Imputation accuracy across global human populations.

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of references from non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative improved the imputation of admixed African-ancestry and Hispanic/Latino samples, but imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we imputed the genotypes of over 43,000 individuals across 123 populations around the world and identified numerous populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for variants with minor allele frequencies between 1% and 5% in Saudi Arabians (n = 1,061), Vietnamese (n = 1,264), Thai (n = 2,435), and Papua New Guineans (n = 776) were 0.79, 0.78, 0.76, and 0.62, respectively, compared to 0.90-0.93 for comparable European populations matched in sample size and SNP array content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European-ancestry reference increased, as predicted. Using sequencing data as ground truth, we also showed that Rsq may over-estimate imputation accuracy for non-European populations more than European populations, suggesting further disparity in accuracy between populations. Using 1,496 sequenced individuals from Taiwan Biobank as a second reference panel to TOPMed, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, but this design did not improve accuracy across frequency spectra. Taken together, our analyses suggest that we must ultimately strive to increase diversity and size to promote equity within genetics research.

The impact of temperature and a chemesthetic cooling agent on lingual roughness sensitivity.

Oral tactile sensitivity underpins food texture perception, but few studies have investigated mechanoreception in oral tissues. During food consumption, oral tissues are exposed to a wide range of temperatures and chemical entities. The objective of the present study was to assess the influence of thermal sensations on lingual roughness sensitivity. Just-noticeable difference thresholds (JNDs) were determined using the staircase method for surface roughness from stainless steel coupons (Ra; 0.177-0.465 µm). Thresholds were assessed when cooling or heating the metal stimuli (n = 32 subjects). Compared to the JND threshold obtained at an ambient stimulus temperature (21 °C: 0.055 ±â€…0.010 µm), a cold (8 °C) temperature significantly (P = 0.019) reduced tongue sensitivity (i.e. increased JND) to surface roughness (0.109 ±â€…0.016 µm, respectively) whereas warm and hot temperatures had no significant effect (35 °C: 0.084 ±â€…0.012 µm; 45 °C: 0.081 ±â€…0.011 µm). To assess whether the effect of cooling on roughness thresholds is TRPM8-dependent, we collected roughness thresholds in a second cohort of subjects (n = 27) following the lingual application of the cooling compound Evercool 190 (24.3 µM). Interestingly, when Evercool 190 was used to elicit the cold sensation, lingual roughness JNDs were unaffected compared to the control application of water (EC: 0.112 ±â€…0.016 µm; water: 0.102 ±â€…0.017 µm; P = 0.604). That lingual roughness sensitivity is decreased by cold temperature, but not chemicals evoking cold sensations, suggests the mechanism underpinning thermal modulation is not TRPM8 dependent.

Development of probiotic yogurt products incorporated with Lactobacillus kefiranofaciens OSU-BSGOA1 in mono- and co-culture with Kluyveromyces marxianus.

The bacterium Lactobacillus kefiranofaciens OSU-BDGOA1 and yeast Kluyveromyces marxianus bdgo-ym6 were previously isolated from kefir grains and have shown probiotic traits in mono- and coculture. This research evaluates the effect of introducing probiotic kefir microorganisms in monoculture and in coculture alongside yogurt starter cultures on the physicochemical and rheological properties, volatile flavor compounds, survival of the microorganisms during simulated digestion, and sensory attributes of the final fermented products. The incorporation of Lactobacillus kefiranofaciens OSU-BDGOA1 in monoculture showed promising outcomes, resulting in a final product showing more solid-like characteristics and potentially improving the texture of the product. There was also a significant increase in the concentration of desirable volatile flavor compounds in the yogurt with the monoculture, particularly 2,3-butanedione, displaying a positive correlation with buttery flavor in the sensory analysis. The inclusion of L. kefiranofaciens in monoculture also promoted better sensory attributes and was significantly better than the yogurt with the coculture with the yeast showing promising results for the incorporation of this probiotic bacterium into functional fermented dairy products.

Identification of Non-Volatile Compounds That Impact Flavor Disliking of Whole Wheat Bread Made with Aged Flours.

Whole wheat flour has a shorter shelf life than refined wheat flour due to off-flavor development. An untargeted liquid chromatography/mass spectrometry (LC/MS) flavoromics approach was applied to identify compounds that negatively impact the flavor liking in whole wheat bread made from aged flours. The chemical profiles of thirteen breads made from aged flours were obtained using LC/MS and modeled by orthogonal partial least squares (OPLS) to predict flavor liking. Top predictive chemical features (negatively correlated) were identified as pinellic acid (9S,12S,13S-trihydroxy-10E-octadecenoic acid), 12,13-dihydroxy-9Z-octadecenoic acid, and 1-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine. The sensory analysis confirmed the three compounds increased the bitterness intensity of the bread samples. The formation of the trihydroxy fatty acid bitter compound, pinellic acid (9S,12S,13S-trihydroxy-10E-octadecenoic acid), was impacted by the lipoxygenase activity of the flour; however, there was no influence on the formation of 12,13-dihydroxy-9Z-octadecenoic acid or 1-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine. Additionally, the concentrations of all bitter compounds were significantly higher in bread made from aged flour versus non-aged flour.

Identification of Non-Volatile Compounds Generated during Storage That Impact Flavor Stability of Ready-to-Drink Coffee.

Coffee brew flavor is known to degrade during storage. Untargeted and targeted LC/MS flavoromics analysis was applied to identify chemical compounds generated during storage that impacted the flavor stability of ready-to-drink (RTD) coffee. MS chemical profiles for sixteen RTD coffee samples stored for 0, 1, 2, and 4 months at 30 °C were modeled against the sensory degree of difference (DOD) scores by orthogonal partial least squares (OPLS) with good fit and predictive ability. Five highly predictive untargeted chemical features positively correlated to DOD were subsequently identified as 3-caffeoylquinic acid, 4-caffeoylquinic acid, 5-caffeoylquinic acid, 3-O-feruloylquinic acid, and 5-O-feruloylquinic acid. The increase in the six acidic compounds during storage was confirmed by sensory recombination tests to significantly impact the flavor stability of RTD coffee during storage. A decrease in pH, rather than an increase in total acidity, was supported to impact the coffee flavor profile.

Sensory perceptions of survivors of cancer and their caregivers upon blinded evaluation of produce from two different sources.

PURPOSE: Evidence documents the role of modifiable lifestyle behaviors in optimizing physical and mental health outcomes for survivors of cancer. Fruit and vegetable consumption is one such behavior, and understanding survivor sensory perceptions of produce can inform interventions aimed at improving dietary patterns. The objective of this study was to assess the sensory perceptions of survivors of cancer and their caregivers when asked to evaluate garden-harvested and grocery-purchased produce. METHODS: Participants enrolled in a garden-based biobehavioral intervention and their caregivers (n=32) were invited to participate in a sensory evaluation of four produce types: tangerine cherry tomatoes, green cabbage, green beans, and green bell peppers. Samples were coded and distributed in a random fashion, and participants completed validated sensory surveys (preference, liking/acceptability, and discrimination) for each type of produce. RESULTS: Upon initial blinded evaluation, a significant preference for grocery-purchased produce was noted for green cabbage, green beans, and green bell peppers but not tomatoes (all p<0.05). After self-labeling, however, participants reported a preference for perceived garden-harvested produce (all p≤0.001) even when incorrectly labeled. Liking/acceptability scores were significantly higher among self-labeled garden-harvested versus self-labeled grocery-purchased for all types of produce (all p≤0.001). These data reveal survivors of cancer and their caregivers perceive garden-harvested produce as superior to grocery-purchased, though were unable to accurately identify the two sources based upon sensory factors such as taste, smell, and texture alone when blinded for three of the four types of produce. CONCLUSION: Findings indicate future interventions should address perceptions of produce to facilitate improvements in consumption in these vulnerable individuals.

Assessing regional sensitivity and desensitization to capsaicin among oral cavity mucosae.

This study aimed to determine perceptual response differences and characterize desensitization to capsaicin over time across several oral cavity mucosae- the tongue, cheek, hard palate, and lip. For each region, subjects rated the intensity of capsaicin and a vehicle control over a 10-minute period. Following a rest period, capsaicin was reapplied on each pretreated area and subjects indicated which side felt more irritated then rated each side every 30 seconds, over 3.5 minutes. Results from the initial task indicated significantly greater irritation on the tongue than hard palate, hard palate than cheek and lip, but no significant differences between the cheek and lip. Time to max intensity was delayed on the hard palate compared to the tongue, cheek, and lip. Desensitization, as indicated by a significant proportion of subjects choosing the vehicle-pretreated side over capsaicin-pretreated side as having stronger irritation, was exhibited on the tongue and hard palate, but not the cheek and lip. Given these data, a secondary experiment that utilized a higher capsaicin concentration was conducted on the cheek and lip only. Results showed significantly higher overall irritation on the lip than the cheek. Desensitization was exhibited on both areas, although the extent was greater on the lip. Based on differences in sensitivity and the extent of desensitization among these areas, these results indicate oral cavity mucosae respond to, but are impacted differently by, capsaicin exposure.

Chemogenic Subqualities of Mouthfeel.

Mouthfeel refers to the physical or textural sensations in the mouth caused by foods and beverages that are essential to the acceptability of many edible products. The sensory subqualities contributing to mouthfeel are often chemogenic in nature and include heat, burning, cooling, tingling, and numbing. These "chemesthetic" sensations are a result of the chemical activation of receptors that are associated with nerve fibers mediating pain and mechanotransduction. Each of these chemesthetic sensations in the oral cavity are transduced in the nervous system by a combination of different molecular channels/receptors expressed on trigeminal nerve fibers that innervate the mouth and tongue. The molecular profile of these channels and receptors involved in mouthfeel include many transient receptor potential channels, proton-sensitive ion channels, and potassium channels to name a few. During the last several years, studies using molecular and physiological approaches have significantly expanded and enhanced our understanding of the neurobiological basis for these chemesthetic sensations. The purpose of the current review is to integrate older and newer studies to present a comprehensive picture of the channels and receptors involved in mouthfeel. We highlight that there still continue to be important gaps in our overall knowledge on flavor integration and perception involving chemesthetic sensations, and these gaps will continue to drive future research direction and future investigation.

Olfactory Adaptation is Dependent on Route of Delivery.

Odorants are perceived orthonasally (nostrils) or retronasally (oral cavity). Prior research indicates route of delivery impacts odorant perception, pleasantness, and directed behaviors thus suggesting differential processing of olfactory information. Adaptation is a form of neural processing resulting in decreased perceived intensity of a stimulus following prolonged and continuous exposure. The present study objective was to determine whether route of delivery differentially impacts olfactory adaptation and whether cross-adaptation occurs between orthonasal and retronasal pathways. Linalool (12%) or vanillin (25%) were delivered orthonasally [6 L/min (LPM)] and retronasally (8 LPM) in air phase through a custom-built olfactometer. Perceived odorant intensity was collected every 5 min over 10-min exposure. Immediately following the exposure period, cross-adaptation was assessed by shunting the delivery of the odorant from the nostrils to the oral cavity, or vice versa. A control study was also completed in which subjects underwent the orthonasal adaptation protocol using stimulus concentrations matched to the intensity of restronasal stimuli (e.g., 1.5% linalool and 6.25% vanillin). Following orthonasal delivery of both high and low vanillin concentrations, results showed perceived intensity decreased significantly at 5 and 10 min. High concentrations of orthonasal linalool similarly decreased significantly whereas lower concentrations decreased but did not reach statistical significance. Linalool and vanillin delivered retronasally did not adapt as perceived intensity actually increased significantly following a 10-min exposure. In addition, evidence of cross-adaptation was not obvious following extended odorant exposure from either delivery pathway. This study suggests that olfactory processing may be affected by the route of odorant delivery.

Different Olfactory Percepts Evoked by Orthonasal and Retronasal Odorant Delivery.

The Duality of Smell hypothesis suggests odorants delivered orthonasally elicit different sensations compared with those delivered retronasally despite activating the same receptors in the olfactory epithelium. Presently, we investigated this further using a matching paradigm free from odorant or semantic memory bias. Subjects were asked to evaluate an aroma delivered in one condition (orthonasal or retronasal delivery) and match the same aroma from 4 unknowns evaluated in the same or different delivery conditions. Panelists matched flavors in 4 delivery conditions: orthonasal-orthonasal, retronasal-retronasal, retronasal-orthonasal, and orthonasal-retronasal. For orthonasal presentation, panelists smelled samples using their nostrils, and for retronasal presentation, panelists swallowed aqueous flavors. In Experiment 1, panelists were instructed to match familiar flavors (banana, grape, orange, raspberry). In Experiments 2 and 3, panelists used the same experimental design with either 4 unfamiliar flavors (kinnow, longan, pawpaw, prunus) or 4 distinct subtypes of a strawberry flavor (woody, green, ripe, candy). In Experiment 1, the number of correct matches in each condition did not significantly differ suggesting stability in the perceptual construct across delivery routes. However, in Experiments 2 and 3, significantly more samples were correctly matched in the orthonasal-orthonasal and retronasal-retronasal conditions compared with the retronasal-orthonasal or orthonasal-retronasal conditions suggesting aroma perception is dependent on delivery route. Additionally, across the 4 delivery methods, the ability to correctly match flavors decreased as flavor familiarity decreased or similarity increased and may reflect the different cognitive strategies employed by subjects when matching these stimuli. Our results suggest odorant percepts are route-dependent and consistent with the Duality of Smell phenomenon.

Quantification of Oral Roughness Perception and Comparison with Mechanism of Astringency Perception.

Texture contributes to food acceptance, but oral texture perception is incompletely understood. Presently, we quantified individual sensitivities to lingual tactile roughness and assessed the impact of age, salivary flow (SF), and fungiform papillae density (FPD) on threshold and suprathreshold perception. Additionally, we tested the hypothesis that individuals highly sensitive to tactile roughness exhibit sensitivity to astringent stimuli. Detection thresholds (DTs) were determined using the staircase method for surface roughness from stainless steel coupons (Ra; 0.177-0.465 µm) and astringency elicited by epigallocatechin gallate (EGCG; 0-1.64 mM) and tannic acid (TA; 0-0.71 mM) from 30 individuals. Suprathreshold sensitivity was assessed from intensity ratings of electroforming comparator surfaces with roughnesses ranging from 0.51 to 22.8 µm and astringent stimuli ranging from 0 to 5.2 mM (EGCG) and from 0 to 1.9 mM (TA). SF, FPD, and astringent food pleasantness scores were collected. Variability in threshold roughness sensitivity enabled dividing subjects into high (RHi; n = 16) and low (RLo; n = 14) sensitivity groups; however, no significant differences in age, FPD, or SF were observed across these cohorts. Interestingly, compared with RLo, the RHi group exhibited greater sensitivity to EGCG but not TA astringency and indicated greater pleasantness from astringent foods (e.g., unripe bananas and dark chocolate). When participants were allocated into high (SalivaHi; n = 15) or low SF (SalivaLo; n = 15) groups, TA-evoked astringency thresholds were significantly lower in SalivaHi whom also indicated greater pleasantness from astringent red wines. For suprathreshold assessments of surface roughness or astringency, no significant associations were identified with age, FPD, or SF. Suprathreshold roughness sensitivity was, however, associated with suprathreshold sensitivity to EGCG but not TA astringency.

Lingual tactile sensitivity: effect of age group, sex, and fungiform papillae density.

Despite its contribution to food perception, lingual tactile sensitivity has been understudied. We hypothesized that sensitivity to threshold and suprathreshold tactile stimuli varies in the population and sought to determine proximate sources of variability. Forty-eight adults were tested for lingual threshold sensitivity via a modified letter identification task and suprathreshold sensitivity via estimation of stimulus size using magnitude estimation. In addition, taste bud density on the anterior tip of each panelist's tongue was estimated by counting the number of fungiform papillae in a 0.317 cm2 circumscribed area. Lingual tactile thresholds were significantly impacted by age group as subjects 40 years or older had higher thresholds than those in their 20s. Moreover, threshold sensitivity increased with increasing fungiform papillae count. Suprathreshold estimates of size were not affected by age group, sex, or fungiform papillae count.

How good is the evidence to support primary care practice?

Our goal was to determine the extent to which recommendations for primary care practice are informed by high-quality research-based evidence, and the extent to which they are based on evidence of improved health outcomes (patient-oriented evidence). As a substrate for study, we used Essential Evidence, an online, evidence-based, medical reference for generalists. Each of the 721 chapters makes overall recommendations for practice that are graded A, B or C using the Strength of Recommendations Taxonomy (SORT). SORT A represents consistent and good quality patient-oriented evidence; SORT B is inconsistent or limited quality patient-oriented evidence and SORT C is expert opinion, usual practice or recommendations relying on surrogate or intermediate outcomes. Pairs of researchers abstracted the evidence ratings for each chapter in tandem, with discrepancies resolved by the lead author. Of 3251 overall recommendations, 18% were graded 'A', 34% were 'B' and 49% were 'C'. Clinical categories with the most 'A' recommendations were pregnancy and childbirth, cardiovascular, and psychiatric; those with the least were haematological, musculoskeletal and rheumatological, and poisoning and toxicity. 'A' level recommendations were most common for therapy and least common for diagnosis. Only 51% of recommendations are based on studies reporting patient-oriented outcomes, such as morbidity, mortality, quality of life or symptom reduction. In conclusion, approximately half of the recommendations for primary care practice are based on patient-oriented evidence, but only 18% are based on patient-oriented evidence from consistent, high-quality studies.

Association between protein intake and muscle wasting in critically ill children: A prospective cohort study.

BACKGROUND: Survival from pediatric critical illness in high-income countries is high, and the focus now must be on optimizing the recovery of survivors. Muscle mass wasting during critical illness is problematic, so identifying factors that may reduce this is important. Therefore, the aim of this study was to examine the relationship between quadricep muscle mass wasting (assessed by ultrasound), with protein and energy intake during and after pediatric critical illness. METHODS: A prospective cohort study in a mixed cardiac and general pediatric intensive care unit in England, United Kingdom. Serial ultrasound measurements were undertaken at day 1, 3, 5, 7, and 10. RESULTS: Thirty-four children (median age 6.65 [0.47-57.5] months) were included, and all showed a reduction in quadricep muscle thickness during critical care admission, with a mean muscle wasting of 7.75%. The 11 children followed-up had all recovered their baseline muscle thickness by 3 months after intensive care discharge. This muscle mass wasting was not related to protein (P = 0.53, ρ = 0.019) (95% CI: -0.011 to 0.049) or energy intake (P = 0.138, ρ = 0.375 95% CI: -0.144 to 0.732) by 72 h after admission, nor with severity of illness, highest C-reactive protein, or exposure to intravenous steroids. Children exposed to neuromuscular blocking drugs exhibited 7.2% (95% CI: -0.13% to 14.54%) worse muscle mass wasting, but this was not statistically significant (P = 0.063). CONCLUSION: Our study did not find any association between protein or energy intake at 72 h and quadricep muscle mass wasting.

The development of an immersive mixed-reality application to improve the ecological validity of eating and sensory behavior research.

Introduction: The modern eating environment has been implicated as a driving force of the obesity epidemic. Mixed reality applications may improve traditional methodological assessments of eating behavior by improving the ecological validity of the laboratory setting. Methods: Research experts evaluated the utility and ecological validity of a mixed reality application that allowed immersion within virtual environments through utilizing the passthrough cameras of the head mounted display to view and interact with real foods. An initial evaluation was conducted that involved three virtual environments: a traditional laboratory booth, a non-textured restaurant, and a full-textured restaurant. The feedback from the initial evaluation was used to create a new virtual restaurant environment and a subsequent evaluation was conducted. Results: Nearly all research experts suggested adding social cues such as people and background noise to create a more authentic and ecologically valid experience. The experts scored the new virtual restaurant environment to be more acceptable than eating or conducting research in a sensory booth but scored lower when compared to conducting research in a real-world restaurant setting. Discussion: The results of this evaluation suggest that mixed reality applications may be a new methodology to assess environmental influences of eating behavior and may be a promising direction for eating behavior and sensory science research.

Understanding the Effects of Smart-Speaker-Based Surveys on Panelist Experience in Immersive Consumer Testing.

Utilizing immersive technologies to reintroduce the environmental context (i.e., visual, auditory, and olfactory cues) in sensory testing has been one area of research for improving panelist engagement. The current study sought to understand whether pairing smart-speaker questionnaires in immersive spaces could positively affect the panelist experience through enhanced ecological validity. To this end, subjects performed an immersive consumer test in which responses were collected using a traditional computer-based survey, a smart-speaker approach incorporating a direct translation of the computer questionnaire into a verbal survey requiring numeric responses, and an optimized smart-speaker survey with alternative question formatting requiring spoken word-based responses. After testing, participants answered the Engagement Questionnaire (EQ) to assess participant engagement during the test, and the System Usability Scale (SUS) survey to understand the ease, and potential adoption, of using the various survey technologies in the study. Results indicated that the traditional computer-based survey was the most engaging (p < 0.001) and usable (p < 0.001), with no differences found between the two smart-speaker surveys (p = 0.803 and p = 0.577, respectively). This suggests that the proposed optimizations for the smart-speaker surveys were not robust enough to influence engagement and usability, and further research is needed to enhance their conversational capabilities.

Characterization of the impact of chlorogenic acids on tactile perception in coffee through an inverse effect on mouthcoating sensation.

Coffee "body" is acknowledged by coffee industry professionals to be an attribute which contributes meaningfully to overall coffee quality and is defined as the collective tactile sensation imparted by the beverage. Currently, there is limited knowledge of the chemical compounds that contribute to tactile attributes in coffee. In the present work, coffee body was determined to be comprised of 4 sub-attributes including mouthcoating, astringency, chalkiness, and thickness and the specific constituents contributing to the tactile sensation of mouthcoating were further pursued using sensory-guided fractionation via preparative-scale liquid chromatography. Signal detection-based sensory methodologies were employed to characterize the sensory effects elicited by selected compounds in water and coffee matrices. Two chlorogenic acids, 3-O-caffeoylquinic acid (3-CQA) and 4-O-caffeoylquinic acid (4-CQA), were observed to impart subtle but significantly perceptible mouthcoating effects in water and/or coffee. Counterintuitively, sensory perception was inversely related to compound concentration. Complex receptor-ligand interactions or salivary lubrication dynamics are discussed as two potential mechanisms to explain this inverse relationship. Taken together, the outcomes of the present study (1) provide new targets for coffee tactile sensation optimization and modulation, (2) identify a novel dimension of sensory impact for two compounds of the chlorogenic acid family, and (3) present a need for deeper investigation into 3-CQA and 4-CQA mechanisms of sensation.

When considering whether to waste food, consumers focus attention on food label dates rather than phrases.

Date labels have been implicated as a driver of premature discard of food by consumers, which has led to recommendations to change date labels as a way to reduce food waste. However, most proposed date label reform has focused on changing the phrase that accompanies the date on the label, and not how the date is selected. To explore the relative importance of these date label elements, we track consumers' eye movements when evaluating milk container images. When making decisions about the possible discard of milk, participants fixate significantly more on the date printed on the container than on the phrase (e.g., "use by") with >50% of decisions involving no visual fixation on the phrase. This relative inattentiveness to phrases suggests regulation of food date labels should include more focus on the process of choosing label dates.

Imputation Accuracy Across Global Human Populations.

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of populations with non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative contains a substantial number of admixed African-ancestry and Hispanic/Latino samples to impute these populations with nearly the same accuracy as European-ancestry cohorts. However, imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we curated genome-wide array data from 23 publications published between 2008 to 2021. In total, we imputed over 43k individuals across 123 populations around the world. We identified a number of populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for 1-5% alleles in Saudi Arabians (N=1061), Vietnamese (N=1264), Thai (N=2435), and Papua New Guineans (N=776) were 0.79, 0.78, 0.76, and 0.62, respectively. In contrast, the mean Rsq ranged from 0.90 to 0.93 for comparable European populations matched in sample size and SNP content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European reference increased, as predicted. Further analysis using sequencing data as ground truth suggested that imputation software may over-estimate imputation accuracy for non-European populations than European populations, suggesting further disparity between populations. Using 1496 whole genome sequenced individuals from Taiwan Biobank as a reference, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, which can combine results from TOPMed with smaller population-specific reference panels. We found that meta-imputation in this design did not improve Rsq genome-wide. Taken together, our analysis suggests that with the current size of alternative reference panels, meta-imputation alone cannot improve imputation efficacy for underrepresented cohorts and we must ultimately strive to increase diversity and size to promote equity within genetics research.

Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation.

The natural switch from fever to hypothermia observed in the most severe cases of systemic inflammation is a phenomenon that continues to puzzle clinicians and scientists. The present study was the first to evaluate in direct experiments how the development of hypothermia vs. fever during severe forms of systemic inflammation impacts the pathophysiology of this malady and mortality rates in rats. Following administration of bacterial lipopolysaccharide (LPS; 5 or 18 mg/kg) or of a clinical Escherichia coli isolate (5 × 10(9) or 1 × 10(10) CFU/kg), hypothermia developed in rats exposed to a mildly cool environment, but not in rats exposed to a warm environment; only fever was revealed in the warm environment. Development of hypothermia instead of fever suppressed endotoxemia in E. coli-infected rats, but not in LPS-injected rats. The infiltration of the lungs by neutrophils was similarly suppressed in E. coli-infected rats of the hypothermic group. These potentially beneficial effects came with costs, as hypothermia increased bacterial burden in the liver. Furthermore, the hypotensive responses to LPS or E. coli were exaggerated in rats of the hypothermic group. This exaggeration, however, occurred independently of changes in inflammatory cytokines and prostaglandins. Despite possible costs, development of hypothermia lessened abdominal organ dysfunction and reduced overall mortality rates in both the E. coli and LPS models. By demonstrating that naturally occurring hypothermia is more advantageous than fever in severe forms of aseptic (LPS-induced) or septic (E. coli-induced) systemic inflammation, this study provides new grounds for the management of this deadly condition.