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Effect of Bifenthrin and Reduced Salinity Exposure on Larval Sheepshead Minnows (Cyprinodon variegatus) and Grass Shrimp (Palaemon pugio)

DOI: 10.31038/AFS.2022453

Abstract

In 2016 America’s coastal counties were home to more than 40 percent of the total population despite accounting for less than 10 percent of the country’s landmass. Large-scale changes in land use lead to proportional increases in impervious ground cover, ultimately resulting in increased input of stormwater runoff into adjacent waterways. Stormwater runoff reduces salinity and increases contaminant loads as rainwater washes pollutants, including pesticides such as bifenthrin, into receiving waters. The present study examined bifenthrin toxicity and the potential combined effect of reduced salinity for larval sheepshead minnows (Cyprinodon variegatus) and grass shrimp (Palaemon pugio). LC50 values were established in salinities of 20, 10, and 5 psu as 0.431, 0.415, 0.377 µg/L and 0.00650, 0.00640, 0.000109 µg/L for larval C. variegatus and P. pugio, respectively. Salinity did not significantly affect bifenthrin toxicity to larval C. variegatus, but mortality rates increased to 90% when larval P. pugio were exposed to 0.0015 µg/L of bifenthrin in 5 psu compared to 20 psu. Given that stormwater input is increasing as a result of increasing impervious cover, it is critical to understand how exposure to bifenthrin in low-salinity regimes affects estuarine organisms.

Keywords

Pesticides, Bifenthrin, Fish, Crustaceans, Toxicity, Salinity, Tidal creeks, Runoff

Introduction

Impervious surface, a result of urbanization, reduces rainwater infiltration and promotes runoff which accelerates input of sediments, microplastics, metals, pesticides, fertilizers, and bacteria into surface waters [1-3]. A study from 2001 found that pesticides are pervasive in waterways nationwide, with at least one pesticide found in more than 95% of streams sampled and in about 85% of fish sampled [4]. The influx of contaminants such as pesticides often result in habitat degradation and impaired ecosystem functions [5,6]. Impervious cover has also been directly linked with ecosystem effects including changes to community structure, a decline in density, as well as reduced species diversity [2,5,7,8].

Pyrethroids currently account for more than 25% of world-wide insecticide use and are widely applied to crops, turf, golf courses, lawns and home gardens in the U.S. [9,10]. Bifenthrin ((2-methyl-1, 1-biphenyl-3-yl)-methyl-3-(2-chloro-3, 3, 3-trifluoro-1-propenyl)-2,2-dimethylcycloprpanecarboxylate) is a fourth generation synthetic pyrethroid insecticide. The use of bifenthrin has increased in the last 20 years as a result of bans on pesticides such as DDT, the establishment of the Federal Clean Water Act, which mandates the reduced use of organophosphate insecticides, as well as the increased effectiveness and stability of this new insecticide [9]. However, with greater photostability and insecticidal efficacy than previous generations of pyrethroids, bifenthrin has the potential to be more toxic to non-target species [11,12].

More than one million pounds of bifenthrin was used agriculturally in the U.S. in 2016, mainly applied to corn, soy, cotton, and orchards [13]. There has also been an increasing trend in urban applications of bifenthrin [14]. Urban applications of bifenthrin in the Central Valley of California were reported at 45,000 pounds, over double that of agricultural applications at 20,000 pounds, in California in 2005 [15]. Additionally, pesticide use by acre on golf courses has been reported as equivalent as or greater than use on agricultural crops [16].

Bifenthrin is currently one of the most frequently detected contaminants in California surface waters in areas of urban and agricultural land development [17,18]. Reported surface water concentrations of bifenthrin ranged from 0.005 to 3.79 μg/L (parts per billion – ppb) and bottom and suspended sediment concentrations have been reported in the range of 1.2 to 437 ng/g (ppb) dry weight. The 96-hour LC50 (estimated concentration in which fifty percent of the test organisms die) for rainbow trout, bluegill sunfish, sheepshead minnow, and mysid was 0.15, 0.35, 17.8, and 0.00397 μg/L (ppb), respectively [19-21].

In general, pyrethroid pesticides, like bifenthrin, have octanol/water partition coefficient (log Kow) values of 5 to 7 and, therefore, partition into the organic carbon fraction of sediments. Although sediment sequestration may lead to confinement in areas of application, pyrethroids are often transported into surface waters via runoff, moving with suspended sediments and dissolved organic matter [22,23]. Additionally, these hydrophobic compounds can become stored in creek-bed sediments to later become resuspended as runoff increases turbidity [18]. Beyond entering waterways via runoff, spray drift, and release of agricultural tailwater also contribute to pyrethroid contamination [22,24,25].

The primary mechanism of pyrethroid toxicity is interference with sodium channel polarization in synaptic nerve terminals [26]. Effectively, this interaction simulates neurotransmission when there is none, causing spastic activity followed by paralysis [20,26]. Additionally, pyrethroids have been shown to inhibit ATPase enzyme production [27]. As pyrethroids impede the ATPase enzyme the critical concentration gradient built to maintain ionic balance and osmoregulation is degraded [27]. Sublethal toxicity has also been reported in organisms exposed to pyrethroids, including altered behavior, reduced growth, immune system effects, endocrine/reproductive effects, histopathological effects, as well as biochemical responses [28-30].

Beyond increased contamination, stormwater runoff as a result of increased impervious cover can also unpredictably and rapidly reduce salinity, with reported drops greater than 26 psu in less than 6 hours [31,32]. While estuarine species have mechanisms to cope with predictable environmental variability (such as tidal phases and seasonal conditions) the rapid and unpredictable effects of stormwater runoff can have serious implications for the biological communities of receiving waterways [1,33]. Numerous studies have demonstrated that reduced salinity can have vastly negative impacts on planktonic larval organisms, including decreased rates of yolk sac absorption, growth, development of feeding apparatus, respiratory tissues, and mortality [1,34-37].

Chemical toxicity may intensify salinity stress, causing an increase in sublethal and lethal effects. In fact, chemical toxicity in combination with salinity stress has been attributed to decreased physiological functions, specifically in the physiological pathways that are responsible for contaminant metabolism and detoxification [38]. Salinity has also been shown to affect biotransformation rates and toxicity for several classes of chemicals [38]. It has been reported that salinity generally decreases water solubility and increases Kow values for pesticides [39]. The water solubility of bifenthrin has been reported as <1 mg/L, with reported log Kow in deionized water as 6.27 ± 0.16, and with 6.78 ± 0.04 in seawater (35 psu) [12,20]. These data suggest that salinity should be considered when bifenthrin toxicity estimates are made for estuarine organisms.

Two abundant, widely distributed, euryhaline, common estuarine test organisms, the grass shrimp, Palaemon pugio, and the sheepshead minnow, Cyprinodon variegatus, in their larval stages, were selected for the current study [40]. Grass shrimp are generalist foragers that may feed as primary or secondary consumers and play a key role in coastal nutrient cycling as detritivores [40]. Additionally, P. pugio are an important prey item for numerous commercially and recreationally important estuarine species [40,41]. Larval P. pugio are approximately 2.6 mm at hatching and subsequently undergo a multistage larval development period that can take from 11 days to several months [42]. Planktonic larvae feed on other zooplankton, phytoplankton, and detritus [40]. South Carolina grass shrimp tolerate salinities from nearly freshwater to full strength seawater, and those collected from low salinity sites were of smaller size than those from higher salinity waters. Ultimately, salinities between 20 and 25 psu are optimal for larval development [40].

C. variegatus can live in ambient salinities ranging from 0 psu to greater than 140 psu but a preference for salinities near or less than 20 psu has been documented [43,44]. They feed mostly on plant matter, algae, detritus, mosquito larvae, and smaller fish [45,46]. Sheepshead minnows serve as an important link in the food chain as a source of nutrient cycling and as prey for larger commercially and recreationally important species such as the spotted sea trout, red drum, Atlantic croaker, turtles, and wading birds [41]. Fertilized C. variegatus eggs incubate for 4 to 12 days before planktonic larvae of ~4 mm hatch [45]. Larval C. variegatus feed on other zooplankton, phytoplankton, and detritus [45,46].

To mitigate negative effects of bifenthrin on natural communities, it is imperative to examine how bifenthrin affects survival rates of important estuarine species. Standard toxicity bioassays, conducted under laboratory conditions, may not be predictive of how changing environmental conditions such as salinity may alter the chemical toxicity of these compounds. The current study sought to evaluate the impacts of acute salinity reduction in combination with bifenthrin exposure on larval estuarine species by using C. variegatus and P. pugio as model species.

As part of a SC Department of Natural Resources study examining the relationship between urbanization and salinity profiles in estuarine tidal creeks, sediment samples were collected from the same tidal creek sites and analyzed for bifenthrin contamination. The measured field concentrations are reported herein and compared to the laboratory-derived toxicity thresholds to assess relative risk to larval estuarine organisms.

Materials and methods

Animal Acquisition and Holding

Sheepshead minnows, Cyprinodon variegatus, collected from a tidal pond on the Fort Johnson campus (32° 44’ 53.60” N; 79° 54’ 4.45” W) were acclimated and maintained in laboratory conditions of recirculating filtered, aerated seawater at 25°C, 20 psu salinity, and a 16-hour light: 8-hour dark photoperiod. Brooding groups of 2-3 males and 4-6 females were placed in spawning chambers within 75-L aquaria. Adult fish were fed once daily with TetraminVR flake food. Fish eggs collected every day were placed in 20 psu aerated seawater, examined on a light box for hatching events, and hatched larvae were counted, separated, held in aerated 20 psu seawater, and fed daily with Artemia.

Adult grass shrimp, Palaemon pugio, were collected from Leadenwah Creek, Wadmalaw Island, South Carolina (32° 38’ 51.00” N; 80° 13’ 18.05” W). Shrimp were acclimated and maintained in 75-L aquaria with aerated, 25°C, 20 psu seawater, and a 16-hour light: 8-hour dark photoperiod. Adult shrimp were fed once daily with TetraminVR flake food. Gravid female shrimp were separated, held in hatching chambers containing 20 psu aerated seawater, and examined daily for hatching events. Chambers were removed after hatching event. Larvae were counted, separated, held in aerated 20 psu seawater and fed daily with Artemia.

Seawater Processing

Seawater collected from Charleston Harbor (32° 45’ 11.52” N; 79° 53’ 58.31” W) was allowed to settle, polished via a sand filtration unit, UV sterilized, and filtered again with 5 μm nominal filtration. The polished seawater was subsequently pumped through a 10 μm carbon filtration before being diluted to 20 psu with deionized water. All water used for testing was additionally pumped through a sterile 0.22-μm filter.

Larval Aqueous Assay

Range finder tests were conducted with both species to determine the definitive test concentrations. A 96-hour aqueous static-renewal toxicity test was conducted to determine the LC50 of bifenthrin in 20, 10, and 5 psu filtered seawater for C. variegatus and P. pugio. All testing started within 48 hours of hatching. Fish and shrimp larvae were fed Artemia prior to testing and at each 24-hour renewal during the 96-hour test. Stock solutions of bifenthrin were made using pesticide-grade acetone and the final acetone concentration in all treatments and the seawater control was 0.1%. Each species was tested using 5 nominal concentrations of bifenthrin plus a control (0.00 μg/L); 0.17, 0.25, 0.37, 0.56, 0.84 μg/L for the C. variegatus assay, and 0.0015, 0.0025, 0.0045, 0.0065, and 0.016 μg/L in the P. pugio assay; at each of the three salinities (20, 10, and 5 psu). Three replicate beakers were loaded with 400 mL of seawater dosed with bifenthrin at the target exposure concentration. Larvae (24-48 h old) were taken through a step-wise reduction in salinity. Individuals were allowed to acclimate in a glass finger bowl containing 20 psu water for 90 minutes before being transferred to 15 psu seawater. This process of 90-minute acclimation followed by a transfer into filtered seawater reduced by 5 psu was repeated until the desired exposure concentration was reached (20, 10 or 5 psu). All larvae were transferred each time regardless of salinity reduction to account for any handling stress. After salinity acclimation was complete, 10 larvae were added to each replicated beaker. Beakers were covered with clean foil and aerated through a hole in the foil using a sterile glass pipette tip. Beakers were randomly distributed in an incubator maintained at 25°C and a16-hour light: 8-hour dark photoperiod. Every 24 hours the water was renewed in the same process as above. Temperature, salinity, pH, and dissolved oxygen values were recorded, and each individual was assessed for survival and survivors were transferred to the renewed beaker.

Tidal Creek Sediment Sampling

Tidal creeks in the greater Charleston area were analyzed in ArcGIS Pro using National Land Cover Data, NOAA Coastal Change Analysis Program land use data, and digital elevation models. Four tidal creeks, Guerin Creek, Seaside Creek, Toomer Creek, and Dupont-Wappoo Creek, with similar watershed area and creek volume but representing a range of development and impervious cover within the watershed were selected. Guerin Creek is the most natural creek with less than 1% impervious cover and development, Seaside and Toomer Creek watersheds have roughly 11% impervious cover and 25.9% and 30.2% of land development respectively. Dupont-Wappoo Creek watershed is the most urbanized with about 64% of the watershed developed and around 36% impervious cover. Within each creek four sampling sites were distributed along the length of the creek, from headwaters to the mouth, with the exception of Guerin Creek, where a site in each branch of the headwaters was selected (Figure 1). In late September, bottom sediment samples were collected at each site using a pre-cleaned stainless steel 0.04 m2 Young grab. A sample was also collected from the Leadenwah Creek control site where P. pugio were collected for testing. The surficial sediment (top ~3 cm) was homogenized and placed in a pre-cleaned container and stored on ice while in the field. Samples were stored at -40°C until analytical chemistry was conducted.

Figure 1: Satellite image of creeks sampled with watershed boundaries and collection sites marked

Analytical Chemistry

Sediment samples collected from each segment of the study site tidal creeks and one sample collected from the reference creek (Leadenwah Creek) were analyzed for a suite of pyrethroid insecticides, including bifenthrin, using accelerated solvent extraction. Sediment samples were weighed (~10 g) and mixed with anhydrous sodium sulfate in a mortar bowl to remove water from the sample. The samples (including method blanks and reference spikes) were transferred to stainless steel ASE cells, spiked with a suite of isotopically labeled internal standards, and extracted with 100% dichloromethane (DCM). Sulfur was removed from the sample extracts using coiled copper strands activated with ~10% hydrochloric acid. Residual water was removed by filtering the sample extract through additional anhydrous sodium sulfate after which the sample was then concentrated to 0.5 mL using TurboVap II Concentration Workstation (40°C, nitrogen at 14 psi). Concentrated samples were cleaned up using activated carbon and alumina solid phase extraction. Eluents were concentrated to 0.5 mL and solvent-exchanged to hexane. Samples were run on an Agilent 6890/5973 gas chromatograph mass spectrometer using a programmable temperature vaporizer inlet connected to a DB-XLB analytical column (30 m x 0.25 mm x 0.25 µm). The mass spectrometer was operated using electron impact and selected ion monitoring modes. Sample chromatograms were analyzed using MSD Chemstation software (ver. E.02.02.1431). An eight-point calibration curve (0. 5-100 ng) was run prior to running samples; r2 values for all analytes of interest were at least 0.995. The method detection limit (MDL) was calculated according to Ragland et al. [47] detectable concentrations of bifenthrin were reported in ng/g dry weight concentrations.

Data Analysis

Two-way analysis of variance with interaction was used to determine significant differences among treatments (RStudio, PBC, Boston, MA). Dunnett’s test was used to assess treatment differences from the control and to determine no observable effects concentration (NOEC) and lowest observable effects concentration (LOEC) values. Median lethal concentration (LC50) values with a 95% confidence interval were determined using nominal chemical concentrations (SAS Probit Analysis, PROC PROBIT, SAS V.9.1.3, Cary, NC). Significant differences (α=0.05) in toxicity thresholds among salinity treatments and between species was determined using the LC50 ratio test [47].

Results and discussion

Cyprinodon variegatus Aqueous Assay

Changes in salinity alone did not significantly affect C. variegatus survival (p value=0.1633) (Figure 2). Results from a two-way analysis of variance with interaction revealed that bifenthrin concentration was the only factor that significantly affected mortality (Table 1). Less than 10% mortality was observed in the 5, 10, and 20 psu control treatments. The LOEC was 0.37 μg/L bifenthrin at all salinity exposures (Table 2). The NOEC was 0.25 μg/L bifenthrin at all salinity exposures. There was 100% mortality in the highest bifenthrin treatment of 0.84 μg/L for all salinity treatments. The 96-hour LC50 values for the 20, 10, and 5 psu salinity treatments were determined to be 0.432 μg/L (95% CI=0.381-0.484); 0.415 μg/L (95% CI=0.367-0.463), and 0.377 μg/L (95% CI=0.337-0.414), respectively (Table 2). These values are in the range of a previously reported LC50 of 0.47 μg/L for larval sheepshead minnows [48]. Previously published bifenthrin LC50 values for adult sheepshead minnows include 17.8 μg/L and 19.8 μg/L [21,30,49-51]. Greater larval sensitivity is often attributed to higher surface-area-to-volume ratio, underdeveloped fat stores that could sequester lipophilic compounds, and immature immune systems and organs that are important for detoxification and elimination of toxicants [52]. The threshold of toxicity and lack of significant effect due to reduced salinity is not surprising for C. variegatus. This species has been reported as a notably hardy organism able to survive in salinities ranging from 0 to 140 psu [43,44,53].

Figure 2: Cyprinodon variegatus mean percent mortality at each bifenthrin treatment and salinity exposure. For each salinity exposure, significant differences in percent mortality from the respective control (p value <0.05) are indicated with an asterisk.

Table 1: Cyprinodon variegatus two-way analysis of variance with interaction

Response: Mortality rate	Sum squared	Df	F value	Pr (>F)
Salinity	226	2	1.906	0.1633
Bifenthrin Dose	77009	5	259.906	< 0.0001^*
Salinity: Bifenthrin Dose	1019	10	1.7187	0.1140
Residuals	2133	36

Table 2: C. variegatus median lethal concentration (LC50), 95% confidence intervals, lowest observable effects concentration (LOEC), no observable effects concentration (NOEC). There were no significant differences in LC50 values at the different test salinities (LC50 ratio test p>0.05).

Salinity	LC₅₀ (μg/L)	95% CI (μg/L)	LOEC (μg/L)	NOEC (μg/L)
20 psu	0.431	0.381-0.484	0.37	0.27
10 psu	0.415	0.367-0.463	0.37	0.27
5 psu	0.377	0.337-0.414	0.37	0.27

Palaemon pugio Aqueous Assay

There was no mortality observed in the 5, 10, and 20 psu control treatments for the P. pugio 96-hour assay (Figure 3). However, 90% mortality was observed in the lowest bifenthrin treatment of 0.0015 μg/L in 5 psu. Results from a two-way analysis of variance with interaction revealed that salinity and bifenthrin dose both significantly affected mortality (p-values <0.0001) and there was a significant interaction between the two variables (Table 3). LOEC values were 0.0065 μg/L at 20 psu, 0.0045 μg/L at 10 psu, and 0.0015 μg/L at 5 psu. NOEC values were 0.0045 μg/L for 20 psu, 0.0025 for 10 psu, and <0.0015 at 5 psu (Table 4). There was 100% mortality in the highest bifenthrin treatment of 0.016 μg/L for all salinity treatments (Figure 3). The 96-hour LC50 values for the 20, 10, and 5 psu salinity treatments were determined to be 0.00650 μg/L (95% CI=0.00637-0.00664); 0.00646 μg/L (95% CI=0.00639-0.00652), and 0.000109 μg/L, respectively (Table 4). Due to the high mortality rates in every bifenthrin concentration tested at 5 psu, 95% confidence intervals could not be calculated. A ratio test comparing the LC50 values revealed no statistically significant difference between 20 and 10 salinity treatments (p=0.9660). Although the lack of confidence intervals in the 5 psu treatment prohibited running a ratio test, salinity clearly affected the mortality rates for larval P. pugio, with the LC50 at 20 psu calculated to be 65 times higher than at 5 psu. The 96-hour LC50 of 0.0065 μg/L in 20 psu found in this study was lower than a previously published 96-hour LC50 value of 0.013 μg/L for larval P. pugio [30] but was consistent with the LC50 of 0.0056 μg/L reported by [48]. While there was no significant difference in mortality between the 20 psu and 10 psu treatment, a marked increase in grass shrimp mortality occurred in the 5 psu treatments. In fact, there was over 90% mortality in the lowest bifenthrin concentration of 0.0015 μg/L at 5 psu compared to less than 10% mortality at the same concentration in the 20 psu salinity exposure.

Figure 3: Palaemon pugio mean percent mortality at each bifenthrin treatment and salinity exposure. For each salinity exposure, significant differences in percent mortality from the respective control (p value <0.05) are indicated with an asterisk.

Table 3: P. pugio two-way analysis of variance with interaction

Response: Mortality rate	Sum squared	Df	F value	Pr (>F)
Salinity	16411	2	49.233	<0.0001^*
Bifenthrin Dose	56622	5	67.947	<0.0001^*
Salinity: Bifenthrin Dose	10900	10	6.54	<0.0001^*
Residuals	6000	36

Table 4: P. pugio median lethal concentration (LC50), 95% confidence intervals, lowest observable effects concentration (LOEC), no observable effects concentration (NOEC). A ratio test comparing the LC₅₀ values revealed no statistically significant difference between 20 and 10 salinity treatments (p=0.966). Although the lack of confidence intervals in the 5 psu treatment prohibited running a ratio test, salinity clearly affected the mortality rates for larval P. pugio, with the LC50 at 20 psu calculated to be 65 times higher than at 5 psu.

Salinity	LC₅₀ (μg/L)	95% CI (μg/L)	LOEC (μg/L)	NOEC (μg/L)
20 psu	0.006500	0.006367-0.006635	0.0065	0.0045
10 psu	0.006459	0.006395-0.006523	0.0045	0.0025
5 psu	0.000109	*	0.0015	<0.0015

*Unable to calculate confidence interval

Larval grass shrimp were two orders of magnitude more sensitive than the larval sheepshead minnows to bifenthrin, an expected result based on previously reported LC50 values for these organisms [30,48]. While salinity did not significantly affect bifenthrin toxicity in the sheepshead minnow, the grass shrimp LC50 value for bifenthrin decreased 65-fold for shrimp tested at 20 psu compared to 5 psu. These findings clearly suggest species-specific interactions, increased toxicity with reduced salinity for grass shrimp, and potential sublethal effects due to combined salinity and chemical stress.

Tidal Creek Pyrethroid Contamination

Detectable levels of bifenthrin were found only in the two watersheds; these watersheds had the highest levels of impervious cover. Dupont Wappoo Creek, within the most developed watershed sampled, returned dry mass concentrations of 16.79, 2.23, 1.39, and 2.40 ng/g bifenthrin, at collection site, 1, 2, 3, and 4, respectively, decreasing in concentration from headwater to mouth of the creek (Figure 4). These concentrations are within the range of previously measured bifenthrin concentrations from sediments sampled in an agriculturally influenced creek in California, reporting values from 1.2 ng/g to 437 ng/g [54]. Sediment from sites 3 and 4 in Toomer Creek had bifenthrin concentrations of 0.479 and 0.155 ng/g, respectively (Figure 4). No pesticides were detected in the sediment sampled from the reference site where the shrimp were collected.

Figure 4: Bifenthrin concentrations (ng/g dry mass) measured in Charleston area tidal creek sediments. Each creek was sampled along a transect from headwater (site 1) to mouth (site 4). Bifenthrin was not detected (<MDL of 0.06-0.17 ng/g) in Guerin Creek or Seaside Creek.

Evaluation of Risk

Given the toxic effect of bifenthrin on aquatic organisms, and the lack of studies examining the interaction between salinity and bifenthrin, ecological impacts of bifenthrin have likely been underestimated. This is the first ecotoxicology study to examine salinity impacts on bifenthrin toxicity in larvae of estuarine ecosystems. This study, among others, demonstrated that the larval stages of two important estuarine species, C. variegatus and P. pugio, are sensitive to acute bifenthrin exposure. Field measurements of aquatic bifenthrin concentrations reported in California exceed previously and currently reported LC50 values [10,15,55]. Current estimated environmental concentrations for bifenthrin range from 0.005 μg/L to 19.5 μg/L in water samples and 0.155 ng/g to 437 ng/g in sediment samples, and concentration may fluctuate based on localized application patterns and impervious ground cover [55,56]. The LC50 values determined for larval C. variegatus and P. pugio at the standard test salinity of 20 psu were 40x and 2500x lower, respectively, than the maximum sediment concentration measured in this study. Compared to the reported surface water concentrations that range from 0.01 to 3.79 μg/L for bifenthrin, the LC50 value determined for larval P. pugio at the standard test salinity of 20 psu was below published concentrations, and the LC50 value determined for larval C. variegatus at the standard test salinity of 20 psu was below three published values [21,57-60]. This indicates significant risk to larval fish and shrimp from bifenthrin at environmentally relevant concentrations. The additional decrease in toxicity thresholds established for grass shrimp at lower salinities further increases their risk for bifenthrin-related mortality during storm water runoff events.

Conclusion

The present study found that bifenthrin was toxic to larval C. variegatus, and larval P. pugio with laboratory 96-hour aqueous LC50 values, in the standard testing salinity of 20 psu, of 0.431 μg/L and 0.0065 μg/L, respectively. Also noting a statically significant increase in mortality was observed in all bifenthrin concentrations in 5 psu for larval P. pugio. However, salinity did not significantly affect toxicity of bifenthrin to C. variegatus. These findings suggest that the toxicity of bifenthrin and the influence of combined salinity stress may vary significantly by species and life stage.

Additionally, bifenthrin concentrations ranging from 0.155 to 0.479 ng/g (dry wt.) were measured in South Carolina tidal creek sediments. Bifenthrin concentrations were highest in sediments with the highest level of anthropogenic development near the creek.

Further it must be considered that salinity drops greater than 26 psu in 24 hours have been recorded in South Carolina tidal creeks after rain events. This freshwater inundation induces salinity stress on the organisms in the receiving waters and reduces salinity to potentially lethal ranges for larval P. pugio. Simultaneously, the salinization of fresh inland waters, as a result of anthropogenic pressures, has been increasingly reported [61-64]. The present study substantiates the need to take salinity into account when performing toxicity assays and conducting pesticide risk assessments.

Acknowledgements

The authors wish to thank South Carolina Sea Grant and SC Department of Natural Resources for graduate research funding and providing tidal creek project data through SC DNR Project #R/CG-4. They also wish to thank Craig Plante and William Roumillat for experimental advice; Pete Key and Cameron Collins for lab assistance; Blaine West for animal collection; Ed Wirth and Brian Shaddrix for assistance with chemical analysis. Fish bioassay protocols were approved by the College of Charleston Institutional Animal Care and Use Committee (IACUC-2019–014). The NOAA, National Ocean Service (NOS) does not approve, recommend, or endorse any proprietary product or material mentioned in this publication.

Statements and Declarations

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors report there are no competing interests to declare.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Breanne Y. Hanson, Katy W. Chung and Emily C. Pisarski. The first draft of the manuscript was written by Breanne Y. Hanson and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author (Katy W. Chung) upon reasonable request.

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Unique COVID/Anti-Spike Protein Immune Responses in Two Elderly Patients without COVID-19 Vaccination

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DOI: 10.31038/MIP.2022311

Abstract

Published reports continue to emerge regarding different health outcomes in patients immunized and not immunized against the SARS-CoV-2 antigen (i.e., spike protein) that were infected with the virus. Because of the vast array of protein isoforms made from the laboratory-created SARS-CoV-2 viral genome, patients with different innate immune systems and underlying health issues responded differently upon coronaviruses/cold virus infection and re-infection. The current perspective highlights two patients during the calendar years 2020/21 and 2022, that presented with cold virus symptoms, tested positive for coronavirus antigens on lateral flow strips, developed bacterial sinus infections, were hospitalized, and treated with pooled antibody plasma. Throughout their medical sequela each patient maintained strong antibody titers against spike protein based on IgG levels in their saliva.

Keywords

Spike protein, antibody, infection, immunity, vaccination, COVID-19, mRNA vaccine

Introduction

The following article provides a perspective on two unique medical cases of male individuals that contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus) and subsequent bacterial infections and did not receive any vaccine against the virus during the calendar years 2020-22. Both patients had underlying health issues that negatively impacted their daily activities and quality of life, and each received convalescent donor plasma enriched with anti-SARS-CoV-2 antibodies. Table 1 is a summary of their health profiles and indicates that each patient had a poor quality of health (Patient A profile described in detail at end of article).

Table 1: General Health Status of Elderly Two Male Patients

Body System – Conditions	Patient A	Patient B
Age	82	65
Cardiac	High BP	High BP
Metabolic Status	Low-Moderate	Low
Immunity	Compromised	Normal
Body Mass Index (BMI)	120% overweight	125% overweight
Activity/Exercise/Lifestyle	Inactive/minimal	Inactive/minimal
Pulmonary status	Below normal	Moderate
Glucose and Insulin scores	Diabetic	Mild Diabetic
Diet Quality	Sub-optimal	Sub-optimal
Stressors in Life	Aging	Aging, ADHD
Lifestyle drug	ED medication	ED medication
Inflammation	Joint issues	Requires joint replacement
Hormone status	Low testosterone	Low testosterone

One of the main findings in the article published October 2022, by Rotello et al. is that the collected saliva antibodies were easily isolated, bound robustly to spike protein (as measured using an ELISA) and were IgG hyperimmune as determined by isotyping. In addition, the patients’ antibodies recognize different isoforms of the early and mature spike protein produced from the Moderna mRNA vaccine after introduction into mammalian cells in cell culture. Each patient indicated that the COVID-19 virus behaved more like a “cold virus” and would have made it difficult to provide immunity protection and overall immunity like typical vaccines, for example, shingles, polio, and respiratory syncytial virus. Recently, a Nature paper described over 100,000 genomes of the COVID virus, demonstrating that these coronaviruses are unlike the shingles virus that rarely mutates. An additional factor is that while dipstick (lateral strip) antigen-based diagnostic tests are sensitive, they do not discriminate between different types of coronaviruses (personal communication from Moderna). In the natural environment, viruses with similar sequences exist and patients that continually self-test are faced with health decisions to treat specifically or generally with a so-called COVID specific dual-acting agent, Paxlovid. This strategy initiates a perpetual test-treat cycle, which can lead to the development of a strong economic forecast that would encourage an emergency use authorization by large pharmaceutical companies (e.g., Pfizer). This combination drug consists of a protease inhibitor that disables viral replication and a CYP3A inhibitor to prevent the drug from being inactivated. Addition of a CYP3A inhibitor is not the most efficient way to combat a respiratory virus specifically for patients that might be taking other medications whose activity is dependent on being metabolized by CYP3A [1-4]

In this mini-review, patient A has a very selective autoimmune disease, received convalescent antibodies, and still contracted the SARS-CoV-2 virus. This individual had no previous history of compromised airflow, except on excursion, which resulted in extreme shortness of breath and tiredness. Patient A was also diagnosed with Myasthenia Gravis (MG) and currently has atypical eye and nasal secretions related to MG.

Patient B has a history of health issues including severe arthritis, gout, and mild diabetes. Patient B routinely suffers from sinus infections and has had previous surgery to remove fluid from frontal sinuses. Key characteristics of both patients, which put them at risk for future infections by cold viruses, include being overweight and diabetic, inactivity, poor diet, and below normal pulmonary status. The inactivity and reduced respiratory capacity generally led to more sickness and allowed fluid to rapidly accumulate in lungs, which contributed to other issues related to cardiac output, oxygen levels, and quality of life. Another consistent finding is each male patient occasionally use erectile dysfunction medication (e.g., Viagra). The other general conclusion is vaccination does not seem to prevent severe disease or viral transmission, but symptoms from infection are determined by a patient’s overall medical history. It appears that mRNA vaccines work for a short period of time and boosters don’t appear to prime the immune system like a bona fide vaccine, which are commonly designed against the most antigenic peptide/protein and allows the subject to create strong memory B-cells and hyper-immune IgGs (personal communication, Moderna 2021). This latter approach was recently adopted by Novavax and approved for targeting COVID variants that includes the adjuvant Matrix-M extract from soapbark tree and the highly variable spike protein with its numerous post-translation modifications, including extensive glycosylation. Each patient’s saliva IgA antibodies were reactive on separate occasions to spike protein, which is one of the predominant antibody isotypes found in saliva [6].

Discussion

Patient A is a 82-year-old male who was diagnosed with COVID-19 on 1/21/2021. He has a history of gout, hyperlipidemia, diabetes mellitus, hypertension, chronic pain syndrome, myasthenia gravis, and chronic kidney disease, type III. He was admitted to an emergency room for evaluation of worsening symptoms of cough and shortness of breath attributable to COVID infection on 1/24/2021. The patient was placed on nasal cannula oxygen and started on an IV of ceftriaxone and doxycycline for bacterial pneumonia. Procalcitonin was negative. The patient met with an infectious disease specialist and was started on IVs of remdesivir, dexamethasone and convalescent plasma. Patient was weaned off oxygen and provided supportive care. Patient completed convalescent plasma transfusions on 1/26/2021. He continued to improve but continued to require nasal cannula oxygen support for hypoxemia. Inflammatory markers began to decrease. On 1/29/2021, the patient planned to receive his last dose of remdesivir and be discharged home, however, after speaking with his daughter he felt he may benefit from rehabilitation and therefore therapy teams were consulted and COVID testing was re-ordered. The repeat COVID test was negative. Infectious disease was narrowed, antibiotics IV ceftriaxone and IV doxycycline were converted to PO doxycycline for bacterial pneumonia. The patient completed all treatments for COVID virus. On 01/29/2021, the patient was discharged to short-term rehabilitation. Patient A on his final discharge report indicated that he had confirmed acute sepsis with fever and tachycardia that required hospitalization. His status/release from hospital and post remdesivir remained as acute viral pneumonia, along with acute possible bacterial pneumonia due to gram negative and gram-positive bacteria. His signs and symptoms present on admission, were acute respiratory failure, elevated D-dimer, hypertension, chronic kidney disease stage lll and Myasthenia Gravis, positive autoantibodies to acetylcholine receptor.

Patient B has fewer details in his medical report and differs from patient A in medications and underlying health issues. Patient B presented with COVID-19 in September 2020 and exhibited a number of symptoms including low grade fever, achy joints, loss of taste and smell, lots of phlegm and sinus drainage, extreme bouts of coughing mild pneumonia and severe fatigue. In bed for 10 days at home. The saliva antibodies evaluated for spike protein reactivity were obtained one month after this episode of COVID. The second bout of COVID for patient B was July 2022, however, he had no loss of taste or smell. The following is a list of medications for patient B; metformin HCL – 500 mg once a day; lisinopril-HTCZ – 20 – 25 mg 2 doses every morning; doxazosin mesylate – 4 mg 1 dose at bedtime; labetalol HCL 200 mg, twice a day, morning and bedtime; spironolactone 25 mg 1 tablet in the morning; potassium chloride 20 meq once day; amlodipine besylate 10 mg at night; magnesium 250 mg once a day; fish oil 1200 mg twice a day and Cholestoff (nature made brand) 2 tablets in the morning.

Conclusion

Patient A is currently managing his Myasthenia Gravis and pursuing enrollment in a clinical trial for a novel antibody therapy. Patient A has unique B-cells that could be used to develop high affinity humanized monoclonal antibodies to target bacteria and/or viruses. Figure 1 demonstrates that saliva from Patient A has robust antibodies that can detect spike protein made from the Moderna vaccine introduced into normal fibroblasts.

Figure 1: This figure shows that antibodies in the saliva from Patient A recognize three high molecular proteins made from the Moderna vaccine that was introduced into normal fibroblasts. These bands are primarily the mature processed forms of the spike protein. The antibodies in patient A saliva were isotype IgG, IgA and IgM (BioRad Laboratories). Lane 10 molecular weight markers, 220 kd-14 kd, lane 2 is 10 ug, lane 3 20 ug of protein loaded. Lanes 4-9 are protein lysates at different concentrations 1, 4, 6, 8 10 and 12 ugs, at early time points after Moderna vaccine introduction into cells.

Various platforms exist in industry to isolate the B-cells from patient A, analyze their IgG genes, produce humanized antibodies against infectious disease targets, and harvest disease-specific antigens. This strategy would be like that used by Regeneron to make its REGEN-COV antibodies from Chinese patients in Wuhan during the initial COVID outbreak. The humanized antibodies from patient A may be useful in terms of targeting bacterial and viral antigens in the next coronavirus (cold virus) outbreak. Patient B very similar to patient A but has chronic inflammation and joint issues mainly within his shoulders and knees. He has had hyaluronic acid injections in his joint spaces to relieve symptoms. His most recent diagnosis recommends full knee replacement. The B-cells present within this patient would also be informative as most elderly patients with chronic health issues have inflammation that is not remedied by OTC medications. In addition, patient B has ADHD and suffers from low testosterone or andropause. The main conclusion is most subjects exposed to the coronavirus/cold virus of 2019 suffered long term side effects because of underlying health issues that impacted brain function and cardiovascular function. As with most serious health concerns, patients are at risk for survival if health issues exist that compromise quality of life [7-11].

Acknowledgement

Authors would like to thank Bradley Pauley for his laboratory management and coordination of sample acquisition and handling. Katie Schultz, for assistance with spike protein analysis and saliva antibody isotyping, she is currently a pre-PharmD student at Ohio State University.

Conflict of Interest

The authors have no conflict of interest.

References

Rocco J. Rotello, Timothy D. Veenstra, Brad Pauley, Elisha Injeti (2022) In vitro Characterization of SARS-CoV-2 Protein. Medrxiv.
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Personal Communication Moderna, September 7, 2021. Thank you for your inquiry regarding the Moderna COVID-19 Vaccine. The following information is enclosed in response to your medical inquiry. The molecular weight of the spike (S) protein that the body produces after receiving the Moderna COVID-19. Vaccine is a proprietary information that Moderna cannot release. We thank you for your understanding. We have attached the Fact Sheet for Health Care Providers Administering Vaccine (Vaccination Providers) along with the Full EUA Prescribing Information for the Moderna COVID-19 Vaccine for your information. The EUA Letter of Authorization can be found at https://eua.modernatx.com/covid19vaccine-eua/
https://www.novavax.com/science-technology/coronavirus-disease-2019-covid-19 Accessed October 6, 2022.
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Richard Copin, Christos A. Kyratsous, Angel Coppola, George D.Yancopoulos, et al. (2022)The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies. A Cell Journal Press 148: 15.
David M. Weinreich, M.D., Sumathi Sivapalasingam,D., Thomas Noton M.D., Shazia Ali, (2021) REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. New England Journal of Medicine 1: 2021.
Florent Besnier, Beatrice Berube, Jacques Malo, Christine Gagnon, Catherine Alexandra, et.al (2022) Cardiopulmonary Rehabilitation in Long-COVID-19 Patients with Persistent Breathlessness and Fatigue: The COVID-Rehab Study. Int J Environ Res Public Health 19:7: 4133. [crossref]

Ambivalent and Conjectural-Synovial Sarcoma

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DOI: 10.31038/CST.2022734

Synovial sarcoma is a malignant, soft tissue neoplasm of uncertain histogenesis demonstrating variable epithelial differentiation. Synovial sarcoma represents as a monophasic or biphasic malignant mesenchymal neoplasm characteristically demonstrating chromosomal translocation t(X;18) (p11; q11) incriminating genes SS18 and SSX1, SSX2 or SSX4. Neoplasm displays variable morphologies as monophasic spindle-shaped cell or monophasic epithelial cell or may manifest biphasic, myxoid, ossifying and poorly differentiated variants. Characteristic morphological features emerge as monotonous spindle-shaped cells permeated with vesicular, plump and overlapping nuclei. Cellular component is intermingled with haemangiopericytoma-like vascular articulations [1,2].

Median age of disease emergence is 35 years although no age of tumour emergence is exempt, and neoplasm may be discerned up to ninth decade (Figures 1 and 2).

Figure 1: Synovial sarcoma depicting fascicles of spindle-shaped cells with uniform, vesicular, overlapping nuclei and minimal atypia. Branching, staghorn vascular articulations appear intermingled with neoplastic component (5).

Figure 2: Synovial sarcoma composed of intersecting bundles of spindle-shaped cells within monotonous, uniform, overlapping nuclei and few mitotic figures (6).

Around ~18% instances occur within children and adolescents. A mild male predominance is observed with male to female proportion of ~1.2:1 [1,2]. Synovial sarcoma preponderantly incriminates extremities, trunk, head and neck, intrathoracic or intra-abdominal region or may arise within diverse locations although no site of tumour emergence is exempt. Soft tissue sarcomas depicting chromosomal translocation t (X;18; p11; q11) are contemplated to be synovial sarcomas. Synovial sarcoma is posited to occur due to chromosomal translocation t(X;18) (p11; q11) incriminating genes SS18 along with SSX1, SSX2 or SSX4 [1,2].

Majority (~90%) of synovial sarcomas manifest characteristic chromosomal translocation t(X;18) (p11.2; q11) along with SYT-SSX1 genetic fusion. Besides, chromosomal translocation t(X;18) (p11.21; q11) and SYT-SSX2 genetic fusion may occur [1,2]. Synovial sarcoma frequently depicts p16INK4A genetic deletion. Enhanced expression of EZH2 differentiates poorly differentiated neoplasms from monophasic or biphasic synovial sarcoma [1,2]. Aforesaid chromosomal translocation variably influences diverse oncogenetic pathways as initiation of SWI/SNF chromatin remodelling complex, polycomb repressor complex or canonical Wnt pathway. Partners of chromosomal translocation guide epithelial differentiation.

Chromosomal translocation SS18-SSX1 is preponderantly associated with monophasic synovial sarcoma (~70%) or biphasic neoplasms (~40%) whereas translocation SS18-SSX2 is predominant within monophasic tumours (~97%) and biphasic neoplasms (~3%). Translocation SS18-SSX1 prohibits Snail gene whereas amalgamation SS18-SSX2 prohibits Slug gene [1,2]. In contrast to Slug gene, intervention within Snail gene engenders intense de-repression of E-cadherin [1,2]. Intense expression of E-cadherin and extracellular matrix protein MMP2 functions as a prerequisite for occurrence of biphasic synovial sarcoma. Of obscure aetiology and pathogenesis, synovial sarcoma is posited to arise from multipotent mesenchymal stem cells or satellite cells as immature myoblasts [1,2].

Preceding radiation therapy exceptionally induces synovial sarcoma. Neoplastic concurrence with diverse syndromes or various diseases remains undocumented [1,2].

Grossly, synovial sarcoma represents as a soft to firm, well circumscribed or infiltrative, multinodular neoplasm. Upon initial representation, tumour magnitude varies from 3 centimetres to 10 centimetres although minute lesions < 1 centimetre diameter may occur, especially upon hands and feet. Cut surface is tan, grey/white, yellow, or pink. Foci of myxoid change necrosis, calcification and metaplastic ossification may be observed [1,2]. Upon microscopy, tumefaction exhibits mild cellular and nuclear pleomorphism [1,2].

Generally, neoplasm depicts subtypes as biphasic or monophasic, spindle-shaped or epithelial cell neoplasm [1,2]. Subcategories as monophasic epithelial, calcifying, ossifying, myxoid or poorly differentiated round cell synovial sarcoma may be exceptionally delineated [1,2]. Biphasic synovial sarcoma is constituted of dual components denominated by spindle-shaped cells and gland-like configurations of epithelial cells. Glandular lumens appear permeated with mucin. Neoplastic epithelial cells depict moderate, distinct amphophilic cytoplasm with spherical to elliptical nuclei. Squamous metaplasia can exceptionally occur [1,2]. Monophasic synovial sarcoma emerges as a hyper-cellular neoplasm with an infiltrative tumour perimeter. Fascicles of tumour cells appear intermingled with minimal stroma. Focal hyalinization or myxoid change is infrequent [1,2]. Neoplastic cells are monotonous and permeated with scanty, amphophilic cytoplasm, elliptical to spindle-shaped, vesicular nuclei with uniformly disseminated chromatin and inconspicuous nuclei. Indistinct nuclear palisading with nuclei overlapping adjacent nuclei may be exemplified [1,2].

Poorly differentiated synovial sarcoma is extensively cellular and is composed of spherical cells imbued with hyperchromatic nuclei. Mitotic activity is significant. Focal calcification and necrosis may ensue. Characteristically, focal staghorn vasculature, haemangiopericytoma-like foci or branching vascular configurations simulating solitary fibrous tumour may be observed. Mast cells are frequently discerned. Commonly discerned biphasic synovial sarcoma demonstrates commingling or distinct foci of dual neoplastic components. Metastatic neoplasms depict variable predominance of epithelial and spindle cell components [1,2].

Epithelial component commonly delineates enlarged; pale, columnar epithelial cells permeated with spherical, vesicular nuclei. Alternatively, cuboidal, flattened or spindle-shaped epithelial cells may occasionally be observed [1,2]. Epithelial cells may configure glandular articulations or tubules imbued with mucin. Papillary articulations or foci of squamous differentiation may exceptionally be discerned. Mucin rich variant of synovial sarcoma is infrequent [1,2]. Spindle cell component is composed of sheets or fascicles of miniature, uniform, plump, elongated cells pervaded with scanty cytoplasm, nuclei with dark, stippled nuclear chromatin and an indistinct cellular perimeter [1,2]. Tumour nodules or myxoid foci are infrequently discerned. Characteristically, intervening stroma enunciates thick, ropy collagen bundles. Commonly, stroma circumscribes cellular tumour nodules which appear intermingled with haemangiopericytoma-like vascular articulations. Foci of calcification may arise [1,2].

Monophasic synovial sarcoma is commonly composed of pure spindle-shaped cellular component demonstrating aforesaid morphological features [1,2].

Synovial sarcoma may minimally demonstrate a singular manifestation denominated as:

Chromosomal translocation t (X;18; p11; q11)
Immune reactivity to keratin
Singular or multiple, aforesaid characteristic stromal features.

A pure epithelial cell component is negligibly observed (1,2). Frequently discerned nonspecific histological features occur as:

Cellular palisading
Pseudo rosettes
Herringbone pattern
Retiform or micro-cystic tumour configuration
Occurrence of metaplastic bone or cartilage
Foci of minimally enlarged cells.

Poorly differentiated synovial sarcoma may delineate a focal or pure, predominantly epithelial or mesenchymal tumour pattern [1,2].

Ultrastructural examination exhibits glandular configurations composed of epithelioid tumour cells demonstrating sparse luminal microvilli [1,2].

Staging of soft tissue sarcoma may be designated as:

Stage I: Tumour is miniature and low grade as GX or G1
Stage II: Tumour is miniature and high grade as G2 or G3
Stage III: Tumour is enlarged and high grade G2 or G3
Stage IV: Tumour dissemination into various body sites. Original tumour may be of variable magnitude (any T), any grade (any G) and may or may not demonstrate regional lymph node metastasis (any N) (2,3) (Table 1).

Table 1: Grading of non- rhabomyomatous paediatric soft tissue sarcoma as per Paediatric Oncology Group (POG) (2-3)

Synovial sarcoma is immune reactive to TLE1 and various cytokeratin wherein epithelial component is consistently immune reactive to CK7, CK8, CK14, CK18, CK19 and variably reactive to CK17, CK13, CK6 or CK16. Spindle cell component is focally and variably immune reactive to CK7, CK19, CK18, CK8, CK14, CK17 or CK20 [3,4]. Synovial sarcoma is immune reactive to epithelial membrane antigen (EMA), BCL2, β-catenin, calponin, CD99, CD56, CD57 or calretinin [3,4]. Epithelial component is comprehensively (100%) immune reactive to keratin or epithelial membrane antigen (EMA) whereas spindle cell component is immune reactive in ~80% instances [3,4]. Besides, neoplasm is immune reactive to SS18-SSX fusion specific antibody, SSX C terminus antibody or NY-ESO-1 [3,4]. Synovial sarcoma is immune non-reactive to CD34, desmin, h-caldesmon, myogenin, MyoD1, FLI1, WT1, SOX10, S100 protein or H3K27me3 [3,4].

Biphasic synovial sarcoma requires segregation from neoplasms such as adenocarcinoma, biphasic mesothelioma, glandular nerve sheath tumour, branchial analage mixed tumour or ectopic hamartomatous thymoma [3,4]. Monophasic synovial sarcoma necessitates demarcation from neoplasms as malignant peripheral nerve sheath tumour, cellular schwannoma, solitary fibrous tumour, leiomyosarcoma, spindle cell rhabdomyosarcoma, adult fibrosarcoma, dermatofibrosarcoma, protuberans with fibrosarcomatous transformation, epithelioid sarcoma, biphenotypic sinonasal sarcoma or sarcomatoid carcinoma [3,4]. Poorly differentiated synovial sarcoma mandates distinction from small round blue cell tumours as alveolar rhabdomyosarcoma, Ewing’s sarcoma, undifferentiated round cell sarcoma or Ewing-like sarcoma. Characteristic genomic modifications may be appropriately discerned upon reverse transcription polymerase chain reaction (RT-PCR). Cogent tissue sampling is mandated for confirmation of synovial sarcoma [3,4].

Corroborative tumour detection may be obtained with molecular or cytogenetic assessment for SS18-SSX genetic fusion with fluorescent in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) [3,4]. Plain radiographs depict a site-specific spherical to elliptical, lobulated tumour mass. Incrimination of bone is infrequent [3,4]. Ossifying synovial sarcoma typically delineates spotty radio-opacities engendered due to focal calcification. Comprehensive surgical resection of neoplasm is a recommended therapeutic strategy [3,4]. Additionally, radiotherapy or adjuvant chemotherapy can be employed to manage challenging clinical scenarios as neoplasms >5 centimetre magnitude or tumours unamenable to surgical resection [3,4]. Adjuvant radiation therapy ameliorates prognostic outcomes and overall disease survival [3,4].

Neoplasms subjected to preceding radiation therapy may demonstrate moderate cellular and nuclear pleomorphism. Adjuvant chemotherapy can be beneficially adopted to treat neoplasms of advanced grade or tumours unamenable to pertinent therapy [3,4]. Agents such as ifosfamide or novel therapies as tyrosine kinase receptor inhibitor pazopanib or EZH2 inhibitor tazemetostat can be beneficially employed for therapeutic purposes. Also, T cell receptor-based immunotherapy implicating NY-ESO-1 within subjects demonstrating HLA-A*0201 is associated with clinical and radiological neoplastic melioration [3,4].

Inferior prognostic outcomes are associated with:

SS18-SSX1 chromosomal translocation
Monophasic and poorly differentiated synovial sarcoma
Incriminated males
Initial disease representation in elderly subjects
Tumour magnitude ≥5 centimetres
Neoplasm confined to centric, non-extremity sites
Deep seated neoplasms
Extensive tumour necrosis
Mitotic activity ≥ 10 per high power field
Elevated Ki67 proliferative index
Precise tumour grade contingent to Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC), as defined in incriminated adults
Immunoreactivity to CXCR4 and IGF1R
Tumour discernible within resected surgical perimeter

Expression of H3K27me3 and VEGF in concurrence with histological grade and stage of neoplasm along with emergence of distant metastasis (3,4).

References

Manizhe AK, Mohseni I et al. 2022 Recurrent primary intracranial synovial sarcoma, a case report and review of the literature. Clin Case Rep 10. [crossref]
Eliason L, Grant L et al. 2022 Qualitative study to characterize patient experience and relevance of patient-reported outcome measures for patients with metastatic synovial sarcoma. J Patient Rep Outcomes. 6. [crossref]
Fice M, Almajnooni A et al. 2022 Does synovial sarcoma grade predict oncologic outcomes, and does a low-grade variant exist? J Surg Oncol. 125: 1301-1311. [crossref]
Ren MY, Li J et al. 2022 Primary orbital monophasic synovial sarcoma with calcification: A case report. World J Clin Cases 10: 1623-1629. [crossref]

The Susceptibility of South Asians to Cardiometabolic Disease as a Result of Starvation Adaptation Exacerbated During the Colonial Famines

2 Replies

DOI: 10.31038/EDMJ.2022621

Abstract

South Asians, representing one quarter of the world’s population, have disproportionally high rates of obesity and cardiometabolic disease thus resulting an epidemic health crisis. This crisis could be the consequence of epigenetic effects exacerbated during the colonial-era famines resulting in a unique starvation-adapted physiology. Due to evolutionary mismatch in circumstances of abundance, this starvation-adapted physiology can become harmful. Evidence for this starvation adaptation in South Asians includes high body fat and unfavorable adipokines; low lean body mass; lower resting energy expenditure (compounded by lack of brown adipose tissue); greater insulin resistance and insulin response; exaggerated lipemic response to fat and sugar intake; less capacity to handle an overabundance of food; lower fat burning (oxidative capacity) and VO2max during aerobic exercise; and energy- conserving response to resistance exercise, as well as increased lipoprotein (a) levels. The Roma people, also of South Asian ancestry, may represent an interesting pre-colonial historical control. Physician and patient knowledge of this unique physiology in South Asians will promote a stronger physician- patient relationship and foster compliance with treatment.

Introduction

At approximately one-quarter of the world’s population, South Asians represent one of the largest populations globally [1]. It is widely recognized that South Asians have higher cardiometabolic risks than people of other ethnicities. South Asians have the highest abdominal and visceral fat (truncal obesity) per given BMI [2,3]. South Asians are up to four to five fold more likely to develop type II diabetes when compared to the white populations of both the United States (US) and United Kingdom (UK), respectively [4,5]. Additionally, South Asians are more than twice as likely to develop metabolic syndrome than Europids in the UK [6]. Their risk of atherosclerotic cardiovascular disease (ASCVD) is four times greater than the general US population [7,8]. Moreover, ethnic Asian-Indians were reported to have higher median coronary artery calcium scores (CAC score, one of the most important predictors for ASCVD risk) [9] than all other ethnicities studied (i.e., Caucasian, Hispanic, African-Americans and East Asians) [8]. This is a veritable health crisis, given the size of the South Asian population and their higher risk of cardiometabolic disease [7].

Some of this risk could be due to lifestyle and dietary factors. South Asians on average spend less time exercising than the general population [10-12]. Studies have shown that the intake of refined carbohydrates, saturated fats, fried foods, and processed foods is high among South Asians [13-19]. However, there is a large amount of evidence pointing to a unique physiology among South Asians that likely has a genetic basis and represents resistance or adaptation to starvation. These adaptations have been suggested to predispose South Asians to cardiometabolic disease in an environment of abundance [20-23]. Therefore, it can be argued that the susceptibility of South Asians to cardiometabolic disease may be linked to starvation and famine adaptation. Furthermore, it is proposed that the near 200- year period of recurring, severe famines that occurred under British colonial rule may have had a role in shaping the current physiology of South Asians. The current review will shed light on the connection between the emerging evidence correlating nutritional deprivation and transgenerational susceptibility to cardiometabolic disease with the culprit being the colonial famines.

The Multiple Famines and Starvation in South Asia During the British Colonial Period

Prior to British colonial rule in South Asia, from the early fourteenth to the end of the seventeenth centuries, major famines occurred once every fifty years. These famines were also limited in geographical extent [24].

During colonial rule the nature and frequency of famines changed drastically. Famines were quite prevalent in South Asia during the British colonial period (1757 to 1947). The economic historian Mike Davis recounts 31 major famines in the 190 years of British colonial rule, compared to only 17 famines in the 2000 years prior [25]. Famines accelerated in frequency as British rule consolidated and spread. This spread is demonstrated by the occurrence of twelve serious famines and four severe scarcities between 1765 and 1858 (roughly the first 90 years of British rule) [24]. This is compared to acceleration in the frequency of severe famines during the period between 1850 and 1899 (50 years during ongoing British rule) where there were 24 major famines in South Asia [26].

The severity of the famines in South Asia made them some of the worst in world history. Three of the ten deadliest famines and six of the twenty-five worst drought-associated famines that were coupled with drought occurred in colonial India [27,28]. Additionally, the geographically widespread nature of the South Asian famines during colonial times was unprecedented in South Asian history. These famines affected areas of South Asia that were previously immune to famine, such as Marwar and Bengal [24]. Thus, the famines were more frequent, widespread, affected larger numbers of people, and increased in intensity (as nationwide catastrophes) during British rule. Even when famines did not occur, undernourishment was the norm during the colonial period [29]. Food grain availability per capita, a quantifiable parameter of the degree of undernourishment, decreased due to impoverishment from 200 kg in 1900 to 157 kg on the eve of World War II and further declined to 137 kg by 1946 [30]. Given South Asians continual exposure to severe famines, it makes sense to look at how that may have had long-term effects.

How Does Famine Affect Cardiometabolic Risk in Future Generations (Epigenetics)?

It has been shown that an adverse environment for a community in the past can have a long-term negative health consequence in the present [31]. Exposure of a population to just one famine is known to increase the risk of diabetes and ASCVD via multigenerational epigenetic effects [32]. These effects and their duration over multiple generations have been observed in worm and mouse models [32,33]. In humans, this epigenetic effect of famines has also been shown to increase cardiometabolic risk. Specifically, multiple studies of different populations in Sweden, China, and the Netherlands have shown this epigenetic-induced increase in cardiometabolic risk among descendants (including the grandchildren) of famine survivors [34- 36]. One evidence of epigenetic change in Chinese famine survivors is the high incidence of DNA methylation [21,22,37].

Based on the severity and frequency of the famines in South Asia during the colonial period, we postulate that these famines had a lasting epigenetic effect on the predisposition of South Asians to cardiometabolic disease. Indeed, South Asians who develop type II diabetes have a much higher rate of DNA methylation, an established indicator of epigenetic change, than do Caucasians. This finding may explain the increased incidence of type II diabetes. The relationship of DNA methylation to type II diabetes is so strong that it has been postulated that this biomarker may be a potential future screening tool for early intervention prior to diabetes onset [38].

The Recent Overabundance of Food Availability in South Asia Causes Evolutionary Mismatch

During the last 25 years, there has been a rapid increase in prosperity, and thus, food availability, in South Asia and amongst the South Asian diaspora [39]. This increase has led to rising incidence rates of noncommunicable diseases (NCDs) such as heart disease, stroke, and type II diabetes. This implies that there may be an evolutionary mismatch of genetic traits that were once advantageous for survival during food scarcity and have since become detrimental in the current environment of abundance; this is also known as the “thrifty gene” or “thrifty phenotype” hypothesis [40].

How do the Unique Physiological Traits of South Asian Populations Point to Starvation Adaptation?

In support of the “thrifty gene” hypothesis, studies in animal models have revealed starvation adaptation (or starvation resistance) after exposure to food shortages. For example, in Drosophila, these adaptations include sequestering greater energy reserves (greater lipid accumulation) and reducing the rate at which energy reserves are used (reduction in the metabolic rate and lower activity level of the organism) [41]. Additionally, the physiological equivalence of insulin resistance has also been demonstrated in Drosophila as a sign of starvation adaptation [42]. These traits of starvation adaption appear to be transgenerational in Caenorhabditis elegans as well [33]. Further investigation is needed, but, on the basis of these animal studies and the historical famines in South Asia, it is hypothesized that South Asians may express some of these traits due to generations of starvation adaptation [43].

The Unique and Different Physiology of South Asians

As suggested above, the physiology of South Asians is different from that of other ethnicities regarding important cardiovascular and metabolic measures. The topics discussed below outline the specific physiological differences seen in South Asians and relate them to starvation/famine adaptation.

High Body Fat and Unfavorable Adipokines

It is reasonable to assume that a propensity to store body fat is conducive to surviving famine. South Asians have a form of obesity that is different from that of most populations, which is referred to as the “thin-fat phenotype.” This characterization refers to a disproportionate amount of body fat typically concentrated in the abdomen in an otherwise lean individual, who often has a normal BMI. In fact, South Asians have the highest body-fat percentages and lowest lean mass of any ethnicity in the USA [44,45]. Compared with populations of European ancestry, South Asians have a total body- fat composition that is 3-5% higher for any given BMI [46]. Notably, South Asians have especially high levels of body fat and are more prone to developing obesity [47,48].

Higher body-fat percentages in South Asians is characterized by increased secondary storage in deep and visceral fat (though superficial subcutaneous fat is reduced); ectopic fat (such as intramyocellular and intrahepatic fat deposition); adipocyte hypertrophy; and a less favorable adipokine profile, which are cytokines produced in fat cells that regulate metabolism, energy, and inflammation; this condition is referred to by some as “ethnic lipodystrophy” [44,49-52]. Of note, South Asians have been shown to have the tendency to store ectopic fat as hepatic fat compared with other ethnicities, which is associated with greater hepatic insulin resistance [53]. Regarding the adipokine profile, the levels of adiponectin, which promotes peripheral insulin sensitivity, are lower in South Asians, and the levels of resistin, another adipokine that promotes insulin resistance and obesity, are higher in South Asians [44,54,55].

Low Lean Body Mass

In addition to having higher body fat percentages, South Asians have lower lean body mass levels than do people of other ethnicities. It is hypothesized that part of the reason for this is that South Asians have higher expression of the gene encoding myostatin [50,56]. Myostatin is a protein found in skeletal muscle that inhibits its growth. This hypothesized effect would explain why a higher body fat percentage and low lean mass exists among newborns of South Asian migrants to the UK, Netherlands, and Surinam that persists for at least four to five generations [57,58]. Low lean body mass is associated with higher rates of insulin resistance and cardiovascular disease (CVD) risk [59-61].

Numerous severe famines affected South Asia throughout the 19th and first half of the 20th centuries. The effects were worsened by British colonial policy, which led to a high mortality rate from the starvation that occurred [57]. Lean mass (especially, muscles and organs) is known to consume calories at a higher rate than fat. Therefore, the intense selection pressure from the numerous severe famines of the 19th and first half of the 20th centuries would have favored low levels of lean mass in addition to a higher body fat percentage.

The low lean mass of South Asians has been postulated to be one of the evolutionary reasons for the higher incidence rates of NCDs, such as cardiometabolic disease, in this population. Previous research has implicated colonial famines as a major exacerbator of the development of low lean mass due to starvation adaptation [58]. One study suggested that South Asians have had historically low lean mass for at least 11,000 years due to a variety of factors (such as delayed transitions from foraging to agriculture and the change to a predominantly vegetarian diet) [57]. However, we believe that the epigenetic effects of the famines on the South Asian physiology during the colonial period cannot be discounted.

Three factors that support the severity of the effects of these colonial famines are the exceedingly high death toll (up to 85 million deaths); the documented decrease in life expectancy during this period; and the decrease in stature (height) compared to an increase in stature in most of the other populations worldwide) [25,58,62-66].

Lower Resting Energy Expenditure

Thermoneutral resting energy expenditure is the energy expended necessary for basic physiological functioning at rest while awake, fasting, and without needing to use energy to regulate body temperature. As a result of their lower lean mass and higher body fat at the same height, weight, and BMI compared with people of other ethnicities, South Asians have lower thermoneutral resting energy expenditure (burning less energy at rest, approximately 32% less than Caucasians) [67-69]. This is another adaptation that may have helped some South Asians survive famines. One study showed that at the cellular level, South Asians seem to have higher mitochondrial efficiency, evidenced by the higher oxidative phosphorylation capacity in this group compared with Americans of North European origin [70]. The excess ATP-produced and higher oxidative state has been shown to prevent insulin receptor deactivation, resulting in insulin resistance [71,72].

One other reason contributing to the relative lower energy expenditure at rest, besides higher percentages of body fat, amongst South Asians is the lower amount of brown adipose tissue (BAT, or brown fat) [69,73]. BAT is a type of adipose tissue that is specialized for heat generation and can be responsible for up to 20% of total energy expenditure in its activated mode [74]. In South Asians, BAT volumes have been shown to be approximately 34% less than Caucasians [69]. BAT is responsible for nonshivering thermogenesis (heat generation). For South Asians this means a reduced capacity to generate nonshivering thermogenesis or waste heat [69]. In cold-adapted populations, higher levels of BAT are protective for cardiometabolic health (including diabetes), as BAT produces uncoupled mitochondrial respiration for heat generation that burns off excess calories (nonshivering thermogenesis) [73]. The protective mechanism likely involves the use of BAT burn or its metabolism of excess calories in states of caloric overabundance [73,75].

These phenomena may explain why amongst diaspora populations of East Asians (who, like Caucasians, are a cold-adapted population with relatively elevated levels of thermogenic capacity) have a much lower predisposition to cardiometabolic disease than South Asian diaspora populations [73]. In fact, among individuals aged 20-29 years living in the US, the incidence of diabetes in South Asians is threefold higher than in Chinese, as well as two times higher when compared with individuals of European origin [53]. This finding occurs despite a similar famine laden history in both South Asia and China [53,76,77].

In summary, regarding energy expenditure, South Asians were substantially impacted by starvation adaptation. These adaptations would have promoted hyperefficient mitochondria and a lack of BAT. Both adaptations would have been helpful in promoting energy efficiency. Having less brown fat is thought to be a tropical adaptation, although an additional benefit may have been less energy consumption during starvation [73]. However, in times of abundance, this lack of BAT predisposes South Asians to cardiometabolic disease.

Greater Insulin Resistance/Insulin Response

Certain genetic factors involved in cardiometabolic processes including prediabetes/diabetes have also been found to be contributing factors to the unique South Asian physiology [43]. A single-nucleotide polymorphism (SNP) of the MC4R gene associated with higher levels of visceral (including hepatic) fat and insulin resistance is highly prevalent in South Asians [78]. Furthermore, at least six genetic variants associated with the premature onset of insulin-resistant diabetes have been found to be much more prevalent in South Asians than in Europeans [79]. Another study suggested that based on genetic data (polygenic risk score), South Asians had about a four times higher risk of type 2 diabetes than the European population [80]. South Asians have a higher postprandial insulin response, with a higher tendency toward insulin resistance in the overfed state (Figures 1 and 2) and there is a three- to four-fold higher prevalence of insulin resistance in lean South Asian men than in lean men of other ethnic groups [81,82].

Figure 1: Plasma insulin (A), glucose (B) and nonesterified fatty acid (NEFA) (C) responses to a 75 g oral glucose load.82 Note the higher insulin response, but the equivalent serum glucose and NEFA responses, to the same glucose load in South Asians (than that in Europeans). Thus, thriftiness with glucose as seen in South Asians would be a useful starvation adaptation. [Reproduced from Hall, et al. (2010) with permission from PLOS].

Figure 2: Comparison of European men to South Asian men shows that South Asian men have a lower insulin sensitivity index (reflecting a higher insulin response to an oral glucose load). The horizontal bars denote mean values. The P values shown are for the difference between the European and South Asian groups, either unadjusted or adjusted for age, BMI and fat mass.82 This finding suggests higher insulin resistance overall in South Asian men. Higher insulin resistance may be a useful starvation adaptation by preserving glucose. [Reproduced from Hall, et al. (2010) with permission from PLOS].

Regarding fat intake, one study showed that five days of consuming a high-fat and high-calorie diet resulted in the development of insulin resistance, manifesting as a reduced nonoxidative insulin-stimulated glucose disposal rate, in all South Asian participants (but in none of the Caucasian participants) [83]. Therefore, high fat intake produces insulin resistance more readily in South Asians. A physiological mechanism underpinning this was recently determined to be related to lipid droplet dynamics linked to perilipin-5 (PLIN5), a protein that interacts with intramyocellular lipids to transport them to mitochondria. High PLIN5 levels typically maintain insulin sensitivity in Caucasians in response to high fat intake.

South Asians have even higher levels of PLIN5 in response to high fat intake, yet despite these higher levels, toxic fat breakdown products accumulate in the muscle, resulting in insulin resistance. Lipid droplet dynamics (which involve the release of fatty acids to fuel mitochondrial oxidation) in South Asians are therefore likely impaired or compromised [84]. Even early in life insulin resistance is more prominent in South Asians as the umbilical cord blood of newborns of South Asian ancestry manifest elevated insulin levels [85,86].

It is known that insulin resistance predisposes and correlates to cardiometabolic risk. Insulin resistance can be ameliorated by exercise. However, in the setting of higher insulin resistance, a greater duration of exercise may be needed to improve insulin sensitivity [87,88]. This occurrence could explain why South Asians may need more exercise. It is known that South Asians may need up to 80% more exercise to stave off cardiometabolic disease. Specifically, to maintain the same level of cardiometabolic health as Caucasians, South Asians need to exercise much more than their Caucasian counterparts. For instance, 150 minutes of moderate intensity exercise per week is recommended for Caucasians, but the time needed for South Asians to achieve the equivalent cardiometabolic benefits of moderate intensity exercise is 232–266 minutes per week [89,90].

Insulin resistance is believed to be beneficial in the starvation- adapted individual by reducing glucose uptake by muscles [91]. More importantly, glucose would be diverted to the brain, which does not need insulin for glucose uptake; this is known as the selfish brain hypothesis [92-94]. Alternatively, it has been suggested that the benefits provided by insulin resistance during starvation may actually be by preventing the net degradation of proteins [95]. Insulin resistance also promotes lipogenesis and fat retention, both of which would be helpful in a starvation state; this would explain why South Asians develop insulin resistance at much lesser levels of body fat and why the lower BMI/waist circumference (WC) cutoffs were established (see below).

Exaggerated Lipemic Response to Excess Sugar and Fat Intake (Predisposes to Insulin Resistance as a Starvation Survival Mechanism)

Due to an elevated predisposition to insulin resistance, South Asians have demonstrated different physiological responses to sugar and fat intake. Dietary sugar intake, like fructose and glucose, in healthy South Asians with normal indices of insulin sensitivity generates a much higher lipemic response when compared with Caucasians, due to an enhanced hepatic de novo lipogenesis (DNL). There is a known negative correlation between de novo lipogenesis and insulin sensitivity [96]. Additionally, when given a high-fat diet, South Asians had greater adverse effects on their lipid profile and insulin sensitivity than Europeans/Caucasians [97]. Such an exaggerated lipemic response would be beneficial as a starvation adaptation to promote fat storage.

Less Capacity to Handle Overabundance of Food

Despite the higher tendency toward insulin resistance and high insulin levels, South Asians have a lower beta cell reserve for insulin secretion compared to people of any other ethnicity [50]. This phenomenon may have been a response to the repeated famines South Asians endured [53]. Physiological changes associated with insulin resistance and metabolic syndrome (dysglycemia and dyslipidemia) occur at much lower body fat levels in South Asians than they do in people of other ethnicities [98]. These data support the establishment of lower BMI/ WC cutoffs for obesity by the World Health Organization (WHO) and International Diabetes Federation (IDF) for the South Asian population [99].

Possible explanations for this inability to handle a surplus of energy is called the adipose tissue overflow hypothesis [100]. The primary compartment in which fat is stored is in the superficial subcutaneous adipose tissue, where excess fat is inert metabolically. As a consequence of enduring severe famine, there would be no physiological need for a fully developed store of excess fats in the superficial subcutaneous adipose tissue. Due to the smaller capacity of subcutaneous fat storage available to South Asians, this compartment is overfilled much earlier than it is in Caucasians. Therefore, fat storage resumes in more metabolically active compartments (deep subcutaneous and visceral adipose tissues), resulting in metabolic complications such as dysglycemia and dyslipidemia at smaller BMIs than other ethnic groups, such as Caucasians.

Such a starvation-adapted body would also need a lower beta cell reserve for insulin secretion, possibly due to hypostimulation of these beta cells [101,102]. Less insulin is necessary to function in a starvation/undernourished state; however, this reduced beta cell reserve would be more easily exhausted during a state of chronic overnutrition (i.e., chronic insulin resistance) [103]. Interestingly, Chinese individuals have the second lowest level of pancreatic beta cell reserve after South Asians [50]. This finding could also be a vestige of adaptation to survival during numerous famines in China.

Lower Fat Burning (Oxidative Capacity) and VO2max during Aerobic Exercise

South Asians have a lower fatty acid oxidation capability in states of aerobic exercise, with a trend towards lower fatty oxidation in the sedentary state [82,97,104]. Normally in the exercise state, fatty acids are released through lipid droplet lipolysis to fuel mitochondrial fatty acid oxidation demands [84]. Related to this, it has been found that the fat oxidative capacity during aerobic exercise is up to 40% lower in South Asians than in Caucasians [82]. In that study, fitness and VO2max were much lower in South Asians than in Caucasians even though mitochondrial content and function were similar or higher in South Asians than in Caucasians [82]. In other words, the intramuscular expression of oxidative and lipid metabolism genes in South Asians is not reduced, but there is still a lower oxidative capacity in the muscle during aerobic exercise. This finding is thought to be another manifestation of insulin resistance in South Asians that may originate as a result of impaired lipid droplet dynamics [84]. Starvation adaptation can explain why the South Asian phenotype favors a lower capability to burn fat during exercise, as well as in sedentary and overfed states.

Starvation adaptation would also explain the accumulation of intramyocellular fat due to the mitochondrial oxidation issues described above. This accumulation allows the oxidation of fat at a lower rate, thereby conserving fat stores. Additionally, intramyocellular fat accumulation impairs insulin receptors, leading to insulin resistance, which in turn prevents the utilization of glucose by muscles [91]. A starvation-adapted body would also be more likely to become insulin resistant more readily from the intake of saturated fat to maximize the storage of calories (in the form of fat, rather than burning it in muscle).

Energy-Conserving Response to Resistance Exercise

Besides differences in fatty acid oxidation during aerobic exercise, there is also a difference in response to resistance exercise among South Asians. The physiological response to identical resistance exercise training is less favorable among South Asians than among Caucasians. Although muscle protein synthesis was equivalent, South Asians had a poorer response with regard to body fat reduction, resting carbohydrate level reduction, fat metabolism increase, VO2max increase, and upper body strength increase [104].

Regarding systolic blood pressure reduction, South Asians also had a worse response to exercise. It was hypothesized this was due to reduced bioavailability (seen in prior studies with South Asians) of nitric oxide (NO2 a potent vasodilator) in resistance endothelial vessels that supply muscle [104-106]. It would be expected there would be a less favorable muscle response to resistance exercise (in regard to VO2max, less upper body muscle strength, and less fat reduction) [104]. Instead, in the starvation-adapted individual, this muscle response would aim to conserve calories and would be blunted. Additionally, in the starvation state, there would be a decrease in blood pressure reduction in response to exercise because of reduced NO2 bioavailability [104]. A decrease in the level of NO2, which has a vasodilatory effect in muscle, would be beneficial for reducing blood flow to the muscle and the subsequent calorie expenditure by muscle to preserve calories for use by the brain (selfish brain hypothesis). This may have taken place in South Asians to conserve energy in a starvation adapted state.

Higher Lipoprotein(a) in South Asians

Vitamin C scarcity during times of famine may have led to an adaptation that predisposes South Asians to cardiovascular disease during times of prosperity. During famine in some areas of colonial India the estimated prevalence of scurvy (or acute vitamin-C deficiency) by a British colonial medical official was as high as 60- 70% [107]. To compensate for this, lipoprotein(a) or Lp(a), may have become elevated in South Asians. This is because Lp(a) is a vitamin C analog that is hypothesized to be protective against vitamin C deficiency [108]. Moreover, Lp(a) as a surrogate of vitamin C helps in wound healing and protects against the effects of scurvy, which is characterized by capillary fragility, hemorrhage, and inadequate wound healing [108]. Here is how Lp(a) and cardiovascular disease are connected. Subclinical vitamin C-deficiency can occur in modern society. This deficiency can weaken arterial walls since vitamin C is critical to maintaining the collagen framework [109]. Lp(a), in functioning as a replacement for vitamin C, tends to also bring LDL-cholesterol to weakened arterial walls and incite plaque development [109]. A study in mice that could not produce vitamin C for themselves, and were enabled to produce Lp(a), showed that mice (lower order mammals that do not usually develop atherosclerotic plaques) developed atherosclerotic plaque when exposed to Lp(a) just like humans [110].

It would follow that starvation-adapted populations, such as South Asians, would have a high prevalence of elevated Lp(a) levels. In fact, South Asians have one of the highest prevalence (40-45%) of abnormal Lp(a) levels [111]. Lp(a) promoted survival during famine and undernourishment when life expectancy was low such as occurred in colonial India when it was as low as 20 years between 1910-1920 [62,63,66]. Lp(a) becomes problematic during times of prosperity and higher life expectancy as an elevated Lp(a) level is one of the strongest independent risk factor for premature cardiovascular disease [110,112].

A Pre-Colonial South Asian Historical Control Population

The Roma people (historically referred to as “gypsies”) in Europe emigrated from northern South Asia during the eleventh century. It is interesting to note that the Roma peoples’ rates of diabetes are similar to or significantly higher than rates of diabetes among white Caucasians [113-117]. However, reports of increased prevalence of diabetes among Roma populations are thought to occur due to predisposing factors of lower socioeconomic status, and increased smoking rates of the Roma people compared with the general population who on average have higher socioeconomic status [117- 119]. This increase contrasts sharply with the four to five times higher rate of diabetes in South Asians living in Western countries compared with white populations [4,5].

Additional evidence has found that the Roma people have no increased genetic susceptibility to diabetes compared with the general population [119]. This finding contrasts with the South Asian populations, which has a known genetic predisposition to diabetes [80].

The Roma may represent a historical control on the rate of diabetes in people of South Asian ancestry without the effect of the colonial famines. This control could potentially show how the colonial famines may have adversely impacted the South Asian rates of diabetes.

Conclusion

Taken together, the data indicate that South Asians have a unique physiology that may have evolved via epigenetic effects to ensure survival during severe and frequent famines. It is likely that these adaptations have predisposed the South Asian population to cardiometabolic diseases in an environment of abundance.

We suggest this perspective of the unique South Asian physiology based on a history of famines will help explain why this population is in a veritable health crisis of cardiometabolic disease and engender future studies. This research could be done using similar methodologies as those used in studies on the multigenerational effects of the Great Chinese Famine or the Överkalix Famine [34,35].

Physicians who are knowledgeable of this physiology will be appropriately more aggressive in diagnosing and treating South Asian patients in an ethnically sensitive fashion [120]. Physicians will also have higher empathy for and credibility with their South Asian patients that may ultimately lead to a higher compliance via a stronger physician-patient relationship [121]. South Asian patients who have a greater insight into their own bodies and history may be able to improve their vigilance and motivation to adhere to suggested lifestyle and medical therapies [122].

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Screening for Human Trafficking: Best Practice Guidelines and Recommendations for Health Care Providers

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DOI: 10.31038/IJNM.2022324

Abstract

Human trafficking (HT) is a federal and international crime and is regarded as one of the most pressing human rights issues. Adult and minor victims are trafficked by force (rape, beatings, confinement), fraud, and coercion resulting in profound physical and psychological injuries; Department of Homeland Security; Vera Institute of Justice. Most clinicians fail to recognize HT victims. This policy brief’s purpose is to provide health care providers with a validated HT screening tool and best practice guidelines and recommendations to aid in victim identification. The strategies outlined are those published by the Vera Institute of Justice’s HT Victim Identification Tool and are endorsed by the Emergency Nurses Association and the International Association of Forensic Nurses. These proposals will increase the likelihood that patients experiencing sexual and labor exploitation will be identified.

Keywords

Human trafficking, Sexual exploitation, Forced labor, Human trafficking screening protocol, Human trafficking policy, Homelessness, Migrants, Runaways, Adults, Children

Screening for Human Trafficking: Best Practice Guidelines and Recommendations for Health Care Providers

Research has shown that human trafficking victims are not recognized by health care providers during their captivity [1-7]. Early identification of human trafficking victims is critical because the average life expectancy of a patient who is either sexually exploited or forced into labor is seven years [6]. A validated screening tool and assessment guideline would reliably identify adult and minor victims of both sex and labor trafficking [1-5,7,8-11].

Background and Scope of the Problem

Prevalence

Globally, sexual exploitation makes up 79 percent of all cases, and forced labor accounts for 18 percent (United Nations Office of Drugs and Crime, 2020) [17]. Human trafficking affects every United States community, regardless of age, gender, ethnicity, and socio-economic background (National Human Trafficking Hotline, 2020) [18-23]. The average American age at the time trafficking began for sex trafficking is 17 years old, for labor is 22 years old (Polaris Project, 2020) [24], 15,222 females, 3,003 males, 135 gender minorities, and 3,966 of unknown gender were victimized. In that same year, there were 1,388 United States citizens/lawful permanent residents, 4,601 foreign nationals, and 16,337 of unknown nationality were identified as victims (Polaris Project, 2020) [24]. In 2019, there were eight trafficking cases in this southwestern state, ranking it 23rd in the nation for active cases; nationwide, there were 606 cases (The Human Trafficking Institute, 2019) [25].

Health and Social Impacts of Trafficking

There is compelling evidence of the health and social impacts of trafficking [1,3,5,7,9,10,26]. Reduced life expectancy was listed (Patient Safety Monitor Journal, 2017) [6], as was severe violent behavior [9]. Urinary tract infections, pelvic or abdominal pain, suicide attempts, and psychogenic nonepileptic seizures were highlighted [1,2] named life-threatening injuries and neglected health conditions (p. 282). Stevens & Dinkle [7] referenced serious health conditions such as “anxiety, depression, aggression, major depression, sleep disorders, suicidal ideation, substance use disorders and addiction” (p. e1). Domestic servitude and violence are included [3,10] identified “chronic medical problems, significant mental health issues, substance abuse/ misuse, reproductive or sexual health problems, diminished quality of life, and trauma” (p. 175). Involvement in the justice and foster care systems, running away, and being kicked out of home were listed [5]. Victims also developed posttraumatic stress disorder [7,26].

Human Trafficking Laws

The United States federal law on child sex trafficking [15] makes it a federal crime to “knowingly recruit, entice, harbor, transport, provide, obtain, or maintain a minor and cause that child to engage in any kind of sexual activity in exchange for anything of value” (para. 1). Child Protection Services must be alerted as required by law [1]. There are child abuse laws [1]. The law specifies that there are no child prostitutes [8]. Child soldiering, debt bondage, and bonded labor are unlawful [1,2]. Child Protection Services must be alerted as required by law [1]. Federal law requests HT training for health care providers [2]. Low HT detection results from ineffective laws [2]. Child soldiering, debt bondage, and bonded labor are unlawful [2]. There are mandatory reporting laws and safe harbor laws [2,10,26]. Surprisingly, federal law does not require proof that a defendant used force, fraud, or coercion to determine the action of trafficking when the victim is a minor [3].

Problem Identification and Understanding

McDow and Dols [4] define human trafficking as the use of force, fraud, or coercion by a trafficker to exploit a vulnerable individual to perform commercial sex or labor (p. e1). Each year between 600,000 and 800,000 men, women, and children are trafficked across international borders worldwide, and between 14,500 and 17,500 are trafficked into the United States (United States Department of State [27].

There is strong evidence health care providers do not recognize victims during their captivity [1-7,28]. Providers are often unfamiliar with human trafficking signs and symptoms [1,2,10]. Estimates are that 87-80 percent of human trafficking victims are seen by a health care provider while under the control of their trafficker [1,2]. Fifty-seven percent of female victims were not identified [4]. Thirteen percent of adult and child victims were recognized. Only nineteen percent of children were screened and referred to authorities [5]. Youth experiencing human trafficking interact with the healthcare and social services systems where they can be but are often not identified [5].

Because of their obligation to promote the well-being of patients, health care providers have an ethical obligation to take appropriate action to avert the harms caused by human trafficking that includes mandatory reporting to remain compliant with state law (New Mexico Department of Health [29]. By following evidence-based practice, health care providers should be compliant with state and federal laws because each patient identified as a human trafficking victim will be reported to agency and city police departments.

At-Risk Populations

Evidence has identified risk factors that contribute to patients’ vulnerability for human trafficking.

Children and Teenagers

Risk factors for children and teenagers becoming victims include “being a runaway, possessing developmental delays, teens identifying as lesbian, gay, bisexual, transgender and queer or questioning (LGBTQ), those who commute to school alone, are hungry or malnourished, are poor, come from dysfunctional families, experience emotional distress, have mental illness, and abuse substances” [1,2,5,6,9,28,30]. Young girls are targeted [3,4,28]. Youth who are at risk for abuse or violence are often targeted [2,28,31]. Adolescents involved in foster care or juvenile justice systems, who were unstably housed or homeless, involved with child protective services or had a negative interaction with law enforcement were also more likely to become victims [1,4,5,28,30,32]. Finally, younger victims are often connected to gangs or are migrants [9,10,28,33].

Females

Most victims of human trafficking are young women and girls [1,3,4,9,28] found that “nearly 70 to 80 percent of trafficking victims are women and girls, and 97 percent of those are trafficked for sexual exploitation” (p. 830). Egyud et al. (2017) [1] ranked the percent of female trafficking victims at 90 percent (p. 527). Greenbaum and Bodrick [34,35] state that globally, between January 2008 and June 2010, human trafficking taskforces discovered that 94 percent of sex trafficking victims were female (p. 2). Young women are at the greatest risk for sexual exploitation and are treated for “unplanned pregnancies, sexually transmitted infections, and traumatic injuries” [4]. They seek out health care providers for reproductive health issues such as miscarriages and to perform abortions or to secure birth control [36]. As a result, “Health care providers who work in women’s health services have a unique opportunity to identify and intervene in the human trafficking operation due to their heightened level of contact with the victims” [36]. In 2018, the National Human Trafficking Hotline- 18] identified over 15,000 female victims [4].

Migrants

Migrant individuals are easy targets for domestic servitude because they are cheap labor, and their abusers face low risk of prosecution [3,5,8,10,33]. Mexican indigenous women are especially vulnerable due to “structural poverty, marginalization, social exclusion, and a traditional[ly] patriarchal culture” [28,33]. Elderly migrant family members are targeted for access to their benefits [3].

Consequences of Human Trafficking

Victims of human trafficking often have “multiple sexually transmitted infections and abortions, poor dental hygiene, and severe or recurring head and neck trauma from forced oral sex” [6,28,30,33]. They develop somatization, immunosuppression, inflammation, headaches, dizzy spells, exhaustion, back pain, memory problems, unintentional weight loss, nausea, indigestion, cancer, heart disease, high cholesterol, asthma, and gastrointestinal, muscular, and neurological symptoms [37]. Trafficked children and adults can develop complex posttraumatic stress disorder [26,31,38]. Victims, regardless of age, can have an increased risk for “anxiety disorders, Stockholm syndrome, major depressive disorder, substance abuse, self-harm, and suicide ideation” [30,31,33]. Traffickers often force drugs on victims as a means of control and exploitation [28,39].

Understanding Healthcare Workers and First Responders’ Roles

This policy brief follows a multidisciplinary approach and follows the Vera Institute of Justice-[40]’s Trafficking Victim Identification Tool (TVIT). The TVIT has been developed based on the latest research and best practices. It was designed for use by behavioral health, health care, social work, and public health professionals. The tool is a reliable, brief screen com1monly used in public health, health care, behavioral health, and social service settings. “The TVIT has been found to be valid and reliable in identifying victims of sex and labor” [8,40]. It is a statistically validated screening tool that encompasses both labor and sex trafficking, adult and child victims, and foreign nationals and United States citizens. It is available in long- and short-form. The tool is also available in Spanish” (National Human Trafficking Hotline, n.d., para. 1)-[18]. If the health care provider believes the patient is a human trafficking victim, they should follow agency policy and file a human trafficking report with the agency and city’s police departments (Vera Institute of Justice [40]. First, front desk staff will discreetly alert the provider if a patient screens positive for any red flags or indicators listed in the National Human Trafficking Resource Center’s (NHTRC) “What to Look for in a Healthcare Setting” (see Table 1, p. 34; Figure 1, p. 45). Examples of red flags or indicators are if a patient does not have a permanent address, if a patient does not appear to have a relation to the person accompanying them, or if a patient’s body language and communication style or those of the partner are combative or abusive [7,10,34,40].

Table 1: Human Trafficking Assessment Tool, Table of Steps for Front Desk Staff

1) Patient presents to clinic or emergency department. Go to step 2.

2) Front-desk staff check-in patient while discreetly screen for red flags and indicators listed in the Vera Institute of Justice’s Trafficking Victim Identification Tool by completing the following steps. Go to step 3.

3) Does the patient lack appropriate clothing for the weather, venue, or age? If yes or no, go to step 4.

4) Does the patient lack identification documents? If yes or no, go to step 5.

5) Does the patient appear to have a relation to the person accompanying them?If yes or no, go to step 6.

6) Is the patient’s companion overly involved (does not let the patient speak for themselves, refuses to let the patient have privacy, or interprets for them)? If yes, go to step 7. If no, go to step 8.

7) Discreetly alert the health care provider for further assessment.

8) Stop the assessment.

Note: Adapted from National Human Trafficking Resource Center. (n.d) Identifying victims of human trafficking: What to look for in a healthcare setting. http://surl.li/dshkj

Figure 1: Human trafficking assessment tool algorithm for front-desk staff

Second, the health care provider will assess the patient by using their own clinical judgment and by assessing for red flags and indicators listed on the NHTRC’s “What to Look for in a Healthcare Setting” (Figure 2 and Table 2) [40]. The NHTRC is referenced within the TVIT and provides a list of general indicators that clinicians may encounter during their assessments. The clinician’s verbiage should not expressly state “human trafficking” but should be generalized to avoid making the patient feel uncomfortable and alerting the patient’s companion (likely their trafficker). If the health care provider believes the patient may be a victim of human trafficking, the provider should discreetly refer the patient to a nurse or social worker for further assessment. Third, if criteria are met, a nurse or social worker should interview the patient in a private setting and out of sight of their companion [40]. The nurse or social worker should ask the victim a series of follow-up questions from the TVIT [8,10,40] (see Table 3, p. 35; Figure 3, p. 47). If the nurse or social worker believes the patient is a victim, and the patient is a minor, follow agency policy, make appropriate service referrals, alert the National Human Trafficking Hotline by calling 1-888-373-7888 or e-mailing NHTRC@PolarisProject.org, and file a report with the state’s Children, Youth, and Families Department as required by law [1] (see Table 3, p. 35; Figure 3, p. 47). If the nurse or social worker believes the patient is a victim, and the patient an adult, follow agency policy, make appropriate service referrals, and file a report with the National Human Trafficking Hotline [18] by calling 1-888-373-7888 or e-mailing NHTRC@PolarisProject.org (see Table 3, p. 35; Figure 3, p. 47).

Figure 2: Human trafficking assessment tool algorithm for health care providers

Table 2: Human Trafficking Assessment Tool, Table of Steps for Health Care Providers

1) Front-staff have discreetly alerted the health care provider about a possible human trafficking victim. Go to step 2.

2) The health care provider will perform a thorough physical examination while assessing for psychological and physical abuse, traumatic experiences, chronic substance abuse, or violent physical and psychological assaults. The clinician will look for signs and symptoms of human trafficking abuse by utilizing the National Human Trafficking Resource Center’s Identifying Victims of Human Trafficking: What to Look for in a Healthcare Setting. Accurate document the patient’s treatment and services offered. Go to step 3.

3) Based on the health care provider’s clinical judgement, does the health care provider believe that the patient may be a victim of human trafficking? If yes, go to step 4. If no, go to step 5.

4) The health care provider should accurately document patient’s injuries and treatment, and discreetly refer patient to an RN or SW for further evaluation.

5) Stop the assessment.

Note: Adapted from National Human Trafficking Resource Center. (n.d) Identifying victims of human trafficking: What to look for in a healthcare setting. http://surl.li/dshkj

Table 3: Human Trafficking Assessment Tool, Table of Steps for Nurse or Social Worker

1) The health care provider has discreetly alerted the nurse or social worker about a possible human trafficking victim. Go to step 2.

2) The nurse or social worker will discreetly conduct the Vera Institute of Justice’s Trafficking Victim Identification Tool in private, away from the patient’s companion. Go to step 3.

3) Based on the nurse or social worker’s clinical judgement, does the nurse or social worker believe that the patient is a victim of human trafficking? If yes, go to step 4. If no, go to step 7.

4) Is the patient a minor? If yes, go to step 5. If no, go to step 6.

5) The nurse or social worker should follow agency policy, make appropriate service referrals, alert the National Human Trafficking Hotline by calling 1-888-373-7888 or e-mailing NHTRC@PolarisProject.org, and file report with the state’s Children, Youth, and Families Department.

6) The nurse or social worker should follow agency policy, make appropriate service referrals, and file a report with the National Human Trafficking Hotline by calling 1-888-373-7888 or e-mailing NHTRC@PolarisProject.org.

7) Stop the assessment. Accurately document patient findings and services rendered.

Note: Adapted from Vera Institute of Justice. (2014). Screening for human trafficking: Guidelines for administering the trafficking victim identification tool. Vera Institute of Justice. https://humantraffickinghotline.org/sites/default/files/human-trafficking-identification-tool-and-user-guidelines.pdf

Figure 3: Human trafficking assessment tool algorithm for nurse or social worker

Impact and Significance

It is imperative that health care providers accurately document patients’ injuries and treatment and clearly distinguish between sexual exploitation or forced labor when reporting to law enforcement officers [41]. Studies have shown that police efforts mainly focus on sex trafficking cases instead of labor trafficking [42] Introduction section). In 2017, only 225 labor trafficking offenses were reported by police to the FBI’s Uniform Crime Reporting Program, representing only 18 percent of the total reported human trafficking offenses reported [42], Introduction section). Law enforcement often has difficulty distinguishing labor trafficking victims from legitimate workers because they work in intermingled conditions [42], Challenge 1 section). Without evidence that the forced labor victims suffered physical abuse, “law enforcement officers are skeptical that prosecutors will accept domestic servitude cases” [42], Challenge 3 section). The Trafficking Victims Protection Act of 2000 and the creation of the Civil Rights Division in the Department of Justice’s Human Trafficking Prosecution Unit within the Criminal Section in 2007 enables prosecutors to work with law enforcement agencies and attorneys to investigate human trafficking cases [30,36]. However, without the exchange of information between health care providers and law enforcement, efforts to identify and rescue human trafficking victims in the community is extremely limited [36]. Generally, victims who escape their traffickers seek assistance from and confide in health care providers instead of police [36]. There exists a gap in the connection between the two entities, which delays the early victim intervention and identification, often resulting in severe physical and mental injuries to victims [30,36]. Evidence suggests that health care providers should be trained by law enforcement officials assigned to a human trafficking task force [19] to ensure that clinicians recognize the warning signs that victims may present with, become familiar with intervention techniques, and understand how to deploy the task force’s protocols for rescue [36]. Collaborating efforts between law enforcement officers and health care providers can assist the human trafficking population. Because health care providers and victims have regular contact, if clinicians worked with law enforcement task forces, more victims could be identified and rescued [36]. Victims benefit from case management services from an interdisciplinary team. This joint approach provides comprehensive protection. Social workers can assist with connecting the patient with community resources for food, shelter, and clothing. Health care providers can render medical aid and provide hotline numbers for local anti-trafficking services such as the NHTRC [6,36]. Therapists can help the victim develop coping skills and reduce the symptoms of mental illness. Law enforcement officers who are trained in human trafficking can “identify the indicators of a human trafficking situation, secure evidence for subsequent prosecution, and refer victims to social service providers” [43].

Evidence Search Strategy, Results, and Evaluation

The search for current, 2016-2021, peer-reviewed articles which were published in academic journals was conducted via the University of St. Augustine for Health Sciences online library. These databases included Search University of St. Augustine (USA), PubMed, GALE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medical Subject Headings (MeSH), and Science Direct. Google Scholar was also utilized to locate open access articles. The following search terms were used to locate articles specific to this study: Human trafficking, sex trafficking, forced labor, human trafficking assessment tool, human trafficking algorithm, human trafficking assessment, human trafficking screening protocol, human trafficking policy, human rights, sexual exploitation, labor exploitation, domestic servitude, sex industry, commercial sex, trauma, United States, America, child welfare, homelessness, migrants, runaways, primary care providers, emergency department, health care providers, clinicians, nurses, nurse practitioners, legal nurse consultant, physician assistants, emergency room, emergency department, human trafficking persons, missing persons, adults, female, prostitutes, pimps, young adults, children, youth, adolescents, juveniles, and pediatrics. Variations of these terms were used to ensure detailed search results. The exclusion criterium was years prior to 2015. The results of the search yielded 21 research articles. One article dealt solely with sanctions and was eliminated from the selection. Several research articles were not of or related to America or the United States and were excluded.

Themes from Evidence Review

The main themes found in the literature were compared with national protocols, regulations, position statements, and accreditation standards. The literature included themes that human trafficking victims often go unrecognized by health care providers, staff lack human trafficking education, there is the need for a validated, reliable, and standardized human trafficking assessment tool, a multidisciplinary team approach is vital, and the law is explicit about human trafficking.

Human Trafficking Victims are not Recognized by Health Care Providers

A trend that was supported by the literature is that the use of a human trafficking assessment tool in the health care setting is necessary to help health care providers recognize victims of human trafficking. Leslie [2-5] and Stevens [7] concluded that health care providers are often the only professionals to interact with trafficking victims who are still in captivity, but these patients go unrecognized because clinicians do not assess for human trafficking (see Appendix A, pp. 49, 51-52, 54; Appendix B, pp. 57-58, 62, 65). Eighty-seven percent of victims were not recognized by their health care providers [1].

Staff Lack Human Trafficking Education

There were several recommendations for providing specialized human trafficking education to bridge the gap in staff knowledge and skills. Health providers and law enforcement officers are often unfamiliar with human trafficking signs and symptoms [10,36,42]. Results of the study reflect the need for formal education, screening, and treatment protocols for health care personnel and forensic investigators to guide the identification and rescue of victims of human trafficking [1,35,41]. Interviews revealed that the experience, approach, and content varied widely [44]. Potential improvements in current training approaches included standardization of training, metrics to evaluate and develop the evidence base for training impact, funding opportunities, survivor integration, and incentives to encourage training [44]. Providing education and screening tools improved recognition of trafficking victims and improved recognition of patients in other types of abusive situations, such as domestic violence and sexual assault [1] (see Appendix A, pp. 54-55; Appendix B, pp. 57-59, 62-63).

Need for a Validated Human Trafficking Assessment Tool

The most frequently cited intervention for identifying human trafficking victims was the use of a validated and standardized human trafficking assessment tool. Of the 14 descriptive non-experimental research articles of good quality, six resources agreed on recommendations to provide health care providers with a reliable and standardized assessment tool to improve recognition of trafficking victims by systematically detecting red flags and indicators [1,2,4,5,7,8,10,34,40] (see Appendix A, pp. 48-49, 52-54; Appendix B, pp. 60, 62-65). Both Leslie [2] and Powell, Dickins, and Stoklosa, [44] found that a validated and standardized method of screening increases the degree at patients experiencing sexual and labor exploitation will be identified (see Appendix A, pp. 52, 54; Appendix B, pp. 60, 63). Utilizing the TVIT to identify human trafficking victims ensures that key information is correctly and consistently provided to all health care providers [8,13,40].

Interprofessional Collaboration

Six articles examined the need for a multidisciplinary team approach [3,4,7,10,36,41] identified emergency room nurses, risk managers, and clinical educators (pp. 30-32). McDow & Dols (2020) [4] named “nurse managers, health care providers, ultrasound technicians, nursing assistants, and volunteers” (p. e1). Health care professionals and law enforcement officials should unite to identify and rescue victims [36]. Multidisciplinary teams should be educated to assist victims [10]. Stevens & Dinkle [7] identified administrators, technology teams, primary care providers, and staff as members of the interdisciplinary team (p. e2) (see Appendix A, pp. 50, 52, 54, 56; Appendix B, pp. 58, 60, 61).

The Law Is Explicit about Human Trafficking

Health care providers are required by this southern state’s Administrative Code NMAC 7.1.14 to call the ANE Hotline, 1-800-445-6242, that an incident of abuse, neglect, exploitation, suspicious injury, environmental hazard, or death has occurred (New Mexico Department of Health-[29], n.d.). Child Protection Services must be alerted as required by law [1]. There are child abuse laws [1]. The law specifies that there are no child prostitutes [8]. Child soldiering, debt bondage, and bonded labor are unlawful [1,2]. Child Protection Services must be alerted as required by law [1]. Federal law requests human trafficking training for health care providers [2]. Low human trafficking detection results from ineffective laws [2]. Child soldiering, debt bondage, and bonded labor are unlawful [2]. There are mandatory reporting laws and safe harbor laws [2,10,21,26]. Federal law does not require proof that a defendant used force, fraud, or coercion to determine the action of trafficking when the victim is a minor [3] (see Appendix A, pp. 48-51, 54-55; Appendix B, pp. 57-60, 62-64).

Best Practice Recommendations

A thorough review of the literature guided these evidence-based guidelines and recommendations to improve human trafficking practice for health care providers. Evidence from the literature proved that human trafficking victims often go unrecognized by health care providers. Based on the conclusions drawn from the evidence, the following practice recommendations are encouraged. 1) Health care providers should seek assistance from multidisciplinary teams comprised of front desk staff, nurses, health care providers, social workers, therapists, ultrasound technicians, nursing assistants, volunteers, and law enforcement. 2) The teams should be trained in human trafficking to keenly identify victims, assess victim needs, efficiently employ a victim-service delivery model, accurately document patient injuries and treatment, and report incidents of violence and victimization according to institutional policy, thereby allowing law enforcement to investigate allegations and rescue victims [41]. 3) Research established the need for a validated, reliable, and standardized human trafficking assessment tool, which would be useful for increasing the number of identified victims by health care providers who are knowledgeable about human trafficking red flags and victim indicators [1,2,4,5,7,8,10,40]. 4) Health care providers in this southwestern American state, because of their obligation to promote the well-being of patients, have an ethical obligation to take appropriate action to avert the harms caused by human trafficking that includes mandatory reporting to remain compliant with state law (New Mexico Department of Health [29].

Endorsements

These human trafficking evidence-based guidelines and recommendations are endorsed by the Emergency Nurses Association (ENA)-[45] and the International Association of Forensic Nurses (IAFN). In their joint human trafficking position statement, the ENA and IAFN support health care providers “appropriate education and training” about human trafficking, working collaboratively with community partners and criminal and civil justice systems, and reporting suspicions or behaviors as required by law (Emergency Nurses Association, 2018) [45]. In addition, the American Academy of Pediatrics Policy Statement on Global Human Trafficking and Child Victimization recommends that health care providers serving children be trained about human trafficking and its relation to immigration [34,35].

Conclusion

Human trafficking is a federal and international crime and is commonly regarded as one of the most pressing human rights issues of our time. Adult and minor victims are trafficked by force (rape, beatings, confinement), fraud, and coercion (Department of Homeland Security, 2020) [12]. Early identification of human trafficking victims by their health care providers is critical because the average life expectancy of a human trafficking victim is seven years [6]. To increase efficacy, research recommends that health care providers should be adequately trained and use a validated, reliable, and standardized human trafficking assessment tool such as the Vera Institute of Justice-[40]’s Trafficking Victim Identification Tool [8,10,40]. Health care providers should seek assistance from multidisciplinary teams that include law enforcement [4,36,40]. This practice will help streamline victim identification, assess victim needs, employ a victim-service delivery model, and report incidents of violence and victimization with efficiency. The purpose of this policy is to increase clinician human trafficking efficacy by introducing best practice guidelines and recommendations for health care providers [46-50].

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Direct Air Capture and Removal of Gigatons of CO2 Offers Hope for Climate Recovery

1 Reply

DOI: 10.31038/GEMS.2022432

Abstract

The Summer of 2022 caused China’s heat wave to shatter records, bringing the country’s hydropower electricity into question, while in the U.S. it delivered five 1,000-year rain events in five weeks to several Midwest states.¹ It is proposed that the linear, inextricably tight correlation between global CO₂ values and global temperature, delineated and publicized by James Hansen and others, will finally create an urgency in the minds and hearts of all people, so that international direct air carbon capture by the gigaton can begin in earnest and in parallel with carbon-free fuels, zero carbon emissions, renewable energy, and even negative carbon emissions, implemented worldwide. This dual track proposal can immediately begin the reversal of global temperature in direct proportion to the decrease in the excess, heat-trapping atmospheric CO₂. In that way, more time will be allocated for the world to convert to 100% renewable energy and thus begin to drastically reduce its carbon emissions, which add about 40 gigatons of CO₂ to the air blanket above us every year. The second phase of the X-Prize Carbon Removal for the 2022 million dollar candidates, among other industrial processes already in motion, will demonstrate novel and inexpensive methods for capturing billions of tons of atmospheric carbon dioxide for permanent removal in 2025. This contest adds to other hopeful signs for global reversal of temperature and sea level rise.

Introduction

As global warming becomes more pronounced, obvious, and severe, the term “climate emergency” is re- emerging as a clarion call. Bill McGuire, author of Hothouse Earth: An Inhabitant’s Guide, says we need to be “hard-hitting enough to galvanize action and trigger behavioral change” with the aftermath of wildfires and floods [1,2]. Others, such as Professor Naomi Oreskes from Harvard University, have a more pessimistic view of “Wishful Thinking in Climate Science” since many programs around the world have small throughput, high cost per ton, or have simply been canceled after millions spent on the attempt [3]. Adam Vaughan agrees, noting that most major carbon capture and storage projects have not met their targets [4]. Meanwhile, the Amazon rainforest may have reached a crucial tipping point which will turn forest into a savannah according to a recent report from nine countries and territories that encompass the Amazon region [5]. Therefore, we need to have a “longtermism” attitude instead of a dystopian view, according to Professor William MacAskill, author of What We Owe the Future, as he insists that “improving the world for future generations is one of humanity’s most pressing tasks that urgently demand our attention [6]. My work in this area [7-9] has focused on the stellar work by James Hansen, who in 1988 was the first to predict a global “greenhouse effect” from a 3-D model developed at the NASA Goddard Institute for Space Studies but using the onerous phrase “climate forcing [10].” Since such a concept was not yet accepted by the public, the paper was shunned by academic critics and Hansen was declared to be “wrong” by most of the media at the time, threatened to lose his job, and generally criticized by everyone. In Figure 1, a slide from one of my presentations (ref. 7), offers a reproduction of Hansen’s now famous climate graph of the earth’s 400,000 year history, including the surprisingly overlapping plots of global temperature, CO₂ and sea levels, along with a corroborating NOAA graph for the same period of time.

Figure 1: Earth’s 400,000 year history of temperature, carbon dioxide and sea levels

In 1999, the Vostok ice core 420,000-year record of carbon dioxide was published by Petit et al. [11] Exhibiting great stability, the CO₂ levels clearly have never exceeded 290 ppm worldwide even through four ice ages. However, in the isolated monitoring station cited above for our modern, with our wanton fossil fuel carnage, the latest global carbon dioxide levels have now exceeded 410 ppm, with apparent disregard for the consequences. Notice in Figure 1 the important clearly tight correlation of temperature (blue graph) and carbon dioxide (red graph) for the past 420,000 years, which leads us to the obvious problem of the red line at the far-right side (present time), which extends dramatically above the maximum seen in the graph for the past 400,000 years. We are forced to admit the historic red and blue data lines don’t lie, so the axis label of CO₂ concentration on the left necessarily correlate to the axis label of global temperature on the right. This is the most important realization that arises from Hansen’s Table of vertical axis variables that are found in this 2006 MIT Technology Review article [12]. While climatologists know this relationship exists, the United Nations Environmental Program (UNEP) and the International Panel on Climate Change (IPCC) among others are slow to realize the consequences of the present CO₂ excess, which now surpasses 40% of the maximum 290 ppm the earth has ever experienced in over 420,000 years. The Hansen Equation that emerges from his Table of data becomes the key with:

(+/-) 20 ppm of CO₂ = 1°C = 20 m change in sea level. Eq. (1).

Thus, it is vital to understand from Hansen’s careful measurement and plotting of the Vostok data, into the Hansen Equation summarizing it in a condensed form that we are indebted for at least 8 degrees C increase in temperature, which will manifest approximately by 2100 with the business-as-usual scenario [13]. Even a 6°C increase worldwide by 2100 will be devastating and is considered a mass extinction event [14]. Mark Lynas, author of Our Final Warning: Six Degrees of Climate Emergency, predicts that a five-degree world is where the tropics and sub-tropical regions are subjected to year-round deadly heat with large areas of uninhabitable zones, due to the high temperatures. Global food production will be decimated with ground-based agriculture only possible in diminishing zones of habitability in the highest latitudes. He also suggests that a five-degree world will have surviving humans crammed into refugee areas in Greenland and the Antarctic Peninsula, similar to the Eocene Period 50 million years ago with similar temperatures and CO₂ levels. “Six-degrees sees the greatest mass extinction ever on Earth, greater than the end-Permian cataclysm that destroyed 90% of species alive at the time.” He further notes that our present rate of carbon emissions is about ten times the rate that of the end-Permian period and actually unprecedented in all of geological history [15]. The uninhabitable earth scenario is presently upon us, with each decade becoming hotter by about one degree C, unless something drastic is done to the atmosphere globally, such as iron fertilization of the oceans to periodically create algae blooms, geoengineering the atmosphere with albedo reflectivity particles which have been proven to settle on the earth’s surface soon after, or the simplest and perhaps the safest: gigaton direct air capture to reduce the amount of carbon dioxide in the air [16].

Direct Air Carbon Capture

To be considered as mankind’s only real recourse to practically reverse the inexorable temperature rise in the same time frame it took to go up, while grabbing the same amount of carbon that went up, Direct Air Capture (DAC) is the latest and growing trend among large movers and shakers, such as the X-Prize Carbon Removal https://www.xprize.org/prizes/elonmusk and Project Vesta https://www.vesta.earth/. Using a special type of carbon-removing sand made of a natural mineral olivine, Project Vesta accelerates the earth’s own long-term process of rock weathering by grinding olivine minerals into sand and letting the ocean react with it to bind CO₂ permanently in seawater over decades [17]. Vesta.earth has received endorsement from MIT Technology Review, The Guardian, and the National Academies of Sciences, Engineering, and Medicine, besides Bill Gates. Along the same lines, Professor David Beerling at the University of Sheffield, UK, has found that ground up basalt can also absorb carbon from the air. His plan is to sprinkle it on farm lands in the UK to absorb 6 to 30 million tonnes of carbon dioxide per year, which would meet about half of the UK’s net-zero target [18]. One of the 15 X-Prize Milestone winners, who go onto the three-year development stage is Captura from Pasedena CA, which is doing just the opposite process. Captura is developing CO₂ capture and sequestration technology for extracting CO₂ from oceanwater that is scalable to Mton/year – Gton/year to meet the rapidly growing demand in the carbon credit market. Captura’s approach leads capture of high-purity CO₂ and restores pH balance in oceanwater. Another Milestone Award Winner is the Pennsylvania State University which proposes to use millions of African farms to sequester up to 1 gigaton per year of CO₂ from the air https://plantvillage.psu.edu/. (Note: The “gigaton” and the metric version “gigatonne” are very close within a few percent in value so they are used interchangeably in this article). Credit must be given to Elon Musk for envisioning this standard process repeatedly used throughout the history of the technological age to rapidly develop a new process that does not presently exist: offer a huge cash prize for the winner. Here, the grand X-Prize winner in 2025 will receive $100 million from the Musk Foundation for the best gigaton carbon dioxide removal scheme. As the xprize.org website states, “The climate math is becoming clear that we will need gigaton-scale carbon removal in the coming decades to avoid the worst effects of climate change. The International Panel on Climate Change (IPCC) estimates the need at approximately 10 gigatonnes of net CO₂ removal per year by the year 2050 in order to keep global temperature rise under 1.5 or 2C. As governments, companies, investors, and entrepreneurs make plans to meet this challenge, it is clear that we will need a range of carbon removal solutions to be proven through demonstration and deployment to complement work that is already underway. If humanity continues on a business-as-usual path, the global average temperature could increase 6°C by the year 2100.

“This four-year global competition invites innovators and teams from anywhere on the planet to create and demonstrate solutions that can pull carbon dioxide directly from the atmosphere or oceans, and sequester it durably and sustainably. To win the grand prize, teams must demonstrate a working solution at a scale of at least 1000 tonnes removed per year; model their costs at a scale of 1 million tonnes per year; and show a pathway to achieving a scale of gigatonnes per year in future. “Any carbon negative solution is eligible: nature-based, direct air capture, oceans, mineralization, or anything else that achieves net negative emissions, sequesters CO₂ durably, and show a sustainable path to achieving low cost at gigatonne scale.” Mission Zero Technologies and Project Hajar became another $1M Milestone Award Winner while developing direct air capture (DAC) technology that will recover high-purity CO₂ from the air while incurring only a fraction of the costs and energy it takes to do so today. It has received seed funding from a number of sources https://www.missionzero.tech/news to produce a 100+ ton/year DAC pilot plant in the UK and elsewhere, which stores atmospheric carbon in the peridotite rock of the upper mantle of the earth. However, very few of these competitors in the X-Prize seem to be capable of providing a “pathway” to even a “net 10 gigatons/year” of carbon removal from the air (which technically should be a gross amount of 50 gigatons/year to offset the 40 Gt/yr we send up there each year). One ray of hope, among many workable climate solutions, is the recent discovery of an alloy of gallium, indium, and tin that is liquid at room temperature and conducts electricity. By spiking the silvery mixture with a sprinkling of catalytically active cerium and placing it inside a glass tube, along with a splash of water, scientists have now proven a room temperature method to convert CO₂ to carbon, instead of the usual high temperature procedure. Chemists Dorna Esrafilzadeh and Torben Daeneke at RMIT University in Melbourne, Australia, turned to a new class of catalysts made from metal alloys that are liquid at room temperature [19]. This is a process that can be scaled up, since it is catalytically driven, and may someday offer a novel and inexpensive method for capturing billions of tons of atmospheric carbon. Such inventions and ongoing projects are the main focus of this short update on carbon capture, removal and storage. A noteworthy comment summarizing large-scale gigaton carbon capture is Professor Chris Jones from Georgia Institute of Technology. “These approaches are low cost at under $100 per ton of captured CO₂, ‘but there’s only so much land change you could make to capture a significant amount,’ he says. ‘We need to capture 10 gigatons per year for negative emissions by 2060. Land and biomass approaches only scale to a few gigatons.’ Of known carbon-removal techniques, two hold the most promise, he says, citing a recent National Academies report. One is DAC and the other is carbon mineralization. “Nothing prevents us from scaling these up to the 10 gigatons per year scale needed aside from a commitment, coordination and cooperation [20]. In the same article, Raghubir Gupta from Sustaera https://www.sustaera.com/ boasts the largest carbon capture record so far at the lowest cost (also a Milestone winner). “One big thing we have that not many others have is practical experience of scaling up the technology to 1,000 tonnes/day carbon dioxide capture,” he says. “With that background when we looked at CO₂ removal from air, we thought the two things that are most important to really make a difference are cost and scale. It’s not the efficiency of the process [21].

Sustaera uses cheap sodium carbonate to adsorb CO₂. It coats the material on a high-surface area ceramic scaffold used in catalytic converters. The high surface area increases access to the sorbent and increases CO₂ adsorption rate significantly. The energy advantage comes from using electricity instead of heat to separate the CO₂ and regenerate the sorbent, at a cost of under $100/ton. To finish this section, my favorite DAC company, working since 2015 on this technology, is Carbon Engineering from Canada (Figure 2) https://carbonengineering.com/our-story/ producing synthetic fuel from the captured CO₂ with AIR TO FUELS^TM plants in several markets around the world. Their latest facility in the Permian Basin, US, is expected to capture one million tons of CO₂ from the air annually when complete, so it can be permanently and safely stored deep underground in geological formations, using a potassium hydroxide sorbent coupled with a calcium caustic recovery loop in the process. They have also partnered with Storegga in the UK https://www.storegga.earth/ to accomplish one million tonnes of DAC annually.

Figure 2: Hansen Challenge: All of the facts to convert any chosen number of excess CO₂ in ppm to gigatons, where A2 is the business as usual scenario for carbon emissions worldwide.

The challenging calculation reflected in Figure 2 of the numbers results from an attempt to sequester 50 gigatons (with 40 Gt subtracted for many more decades to come) every year if the world is fortunate enough to discover a very inexpensive means to capture CO₂ in that quantity reliably [22].

Conclusion

A proposed world recovery plan is directed the world’s government leaders and approximately one thousand billionaires to form a DAC Gigaton Consortium that takes multi-gigaton DAC seriously, beginning as soon as possible, in order to actually LOWER the earth’s 412 ppm of CO₂ steadily each year for decades until 350 ppm and furthermore, the long-sought-after 290 ppm global level is reached. It is a guarantee, even as IPCC is now in 2022 beginning to realize, that without any more excess levels above 290 ppm (global maximum seen in 400,000 years of Figure 1), the world’s temperature will literally, inevitably, and steadily lower itself back down to a comfortably temperate zone. To the mathematicians and scientists who read this, Equation 1 is both positive and negative with all three variables proportionally and linearly dependent on the leading change which occurs first in time (CO₂, temperature, or sea level), whether plus or minus. We as a species have been spoiled with about 10,000 years of an interglacial period, giving us moderate temperatures worldwide and now we have to pay dearly for the self-created disruption in the former stability in order to regain it once again. Each year that we wait to perform 50 GT/yr of DAC adds about 40 Gt to the total excess 466 Gt that needs to be removed to restore our planet to livable conditions.

References

Cappucci, Matthew, Five 1,000-year rain events hit the U.S. in five weeks, Washington Post, Aug. 26, 2022.
McGuire Bill (2022) Advertising Crisis, New Scientist.
Oreskes, Naomi (2022) Wishful Thinking in Climate Science. Scientific American.
Vaughan, Adam (2022) Most major carbon capture and storage projects haven’t met targets. New Scientist.
Taylor Luke (2022) The Amazon rainforest has already reached a crucial tipping point. New Scientist.
MacAskill William (2022) Planning Ahead. New Scientist.
Valone Thomas (2019) Jacqueline Panting. Quantitative Carbon Dioxide, Temperature, and Sea Level Relation for the Future of Terrestrial Fossil-Fueled Technology, An Accurate Predictive Model Based on Vostok 420 kY Historical Record. IEEE International Symposium on Technology and Society (ISTAS) Proceedings, 15-16 November, School of Engineering, Tufts University, Medford MA. https://wwslideshare.net/ThomasValonePhD/valone-ieee-istas2019ppt-ver4-with-extra-slide-withlinks-at-end, sponsored by the IEEE Society for Social Implications of Technology.
Valone, Thomas, Predictive Connection for 2100 between Atmospheric Carbon, Global Warming and Ocean Height Based on Climate History, International Journal of Environment and Climate Change, 9(10): 562-594, 2019; Article no.IJECC.2019.048, ISSN: 2581-8627, DOI: 10.9734/IJECC/2019/v9i1030140
Valone Thomas (2020) Global Environmental Forecast and Roadmap Based on 420 kY of Paleoclimatology. Journal of Atmospheric Science Research 3.
Hansen J, Fung I, Lacis A, Rind D, Lebedeff S, et al. (1988) Global climate changes as forecast by Goddard Institute for Space Studies three-dimensional model. Geophys. Res. 93: 9341-9364.
Petit JR, Jouzel J, Raynaud D, Barkov NI, Barnola JM, et al. (1999) Climate and Atmospheric History of the Past 420,000 years from the Vostok Ice Core, Antarctica. Nature 399: 429-436.
Hansen James (2006) CO2 and the Ornery Climate Beast. Technology Review.
Brown Patrick, Ken Caldeira (2017) Greater future global warming inferred from Earth’s recent energy budget. Nature 552: 45-50.
Six Degrees Could Change the World Geographic Society.
Lynas, Mark (2020) Our Final Warning: Six Degrees of Climate Emergency, HarperCollins Publishers.
Goodell Jeff (2010) How to Cool the Planet, Mariner Books, Houghton Mifflin Harcourt.
Temple James (2020) How green sand could capture billions of tons of carbon dioxide. MIT Technology Review.
Kantzas EP, Maria VM, Mark RL, Rafael ME, Phil R et al. (2022) Substantial carbon drawdown potential from enhanced rock weathering in the United Kingdom. Nature Geoscience 15: 382-389.
Service, Robert F (2019) New way to turn carbon dioxide into coal could ‘rewind the emissions clock’, Science.
Patel P (2022) XPrize Competitors Capture Carbon > $100 million at stake in CO2-removal face-off, IEEE
Ibid, p. 6.
Zeman F (2014) Reducing the cost of Ca-based direct air capture of CO2. Sci. Technol 48: 11730-11735.

Foraminifera from a Middle Eocene Algal Reef Limestone at Burton Guyot (IODP Site U1376) in the Southwest Pacific

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DOI: 10.31038/GEMS.2022431

Abstract

IODP site U1376 was drilled on Burton Guyot on the Louisville Seamount Trend in the South Pacific. Site U1376 encountered an algal reef limestone from 23.45-38.60 mbsf immediately overlying a 3 m thick basalt pebble conglomerate above the volcanic basement rocks in the area. This limestone section was reported as Cretaceous in age by the shipboard party based on possible late Cretaceous rudist fossils in the underlying conglomerate, but planktonic foraminifera suggest a Paleogene (possibly Eocene) age. Paleogene algal reefs are of interest as many have rhodophyte and macroforaminifera as the framework builders of the reef (foralgal reefs) and many represent an equilibrium reef stage during global warmth. Most known foralgal reefs such as the Salt Mountain Limestone of Alabama developed along continental shelves. Others such as Red Gal Ring in Jamaica and the Uitoé Limestone in New Caledonia developed within active tectonic zones. Site U1376 represents a unique opportunity to examine a foralgal reef which developed in isolation. The limestone section in site U1376 (referred to henceforth informally as the Burton Guyot limestone) consists of 15.15 m of rhodophyte coralline algal boundstones. Assemblages of both crustose and frondose forms of the rhodophytes occur in five distinct zonations within the Burton Guyot limestone. The zones of frondose rhodophytes represent a response to increasing accommodation (catch-up growth) produced by some combination of subsidence and rising eustatic sea level. The zones of crustose rhodophytes in the core represent the growth response during high stand (keep-up growth) and likely represent limited available accommodation space. Erosional surfaces at the tops of the crustose zones represent sea level change. In the initial shipboard description of the Burton Guyot limestone, only isolated foraminifera was reported. Examination of the thin-sections revealed numerous foraminifera. Planktonic foraminifera are more abundant than benthonic, and macroforaminifera are less abundant than in other foralgal reefs. In contrast to the foralgal reefs in the Gulf Coastal Plain, Jamaica, and New Caledonia, macroforaminifera play only a minor role in the framework of the reef structure. The planktonic foraminifera identified are Subbotina eocaena, Catapsydrax univcaus, Catapsydrax sp., Globorataloides quadrocarmeratus, Parasubbotina eocclova, Globigerina officinalis, Parasubbotina varianata, Turborotalia pomeroli, and Turborotalia frontosa. This assemblage indicates an age of middle Eocene (late Lutetian 41 Ma).

The middle Eocene foralgal reef that developed on Burton Guyot has a much simpler sedimentary architecture than the other foralgal reefs studied. This may be due to a dominant role of subsidence in the creation of accommodation on Burton Seamount. It may also be due to the direct interaction of oceanic process with the reef framework builders as opposed to interaction with continental margin processes. Further study of the Burton Guyot limestone may refine the paleoecologic controls on the development of isolated reefs during the Paleogene.

Introduction

The Integrated Ocean Drilling Program (IOPD) site U1376 was drilled on Burton Guyot as a part of Expedition 330 on the Louisville Sea Mount Trail in the Southwest Pacific (Figure 1). During drilling, an algal reef limestone (Subunit IIA of the expedition 330 Scientist, 2012) was encountered immediately overlying the volcanic basement units and a thin (3.3 m) basalt conglomerate. The algal reef limestone unit (here in referred to informally as the Burton Guyot limestone) is 15.15 meters in thickness and is overlain by shallow water volcanic sandstone and breccias. The unit is underlain by 3.3 m thick heterolithic basalt conglomerate lying directly on the volcanic basement. The Burton Guyot limestone is primarily a rhodophyte boundstone. The age of the Burton Guyot limestone is uncertain, having been reported as late Cretaceous by the Expedition 330 Scientist (2012) [1]. The age assessment was inferred by the presence of rudist fragments in the underlying conglomerate bed. The lack of rudists in the Burton Guyot limestone suggests a younger (Paleogene) in age. Koppers et al. (2012) suggested an age of ~65 Ma for the volcanic basement of the Burton Seamount. This is a Paleocene (Danian) age according to Gradstein et al. 2012 [2] and 2020 [3] and indicates that the Burton Guyot limestone is younger. Preliminary macroscopic examination of samples of the Burton Guyot limestone indicated the presence of both crustose and frondose rhodophytes. Additionally, some macroforaminifera were seen in the samples. The presence of these fossils and the inferred Paleogene age suggests the possibility that the Burton Guyot limestone may have originated as a foralagl reef. A foralgal reef is a bioherm where rhodophytes and macroforaminifea are the primary framework builders. They are the dominant type of reef found in the Paleocene and Eocene rocks worldwide. Foralgal reefs are of interest as they may represent a reef type which is in equilibrium with greenhouse climatic condition. Foralgal reefs may represent a model for future change in Neogene and Quaternary coral reefs. Some of the better known foralgal reefs include the Paleocene Salt Mountain Limestone of Alabama (Toulmin, 1941; Bryan et al. 1997) [4], the middle Eocene Red Gal Ring section in Jamaica (Robinson, 1974) and the middle Eocene Uitoe Limestone of New Caledonia (Harrison, 2013). While these three foralgal reefs are known to respond to change in relative sea level change, all three are in settings where the preserved eustatic signal is weak. The Salt Mountain foralgal reef developed at lowstand in a coastal plain setting influenced by salt tectonics. Both the Red Gal Ring and Uitoe foralgal reef s developed in active convergent tectonic settings. By contrast, the foralgal reef of the Burton Guyot limestone developed in isolation with accommodation produced by subsidence associated with Louisville Seamount Trail hotspot. Sequential change in the biofacies identified within the Burton Seamount limestone should record changes sea level associated with subsidence of the Louisville Seamount Trail and eustasy.

It is the purpose of this paper to examine thin sections of the Burton Guyot limestone for foraminifera with the goals of:

Correlating this limestone to the geologic time scale of Gradstein et al. (2012) [2] via planktonic foraminiferal
Describe the succession of the biofacies present in the Burton Guyot limestone to produce a relative sea level curve for the

Figure 1: The general location of the study area [5]

Geologic Setting

The Louisville Seamount Trail is a Southeast-Northwest linear trend of seamounts located on the southwestern Pacific Plate from approximately 45^° 32’ S, 157^° 23’ W to the convergent boundary with the Australian Plate. OPD Expedition 330 the trend to better understand better the relationship between the geologic history of the Louisville Seamount Trail and the Hawaiian –Emperor Seamount Trail and whether a motion on two associated hotspots moved in concert (IOPD Expedition 330, 2012) [1]. IOPD site U1376 on Burton Guyot was the only site among the six drilled in Expedition 330 which encountered biohermal limestone. The Burton Guyot limestone is found from 23.45 meters below seafloor (mbsf) to 38.60 mbsf in site U1376 (Figure 2). The lithologic characteristics and core recovery of this unit did not permit an even sampling interval. A total of 22 samples were collected, and thin sections were prepared. These thin sections are housed in the biostratigraphy Laboratory at Ball State University. The sample location in the core and the lithologic description of each thin section are shown in Table 1. The Burton Guyot limestone was identified by Expedition 330 Scientists (2012) [1,5] as rhodophyte boundstone. While rhodophytes are abundant, detailed examination of the Burton Guyot limestone in thin sections reveals a diverse suite of carbonate lithologies. Wackestone, packstone, and grainstone are present in the thin section. All these lithologies contain abundant fossils fragments. Both crustose and frondose forms of the rhodophytes occur throughout the Burton Guyot limestone. In addition to the rhodophytes, abundant by fossil fragments of echinoderms, pelecypods, gastropods, ostracodes, and coral are present. Planktonic foraminifera, small benthic foraminifera, and macroforaminifera are rare throughout the core with the planktonic foraminifera being the most abundant. The detailed lithology of the studied interval is shown in Figure 1.

Figure 2: The columnar section of the study area

Table 1: Description of the core samples

Location/Location IOPD Expedition 330 -site U1376	Code Side	Sample NO	Depth	Dunham Classification	Lithology Description
	3R 4W 31/33	1	0.69 cm	Mudstone	Yellow to a creamy color, medium hard.
	3R 4W 108/110	2	0.32 cm	Grainstone	White color, hard, coral fragments, and fossils fragments.
	3R 4W 133/135	3	1 m	Grainstone	White to yellow color, hard, coral fragments. Subbotina eocaena
	3R 5W 40/42	4	0.28 cm	Grainstone	White color, hard, Coral sp?, fossils fragments. Alabamina sp.,
	3R 5W 98/100	5	0.3 cm	Grainstone	White color, hard, fossils fragments.
	3R 5W 135/137	6	1 m.166 cm	Pack-Grainstone	White color, hard, and fossils fragments. Catapsydrax univcaus. Catapsydrax sp.,
	3R 6W 37/38	7	0.68 cm	Grainstone	White color, hard, fossils fragments. Heterostegina sp.,
	3R 4W 4/6	8	2 m.204 cm	Pack-Grainstone	Yellow to brown color, medium hard
	4R 1W 25/27	9	0.69 cm	Pack-Grainstone	White color, hard, fossils fragments. Catapsydrax univcaus.
	3R 6W 4/5	10	0.75 cm	Grainstone	White color, medium hard, fossiliferous. Note: black grains might be resulted from leaching igneous rock
	4R 2W 20/22	11	0.26 cm	Boundstone	White to brown color, hard, a trace of fossil fragments. Parasubbotina varianata
	4R 2W 45/47	12	1 m.08 cm	Pack- Grainstone	White to brown color, medium hard, traces of gastropod.
	4R 3W 6/8	13	1 m	Grainstone	White color, medium hard, fossiliferous. Globorataloides quadrocarmertus Parasubbotina eocclova Lagena sp., Discocyclina ( Discocyclina) marginata?
	4R 3W 96/98	14	0.41 cm	Wack- Packstone	White color, hard, fossils fragments. Parasubbtina ecoclava.
	4R 4W 5/6	15	0.50 cm	Grainstone	White to brown color, medium hard Turborotalia pomeroli Cibicidoides micrus
	4R 4W 27/29	16	0.78 cm	boundstone	White color, medium hard, fossiliferous. Globigerina officinaliss
	4R 4W 90/92	17	0.35 cm	Grainstone	White color with pink spots, medium hard, fossil fragments
	4R 4W 75/77	18	0.5 cm	Grainstone	Yellow to brown Color, medium hard, calcite grains appearance. Paragloborotalia (Turborotalia)griffinoides
	5R 1W 5	19	0.97 cm	Mud-Wackstone	Gray to black color, very hard.
	5R 1W 8/10	20	0.64 cm	Packstone	White color, medium hard, abundant by gastropods and fossils fragments.
	5R 1W 77/79	21	0.97 cm	Wack-Pacstone	Brown to Black color, very hard. Turborotalia frontosa
	5R 1W 95/96	22	1m	Mudstone to Wackstone	Gray to black color, medium hard

Results and Discussions

Abundance and Stratigraphic Distribution of Foraminifera, Site-U1376

Planktonic foraminifera were identified in thin-section throughout the Burton Guyot limestone. Ten species were identified in the studied interval. They include Catapsydrax unicavus, Catapsydrax sp., Globorotaloides quadrocameratus, Paragloborotalia griffiniodes, Parasubbbotina eoclava, Parasubbbotina varianta, Globigerina officinalis, Subbbotina eocaena, Turborotalia frontosa and Turborotalia pomeroli. Planktonic foraminifera are rare in the Burton Guyot limestone occurring in only 10 of the 22 studied thin-sections. Additionally, most of the species are represented by only a single specimen. The distribution of the planktonic foraminifera from the Burton Guyot limestone is shown in Table 2. Some benthic foraminifera were found in the thin-sections. These have been identified as Alabamina sp., Cibicidoides micrus, and Lagena sp., all long ranging taxa. Two specimens of macroforaminifera (Discocyclina marginata and Heterostegina sp,.) were also found in the thin-sections of the Burton Guyot limestone. The low number of macroforaminifera was surprising as other foralgal reefs around the world contain macroforaminifera as a conspicuous part of the fauna. The distribution of smaller benthic foraminifera and macroforaminifera in the Burton Guyot limestone are shown in Table 3. Assemblages of both crustose and frondose forms of the rhodophytes occur in five distinct zonations within the Burton Guyot limestone. The zones of frondose rhodophytes represent a response to increasing accommodation space (catch-up growth) produced by some combination of subsidence and rising eustatic sea level as shown in Figure 2.

Foraminiferal assemblages, it is only a minor component of those assemblages. Isotopic studies of C. unicavus indicate it occupied a deep planktonic habitat and its relative abundance at Burton Guyot are consistent with an environment characterized by subsidence. By comparison, the foraminifera from the other Paleogene foralgal reefs in the Salt Mountain Limestone of Alabama and the Uitoé Limestone of New Caledonia, are relatively more abundant in their respective sections as shown in Figure 3.

Table 2: Distribution of biostratigraphically important foraminifera in the Burton Guyot limestone

Figure 3: The abundance and stratigraphic distribution of planktonic foraminifera at Site – U1376, in the form of a frequency diagram. The y-axis represents the species name, and the x-axis represents the percentage of species.

Across the LLTM (The Late Lutetian Thermal Maximum) Benthic foraminifera species were not extinct, but mild assemblage shifts indicate environmental disturbances, perhaps due to variations in the type of organic materials transported to the seafloor. Based on thin sections from this core, the representative benthic foraminifera assemblages are less prevalent in this section, with a distribution of less than 1% This provides insight into how the depth of the sea level has changed and been impacted by it as seen in Figure 4.

Figure 4: The stratigraphic distribution and abundance of benthic foraminifera at Site U1376. Note that the x-axis displays the proportion of species.

Stratigraphic Range of Planktonic and Benthic Foraminifera (Eocene) Species

The two next figures show the age estimate of both planktonic and benthic foraminifera based on the biohrizonsLourens et al. 2004, which confirmed all the species are Eocene in age, as shown in Figures 5 and 6.

Figure 5: Stratigraphic range of planktonic (Eocene) species

Figure 6: Stratigraphic range of benthic foraminifera (Eocene) species

Biostratigraphy

The biozonation used in this study is that of Berggren [6] with modifications of Wade et al. (2011). he greatest number of samples containing planktonic foraminifera was obtained from the Burton Guyot Limestone Unit. At this locality, only nine biozones from the Paleocene and lower Eocene were recognized with certainty. The age of this unit based on the overlapping ranging of the rare planktonic foraminifera is Middle Eocene (late Lutetian- 47.8 Ma) in age as shown in Table 2.

Taxonomy of Foraminifera Planktonic Foraminifera

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

1- Subbotina eocaena (Guembel, 1968)

These species have a large size subbotiondes during the Eocene.

Stratigraphic range Zone E6?- to Zone O1. Early Eocene to Early Oligocene [6]

Geographic distribution at the middle latitude range.

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

2- Catapsydrax Univcaus (Bolli, Loblich, and Tappan, 1957) [7]

These species have a large size represent (only) in the Middle to Upper Eocene.

Stratigraphical range Zone E2 to Zone N6.

Geographical distribution at the Global range.

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

3- Globorataloides quadrocameratus [6]

Stratigraphic range Zone E2 to E16.

Geographic distribution these species have widely distributed in the tropical and high latitude.

The Age is Early Eocene to Early Oligocene.

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

4- Parasubbotina eocclova (Coxall et al. 2003)

Age Middle Eocene [6]

Stratigraphic Range Zone E7 to E9 (Coxall et al. 2003).

Geographic distribution; Theses species have widely distributed in the low to Middle latitudes.

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

5- Globigerina Officinaliss [8]

Age Middle Eocene to Oligocene [6]

Stratigraphical Range Zone E10 to Oligocene.

Geographical distribution; Theses species have widely distributed in the low to Middle Latitudes.

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

6- Parasubbotina varianata? (Olsson et al. )

Age is restricted from The Paleocene to lowermost Eocene

Stratigraphical Range Zone P1c to Zone E10.

Geographical distribution; Theses species have widely distributed in the high to low latitudes.

Order Foraminiferida (Eichwald, 1830)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Hedbergellidae (Loeblich and Tappan, 1961)

7- Turborotalia pomeroli [9]

Age Lower Eocene to Oligocene.

Stratigraphic Range Zone E10 to Oligocene.

Geographical distribution; Theses species have widely distributed in the Middle Latitudes.

Order Foraminiferida (Eichwald, 1830)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Hedbergellidae (Loeblich and Tappan, 1961)

8- Turborotalia frontosa [8]

Age Lower to Middle Eocene

Stratigraphical Range Zone E7 to Zone E11.

Geographical distribution; Theses species have world distributed.

Order Foraminiferida (Eichwald, 1930)

Super Family Globigerinaceae (Carpenter, Parker and Jones, 1862)

Family Globigerinidae(Carpenter, Parker and Jones, 1862)

9- Paragloborotalia (Turborotalia) griffinoides [6]

Age Eocene

Stratigraphical Range Zone E1 to Zone E16.

Geographical distribution; Theses species have widely distributed in the high latitudes.

B-Benthic Foraminifera

Class Foraminifera incertae sedis Order Lagenida

Superfamily Nodosarioidea Family Lagenidae

1- Lagena sp., (Walker and Boys, 1784) Age Eocene age

Geographical distribution; Theses species have world distributed.

Sub Order Rotaliina

Super Family Nummulitacea

Family Nummulitidae (de Blainville, 1827)

Subfamily Heterostegininae (Galloway, 1933)

2- Heterostegina sp., (Orbigny, 1826)

Age Eocene to Holocene

Geographical distribution; Theses species have world distributed.

Class Globothalamea

Order Rotaliida

Superfamily Planorbulinoidea

Family Cibicididae (Cushman, 1927)

Superfamily Planorbulinoidea Cushman, 1927

3-Cibicidoides micrus [10-29]

Age Early Eocene

Geographical distribution; Theses species have world distributed.

Class Globothalamea

Order Rotaliida

Family Alabaminidae Hofker, 1951

Genus Alabamina Toulmin, 1941

4- Al abamina sp.,

Age Eocene

Geographical distribution; Theses species have world distributed.

Class Globothalamea (Gumbel, 1870)

Order Rotaliida

Superfamily Nummulitoidea

Family Discocyclinidae

Genus Discocyclina

5- Discocyclina (Discocyclina) marginata?, (Cushman, 1919)

Age Middle Eocene.

Geographical distribution; Theses species have distributed in middle latitude.

Conclusion

The availability of food and oxygen were the two main elements affecting the foraminiferal distribution. The number of species of (benthic, planktonic) foraminifera was directly impacted by the low oxygen levels caused by sediment intake at the time. It is revealed by the temporal decline in the proportion of infaunal benthic foraminifera that there was a brief period of reduced bottom-water oxygenation and nutrient availability (associated with the tectonic activities in the study area). The Paleocene-Eocene biostratigraphy of the area was examined in the Burton Guyot limestone column. The biostratigraphy of planktonic foraminifera in Burton Guyot limestone is complete, and this section’s age is based on overlapping ranges from the E10 (Luteian) to Middle Eocene. Nine planktonic foraminiferal biozones have been identified there.

References

Expedition 330 Scientists (2012) Site U1376. In Koppers AAP, Yamazaki T, Geldmacher J and the Expedition 330 Scientists, Proe. IODP, 330: Tokyo (Integrated Ocean Drilling Program Management International, Inc.
Gradstein FM, Ogg JG, Schmitz M, Ogg, G (2012) The Geologic Time Scale2012. Elsevier 2.
Gradstein FM (2020) Chapter 3 – Evolution and Biostratigraphy, Eds: Felix M. Gradstein, James G. Ogg, Mark D. Schmitz, Gabi M. Ogg, Geologic Time Scale 2020. Elsevier Pg: 35-137.
Bryan JR, Carter BD, Fluegeman RH, Krumm DK, Stemann TA (1997) The Salt Mountain Limestone of Alabama. Tulane Studies in Geology and Paleontology. 30: 1-60.
Stainforth RM, Lamb JL, Luterbacher HP, Beard JH, Jeffords RM (1975) Cenozoic planktonic foraminiferal zonation and characteristics of index forms. Paleontological Contributions Article 62. P. 425 Smith WHF, Sandwell DT, 1997. Global sea floor topography from satellite altimetry and ship depth soundings. Science, 277: 1956-1962.
Pearson PN, Olsson RK, Hemleben C, Huber BT, BerggrenWA (2006) Atlas of Eocene Planktonic Foraminifera. P. 1-513.
Bolli HM (1957) Planktonic Foraminifera from the Eocene Navet and San Fernando formations of Trinidad. W.I. Bull. U.S. natl. Mus. 215: 155-172.
Subbotina NN (1953) Iskopaemye foraminifery SSSR (Globigerinidy, Khantkenininidy i Globorotaliidy). Trudy Vsesoyznogo Nauchno-Issledovatel’skogo Geologo-razvedochnogo Instituta (VNIGRI) 76. P: 296.
Toumarkine M, Bolli HM (1970) Evolution de Globorotalia cerroazulensis (Cole) dans l’Eocene moyen et superieur de Possagno (Italie). Revue de Micropaleontologie 13: 131-145.
Bermudez PJ (1961) Contribucion al estudio de las Globigerinidea de la region Caribe-Antillana (Paleocene-Reciente). In: Boletino Geologia (Venezuela), Special Publicacion Vol. P. 22.
Blow WH (1979) The Cainozoic Globigerinida. 3 Vols. P. 12.
Jenkins DG (1971) New Zealand Cenozoic Planktonic Foraminifera. New Zealand Geological Survey Paleontological Bulletin 42.
Kell JP, Watkins DK (2014) Data report: Calcareous nannofossil biostratigraphy of Expedition 330, Louisville Seamount Trail, Sites U1372-1377. In Koppers AAP, Yamazaki T, Geldmacher J and the Expedition 330 Scientists, Proe.IODP, 330: Tokyo (Integrated Ocean Drilling Program Management International, Inc.
Khameiss B, Fluegeman R, Grigsby J, Malone S, Bernot R, et al. (2017) Biofacies Analysis of the Tertiary algal reef (Pinnacle Reef – Middle Eocene), IIA (Limestone Unit) At Burton Guyot (IODP Site U1376). 2017 -AIPG National Annual Conference. P. 23.
Khameiss B, Fluegeman R (2017) Eocene Foraminifera from an Algal Reef Limestone at Burton Guyot (IODP site U1376), in the Southwest Pacific Geologic Problem Solving with Microfossils Conference. Microfossils IV. pg: 83-84.
Khameiss B, Richard F (2017) Benthic Foraminifeal Paleoecology of Depositional Sequence TE 3.2 (Eocene; Bartonian) of the Eastern Gulf Coastal Plain. Geologic Problem Solving with Microfossils Conference. Microfossils IV.P. 67-68.
Krasheninnikov VA, Basov IA (1983) Cenozoic planktonic foraminifers of the Falkland Plateau and Argentine Basin, Deep Sea Drilling Projejt Leg 71. In: Initial Reports of the Deep Sea Drilling Project Vol. 71 Eds: Ludwig WJ, Krasheninninov VA, P. 821-845.
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Pearson PN, Shackleton NJ, Hall MA (1993) The Stable Isotope Paleoecology of Middle Eocene Planktonic Foraminifera and Multi-species integrated Isotope Stratigraphy. Journal of Foraminiferal Research 23: 123-140.
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Extend Calibration Cycle of Homocysteine Measurement System in Clinical Laboratory

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DOI: 10.31038/JCRM.2022562

Abstract

Calibration is the basis of traceability of clinical biochemistry results. Different calibration cycle will bring different difficulties and economic costs to clinical laboratory. By extending the Homocysteine calibration cycle, the 72 hours given by the manufacturer were extended to 7 days. The new calibration cycle can significantly reduce the cost of the laboratory and improve the work efficiency.

Keywords

Homocysteine, Calibration cycle, Measurement system

Calibration is the basis of traceability of clinical biochemistry results. In some cases, the measurement system need to be recalibrated, such as changing the reagent lot number, replace the important parts of the instrument, the instrument has been maintained greatly, and internal quality control is abnormal. Even if the above situation does not occur, it should be noted that is necessary to recalibrate the item before the end of the reagent calibration cycle, so as to ensure the accuracy of patient detection results. Each commercial kit will establish its calibration cycle before leaving the factory. The calibration cycle of kits for different biochemical items may be different. The shorter calibration cycle may be several hours, and the longer one may be several months. Therefore, different calibration cycle will bring different difficulties and economic costs to clinical laboratory.

Homocysteine (Hcy) is a non-protein, neurotoxic, sulfur containing amino acid that originates from methionine metabolism [1]. Hcy is associated with increased risk of numerous pathological conditions, including cardiovascular Disease (CVD), stroke, Alzheimer’s disease (AD), eye diseases, pregnancy complications, and neural tube defects (NTDs) [2]. Therefore, it is very significant to detect Hcy in laboratory. The calibration cycle of Hcy kits from different manufacturers is different. In our laboratory, the calibration cycle of Hcy test kit is short, 72 hours. And the calibration material of the project has five levels, which will increase the cost of the laboratory and reduce the efficiency of the work. From above analysis, we decide to extend the calibration cycle of Hcy measurement system in our clinical laboratory.

The biochemical analyzer is Beckman Coulter AU5800, the Hcy reagent is Beijing Jiuqiang (lot: 19-0226), and the calibrator is Beijing Jiuqiang (lot: 18-1115). After calibration, two quality control samples (QC-1 and QC-2) and one clinical serum sample (CS-1) were tested 4 times respectively (2 times in the morning and 2 times in the afternoon). The determination lasted for seven days. The difference between the maximum and minimum values of the same sample should be less than the bias required by external quality assessment (EQA) of National Center for Clinical Laboratories (NCCL). The result is listed in Table 1. We can find that the difference between the maximum value and the minimum value in these seven days is less than 10%.

Table 1: Analysis of Hcy test data

Sample	Mean	SD	CV（%）	Max	Min	Bias (%)	Standard (%)
QC-1	11.3	0.22	1.91	11.0	11.7	6.36	10
QC-2	30.2	0.42	1.40	29.1	31.1	6.87	10
CS-1	7.2	0.22	3.12	6.9	7.5	8.69	10

By extending the Hcy calibration cycle, the 72 hours given by the manufacturer were extended to 7 days. The new calibration cycle can significantly reduce the cost of the laboratory and improve the work efficiency. Therefore, other biochemistry essays in the laboratory can also use this method to extend the calibration cycle.

Research funding: This work was supported by the National Natural Science Foundation of China (81870683, 82121003), the Department of Science and Technology of Sichuan Province (2020JDTD0028), the CAMS Innovation Fund for Medical Sciences (2019-12M-5-032).

References

Setien-Suero E, Suarez-Pinilla M, Suarez-Pinilla P, Crespo-Facorro B, Ayesa-Arriola R (2016) Homocysteine and cognition: A systematic review of 111 studies. Neurosci Biobehav Rev 69: 280-298. [crossref]
Jakubowski H (2019) Homocysteine Modification in Protein Structure/Function and Human Disease. Physiol Rev 99: 555-604. [crossref]

Evaluation of the Validity of the Richmond Agitation Sedation Scale in Critically Illness Infants and Children: A Retrospective Cohort Study

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DOI: 10.31038/IJNM.2022323

Abstract

Purpose: Sedation is one of the essential interventions in ICU. The Richmond Agitation- Sedation Scale (RASS) has commonly been used in adult patients; however, no specific scale for pediatric patients is available. Thus, it is necessary to develop a simple sedation scale according to children’s developmental stages. The purpose of this study is to evaluate the efficacy of the RASS for sedation evaluation in pediatric patients.

Methods: The study included 1715 children admitted to a pediatric intensive care unit (PICU) between 2012 and 2016, where they received artificial respiration management under sedation. To assess the efficacy of the RASS, univariate and multivariate analyses were performed for determining the mean duration of stay in the PICU pre- and post-introduction of RASS, the number of days of artificial respiration management, and the number of adverse events. P-values <0.05 were considered statistically significant. All tests were performed using SPSS ver. 27.0J (IBM Corp., Armonk, NY).

Results: Analyses showed statistically significant differences in the number of ventilator-associated pneumonia (VAP) cases pre- and post-introduction of RASS (p=0.007 for univariate analysis; multivariate odds ratio=0.518, 95％ confidence interval: 0.296–0.905, p=0.021). These results indicated that RASS introduction reduced the risk of VAP by one-half.

Conclusions: Appropriate use of sedatives contributes to improved patient outcomes, such as the prevention of VAP and reductions in the duration of artificial respiration management. Study results suggest that use of the RASS, an important measure in the VAP prevention bundle, can be effective in reducing the risk of VAP in pediatric patients.

Keywords

Richmond agitation sedation scale, Pediatric intensive care unit, Ventilator-associated pneumori, A retrospective cohort study

Introduction

Sedation is one of the essential interventions in ICU. To increase the patient’s comfort and reduce complications associated with sedation, it is essential to precisely set the target of sedation depth for each patient and appropriately maintain the particular depth [1-3]. For instance, excessively deep sedation would cause difficulty in ventilator weaning due to the atrophy and weakness of respiratory muscles, which may result in prolonging a ventilator fitting period or developing ventilator-related pneumonia (VAP) [4]. On the contrary, under a shallow sedation depth, a report shows that the case of accidental extubation in ventilators increases, followed by restlessness or agitation [5]. Therefore, establishing an objective “sedation scale,” a common standard among medical professionals in evaluating the sedation depth, should be mandatory. The use of the sedation scale is currently recommended in practice on patients under intensive care management, particularly during mechanical ventilation management [6]. Given this situation, the use of the Richmond Agitation Sedation Scale (hereinafter referred to as “RASS”) has been recently recommended, mainly for adult patients, as an appropriate sedation scale [7-9]. However, on the other hand, no recommendation has been made to use a specific sedation scale in the field of Pediatrics [10]. The cognitive and language abilities of pediatric patients are underdeveloped, in which the process of informed consent is often problematic. To make matters worse, those infants may suffer significant stress, not only from medical treatment or surroundings of a unique ICU environment but also from being separated from their family. Therefore, the management of pediatric patients in ICU is often challenging, which requires deeper sedation depth and a higher level of pain relief than those of adult patients [10]. However, the number of sedation scales assessed for their reliability and validity in pediatric patient management in mechanical ventilation is quite limited [11]; although the state behavioral scale (SBS) has been reported as a candidate for sedation scale of pediatric patients, no recommended sedation scale has been established in the treatment of pediatric patients as in its adult counterpart. Consequently, a simple and reliable scale in determining appropriate sedation depth according to each patient’s growth development stages is required. A pediatric hospital adopted the use of the Richmond Agitation-Sedation Scale (RASS) in 2014, and physicians and nurses have since determined optimal levels of sedation based on their patients’ scores. This study was based on children who underwent artificial respiration management in the pediatric intensive care unit (PICU), and evaluated the impact on clinical outcomes of using RASS to evaluate their sedation levels.

Design and Methods

Patients

This study included children admitted to the hospital’s PICU between 2012 and 2016. All children had received artificial respiration management under sedation during their PICU stay. We excluded patients who received muscle relaxants or who underwent artificial respiration management using high-frequency oscillatory ventilation or airway pressure release ventilation. The RASS was used to measure the level of sedation because its reliability and validity have been established in adults.

Data Analysis

Univariate analysis was performed for the mean duration of stay in the PICU before and after the introduction of RASS, the number of days of artificial respiration management, the number of pneumonia cases associated with artificial respiration machines, and the number of unplanned extubations. Subsequently, multivariate analysis was conducted to confirm the efficacy of the RASS for each outcome measure, with the potential confounders found to be statistically significant in the univariate models included as covariates. P-values less than 0.05 were considered statistically significant. All tests were performed using SPSS ver. 27.0J (IBM Corp., Armonk, NY).

Ethical Considerations

This study was carried out in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects established by the Ministry of Health, Labor, and Welfare and was approved by the hospital’s Institutional Ethics Committee (Approval Number: 998). This hospital has been designated as the national research center for advanced and specialized medical care, and promotes the treatment and research of diseases during the reproductive cycle.

Findings

Patient Characteristics and Clinical Outcomes

A total of 1715 patients were included in the study; their median age was 18 months (6–60 months). The median Proviral Integrations of Moloney virus 2 (PIM2) was 2.3 (1.0–5.4), the median Pediatric Cerebral Performance Category (PCPC) before admission to the PICU was 1.0 (1.0–3.0), the median number of days of artificial respiration management was 4.0 (2.0– 8.0), and the median PICU stay was 7.0 days (4.0–12.0) (Table 1).

Table 1: Patient characteristics and clinical outcomes(N=1715)

table 1

Midazolam and opioids were mainly used as analgesics and sedatives. Dexmedetomidine, ketamine, and phenobarbital were used as second-line drugs or adjuvants. The dose was adjusted as necessary according to the instructions of the on-site intensivist.

Verification of Effectiveness of Each Variable Pre-and Post-introduction of RASS

Study outcomes were compared for the periods pre- and post-introduction of the RASS in 2014. Changes in the number of days of artificial respiration management and in the duration of PICU stay were assessed using the Mann–Whitney U test for non-parametric variables. In addition, the chi-square test was used to compare changes in the number of cases of ventilator-associated pneumonia (VAP) and of unplanned extubations. There were no significant differences in the number of PICU days (p=0.296), artificial respiration management days (p=0.499), or number of unplanned extubations (p=0.456) pre- and post- introduction of RASS. In contrast, a statistically significant difference was observed in the number of VAPs (p=0.007) (Table 2).

Table 2: Verification of effectiveness of each variable pre-and post-introduction of RASS

table 2

^a Mann–Whitney U test
^b the chi-square test
p ＜ 0.05* p ＜ 0.01**

Verification of Effectiveness for VAP Post-introduction of RASS

Multivariate analysis using logistic regression was performed for the number of VAPs, controlling for patient sex and age (months), PIM2, PCPC before admission to the PICU, the number of days of artificial respiration management and of ICU stay, and whether RASS was used as an assessment tool. A variable reduction technique, based on the likelihood ratio test, was used to select the covariates tested in the models. The results indicated that patient age, PIM2, PCPC, the number of days of artificial respiration management, and RASS introduction affected the number of VAPs. Specifically, the number of VAPs was significantly associated with patient age (odds ratio [OR]=1.010, 95％ confidence interval [CI]: 1.000- 1.010, p=0.002), number of days of artificial respiration management (OR=1.05, 95% CI:– 1.040-1.060, p<0.001), PIM2 (OR=1.010, 95 ％ CI ： 1.010-1.020, p<0.001), PCPC (OR=0.847, 95% CI: 0.717-1.000, p=0.04), and RASS introduction (OR=0.518, 95 ％CI: 0.296-0.905, p=0.021). The Hosmer–Lemeshow test showed a goodness of fit for the logistic regression model (p=0.753). The discrimination rate between the predicted and actual values was 91.3% (Table 3).

Table 3: Verification of effectiveness for VAP post-introduction of RASS (N=1715)

table 3

The Hosmer–Lemeshow test showed a goodness of fit for the logistic regression model (p=0.753) The discrimination rate between the predicted and actual values was 91.3%
p ＜ 0.05* p ＜ 0.01**

Discussion

Clinical sequelae of artificial respiratory management were compared for the periods before and after the RASS was introduced as an assessment tool in the PICU. After controlling for demographic and clinical factors, use of the RASS did not make a significant difference in the number of days patients spent in the PICU, the number of days of artificial respiration management, or the number of unplanned extubations. However, a statistically significant difference was observed in the number of VAPs, representing a 50% reduction in the risk of their occurrence. Analysis was performed to clarify the association between the number of VAPs and sex, age (months), PIM2, PCPC before admission to the PICU, the number of days of artificial respiration management and ICU stay, and the presence or absence of RASS. An appropriate use of sedatives contributes to improving outcomes in adults, such as prevention of VAP, reduction in the period of artificial respiration management, and improvement in survival [12-14]. The results of the present study demonstrated that using RASS to optimize sedation management significantly reduced the risk of VAP. Muscle weakness and functional impairments, such as cognitive/mental function disorder, are known complications after artificial respiratory management and have been labeled as ICU-acquired weaknesses [15]. To prevent these conditions, it is necessary to appropriately manage the risk factors in the acute phase, with particular attention to the appropriate management of sedatives. RASS assessments are thus an important component of the PICU VAP prevention bundle. The reliability and validity of the COMFORT scale, a sedative scale for children, has been established [16]. However, this scale cannot discriminate between analgesic and sedative effects as it assesses patients’ distress as well as pain. Furthermore, the results are represented as the total score of each item (range: 8–40 points), making it difficult to set target values in advance. The reliability and validity of the State Behavioral Scale have been established, a Japanese version is also being developed [17]; however, its application in the PICU is complicated by the number of evaluation items. Based on the above facts, we used the RASS to evaluate the patients’ level of sedation in the PICU. Previous studies have shown that the RASS is quick, intuitive, and an excellent tool for use in the PICU [18,19]. In adult patients, the RASS is used as part of the Confusion Assessment Method (CAM- ICU) for delirium evaluation of ICU patients. There is also a modified version, the pCAM-ICU, for children [9,20]. pCAM-ICU is to be evaluated using RASS. However, assessing the consciousness level by eye contact and gaze, as used in the RASS scoring system, can be difficult in infants. Evaluating sedation and excitement using RASS may improve delirium evaluation in the future.

Limitations and Future Tasks

This study has several limitations. First, this was a single-center study. Second, we did not have information to evaluate the effects of nurses’ and physicians’ clinical experience or skills in RASS assessments. In fact, it has been suggested that RASS can be an evaluation tool for pediatric patients through educational intervention [21]. Further, the validity of the RASS for children has not been adequately evaluated. The RASS is adapted for children by developing evaluation criteria according to their age and conscious levels, and the validity of this scale needs to be assessed with more patients.

Conclusions

The RASS is an important measure in the adult VAP prevention bundle. Results of the present study suggest that its use may also be effective in the PICU. Further studies are needed to verify our results.

Conflicts of Interest

This study received research funding from the policy-based Medical Services Foundation in 2017. The authors declare no conflict of interest.

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Professionalism in the Digital Era

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DOI: 10.31038/IJNM.2022322

Abstract

Background: Advancing technologies facilitate the transfer of medical services from the office practice to the patient home in a virtual format, offering comfort in e-communication.

Aim: To highlight the patient’s preference fulfilled in the digital era when necessary.

Method: A qualitative study was performed by the author in the community in 2022, relating to the healthcare model improvement by using IT devices.

Findings: In April 2022, the patient, 73, experienced a worsening heart function.

Patient health history: Hypertension from 2006; heart failure, NYHA class II, 2022.

Patient’s family health history: Parents: hypertension.

Actions were taken: The patient called the family doctor. The physician used mainly his voice in analysis and decisions. She recommended the treatment in the hospital, but the patient disagreed. The family doctor used drugs, behaviour change information, and communication skills to manage the situation. The follow-up call visits were scheduled twice a day in the first week, daily the following week, and then twice a week. In May 2022, the physician visited the patient at home; the face light of the patient expressed delight in his health improvement and the luxury of meeting his doctor who lives in another region after fourteen years.

Results: Clinical outcomes were improved in a few weeks. No relapse was reported.

Conclusion: IT devices are convenient options for treatment.

Discussions/Implications: Patient’s experience influences his decision in selecting the healthcare provider; this physician offered expertise to his family for three generations, from 1987-2008. Patient preference may be a tool to validate professionalism in healthcare.