)
Age Distribution    
15-24 years

72

75
25-34 years

32

70
35-44 years

53

47
45-56 years

21

31
Education Level    
Elementary/Associate

71

110
Bachelor’s Degree

68

81
Master’s Degree

18

36
Doctoral Degree

3

5
Marital Status    
Single

94

112
Married

36

52
Divorced

21

41
Widowed

10

16
Employment Status    
Employed

93

139
Unemployed

67

80
Number of Surgeries    
Two or fewer surgeries

113

113
More than two surgeries

122

122
Total Respondents

235

235

Table 2: Quality of life, physical health, social health, and self-esteem before and after surgery.

Variable

 Mean (SD) Before Surgery Mean (SD) After Surgery Cohen’s d t

p
Quality of Life

3.16 (0.86)

 3.52 (0.89) 0.41 6.91

<0.001
Physical Health

3.84 (0.61)

 3.85 (0.58) 0.02 0.24

0.81
Social Health

3.09 (0.49)

 3.16 (0.51) 0.15 2.34

0.02
Mental Health

1.57 (0.60)

 1.52 (0.55) 0.08 1.24

0.22
Self-Esteem

3.24 (0.67)

3.41 (0.76)

0

4.5.637

<0.001

In contrast, no significant changes were observed in physical or mental health after surgery. Physical health scores remained nearly unchanged, with pre-surgery mean scores of 3.84 (SD=0.61) and post-surgery mean scores of 3.85 (SD=0.58), (t (239)=0.24, p=.81, d=0.02), suggesting no meaningful impact. Similarly, mental health scores showed no significant difference, with a slight decrease from 1.57 (SD=0.60) to 1.52 (SD=0.55) post-surgery, (t (239)=1.24, p=.22, d=0.08), indicating a minimal or negligible effect. These findings suggest that while cosmetic surgery significantly improved self-esteem, quality of life, and social well-being, it had no substantial impact on physical or mental health. This underscores the selective benefits of cosmetic surgery in addressing psychosocial dimensions without extending to physical or mental health outcomes.

Discussion

This study makes a significant contribution to the expanding literature on cosmetic surgery by specifically examining the psychosocial and quality-of-life outcomes of rhinoplasty in Iranian women, a population uniquely shaped by cultural and societal expectations. While rhinoplasty is globally recognized as one of the most common cosmetic procedures, its impacts on psychological and social well-being are underexplored, particularly in culturally distinct contexts like Iran. By evaluating outcomes such as self-esteem, quality of life, and social and mental health, this research provides a comprehensive understanding of the broader implications of rhinoplasty. Findings revealed marked improvements in self-esteem and quality of life, suggesting that rhinoplasty can positively influence psychosocial well-being. This aligns with previous studies that emphasize the role of cosmetic procedures in reducing social anxiety and fostering a positive self-concept. These insights provide a valuable framework for healthcare providers, enabling them to address the psychological dimensions of cosmetic surgery and support patients in achieving holistic benefits [15,16].

The demographic characteristics of the participants underscore important trends among rhinoplasty candidates, offering insights into their underlying motivations. This study identified a predominance of younger individuals, especially those aged 15–24, consistent with existing research that associates youth with heightened sensitivity to societal beauty standards and peer influences. Medical recommendations to delay cosmetic surgery until facial growth is complete may explain the lower representation of individuals under 20 years old. The decline in demand among older participants may reflect shifting priorities with age, as seen in other studies highlighting a focus on inner well-being over physical appearance in later life stages. These findings emphasize the role of societal norms and age-specific pressures in shaping cosmetic surgery trends, underscoring the need for tailored preoperative education that reflects patients’ developmental and social contexts [17-19].

Education and marital status trends observed in the study further reveal the evolving motivations for rhinoplasty. The significant representation of participants with higher education levels contrasts with earlier research that reported a dominance of candidates with lower educational attainment. This shift may reflect broader access to education and heightened awareness of cosmetic procedures among more informed populations. Additionally, the higher prevalence of single women undergoing rhinoplasty, consistent with findings (2022), suggests that societal pressures to enhance physical appearance may be more pronounced among individuals seeking romantic or social opportunities. However, the substantial representation of married women highlights the changing perceptions of cosmetic surgery as a form of self-care and empowerment across different life stages. Employment status also emerged as a key factor, with employed individuals comprising a large proportion of candidates, underscoring the increasing importance of physical appearance in professional and social domains [20-24].

The study further highlights the impact of rhinoplasty on quality of life, corroborating findings from previous research that emphasize the psychological benefits of aesthetic surgery. Significant improvements in self-image and reductions in emotional distress were reported, contributing to greater social confidence and life satisfaction [25,26]. Consistent with studies by [27,28], this research affirms that aesthetic rhinoplasty can enhance quality of life by addressing dissatisfaction with appearance. Moreover, studies by [29,30] suggest that satisfaction with cosmetic surgery outcomes increases over time, indicating that patients may benefit from long-term psychosocial improvements. However, some studies have challenged these findings, emphasizing the need for a nuanced understanding of the multi-dimensional nature of quality of life and its interplay with socio-economic variables [31]. Integrating psychological preparation into preoperative care could help patients set realistic expectations and maximize the benefits of rhinoplasty.

While this study observed no significant changes in physical health outcomes, this aligns with the nature of cosmetic surgeries, which are primarily aesthetic rather than functional. This finding underscores the importance of managing patient expectations regarding the procedure’s limitations, focusing instead on its psychological and social benefits. The modest improvements in social well-being, including enhanced interpersonal relationships and reduced social anxiety, suggest that rhinoplasty can serve as a catalyst for improved social functioning. However, these outcomes are influenced by cultural and individual factors, such as societal beauty norms and personal resilience. To maximize these benefits, a multidisciplinary approach that includes counselling and social skills training may be necessary. By integrating these findings into clinical practice, healthcare providers can offer more comprehensive care, ensuring that patients achieve both psychological and physical satisfaction from cosmetic procedures [32-35].

In conclusion, this study emphasizes the profound psychosocial benefits of rhinoplasty, particularly its ability to enhance self-esteem and quality of life. The findings support the incorporation of psychological evaluations and support mechanisms into pre- and postoperative care plans, allowing healthcare providers to address the holistic needs of patients. Additionally, the interplay between societal, cultural, and individual factors in shaping rhinoplasty trends highlights the need for personalized patient education and care strategies. By fostering realistic expectations and addressing both aesthetic and emotional dimensions, healthcare providers can ensure the long-term success and satisfaction of cosmetic surgery patients. Further research into the cultural and psychosocial determinants of cosmetic surgery demand can enrich understanding and inform best practices in this evolving field [36].

Limitations and Future Directions

This study has several limitations. The short follow-up period (three months post-surgery) restricts the ability to assess long-term psychosocial and clinical outcomes, such as sustained changes in mental or physical health. Additionally, the random sampling from two clinics in Tehran may not represent the entire Iranian population, given the country’s geographic and cultural diversity. Reliance on self-report measures introduces potential biases, including social desirability and recall bias. Future research should incorporate longitudinal designs to explore long-term effects and include more diverse samples to improve the generalizability of results. Moreover, employing qualitative methods, such as interviews, could provide deeper insights into patients’ subjective experiences. Investigating the role of pre-existing mental health conditions and their influence on postoperative outcomes could also enhance understanding and improve pre-surgery psychological screening and support programs.

Conflict of Interest

The authors declare that there is no conflict of interests.

References

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Beyond Birth Control: Hormonal Contraceptives May Provide Protection from Knee Ligament Injury Requiring Surgery

3 Replies

DOI: 10.31038/AWHC.2025813

Abstract

Women who take birth control have a protective benefit of a lesser risk of anterior cruciate ligament injury. This protective effect occurs with all forms of hormonal birth control regardless of the combination of medications or if the method is oral, a device, or systemic. Attempts to establish a specific cause to this benefit have centered on mechanical strength studies of ligaments, flexibility and muscular strength. These studies have failed to appreciate the complexity and interactions of hormones in the complex physiology that includes cognitive performance, postural stability, and brain function that includes risk avoidance. Although there are proven benefits of hormonal birth control on decreasing the risk of knee surgery, the causative reasons are not simple to define.

It has been established that females are at higher risk of anterior cruciate ligament injury than their male counterparts [1-3]. Numerous studies have been performed to determine the reason for this . Among possible causes for this disparity are the changes in hormones that occur during the female ovulatory cycle. it has been found that there is a definite increased risk of ligament injury with hormonal fluctuation [4,5].

This knowledge was the basis of a recent detailed study by Fry, Hirpara, Whitney, Keeter, Constantine, Williams, and Dragoo. Using a computer database from the Colorado Health Data Compass system, 14,886,766 females were evaluated for having had an ACL injury requiring surgery. Of this group the 2,120,628 females taking hormonal contraceptives had a lower ACL surgical incidence than the 12,766, 38 females who did not take any contraceptive. This lower risk was present irrespective of the type of hormonal birth control used, (oral, IUD, implant), or the formulation of the method used. When stratified by age, only the 15-19 year age group showed no difference in risk of needing ACL surgery. It was concluded that hormonal contraceptive use is associated with a lower incidence of ACL injury requiring surgery [6].

Within the orthopedic community there have been many studies directed at finding out the reason to explain this protective mechanism. As orthopedics is a field predominantly directed at the treatment of musculoskeletal issues, attention has been directed at the effects of hormones on musculoskeletal strength, flexibility and effects on loads causing ligament failure. However, this prior research gives no definitive answer and there is no proven cause and effect regarding hormonal effect on ligament strength, flexibility, and anterior cruciate ligament failure [7,8].

It has been established through prior research that the female sex hormones, (estrogen, progesterone and relaxin),rise and fall dramatically during the normal menstrual cycle. These changes have been associated with findings of increased ligamentous laxity and a decrease in neuromuscular performance, Because of these changes, it has been theorized that this results in a decrease in passive knee stability and resultant greater chances of injury [9]. Unfortunately, it is simplistic to assume that hormonal effects on the need for ACL surgery are solely due to the biomechanics of ligament strength or muscular strength.

If one looks beyond the biomechanical studies, there are studies which give additional insight regarding how hormonal fluctuations change athletic performance. Consider the study by Lee et. al. An evaluation of balance during the menstrual cycle, postural sway was significantly higher 13 days after the onset of menstruation. Their change was sufficient to effect static balance and could potentially increase risks of injury. Specific exercises were recommended in order to prevent injury during this hormonal phase [10].

Additional balance changes were noted by Friden. His study revealed that during a one-legged stance with eyes wide open, there was a significant increase in postural displacement during the mid- luteal phase. Such changes were associated with postural instability and a reported increase in injury rate [11].

Recent studies have evaluated the effect of sex hormones on both cognitive performance and brain function that are involved directly in movement control. There is a direct impact on behavioral consequences and neuropsychological processing [12]. This will result in how a person reacts and responds to challenging situations in a sports environment.

Reviewing the influence of sex hormones on non-biomechanical properties, Souza et. al. found an influence on visuospatial and motor skills, attention and concentration, verbal memory, visual memory, working memory, and reaction time. When evaluating performance scores, there was a tendency towards a worse performance in the luteal phase [13]. Reaction time was changed which may result in an increased risk of injury and subsequent need for ligament surgery.

Included in the non-biomechanical effects of hormones are the direct effect of hormonal associated changes on brain function and risk aversion. It is found that risk aversion is greater in women than men. Women are less risk tolerant than men. This is thought to be a reason why there is a lower return to sport after ACL reconstruction in females when compared to males of equal post-operative function [14]. There is a more favorable response to a physical stressor during the late follicular to ovulatory period of the menstrual cycle. This results in changes to the risk taking behavior [15,16]. Hormonal birth control affects the cycle and associated brain function that controls risk aversion.

Returning to the study by Frye et. al., it was reported that the use of hormonal contraceptive is associated with a lower incidence of ACL injury requiring reconstruction when compared to no contraceptive use [6]. From the data, it is clear that there is a benefit regarding the use of contraceptives in decreasing the chance of an injury resulting in surgery. However, the causation is multifactorial. One must not assume that the direct effects of hormones on ligament or muscular biomechanics is the causative reason for these findings.

There is a paradox in the study by Frye, et.al. The protective benefits of hormones on ligament injury needing surgery was not as apparent in the 15-19 year age group. This data was in direct contradiction to work by DeFroda who reported a protective benefit in this age group [17]. Frye et al. explains this problem of no protective benefit from hormonal contraceptive as being secondary to possible hormonal irregularity that may occur in this age group.

A detailed review of the methodology used by Frye et. al. finds that the data collection for this age group was flawed and may explain the results. As previously described, the study was performed using an insurance database to confirm the use of oral contraceptive pills, (OCP). It was assumed that all OCPs are given by prescription and would appear as an insurance claim. For this age group, 15-19, this is an inherently poor way to determine OCP usage.

Frye, et. al. states females in this age group, 15-19, had a reported use of OCPs at 13.6% [6]. However, use of OCPs in this age group has been reported to be as high as 80% [18].

The error in utilization occurs because an insurance database is an inherently flawed way to determine usage of OCPs in 15-19 year olds. Surreptitious use of OCPs by teenagers, without the usage of parental insurance, is an established fact. Multiple organizations provide OCPs to teenagers irrespective of parental knowledge or insurance [19]. As such, the use of OCPS as measured by insurance database information is grossly underreported with secondary data distortion.

What is apparent is that the use of hormonal birth control, regardless of the method used, can and does have an association with a decreased incidence of ligament injury resulting in surgery. The reason for this is unclear. It may be secondary to biomechanical ligament strength, postural adaptiveness, cognitive awareness, risk aversion, visual spatial interpretation or a multitude of other physiological changes that occur under hormonal fluctuations.

Whether there is a specific singular cause or if it is secondary to dozens of neuromuscular, physiologic and neurologic effects, the end result has a small protective benefit to the knee. This information provides the female athlete with added options when considering methods of decreasing the risks of ligament injury needing surgery.

References

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  6. Fry SA, Hirpara A, Whitney KE, Keeter CL, Constantine EP, et (2025) Use of Hormonal Contraceptives is Associated with Decreased Incidence of ACL Injuries Requiring Reconstruction in Females. Arthroscopy.S0749-8063(25)00133-1. [crossref]
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  14. Siegel MG (2024) Editorial Commentary: Women Do Not Return to Sport at the Same Level After Anterior Cruciate Ligament Reconstruction as Often as Men: This May Be Associated With Lower Risk Tolerance-and Not Necessarily a Bad Thing! Arthroscopy. 40(6): 1879-1881. [crossref]
  15. 15) Cook CJ, Kilduff LPBT (2018) Crewther, basal and stress-induced salivary testosterone variation across the menstrual cycle and linkage to motivation and muscle Scand J Med Sci Sports 28(4): 1345-1353. [crossref]
  16. Cook CJ, Crewther BT (2019) Within- and between-person variation in morning testosterone is associated with economic risk-related decisions in athletic women across the menstrual cycle. Horm Behav. 112: 77-80. [crossref]
  17. DeFroda SF, Bokshan SL, Worobey, S, Ready, L, Daniels AH, et (2019) Oral contraceptives provide protection against anterior cruciate ligament tears: a national database study of 165,748 female patients. Phys Sportsmed. 47(4): 416-420. [crossref]
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  19. Reilly K, Schmuhl KK, Bonny AE (2024) Removing Barriers to Contraceptive Access for Adolescents. J Pediatr Pharmacol Ther. 29(3): 331-335. [crossref]

Beyond Diabetes Care, Sodium-Glucose Co-transporter-2 (SGLT2) Inhibitors in Cardiovascular and Renal Health: Evidence and Implementation

2 Replies

DOI: 10.31038/EDMJ.2025924

Abstract

Multiple studies have established the benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in heart failure and chronic kidney disease (CKD) in patients with type 2 diabetes. Following these studies, additional large randomized controlled trials were conducted to assess their efficacy across various stages of heart failure and CKD and demonstrated benefit in patients regardless of diabetes status. While the data supporting the use of SGLT2 inhibitors is robust and national guidelines now recommend their use, the adoption of these treatments in clinical practice remains suboptimal. To improve patient outcomes, leveraging a multidisciplinary team-based approach can help accelerate widespread adoption.

Review of the Evidence in Heart Failure

Numerous randomized controlled trials in patients with type 2 diabetes have demonstrated the benefits of SGLT2 inhibitors in managing cardiovascular disease and chronic kidney disease [1-7]. In the initial SGLT2 inhibitor trials, these therapies significantly reduced heart failure hospitalizations compared to placebo in patients with established cardiovascular disease or those at high risk, a benefit that is primarily attributed to the prevention of incident symptomatic heart failure. Another placebo-controlled study found that initiating a combined SGLT1/2 inhibitor (sotagliflozin) either before or shortly after discharge in patients with diabetes and recent worsening heart failure led to a significant reduction in cardiovascular mortality as well as the number of hospitalizations and urgent visits for heart failure [8]. SGLT2 inhibitors have similarly been shown to slow the progression of kidney disease and reduce the incidence of renal events when added to standard care. The mechanisms underlying these benefits are believed to extend beyond glucose, weight, and blood pressure reduction; they are hypothesized to be driven by reductions in plasma volume, decreased cardiac preload and afterload, alterations in cardiac metabolism, and tubuloglomerular feedback which in turn lowers intraglomerular pressure [9,10].

Given the benefit seen in patients with type 2 diabetes, several landmark large clinical trials were conducted to analyze the benefits of these medications for these indications in patients with or without diabetes. These trials investigated the benefit of SGLT inhibitors in patients with heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and chronic kidney disease. A summary of these trials and their findings are presented in Table 1.

Table 1: Summary of randomized controlled trials for non-diabetes indications.

Heart Failure with Reduced Ejection Fraction
Trial Intervention Key Patient Characteristics

Results
DAPA-HF11

Dapagliflozin 10 mg once daily (n=2373) or placebo (n=2371)

·   NYHA Class II 67.7% (dapa); 67.4% (placebo)

·   Systolic blood pressure (mmHg) 122.0 + 16.3 (dapa); 121.6 + 16.3 (placebo)

·   Mean LVEF (%) 31.2 + 6.7 (dapa); 30.9 + 6.9 (placebo)

·   Mean eGFR (mL/min/1.73m2) 66.0 + 19.6 (dapa); 65.5 + 19.3 (placebo)

o    eGFR < 60 40.6% (dapa); 40.7% (placebo)

·   Background therapy with ACE/ARB/ARNI 95% (dapa); 93.7% (placebo)

Primary composite outcome of worsening heart failure (hospitalization or an urgent visit resulting in IV therapy for heart failure) or death from cardiovascular causes: 16.3% dapa vs 21.2% placebo (HR 0.74 [0.65-0.85]; p<0.001)
EMPEROR-Reduced12 Empagliflozin 10 mg once daily (n=1863) or placebo (n=1867) ·   NYHA Class II 75.1% (empa); 75.0% (placebo)·   Systolic blood pressure (mmHg) 122.6 ± 15.9 (empa); 121.4 ± 15.4 (placebo)

·   Mean LVEF (%) 27.7 ± 6.0 (empa); 27.2 ± 6.1 (placebo)

o    LVEF < 30% 71.8% (empa); 74.6% (placebo)

·   Mean eGFR (mL/min/1.73m2) 61.8 ± 21.7 (empa); 62.2 ± 21.5 (placebo)

o    eGFR < 60 48.0% (empa); 48.6% (placebo)

·   Background therapy with ACE/ARB/ARNI 88.8% (empa); 89.6% (placebo)

 

 Primary composite outcome of death from cardiovascular causes or hospitalization for heart failure: 19.4% empa vs 24.7% placebo (HR 0.75 [0.65-0.86]; p<0.001)

Heart Failure with Preserved Ejection Fraction
Trial Intervention Patient Characteristics

Results
EMPEROR-Preserved14 Empagliflozin 10 mg once daily (n=2997) or placebo (n=2991) ·   NYHA Class II 81.1% (empa); 81.9% (placebo)·   Systolic blood pressure (mmHg) 131.8 ± 15.6 (empa); 131.9 ± 15.7 (placebo)

·   Mean LVEF (%) 54.3 ± 8.8 (empa; placebo)

·   Mean eGFR (mL/min/1.73m2) 60.6 ± 19.8 (empa); 60.6 ± 19.9 (placebo)

o    eGFR < 60 50.2% (empa); 49.6% (placebo)

 

 Primary composite outcome of death from cardiovascular causes or hospitalization for heart failure: 13.8% empa vs 17.1% placebo (HR 0.79 [0.69-0.90]; p<0.001)
DELIVER15 Dapagliflozin 10 mg once daily (n=3131) or placebo (n=3132) ·   NYHA Class II 73.9% (dapa); 76.6% (placebo)·   Mean LVEF (%) 54.0 ± 8.6 (dapa); 54.3 ± 8.9 (placebo)

·   Mean eGFR (mL/min/1.73m2) 61.0 ± 19.0 (dapa; placebo)

 Primary composite outcome of worsening heart failure (hospitalization or urgent visit for heart failure) or death from cardiovascular causes: 16.4% dapa vs 19.5% placebo (HR 0.82 [0.73-0.92]; p<0.001)

Chronic Kidney Disease
Trial Intervention Patient Characteristics

Results
DAPA-CKD20 Dapagliflozin 10 mg once daily (n=2152) or placebo (n=2152) ·   Systolic blood pressure (mmHg) 136.7 ± 17.5 (dapa); 137.4 ± 17.3 (placebo)·   Mean eGFR (mL/min/1.73m2) 43.2 ± 12.3 (dapa; 43.0 ± 12.4 (placebo)

o    eGFR 30-45 45.5% (dapa); 42.7% (placebo)

·   Median urinary albumin-to-creatinine ratio(IQR) 965 (472-1903; dapa); 934 (482-1868; placebo)

·   Serum potassium (mEq/L) 4.6 ± 0.5 (dapa); 4.6 ± 0.6 (placebo)

·   Background therapy with ACE/ARB 98.4% (dapa); 97.9% (placebo)

 Primary composite outcome of sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes: 9.2% dapa vs 14.5% placebo (HR 0.61 [0.51-0.72]; p<0.001)
EMPA-KIDNEY21 Empagliflozin 10 mg once daily (n=3304) or placebo (n=3305) ·   Systolic blood pressure (mmHg) 136.4 ± 18.1 (empa); 136.7 ± 18.4 (placebo)·   Mean eGFR (mL/min/1.73m2) 37.4 ± 14.5 (empa); 37.3 ± 14.4 (placebo)

o    eGFR 30-45 44.4% (empa); 44.2% (placebo)

·   Median urinary albumin-to-creatinine ratio(IQR) 331 (46-1061; empa); 327 (54-1074; placebo)

·   Background therapy with ACE/ARB 85.7% (empa); 84.6% (placebo)

 Primary composite outcome of progression of kidney disease or death from cardiovascular causes: 13.1% empa vs 16.9% placebo (HR 0.72 [0.64-0.82]; p<0.001)

The Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) and Empagliflozin in Heart Failure with a Reduced Ejection Fraction (EMPEROR-Reduced) trials were the two earliest trials to evaluate the benefit of SGLT2 inhibitors in patients with heart failure and reduced ejection fraction (HFrEF) independent of diabetes status [11,12]. These studies compared dapagliflozin and empagliflozin, respectively, with placebo. Participants in both trials were predominantly male with a mean age of approximately 65 years, and less than half had a history of type 2 diabetes. Most patients presented with New York Heart Association (NYHA) class II symptoms and were on background therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or angiotensin receptor-neprilysin inhibitors (ARNIs). In both studies, the use of an SGLT2 inhibitor resulted in significant improvements in the primary composite outcomes including heart failure-related hospitalizations and cardiovascular mortality. These benefits were consistent across various subgroups, though the effects were particularly pronounced in patients with NYHA class II symptoms and an LVEF of less than 30%. Additionally, no significant differences were observed in the incidence of side effects including volume depletion, renal adverse events, or major hypoglycemia in either trial.

With the clear benefits of SGLT inhibitors established in the HFrEF patient population, the question remained whether this benefit persists across the spectrum of heart failure. Left ventricular ejection fraction (LVEF) has historically been used for trial inclusion and exclusion criteria, creating a body of evidence that is therefore subcategorized based on ejection fraction, when the reality is that heart failure is a clinical syndrome that exists along a spectrum of ejection fraction. There is broad agreement on the definitions of HFrEF (LVEF ≤ 40%) and HFpEF (LVEF ≥ 50%) while much ambiguity remains for those with LVEF between 40% and 50% as well as those who previously qualified as HFrEF with subsequent improvement in LVEF to ≥ 40% [13].

The Empagliflozin in Heart Failure with a Preserved Ejection Fraction (EMPEROR-Preserved) and Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trials sought to assess the potential benefits of SGLT2 inhibitors in patients with heart failure and LVEF > 40%; importantly, DELIVER allowed enrollment of patients with prior LVEF ≤ 40% provided their LVEF was > 40% at the time of study enrollment (a group that has been labeled heart failure with “improved” EF according to the Universal Definition of heart failure) while EMPEROR-Preserved did not [13-15]. These trials involved a slightly older population with a mean age of approximately 72 years, and nearly half of the participants were female. Like EMPEROR-Reduced and DAPA-HF, about half of the patients had a history of type 2 diabetes, although approximately 90% participants enrolled in EMPEROR-Preserved and DELIVER had a history of hypertension. In both trials, patients were evenly distributed across the spectrum of eligible LVEF. The use of SGLT2 inhibitors in both studies resulted in significant improvements in primary composite outcomes including heart failure-related hospitalizations and cardiovascular mortality. These benefits were consistent across subgroups; however, the EMPEROR-Preserved trial showed a signal towards greater benefit in patients with lower-range LVEF, while the DELIVER trial suggested more pronounced benefits in those with higher-range LVEF. These differences may be attributed to variations in primary outcomes (such as the addition of urgent HF visits to the composite endpoint in DELIVER), patient inclusion criteria (such as the inclusion of patients with heart failure with recovered ejection fraction in DELIVER), and the duration of heart failure symptoms prior to enrollment. While there is likely a class effect of SGLT2 inhibitors in heart failure and there is evidence that canagliflozin can improve activity and patient-reported outcomes compared with placebo, there are currently only three FDA approved SGLT2 inhibitors for broad heart failure use with varying approved eGFR cutoffs based on study inclusion criteria: sotagliflozin (eGFR > 30 ml/min/1.73 m2), empagliflozin (eGFR > 20 ml/min/1.73 m2 ), and dapagliflozin (eGFR > 25 ml/min/1.73 m2) [16-19].

Review of the Evidence in Chronic Kidney Disease

Another key patient population hypothesized to benefit from SGLT2 inhibitors is those with chronic kidney disease. The DAPA-CKD and EMPA-KIDNEY trials therefore sought to evaluate the potential benefits of SGLT2 inhibitors in patients with chronic kidney disease independent of diabetes status, though the characteristics of participants enrolled in these studies differed in a few key ways [20,21]. The DAPA-CKD trial enrolled a higher proportion of patients with a history of cardiovascular disease and diabetes, while the EMPA-KIDNEY trial included a greater percentage of patients with an eGFR < 30 and a broader range of baseline urinary albumin-to-creatinine ratios (UACR). Both trials demonstrated that SGLT2 inhibitors (dapagliflozin and empagliflozin, respectively) provide significant benefits in slowing CKD progression and reducing cardiovascular risk regardless of diabetes status and across a wide spectrum of renal function. However, in EMPA-KIDNEY, subgroup analysis revealed that the benefits may be more pronounced in patients with lower baseline UACR levels (Table 1).

Guideline Recommendations

As a result of these trial findings, national guidelines for heart failure, chronic kidney disease, and diabetes now recommend initiating SGLT2 inhibitor therapy in eligible patients (Table 2).

Table 2: Summary of guideline recommendations.

National Guideline

 Class of Recommendation/Level of Evidence

Recommendation
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines22 1/A Initiate SGLT2 inhibitor for patients with type 2 diabetes and CVD or high risk for CVD
1/A In patients with symptomatic chronic HFrEF, SGLT2 inhibitors are recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes
2/A SGLT2 inhibitor use recommended in patients with HF with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%)
2/A SGLT2 inhibitor use recommended in patients with HF with preserved ejection fraction (HFpEF; LVEF > 50%)
KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease23 1/A Recommend treating patients with type 2 diabetes, CKD, and an eGFR > 20 ml/ min per 1.73 m2 with an SGLT2 inhibitor
1/A Recommend treating adults with CKD with an SGLT2 inhibitor for the following:·         eGFR > 20 ml/min per 1.73 m2 with urine ACR > 200 mg/g (> 20 mg/mmol)

·         Heart failure, irrespective of level of albuminuria
2/B Treat adults with eGFR 20 to 45 ml/min per 1.73 m2 with urine ACR < 200 mg/g (< 20 mg/mmol) with SGLT2 inhibitor
American Diabetes Association Standards of Care in Diabetes – 202524 A In adults with type 2 diabetes and established or high risk of atherosclerotic cardiovascular disease, the treatment plan should include medications with demonstrated benefits to reduce cardiovascular events (e.g., GLP-1 and/or SGLT2 inhibitor) for glycemic management and comprehensive cardiovascular risk reduction (irrespective of A1c)
A In adults with type 2 diabetes who have heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor is recommended for both glycemic management and prevent of HF hospitalizations (irrespective of A1c)
A In adults with type 2 diabetes who have CKD (with confirmed eGFR 20-60 mL/min/1.73 m2 and/or albuminuria), and SGLT2 inhibitor or GLP-1 RA with demonstrated benefit in this population should be used for both glycemic management (irrespective of A1c) and for slowing progression of CKD and reduction in cardiovascular events. The glycemic benefits of SGLT2 inhibitors are reduced at eGFR < 45 mL/min/1.73 m2

Important Considerations for Safe Use and Adverse Events

Many patients do not carry only a single indication for treatment with an SGLT2 inhibitor. In fact, a 2018 study of 530,747 patients with type 2 diabetes found that over 90% had concomitant cardiovascular or kidney disease [25]. Given the interconnectedness of metabolic syndrome, cardiovascular disease, and chronic kidney disease, it is crucial for clinicians managing patients with these conditions to consider initiating SGLT2 inhibitors in eligible individuals from multiple vantage points. Clinicians should be mindful of dual disease purposes and screen appropriately for benefit using UACR and NT-proBNP for CKD and heart failure, respectively.

According to the KDIGO guidelines, once an SGLT2 inhibitor is initiated, it is generally appropriate to continue the therapy even if the eGFR drops below 20 mL/min/1.73m², unless the medication is poorly tolerated or kidney replacement therapy (KRT) is require [26 ]. Additionally, starting or continuing SGLT2 inhibitors does not necessitate a change in the frequency of CKD monitoring. There is often a reversible decrease in eGFR observed at the start of therapy that is typically not a reason to discontinue treatment. It is important to note that while glycemic control may be less effective when eGFR falls below 45 mL/min/1.73m², the cardiovascular and renal benefits of SGLT2 inhibitors remain, and therefore these agents should still be initiated as long as the eGFR prior to initiation is >20 mL/min/1.73m².23 In the HFrEF and CKD trials previously described, most patients were already on background therapy with ACE inhibitors, ARBs, or ARNI, suggesting that SGLT2 inhibitors can safely and effectively be added to these guideline-directed medical therapies with few adverse effects. Given the generally favorable hemodynamic and laboratory tolerability of SGLT2 inhibitors, clinicians may consider initiating them before other classes of guideline-directed therapies based on individual patient factors. However, special consideration should be made for management of diuretics, anti-hypertensive regimens, and anti-hyperglycemic regimens to reduce risk of side effects and simplify complex medication regimens.

Specifically, because hyperkalemia often limits the use of combination therapy with renin-angiotensin system inhibitors (RASi) and/or mineralocorticoid receptor antagonists (MRAs), the hypokalemic side effect of SGLT2 inhibitors may help balance potassium levels in patients on combination therapy. Indeed, there is evidence that SGLT2 inhibitors reduce hyperkalemic events in patients with and without diabetes making early initiation of this therapy enabling of combination GDMT [27]. With recently published evidence for the non-steroidal MRA finerenone showing clinical benefit in reducing heart failure morbidity, but with higher than expected hyperkalemic events, upfront initiation of SGLT2 inhibitors with MRAs in patients with heart failure and/or CKD indication(s) is an attractive strategy that may improve tolerability [28].

Though not the focus of this review, combination therapy in treating cardiovascular, kidney, and metabolic disease has gained traction over the prior several years. The pathophysiology of both CKD and heart failure are complex with multiple targetable pathways of injury including the renin-angiotensin system, inflammation and fibrosis, and metabolic derangement; as such, a single therapy is highly unlikely to modulate all involved pathways. In addition, cardiovascular disease (including heart failure, stroke, and myocardial infarction [MI]) is a significant cause of morbidity and mortality among patients with metabolic syndrome and those with CKD. However, each of these cardiac comorbidities is affected differently by each class of CKD therapy: SGLT2 inhibitors and ns-MRAs appear to most modulate heart failure outcomes, while RASi more significantly reduce blood pressure and GLP-1 receptor antagonists modulate metabolic syndrome, reduce ASCVD risk, and modify CDK outcomes. Additionally, though efficacy of empagliflozin in HFrEF and HFpEF has been demonstrated, inhibition of these pathway did not demonstrate meaningful impact in patients with MI with regards to first hospitalization for HF or death when compared to placebo. Subsequent post hoc analyses revealed a decreased risk of heart failure (HF) in patients with left ventricular dysfunction or congestion following acute MI, as well as a reduction in both first and total HF hospitalizations among individuals with type 2 diabetes [29-31]. We believe that aggressive and early combination therapy in treating the distinct but interrelated conditions of cardiovascular, kidney, and metabolic disease (align with CKM) should become the norm moving forward.

Although the benefits of SGLT2 inhibitors extend across multiple physiological pathways, this medication class is not without adverse effects. SGLT2 inhibitors have been linked to an elevated risk of genitourinary infections, hypovolemia, and diabetic ketoacidosis (DKA). The increased risk of genitourinary infections is primarily attributed to the glucosuric effects of these medications, a relationship highlighted in previous meta-analyses [32]. The use of canagliflozin, dapagliflozin, and empagliflozin in patients with diabetes is particularly linked to a higher risk of genitourinary tract infections, especially in women, with this risk further heightened in those with a history of urinary tract infections (UTIs) and obesity [33]. Among these patients, there have been reports of Fournier’s gangrene; however, the connection between SGLT2 inhibitor therapy and this severe perineal infection remains weak, as patients with diabetes already have a higher baseline risk for such infections. Across all heart failure and CKD trials reviewed, although SGLT2 inhibitor groups exhibited a higher rate of genitourinary tract infections, there were no reported cases of Fournier’s gangrene in either the placebo or intervention arms.

Volume depletion has been consistently observed in multiple randomized controlled trials, including those focused on heart failure and CKD, due to osmotic diuresis induced by SGLT2 inhibitors, which may lead to symptomatic hypotension. The induction of DKA by this medication class has been postulated to occur due to different mechanisms, including impairment in ketone clearance. While the overall incidence of DKA remains rare across trials included in this review (<0.1%), the risk may be higher in patients hospitalized on SGLT2 inhibitor therapy, particularly when additional risk factors such as dehydration, infection, or changes in medication regimens including insulin or other glucose-altering agents are present. Due to these concerns, perioperative discontinuation and avoidance of this therapy on sick days has been advocated [34].

Furthermore, earlier concerns regarding potential associations between SGLT2 inhibitors and bone fractures, amputations, or malignancies have not been substantiated by more recent data, with variations in findings depending on the specific medication within the class.

SGLT2 inhibitors have been widely used and an effective therapeutic option for managing diabetes for several years. As our understanding of the potential side effects of this medication class evolves, especially in patients with multiple comorbidities, the benefits of SGLT2 inhibitors remain well-established and significant. These benefits are most pronounced when used in appropriately selected patients, with close monitoring by the multidisciplinary care team.

Translating Evidence to Implementation

A decision-analytic modeling study of heart failure patients in the United States estimated that optimal implementation of SGLT2 inhibitors over three years could prevent or delay approximately 630,000 worsening heart failure events across the entire LVEF spectrum. Of these, roughly 230,000 to 280,000 events would be prevented or postponed in patients with heart failure and LVEF greater than 40% [35]. Population health initiatives focused on managing chronic kidney disease, diabetes, and cardiovascular disease aim to prevent, manage, and reduce the impact of these conditions across diverse populations. These initiatives typically emphasize disease detection, improved access to therapeutics, patient and provider education, and initiation/titration of medical therapy.

Particularly in a value-based care context, wherein there are existing resources targeting better chronic disease management that are sustainable and not simply being used for demonstration projects, access to regularly updated patient, prescribing, and provider data is paramount [36 ]. Health system data can be leveraged to target therapeutic gaps, reduce practice variation and idiosyncratic use of evidence-based therapy, address disparities in care, and, ultimately improve health outcomes at scale. Furthermore, multiple strategies can be tested and iteratively improved. As outlined in national guidelines for these diseases, care delivery models at the local level that engage multidisciplinary teams, provide targeted interventions and education, and focus on improving outcomes are essential for achieving these goals (Figure 1). Telehealth strategies may be incorporated to increase utilization of remote monitoring, improve education delivery, and incorporate more frequent touch points to provide care [22-24].

Figure 1: Multidisciplinary Management Strategy to Optimize Guideline-Directed Medical Therapy in Patients with Heart Failure.

For example, through daily electronic health record (EHR) identification of inpatients with heart failure patients with suboptimal GDMT, the IMPLEMENT-HF trial demonstrated that the integration of pharmacist consultative services into inpatient workflows can improve medication access to novel GDMT. Through streamlined prior authorization and use of patient assistance programs (PAPs), pharmacists and heart failure specialists in collaboration facilitated the safe initiation and titration of heart failure GDMT through targeted recommendations to rounding generalist physicians [37].

In the outpatient setting, PROMPT-HF was a pragmatic, EHR-based trial in which 100 healthcare providers treating patients with HFrEF were randomly assigned to receive either an alert or usual care [38]. The alert provided individualized, guideline-directed medical therapy recommendations along with patient-specific details. As a result, the alert group demonstrated significantly higher rates of guideline-directed medical therapy use at 30 days compared to those receiving usual care. The authors emphasized that this low-cost intervention could be quickly integrated into clinical practice, promoting faster adoption of high-value therapies in heart failure.

Another example of an ambulatory study that utilized EHR-identification of patients with GDMT gaps was the DRIVE study that enrolled 200 patients with indications for, but not currently on, an SGLT2 inhibitor or GLP1 receptor agonist [39]. This trial used a remote, team-based education and medication management program either simultaneously with a navigator/pharmacist outreach effort with or prior to navigator/pharmacist outreach effort; patients were randomized in a blinded fashion to one of these strategies. After 6 months, 64% of patients received a new prescription for either SGLT2 inhibitor or GLP1 agonist. These trials highlight how EHRs, telehealth models, and remote multidisciplinary interventions can be leveraged to improve patient care; one example of how to leverage the patient messaging portal to prompt uptake of SGLT2 inhibitor prescription can be seen in Figure 2. Importantly, once patients are in front of clinicians with knowledge and expertise to initiate GDMT, there is a high degree of success. Unfortunately, even with dedicated navigation resources, the ability to identify and connect patients with these expert providers remains a significant challenge. In the aforementioned DRIVE study, 1289 eligible patients were contacted: 771 were unreachable, 288 declined participation, and ultimately 200 patients were enrolled. Though these results show the value of dedicated pharmacists as a strategy to improve GDMT prescription, they also highlight the challenges in activating the pipeline of eligible patients into the pharmacist visit.

Figure 2: Educational Outreach Embedded In Direct Patient Messaging to Facilitate Uptake of SGLT2 Inhibitors in the Outpatient Setting.

Conclusion

While SGLT2 inhibitors began as antihyperglycemic therapy for type 2 diabetes, the indications and benefits of this class of medications have expanded rapidly over the past decade. Despite the broad body of literature supporting their benefits across the spectrums of both heart failure and chronic kidney disease, there remains significant work to be done to improve national adherence to guideline recommendations and increase prescribing of these medications especially as most patients carry at least two indications for treatment with SGLT2 inhibitors. A multidisciplinary, team-based approach to treatment of patients with type 2 diabetes, heart failure, and chronic kidney disease is therefore crucial in the care for these patients. With increasing sophistication in both the ability to identify patients at risk and to provide personalized clinical decision support, remote patient data coupled to multidisciplinary teams can iteratively improve care delivery [40,41].

Disclosures

Dr. Bhatt has received research grant support to his institution from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention and consulting fees from Heart Health Leaders, Sanofi Pasteur, Merck, Amgen, AstraZeneca, and Novo Nordisk. Dr. Martyn serves as an advisor or receives consulting fees from, Fire1, Prolaio, Boehringer Ingelheim/Eli Lilly, Dyania Health, Novo Nordisk, AstraZeneca, Cleveland Clinic/American Well Joint Venture, BridgeBio, Pfizer, Apricity Robotics, and Kilele health and receives grant support from Ionis Therapeutics, AstraZeneca and the Heart Failure Society of America (HFSA). All other authors report no relevant disclosures.

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Patient Education in Primary Health Care by Advanced Practice Nurses (APN) in Germany

2 Replies

DOI: 10.31038/IJNM.2025614

 
 

Experiences of Advanced Practice Nurses in the FAMOUS Research Project

Examples from practice experiences of advanced practice nurses (APNs) in Germany are shown in this article by illustrating various approaches to patient education in primary healthcare.

Advanced Practice Nurses in Germany

The academization of nursing is still in its very first steps in Germany. Bachelor’s degree programs in nursing were first introduced in 2006. Advanced practice nursing has not yet been established in primary health care in Germany and legal requirements for this role still do not exist [1]. Nevertheless, many efforts within nursing practice and research aim to promote the use of APNs. One such effort was the FAMOUS (effects of care of multimorbid patients in general practices by advanced practice nurses) research project [2].

FAMOUS

The purpose of this controlled nonrandomized mixed methods study was to evaluate the care for multimorbid patients by APNs deployed in general practices in rural areas in Germany. Every patient in the FAMOUS project had at least three or more chronic diseases. The objective of FAMOUS was to stabilize the homecare situation of these patients through the involvement of APNs. The intervention took place from October 2021 to March 2024. Each patient in the intervention group (N=859) received evidence-based and person- centred care by an APN for 12 months. The control group (N=1700) received standard care. For evaluation, routine data from health insurance companies for the control group was used [2,3].

Patient Education and Person-centred Care

Patient education played a significant role in the care for multimorbid patients by APNs in the FAMOUS project, with person- centred care being a requirement for successful education. Person- centred care is about engaging with patients’ life contexts based on a mutual valued relationship. Recognizing and respecting individual values, attitudes, and needs builds the basis for the shared decision- making process, a core element of person-centred care. Family members and relevant healthcare providers are also included in the person-centred care process [4]. The following case examples are a selection of the varied educational situations that the APNs encountered. They intend to provide an insight into the complex care and education needs of multimorbid patients in primary health care and show how the APNs managed to meet them.

Complex Education for Complex Needs

The APN visits Ms A. a few weeks after her discharge from hospital, where treatment for her newly diagnosed type 2 diabetes mellitus was initiated. In addition to grade 1 obesity, she has a mild intellectual impairment and urinary incontinence. Ms. A. is 62 years old and lives by herself. She is illiterate. A domestic help, funded through her care insurance relief allowance, supports her with household tasks and shopping. A home care service handles blood glucose monitoring, medication management, and insulin administration. Due to her illiteracy, Ms. A. has never participated in a diabetes education program. She hardly ever leaves the house because of her incontinence. The lack of exercise increases her obesity. As a result of the in-depth medical history assessment, the APN identifies a lack of knowledge in Ms. A. regarding diabetes management and healthy lifestyle. Together they discuss the goals that Ms. A. would like to achieve. Ms. A. wants to feel confident when choosing suitable foods for a healthy diabetes diet. She would also like to go for more walks outside again despite her incontinence. During the next home visit, the APN provides individualized nutrition education using visual materials like a food pyramid to explain food choices and the importance of exercise. The APN repeats key points and uses comprehension questions to assess the gain of knowledge. Discovering that Ms. A. enjoys drawing, the APN encourages her to draw a picture of the food pyramid and to use it on the next shopping trip. The APN involves the domestic help for the practical part of the training. At the supermarket, Ms. A. and the domestic help compare groceries with the hand-drawn food pyramid to choose appropriate items. Later, Ms. A. reports feeling more confident selecting suitable foods. The involvement of the domestic help contributes to a long-lasting effect of this education. On the next visit the APN discusses methods to promote continence with Ms. A. At the patient’s request, the APN instructs her on bladder training to increase the intervals between visits to the toilet. Furthermore, Ms. A. receives a prescription for pelvic floor exercises with the Maria Gerz (2025) Patient Education in Primary Health Care by Advanced Practice Nurses (APN) in Germany physiotherapist and sanitary pads. After a few weeks, the incontinence has improved to such an extent that Ms. A. can go for outdoor walks again. The regular exercise also led to an improvement in her blood sugar levels and body weight.

App-supported Medication Adherence

Mr. M., aged 78, lives by himself and was recently diagnosed with heart failure, requiring regular medication. However, he frequently lacks to follow his medication, leading to several urgent house calls from his physician due to dyspnea and leg edema. To address this, the APN visits Mr. M. and discusses his medication habits. He admits that he often forgets his medications and is unaware about the importance of adherence. The APN explains the nature of heart failure and the necessity of regular medication. Further evaluation reveals that Mr. M.’s lack of daily routines contributes to his forgetfulness. Since he regularly uses a smartphone, the APN suggests a medication reminder app. Together, they set up the free app, which will alert him with audio signals when it is time for his medication. The APN informs his general practitioner, ensuring that any future medication adjustments are reflected in the app. This approach uses technology effectively to address Mr. M.’s adherence challenges.

Acute Intervention Needs

Mrs. L. suffers from dementia, and her husband, Mr. L., uses a wheelchair due to a below-knee amputation. They share a household with their daughter, who is their primary caregiver. During an initial assessment, the APN observes the daughter’s significant emotional strain. Tearfully, she explains, “I can’t even leave the house for two hours to shop in peace.” The family has limited external support. The APN sets care priorities based on the family’s needs. Four days before the next home visit, the daughter is involved in a car accident, resulting in a tibia fracture requiring surgery. She can no longer fully care for her parents. With no supportive network, the family faces a sudden and complex crisis. The APN conducts a comprehensive family mediation to address their current concerns, especially the couple’s fear of being placed in a nursing home. The daughter is mainly worried about ensuring her parents’ personal care, mobility, and nutrition. Based on this assessment, the APN identifies local support services and, through shared decision-making, implements the following measures: a combination of visiting services and day care for the couple, along with home healthcare services. Additionally, neighborhood assistance is activated to expand the support network. Over the following six weeks, the family adjusts well, later reporting that they feel secure with the established support system.

Summary

The APNs applied multiple methods of education according to the individual case situations and used different materials and media to deal with the complex situations. These practical examples illustrate that patient education is a blend of structured and spontaneous approaches. The counseling process is non-linear and requires a high degree of flexibility. Simple situations often show complex intervention needs. This dynamic demands not only professional competence from APNs but also empathy and the ability to collaborate with patients to find solutions. APNs have the potential to play a significant role in primary healthcare. Their skills and expertise are essential for ensuring high-quality patient care and education.

References

  1. Henderson Colette, Mackavey Carole, Petri Sophie; Wöhrle Olivia (2023) Germany pioneers an expansion of the advanced practice role. International Journal of Advancing Practice 1.
  2. Stemmer Renate, Büchler Britta, Büttner Matthias, Dera-Ströhm, Christina Klein, et al. (2023) Effects of care of multimorbid patients in general practices by advanced practice nurses (FAMOUS): study protocol for a nonrandomized controlled trial. BMC Health Services Research 23.
  3. Brehm Lara, Drevermann Ute, Gerz Maria, Kopp Ines, Leyendecker Christine (2024) Patientenedukation in der Primärversorgung. Erfahrungen von Advanced Practice Nurses im Forschungsprojekt FAMOUS. Padua. 19: 215-219.
  4. McCormack, Brendan (2022). Person-centred care and measurement: The more one sees, the better one knows where to look. Journal of Health Services Research & Policy. 27: 85-87.

Correlation Between Pregnant Women’s Childbirth Attitude and We-media Use

2 Replies

DOI: 10.31038/EDMJ.2025923

Abstract

Objective: To investigate the status quo of pregnant women’s attitude towards childbirth and the use of we-media to browse childbirth-related information, and to analyze the correlation between the two.

Methods: The Chinese version of female childbirth Attitude questionnaire was used to conduct a questionnaire survey on 304 pregnant women who were conveniently sampled from a Grade 3 A hospital in Hangzhou and recruited online.

Results: The score of women’s attitude toward childbirth during pregnancy was (90.30 ± 14.65), and the characteristics of the use of we-media to obtain maternity information showed diversification. The frequency and duration of we-media use were positively correlated with the score of the attitude toward childbirth. In terms of the use motivation, the attention of specific content may have a negative impact on different dimensions of women’s attitude toward childbirth.

Conclusion: The more frequently and longer pregnant women browse pregnancy-related information on we-media platforms, the more likely they are to hold negative attitudes towards childbirth. It is suggested that we media be used to disseminate more authoritative content of childbirth education to help women deeply understand the physiological process of childbirth, so as to reduce the fear of the unknown.

Keywords

Pregnant women, Childbirth attitude, We media use, Influencing factors

Introduction

Childbirth is a major turning point in a woman’s life and has a profound impact on her physical and mental health [1]. As a special physiological and psychological stage for women, pregnancy has increased the demand for maternal and child health information [2]. In recent years, we-media platforms have increasingly become an important channel for pregnant women to obtain maternity information due to their characteristics of immediacy, interaction and decentralization [3]. Childbirth attitude refers to an individual’s subjective cognitive, emotional and behavioral tendencies towards childbirth, including fear of childbirth, childbirth pain, childbirth mode choice and views on the use of medical interventions. A positive attitude towards childbirth contributes to maternal confidence and reduces the risk of postpartum depression [4]. Birth attitudes are shaped by a variety of factors, including personal subjectivity, traditional factors such as family support [5,6], and by the emerging media environment [7]. However, the quality of information on we-media platforms is uneven, and false or inaccurate maternity information may exacerbate the anxiety and fear of pregnant women, thus affecting their attitude towards childbirth [8]. Previous studies have shown that media exposure is associated with women’s childfear behavior [9], but there is still a lack of research on the relationship between we-media use and women’s attitude toward childbirth during pregnancy. Therefore, the purpose of this study is to explore the correlation between we-media use and pregnant women’s attitude towards childbirth, in order to provide a scientific basis for optimizing pregnant women’s access to information, improving their attitude towards childbirth and enhancing their childbirth experience.

Methods

This study was conducted from July to October 2024, through a combination of online and offiine methods, and adopted the snowball method recommended by friends to recruit research subjects. The researcher published a post on rednote to recruit research subjects, attracted potential participants by providing professional nutrition knowledge during pregnancy, and recruited them offiine simultaneously. Pregnant women who underwent prenatal check-up in a third-level A hospital in Hangzhou were selected as research objects by convenient sampling method. They were then encouraged to recommend their friends or relatives to participate, thereby gradually expanding the study sample. Inclusion criteria: ① in the gestation period; ② Age ≥18 years old; ③ In the past six months, I have used the small Red book platform to browse the content related to childbirth; ④ Normal cognitive function, with basic communication and writing skills; ⑤ Know about this study and agree to participate in the study. Exclusion criteria: ① Pregnant women with a history of mental illness. Before collection, obtain approval from the hospital Ethics Committee (No. ZN- 20240327-0098-01). The research team sent the two-dimensional code of the questionnaire was distributed to the study subjects through the questionnaire star link, and the research purpose, content and informed consent were set as required reading items. Participants could read and agree before filling in the questionnaire; The system sets that each IP address can be entered only once to avoid repeated entries. Adopt the form of anonymous independent filling, for regular answers, the answer time is too short less than 3min questionnaires will be excluded. After the survey, the collected questionnaires will be reviewed. A total of 310 questionnaires were sent out in this survey.

Measurement

General Information Questionnaire

Based on the literature review and combined with the purpose and content of this study, the design was self-designed, including general information such as age, ethnicity, education level, household registration type, marital status, expected delivery mode selection, delivery information sources, and use of we-media.

Chinese Version of Women’s Attitudes Towards Birth Questionnaire (WATBQ)

The Chinese version of the Female Childbirth Attitude Questionnaire was compiled by Stoll et al. [10] in 2014. The questionnaire consists of 22 items, including four parts: views on pregnancy and childbirth, views on delivery techniques, views on cesarean section and views on physical changes after delivery. Likert6- level scoring method was adopted, with scores ranging from 1 to 6 for “strongly disagree” to “strongly agree”. The higher the score of each dimension, the more negative the attitude towards childbirth in this dimension. The Chinese version of the Women’s Childbirth Attitude Questionnaire (WATBQ) was developed by our research team in strict accordance with the Brislin model. After cross-cultural adjustment, the Chinese version of the female childbirth attitude questionnaire included 22 items in 5 dimensions: views on childbirth, views on complications, views on delivery techniques, views on caesarean section and views on body changes after childbirth. The Cronbach’s α coefficient of the questionnaire was 0.890, and the retest reliability was 0.824, with good reliability and validity.

Data Analysis

All data were entered into Excel by double checking. SPSS 27.0 software was used for data processing and analysis. For categorical variables, frequency and percentage were used to describe them, and Chi-square test and Fisher exact test were used for comparison. The mean ± standard deviation was used for descriptive statistical analysis of the study variables conforming to the normal distribution. With the scores of childbirth attitude questionnaire as the dependent variable, single factor analysis was performed by t test and variance analysis. Pearson correlation analysis and Point-biserial correlation analysis are used for correlation analysis.

Results

General Information About Women During Pregnancy

A total of 304 pregnant women who met the eligibility requirements completed the survey, of which 78 were recruited online through rednote and 226 were recruited offiine in hospitals, as shown in Table 1.

Table 1: Demographic characteristics of the study participants (n=304).

Variable

 Characteristics Number (n)

Percentage (%)
Age 18-24 years

88

28.9
  25-30 years

187

61.5
  31-34 years

23

7.6
  ≥35 years

6

2.0
Residence Type Agricultural Household

179

58.9
  Non-Agricultural Household

125

41.1
Ethnicity Han Ethnicity

277

91.1
  Others

27

8.9
Education Level High School or Below

17

5.6
  Associate Degree

51

16.8
  Bachelor’s Degree

150

49.3
  Master’s Degree or Above

86

28.3
Marital Status Married

294

96.7
  Unmarried

10

3.3
Occupation Medical Staff

30

9.9
  Civil Servant/Teacher

69

22.7
  Worker

17

5.6
  Company Employee

97

31.9
  Self-Employed

37

12.2
  Farmer

5

1.6
  Unemployed

20

6.6
  Others

29

9.5
Monthly Household Income ≤4000 RMB

66

21.7
  4001-6000 RMB

115

37.8
  6001-8000 RMB

71

23.4
  ≥8001 RMB

52

17.1
Source of Medical Expenses Medical Insurance

225

74.0
  Rural Cooperative Medical Insurance

26

8.6
  Self-Paid

53

17.4
Gestational Week <14 weeks

91

29.9
  14-27 weeks

115

37.8
  ≥28 weeks

98

32.2
Number of Pregnancies 1

223

73.4
  2

67

22.0
  3

14

4.6
Number of Deliveries 0

258

84.9
  1

39

12.8
  2

7

2.3
Unplanned Pregnancy Yes

43

14.1
  No

261

85.9
Participation in Prenatal Education Yes

196

64.5
  No

108

35.5
Family Support for Delivery Method Choice Yes

295

3.0
  No

9

97.0
Witnessed Delivery Process Yes

111

36.5
  No

193

63.5

Women’s Childbirth Attitude Score During Pregnancy

The results showed that the total score of pregnant women’s attitude towards childbirth was (90.30 ± 14.65), and the scores of each dimension were shown in Table 2.

The Result of Characteristic Clustering of Pregnant Women’s Delivery Attitude Score

Table 2: Total and dimension scores of childbirth attitude questionnaire (n=304).

Dimension

 Items Total Score (Mean ± SD)

Average Item Score (Mean ± SD)
Total score

22

 90.30 ± 14.65

4.10 ± 0.67
Perspectives on pain and loss of control

5

 20.95 ± 5.13

4.19 ± 1.03
Perspectives on complications

3

 13.15 ± 3.03

4.38 ± 1.01
Perspectives on obstetric technology

6

 27.60 ± 5.77

3.89 ± 1.05
Perspectives on cesarean section

5

 15.35 ± 3.52

3.93 ± 1.00
Perspectives on postpartum body changes

3

 13.25 ± 3.04

4.42 ± 1.01

According to the total score of the childbirth attitude questionnaire and the average scores of items in each dimension, the pregnant women were divided into 2 clusters by K-means clustering. The distribution of the two groups was average, and the clustering effect was good. Table 3 shows the average scores of the two clusters in the total score of the childbirth attitude questionnaire and items in each dimension. There are significant differences in their mean values, reflecting different characteristics. Therefore, Cluster1 is named “Negative childbirth Attitude Group” and Cluster2 is named “positive childbirth Attitude Group”. In this study, there were 152 pregnant women in the positive childbirth attitude group and the negative childbirth attitude group, each group accounted for 50%.

Table 3: Comparison of two clusters across five dimensions.

Dimension

 Cluster1 (n=152) Cluster2 (n=152) F

P
Total score

102.05 ± 8.55

 78.55 ± 8.94 548.751

0.000**
Perspectives on pain and loss of control

4.85 ± 0.79

 3.53 ± 0.78 216.485

0.000**
Perspectives on complications

4.93 ± 0.77

 3.84 ± 0.93 123.664

0.000**
Perspectives on obstetric technology

4.56 ± 0.70

 3.21 ± 0.90 214.504

0.000**
Perspectives on cesarean section

4.18 ± 0.98

 3.68 ± 0.95 20.381

0.000**
Perspectives on postpartum body changes

4.92 ± 0.75

 3.91 ± 0.99 100.054

0.000**

**P<0.01

Univariate Analysis of Pregnant Women’s Attitude Towards Childbirth

The results showed that there were 5 variables related to women’s attitude towards childbirth, including household registration type, monthly income per capita, gestational week, number of pregnancies and pregnancy education. For details, see Table 4.

Table 4: Univariate analysis of childbirth attitudes by demographic factors (n=304).

Variable

 Category Childbirth Attitude Score (Mean ± SD) t/F-value

P-value
Household registration Agricultural household

83.03 ± 10.47

 -12.833a

<0.001
  Non-agricultural household

100.70 ± 13.50

    
Monthly household income ≤4000 RMB

106.79 ± 11.96

 141.152b

<0.001
  4001-6000 RMB

92.69 ± 9.74

    
  6001-8000 RMB

84.31 ± 6.94

    
  ≥8001 RMB

72.25 ± 8.28

    
Gestational Week <14 weeks

77.69 ± 9.65

 114.508b

<0.001
  14-27 weeks

90.21 ± 9.11

    
  ≥28 weeks

102.10 ± 14.03

    
Number of Pregnancies 1

95.25 ± 13.36

 85.691b

<0.001
  2

79.49 ± 4.86

    
  3

63.14 ± 4.66

    
Participation in Prenatal Education Yes

102.76 ± 12.19

 14.186a

<0.001
  No

83.43 ± 10.90

    

at-value and bF-value

Multiple Linear Regression Analysis of Pregnant Women’s Attitude Towards Childbirth

Five indicators with statistical significance in the univariate analysis were taken as independent variables, and the total score of pregnant women’s attitude towards childbirth was taken as dependent variable. The results of multiple linear regression show that the type of household registration, per capita monthly income of the family, the number of pregnancies and pregnancy education affect their attitude towards childbirth, as shown in Table 5.

Table 5: Multivariate linear regression analysis of childbirth attitudes (n=304).

Model

 Unstandardized oefficients B SE Standardized Coefficients β t-value

P-value
Constant

104.121

 3.242   32.112

<0.001
Household registration

5.234

 1.608 0.176 3.256

0.001
Monthly household income (Reference: ≤4000 RMB)          
4001-6000 RMB

-9.015

 1.660 -0.299 -5.429

<0.001
6001-8000 RMB

-12.013

 1.940 -0.347 -6.191

<0.001
≥8001 RMB

-22.245

 2.199 -0.573 -10.115

<0.001
Gestational weeks (Reference: < 14 weeks)          
14-27 weeks

2.044

 1.678 0.068 1.218

0.224
≥28 weeks

2.467

 2.046 0.079 1.206

0.229
Number of Pregnancies

-3.567

 1.394 -0.135 -2.560

0.011
Whether to attend pregnancy education

-4.408

 1.740 -0.144 -2.533

0.012

R=0.826, R2=0.682, after adjusting R2=0.673, F=79.028, P<0.001

We-media Use in Pregnant Women

In this study, the average weekly frequency of non-medical we- media platforms used by pregnant women to browse childbirth- related information, the time of each use of non-medical we-media platforms to browse childbirth-related information, and the use of we- media platforms to browse childbirth-related content were counted. For details, see Table 6.

Table 6: Social Media Usage Characteristics of Participants

Item

 Category Number (n)

Percentage (%)
Usage frequency <1 day/week

61

20.1
  2-3 days/week

76

25.0
  3-4 days/week

104

34.2
  5-6 days/week

52

17.1
  Daily

11

3.6
Usage duration per session <1 hour

71

23.4
  1-2 hours

86

28.3
  2-3 hours

91

29.9
  3-4 hours

45

14.8
  >4 hours

11

3.6
Motivation for Use Dietary and Lifestyle Advice During Pregnancy

243

24.2
  Other Women’s Delivery Experience

198

19.7
  Preparation for Delivery

210

20.9
  Process of Delivery and Potential Issues

191

19.0
  Risks and Benefits of Common Interventions and Techniques During Pregnancy and Delivery

162

16.1

Correlation Between Pregnant Women’s Childbirth Attitude and We-media Use

The results of correlation analysis showed that the total score and each dimension of female childbirth attitude were significantly positively correlated with the frequency of use of we-media (r=0.431, P < 0.01) and duration of use (r=0.435, P < 0.01). In terms of motivation, browsing diet and lifestyle recommendations during pregnancy through we-media platforms was only positively correlated with the perception dimension of complications (r=0.136, P < 0.05), while the risks and benefits of browsing common interventions and technologies that could be used during pregnancy and delivery were significantly positively correlated with the total score of childbirth attitudes and the perception dimension of cesarean section (r=0.211, P < 0.05). P < 0.01), browsing other women’s childbirth experience was significantly positively correlated with the total score of female childbirth attitude (r=0.230, P < 0.01), and there was no statistical difference between the preparation for childbirth and browsing the process and possible problems of childbirth through we-media platforms and the total score and all dimensions of female childbirth attitude (P < 0.05). See Table 7 for details.

Table 7: Correlation analysis between social media usage and childbirth attitudes (r-value, n=304).

Variable

 Perspectives on pain and loss of control Perspectives on complications Perspectives on obstetric technology Perspectives on cesarean section Perspectives on postpartum body changes

Total score
Usage frequency

0.304**

 0.215** 0.352** 0.351** 0.275**

0.431**
Usage duration

0.302**

 0.220** 0.359** 0.365** 0.264**

0.435**
Dietary and Lifestyle Advice During Pregnancy

-0.004

 0.136* 0.035 -0.066 0.068

0.034
Other Women’s Delivery Experience

0.204**

 0.118* 0.140* -0.075 0.481**

0.230**
Preparation for Delivery

0.051

 0.028 -0.017 0.111 0.102

0.075
Process of Delivery and Potential Issues

0.041

 0.067 0.082 0.020 0.039

0.078
Risks and Benefits of Common Interventions and Techniques During Pregnancy and Delivery

0.059

 0.011 0.030 0.513** 0.008

0.211**

*P<0.05, **P<0.01

Discussion

Status Quo of Childbirth Attitude of Pregnant Women

The cluster analysis results of this study revealed that the negative childbirth attitude group scored 102.05 ± 8.55, while the positive childbirth attitude group scored 78.55 ± 8.94. The total childbirth attitude score among pregnant women was 90.30 ± 14.65, falling between the two groups but closer to the negative attitude group. Analysis identified key concerns among pregnant women, including fears about physical harm from childbirth, intensity of labor pain, potential harm to the fetus, and possible complications during delivery. These concerns align with findings from a prior study conducted in the United States [11].

Within the “Perspectives on Pain and Loss of Control” dimension, Item 1 (“I worry childbirth pain will be too intense”) had the highest score, indicating that pain is one of the most pressing concerns for pregnant women. Research by Joshi et al. [5] demonstrated that younger, educated career women place greater emphasis on pain management during childbirth, which aligns with the demographic characteristics of participants in this study. Additionally, the high scores for Item 5 and Item 7 reflect anxieties about fetal safety and childbirth complications, respectively. This underscores pregnant women’s heightened focus on the safety and outcomes of delivery, likely influenced by media coverage of childbirth complications and an inherent anxiety toward uncertainty, consistent with findings by Kurz et al. [12].

In contrast, the lower scores for Item 13 and Item 15 suggest that most women remain cautious about the use of obstetric technology and prefer natural childbirth. Aligning with Stoll et al. [10], this indicates that while pregnant women increasingly demand medical management during delivery, they simultaneously value the importance of natural childbirth and tend to opt for non-interventional approaches in the absence of medical indications. Women’s predominantly negative perceptions of childbirth, particularly the higher scores in the “Perspectives on Obstetric Technology” dimension, reveal a reliance on medical interventions during labor. These results are consistent with the survey of outpatient pregnant women reported by Pan Feng et al. [13], reflecting high trust in modern medical technology. Therefore, we should focus on the management of maternal pain and provide personalized psychological support. Medical staff should pay attention to the pain of childbirth, and formulate personalized care plan after timely evaluation of the pain degree. It is recommended that medical workers provide pregnant women and their families with comprehensive delivery information support, including labor progress, pain management and coping strategies, so as to enhance the sense of security and physical control of pregnant women.

Status Quo of We-media Use in Pregnant Women

This study investigated the frequency, duration, and motivations of pregnant women’s use of non-medical self-media platforms to access childbirth-related information. The results indicate that over one-third of participants (34.2%) used self-media platforms 3-4 days per week, reflecting a proactive attitude toward seeking childbirth- related information. However, the proportion of daily users (3.6%) was relatively low, which may be attributed to time constraints and selective information-seeking behaviors in their daily lives.

Regarding usage duration, 2-3 hours per session was the most common (29.9%), a finding significantly higher than the average 2.38 hours per week spent on pregnancy-related websites reported in the study by Wallwiener et al. [14]. This discrepancy may stem from differences in content and interaction styles: self-media platforms often provide richer interactivity and instant feedback, potentially increasing engagement and prolonging usage time. Only 3.6% of participants spent over 4 hours per session, suggesting that most pregnant women moderate their browsing time to avoid anxiety caused by information overload.

In terms of motivations, pregnant women primarily sought content related to diet and lifestyle (e.g., nutritional guidance, exercise routines), highlighting their strong focus on personal and fetal health. This aligns with findings from a Chinese study [15]. A separate Korean study further revealed that pregnant women prioritize daily life adjustments during early pregnancy and shift toward fetal development information in the second trimester [16]. Additionally, childbirth preparation and browsing others’ experiences were significant motivators, consistent with research by Fleming et al. [17] and Bjelke et al. [18], indicating that women seek to enhance their preparedness through shared narratives.

The diversity of information needs underscores the dual role of self-media platforms: while they serve as vital resources for pregnant women, they also raise concerns about information credibility. To address this, we recommend that healthcare professionals leverage the strengths of self-media—such as videos, infographics, and other multimedia formats—to establish scientifically validated information- sharing mechanisms. By disseminating evidence-based childbirth knowledge, these efforts can help pregnant women develop rational perceptions of delivery, alleviate prenatal anxiety, and empower them to embrace this critical life event with confidence.

Correlation Between Pregnant Women’s Childbirth Attitude and We-media Use

This study employed Pearson correlation analysis and Point- biserial correlation analysis to explore the relationship between pregnant women’s social media usage and their childbirth attitudes. The results revealed a positive correlation between both the frequency and duration of self-media use and childbirth attitude scores. This suggests that frequent and prolonged exposure to self-media content dominated by negative narratives may foster negative cognitive biases toward childbirth, thereby shaping psychological expectations and attitudes. Notably, Serçekuş et al. [19] found that 14.8% of women reported heightened fear of childbirth due to online information, underscoring the potential adverse influence of self-media content on maternal perceptions. Such effects may stem from the prevalence of fear-inducing stories, exaggerated emphasis on delivery risks, and sensationalized portrayals of complications on these platforms.

Further analysis of usage motivations showed that browsing dietary and lifestyle advice on self-media platforms was only weakly correlated with the “Perspectives on Complications” dimension (r = 0.136, P < 0.05). While such content may improve awareness of complications, it fails to positively influence overall childbirth attitudes and might inadvertently amplify concerns about risks. Conversely, accessing information about medical interventions (e.g., risks and benefits of cesarean sections) was significantly correlated with both total childbirth attitude scores and “Perspectives on Cesarean Section” (r = 0.211, P < 0.01). This aligns with evidence that mass media amplifies perceived birth risks [20] and often frames cesarean sections as life-saving interventions [21], potentially driving women to prioritize perceived safety over natural delivery.

Interestingly, no correlation was found between childbirth attitudes and activities such as childbirth preparation or browsing information about potential delivery complications on self-media. This implies that mere information access or preparatory behaviors may not suffice to shift entrenched attitudes. Therefore, this study recommends that internet regulatory authorities strengthen oversight of health-related content and standardize the dissemination mechanisms for pregnancy and childbirth information in media environments. By establishing an authoritative childbirth knowledge dissemination platform—serving as a hub for information exchange—the public can access accurate and reliable childbirth-related information. Concurrently, efforts should be made to balance childbirth narratives on self-media platforms, minimizing the sensationalization of negative content. These measures aim to empower women to develop positive perceptions of childbirth and gradually reshape societal stereotypes surrounding the delivery process.

Strengths and Limitations

This study offers novel insights into the interplay between self- media consumption and childbirth attitudes among pregnant women, providing a foundation for improving maternal support systems. By integrating both online and offiine recruitment strategies, the sample captured diverse demographics, enhancing the generalizability of findings.

However, the study has limitations. Its cross-sectional design precludes causal inferences, and the reliance on self-reported data introduces potential response bias. Additionally, the focus on a single geographic region (Hangzhou) and the exclusion of women with psychiatric histories may limit external validity. Future longitudinal studies should explore how interventions—such as curated educational content on self-media—could shift attitudes over time.

Conclusion

Pregnant women who frequently and extensively engage with self- media platforms for childbirth-related information are more likely to develop negative attitudes toward delivery. Specific content types, such as discussions of medical interventions or others’ childbirth experiences, further exacerbate these concerns. To mitigate this, regulatory bodies should enforce stricter oversight of health-related content on self-media, promoting scientifically accurate and balanced narratives. Healthcare institutions should leverage these platforms to disseminate authoritative guidance, empowering women with knowledge to reduce fear of the unknown. Future research should investigate how content quality, source credibility, and algorithmic curation on self-media shape maternal perceptions, enabling targeted strategies to foster positive childbirth experiences.

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Bilateral Presumed Nocardia Subretinal Abscesses Treated with Serial Intravitreal Injections in an Immunocompromised 20-Year-Old Female

2 Replies

DOI: 10.31038/IDT.2025611

Introduction

Nocardia species are found in contaminated water and soil [1]. Infections occur due to inhalation of contaminated particles and manifest typically in the lungs, central nervous system, skin, and joints [1,2]. Ocular manifestations include keratitis, scleritis, subretinal abscesses, and endogenous endophthalmitis [1]. Cases of endogenous endophthalmitis have poor visual outcomes and require intravitreal antibiotics [3]. Here we describe a 20-year-old female who presented with pulmonary nocardiosis that disseminated to her brain, lumbar spine and eyes.

Case Report

The patient is an immunosuppressed 20-year-old female with a significant past medical history of moderate developmental delay and systemic lupus erythematosus (SLE) who presented to Akron Children’s Hospital with worsening chest pain following recent pneumonia treatment. A chest CT showed recurrent pleural effusions and pleural fluid culture grew Nocardia cyriacigeorgica. A brain MRI showed numerous enhancing lesions suggestive of disseminated nocardiosis. She was started on oral linezolid and IV ceftriaxone due to a trimethoprim sulfamethoxazole (TMP/SMX) allergy. Ophthalmology was consulted for baseline examination given initiation of long-term oral linezolid therapy.

On initial examination, visual acuity was 20/800 in the right eye and 20/100 in the left. Dilated exam was limited due to patient cooperation but revealed suspected exudative retinal detachment in both eyes. Exam under anesthesia showed subretinal abscess with large serous retinal detachment of the right eye (Figure 1) and a temporal subretinal abscess with serous retinal detachment of the left eye (Figure 2). These findings prompted bilateral intravitreal tap and inject with amikacin. Both vitreous and anterior chamber taps did not yield a positive culture. Weekly intravitreal ceftazidime injections were administered over the next 4 weeks. At discharge, visual acuity was hand motion in the right eye and 20/40 in the left with improvement of serous detachment and abscesses in both eyes. She was discharged on oral TMP/SMX 160mg TID after sensitization and IV ceftriaxone 2g BID with plans to remove the PICC line and switch to oral linezolid 200mg daily in 6 months.

Figure 1: Color fundus photo of right eye with active ocular nocardiosis on initial presentation.

Figure 2: Color fundus photo of left eye with active ocular nocardiosis on initial presentation.

Nine months after discharge, she returned to clinic with increased right eye pain and photophobia raising concern for nocardiosis reactivation. The patient was readmitted and an intravitreal tap and inject with ceftazidime was performed. The sample was improperly processed and did not yield useful data. Topical moxifloxacin, prednisolone QID, and daily atropine were initiated. After five days, her vision was hand motion right eye and 20/60 left eye with almost near resolution of the anterior chamber inflammation. Macular OCT and dilated exam showed stable subretinal fibrosis in both eyes (Figure 3). A PICC line was reinserted, and she was restarted on IV Ceftriaxone 2g BID at the end of her admission.

Due to age and comorbidities, the patient transitioned out of pediatric care. On last chart review, she has since developed choroidal neovascular membrane (CNVM) in the left eye for which she is receiving intravitreal bevacizumab injections.

Figure 3: Color fundus photo 9 months after serial intravitreal injections.

Discussion

Nocardia is a gram positive, filamentous, partial acid-fast bacteria that can be found in contaminated water and soil [1]. This patient with SLE on hydroxychloroquine, rituximab and a recent oral steroid taper highlights the increased vulnerability of the immunocompromised population. Primary Nocardia infection is most common in the lungs with the brain being the most likely site of dissemination [1,2]. Ocular involvement is seen in 3-5% of cases often affecting the cornea, sclera, and retina [1-3]. Furthermore, Nocardia is a rare source of endogenous endophthalmitis comprising only 3% of all endophthalmitis cases [2]. Treatment is difficult and visual outcomes are poor.

We present an immunocompromised patient with bilateral subretinal abscesses that were treated successfully with intravitreal antibiotics. Subretinal abscesses can be biopsied to confirm the diagnosis. In our patient, however, the combination of pulmonary, CNS and ocular lesions with a positive pleural fluid culture were sufficient to suggest a Nocardia intraocular infection [4]. Amikacin is a popular antibiotic utilized to treat Nocardia and was used for her first injection [3]. Given sensitivity studies showing susceptibility to ceftazidime and the small risk of associated amikacin macular toxicity, ceftazidime was used for all subsequent intravitreal injections [5]. Our case presented similarly to others in literature in that subretinal fibrotic scarring formed in place of the clearing abscesses [3].

There is no definitive regimen for duration or frequency of intravitreal injections to successfully treat ocular nocardiosis. Our patient developed a suspected reactivation in her right eye after she was switched from IV ceftriaxone to oral linezolid. The reason for the reactivation is unclear given that Nocardia species have near 100% susceptibility to linezolid [6]. Resistance to linezolid is also unlikely given the resolution of the lung and brain lesions. We hypothesize that her reactivation could be due to ending intravitreal injections too early. This case highlights the importance of close multidisciplinary follow up of immunocompromised patients when systemic immunosuppressive medications are adjusted.

References

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Determinants of Subjective States in Combat Aviation

2 Replies

DOI: 10.31038/PSYJ.2025712

Abstract

Combat pilots are responsible for ensuring the best they can towards their service and mission accomplishment. The operation of key cognitive determinants mediates between antecedent processes including actual abilities and anticipated fulfilment of future outcomes. In assessing the vocational development construct of combat pilots, we have underlined the limitations of their perceived abilities and belief enacting self-efficacy and response to relevant task information from the environment, both spatial and temporal. The appraised cognitive determinants engaged in information processing were essentially tied for expressing subjective states of knowledge, feelings, emotions and health threat perceived with a conscious experience. We externalized their subjective states by showing mental health difficulties in the demanding high-stakes environment of air combat.

Keywords

Cognitive load theory, Self-efficacy, Emotions, PTSD, PTSS

Introduction

The journey of the heroic Airman begins through the unbreakable commitment to a cause, nurturing the legacy of past comrades and personal conduct to promote a leader of character, courage and competency. This calls on the vital role of a cognitive oriented career development in ensuring combat effectiveness rigorously tied to the mission success. Cognitive factors such as mental workload and human performance are crucial to the pilot’s survival and recovery process. While, subjective states can materially contribute to accidents, much of the accident causation is attributed to suboptimal performance to various categories of errors associated with the increased level of automation complexity in the cockpit. Although aviators are selected on factors that are highly correlated with cognitive ability, thoughts and feelings maybe controlled but not eliminated.

The Vocational Journey

Probably the great battle of all for combat pilots begins with the conscious trained mind and the subjective psyche to hold the high standards interwoven in the creation of professional airmen. Accordingly, the vocational nature of airmen evolves with discipline correlated with perceived abilities, expected mission success and the innate desire to anticipate great achievements. This triangulation of cognitive determinants is continuously shapes the psychological construct of pilots’ recovery chances in any survival situation. The perceived ability of pilots to be maintained through continuous improvements, the expected fulfilment of a mission and the anticipated outstanding achievements are experience and knowledge acquired and stored in terms of building blocks known as schemas. Schemas are generalized knowledge structures of the Cognitive Load Theory that are renewed every time new information is ingested [1].

In underpinning the state of technology that the mission requires a pilot conversely trigger automated schemes and induces automatic responses [2]. Moreover, internal representations are continuously seeking internal cognitive consistency and validation against one another [3]. While the three determinants are highly correlated and augmenting the cognitive processing resources, they diverge with the mission situational factors. In particular, pilot’s effort and attention are devoted to the constant fluctuations of task demands [4]. Therefore, on assessing and interpreting this change, “There is evidence that people can fall into a trap of executing habitual schema, doing tasks automatically, which render them less receptive to important environmental cues” [5]. This dynamic process is highly dependent on pilot-aircraft-environment interaction. From a cognitive viewpoint the pilot attribute a certain degree of confidence towards the validity of information regardless of their source. This increases the odds of a pilot making errors or create biases [6]. While the basis for automating the cockpit was to reduce cockpit workload by off-loading many of the duties performed by the pilots to digital processors, it increased the pilot’s beliefs of imagined success and satisfactory performance [7]. Similarly, they perceived higher cognitive abilities consistent with their vocational background. In this position, the effects of career self- efficacy generated distortion mechanisms of their cognitive schema. It should be kept in mind that automated systems characterized by their authority, autonomy and complexity has continuously expanded interaction from individual (one pilot, one aircraft) to local interactions (one team, one squadron, ground control staff), then to organizational interactions (one nation, Air Force personnel) to global interactions (inter-nation deployment).

Subjective State of Knowledge

Self-efficacy belief hypothesized by pilots to attain specific performance goals is highly prone to bias since it influences their behavior and interactions. This condition is mostly evaluated with a degree of confidence influencing behavioral intentions rather than actual behavior along the temporal dimension of a flight sortie, or the whole mission. This favorable attitude and the subjective norm (professional expectations) leads to a targeted and improved behavior. However, when focusing on the inner experience, subjective states are challenging to decipher and separate from objective knowledge. Nonetheless, the pilot must “Stay ahead of the airplane” and anticipate future events [8]. More specifically, pilots are not passive spectators and must rely on their expectancy of recovery to determine the outcome of future events, not only with the conscious trained mind but also with the subjective psyche. Expectancy do not always come true and play a fundamental role in the accident causation, which is attributed to suboptimal performance and is prone to various categories of errors. This is determined by how a pilot approaches a situation and the relevance of cues adopted for the formation of a situation assessment [9]. The integration of expectancy into situational attributes and elicited degree of belief overestimates the confidence of pilots’ capability in the use of automation. Such a degree of confidence is seen as restraining factor in tactical situations which tend to “over generalize, over summarize and over rationalize” past mental events [10]. Subsequently, the fact that situation awareness represents a mixing of prior knowledge and current perception creates challenges for pilots’ recovery acts in emergency situations, in which stress affect the pilot’s working memory through provoked perseveration. This repetitive behavioral state along with difficult-to-control thoughts can have dramatic consequences during safety-critical tasks or progress towards goals [11].

Subjective State of Feelings and Emotions

The essence of the problem in many accidents involves difficult- to-control thoughts resting on emotions that won out over good sense. Emotions are just as important as cognitive abilities since emotional reactions during human-computer interaction have induced psycho-physiological conditions eliciting engagement, relaxation and stress that can alter a pilot’s arousal level [12]. Emotions are normally well controlled but not eliminated; increased emotional imbalance requires self-control and an effective attitude driven by personally relevant goals [13]. Any intense emotional reaction can blur a task activity with a lapse in control [14,15]. This sense of rapture, probably the sharpest of subjective feelings would steam a feared outcome lacking a time and context perspective [16]. The stimulus of fear ruminating with anxiety would affect the pilot’s arousal level in a threatening situation with a sense of escaping dangers. However, such a natural instinct remains controllable when pilots are willing to take part in combat and face an emergency. Fear opts the course of accident sequences while anxiety echoes a combat harrowing experience that is more intense than the situation at hand. This allows to elevate a priori the panicky avoidance (phobia) of a complicated situation [17]. In such a case, adaptation to flying is seen as a positive form of denial without experiencing fear [18]. Additionally, pilots who develop “fear of flying” might result from the breakdown of their defense mechanisms [19]. This is particularly true for pilots exposed to emergency scenarios seeking to reconstruct their fear defense. On the other hand, there are those willing to push the flying envelope with challenging physical demands and high information loads prone to potential stress. In this setting, counterphobic attitude to react to stress and emotional control are essential factors for distinguishing combat pilot aces from average combat pilots [20]. One emotion worth considering is a sense of resignation, the very absence of fear, pride or anger. Such a passivity state is a personal emotion, grounded partly in automation set to transform the pilot into a passenger who feels powerless to alter the course of events. However, pilots’ intension to resign from a encourage reengagement of new goals [21]. After all, humans are capable of maintaining the big picture and still need to be aware of what is happening when something goes awry.

Subjective State of Suffering

One of the most extreme human emotions is the occurrence of a major depression disorder (MDD) with the risk of suicide [22]. This symptom is usually well hidden amongst military and civil pilots and can have devastating effects on the population when pilots deliberately perform this act employing aircraft. During the last war, this risk foresaw a strategy for diagnosis of significant mental disorders of pilots suffering from psychological and psychoneurotic conditions. These states were strongly correlated with personality traits, and the interaction with stress and neuroticism decay over time [23]. In other circumstances, the mind gags (more akin to phobia) where the awareness of extreme detachment known as the breakaway phenomenon has been seen most likely attributable to the pilots’ insistence in pursuing an action against all the odds of survival. This separation transcends a profound sense of loneliness, typically occurring at high altitude. Although reassurance and resolution occur through the descent and approach phase, often it sensitizes the pilot and can recur. In extreme cases, especially after an accident signs of Post Traumatic Stress Disorder (PTSD) may develop with depression and abusive behavior, nightmares and phobic avoidance of flying. While the implication of problem-solving, attention and working memory are closely linked to traumatic experiences associated with post-traumatic stress symptomology (PTSS) [24]. Adverse mental states have been also associated with the analysis of physical/mental limitations and perceptual errors. On the former, this indicates that highest levels of exhaustion/fatigues as causes of that burnout negatively affect pilots’ performance. Moreover, emphasis has been placed on their working conditions and the lack of professional advancement [25]. On the latter, a common manifestation of perceptual errors relates to the profound disconnect from reality. This disentanglement is manifested through altered perception of time and space most commonly induced by Gravity-Induced Loss of Consciousness (G-LOC). Whereas pilots’ perceptual errors in the position, motion and attitude of the aircraft have been included spatial disorientation episodes and the concept of situational awareness (SA). G-LOC and spatial disorientation are the results of human sense organs adapted to the earthly life and a stable 1-G environment. This adaptation is highly disrupted when pilots are exposed to motion stimuli of different magnitude, frequency and direction than those practiced on the ground [26].

Conclusion

Technological advances have shaped human-systems interaction and contributed to improved SA. However, it is a paradox that when the workload is very high the pilot reverts to a more manual role. The people who report losing self-control over intense or unwanted emotions much of the time are subjected to some conscious overriding. While flying a pilot should ponder the implausible separation from the objective truth and subjective knowledge. Conversely, subjective processes can enhance the objective comprehension of the world. On fifth-generation combat aircraft, the visual intake is displayed on the helmet’s visor and therefore subjected to the pilot’s active scan and selection until a stimulus to prioritize the most relevant input for the immediate task. This capability entails to processing enough information to solve the problem through a “window of consciousness” as James W. (1890) prophesied, rather than become caught in a catch- up game. The psychological discern yearned to conquer the air ex-ante still provides room of an active topic in contemporary ex-post research.

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