Sex Differences in Screening Positive for Post-Traumatic Stress Disorder After Combat Injury.

INTRODUCTION: U.S. military women were at risk of combat exposure and injury from asymmetric warfare during the conflicts in Iraq and Afghanistan. Previous research has yielded mixed results when examining sex differences in PTSD following operational deployment. To date, no study has explored sex differences in PTSD after combat injury. MATERIALS AND METHODS: This retrospective study included U.S. military service men and women who experienced a combat injury in Iraq or Afghanistan (March 2003 to March 2013) and completed a Post-Deployment Health Assessment (PDHA) within 1 year of injury. The PDHA is administered at the end of deployment and includes the 4-item Primary Care PTSD Screen. The prevalence of screening positive for PTSD was evaluated by sex using a chi-square test. Multivariable logistic regression was used to assess the association between sex and PTSD while adjusting for covariates. RESULTS: The study sample included 16,215 injured military personnel (666 women and 15,549 men). The average time between injury and PDHA was 132 days (SD = 91.0). Overall, women had a higher prevalence of screening positive for PTSD than men (48.3% vs. 40.9%, P < .001). In multivariable regression, women had higher odds than men of screening positive for PTSD (odds ratio, 1.34; 95% confidence interval, 1.14-1.57). Psychiatric history was the strongest predictor of screening positive for PTSD regardless of sex (odds ratio, 1.59; 95% confidence interval, 1.45-1.74). CONCLUSIONS: In this novel study of military service members, women were more likely to screen positive for PTSD than men after combat injury. Strategies to mitigate PTSD, enhance resiliency, and incorporate psychological care into injury rehabilitation programs for women may be needed for future U.S. military conflicts where they will play a larger role in combat operations.

Sex Differences in Postinjury Health Profiles Among U.S. Military Personnel Following Deployment-Related Concussion.

Background: Women in the U.S. military are now authorized to serve in direct combat occupations. This may increase their risk of combat injuries, such as concussion, in future conflicts. Knowledge of sex differences in health profiles after concussion is paramount for military medical planning efforts. The purpose of this study was to assess sex-related differences in health profiles among U.S. military personnel following deployment-related concussion. Materials and Methods: We conducted a retrospective study of service members who sustained a concussion during combat deployment between 2004 and 2013. Postinjury diagnoses were abstracted from outpatient encounters in electronic health records for 24 months after concussion. We used hierarchical clustering to identify clusters, termed "health profiles," and logistic regression to determine whether sex predicted membership in the health profiles. Results: The study sample included 346 women and 4536 men with deployment-related concussion. Five postinjury health profiles were identified and classified as no morbidity, back pain, tinnitus/memory loss, posttraumatic stress disorder/postconcussion syndrome, and multimorbidity. Women relative to men had higher odds of membership in the back pain (odds ratio [OR] = 1.32; 95% confidence interval [CI] = 1.05-1.67) and multimorbidity profiles (OR = 1.44; 95% CI = 1.03-2.00) and lower odds than men in the tinnitus/memory loss profile (OR = 0.62; 95% CI = 0.42-0.91). Conclusions: Postinjury health profiles among U.S. service members differ by sex following deployment-related concussion, particularly with a higher burden of multimorbidity among women than men, which may require interdisciplinary care. Women also had higher odds of membership in the back pain profile and lower odds in the tinnitus/memory loss profile than men. To prepare for future military operations where women may have greater exposure to combat, continued research elucidating health-related sex differences after deployment-related concussion is imperative.

Noninvasive Assessment of Impaired Gas Exchange with the Alveolar Gas Monitor Predicts Clinical Deterioration in COVID-19 Patients.

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic magnified the importance of gas exchange abnormalities in early respiratory failure. Pulse oximetry (SpO2) has not been universally effective for clinical decision-making, possibly because of limitations. The alveolar gas monitor (AGM100) adds exhaled gas tensions to SpO2 to calculate the oxygen deficit (OD). The OD parallels the alveolar-to-arterial oxygen difference (AaDO2) in outpatients with cardiopulmonary disease. We hypothesized that the OD would discriminate between COVID-19 patients who require hospital admission and those who are discharged home, as well as predict need for supplemental oxygen during the index hospitalization. METHODS: Patients presenting with dyspnea and COVID-19 were enrolled with informed consent and had OD measured using the AGM100. The OD was then compared between admitted and discharged patients and between patients who required supplemental oxygen and those who did not. The OD was also compared to SpO2 for each of these outcomes using receiver operating characteristic (ROC) curves. RESULTS: Thirty patients were COVID-19 positive and had complete AGM100 data. The mean OD was significantly (p = 0.025) higher among those admitted 50.0 ± 20.6 (mean ± SD) vs. discharged 27.0 ± 14.3 (mean ± SD). The OD was also significantly (p < 0.0001) higher among those requiring supplemental oxygen 60.1 ± 12.9 (mean ± SD) vs. those remaining on room air 25.2 ± 11.9 (mean ± SD). ROC curves for the OD demonstrated very good and excellent sensitivity for predicting hospital admission and supplemental oxygen administration, respectively. The OD performed better than an SpO2 threshold of <94%. CONCLUSIONS: The AGM100 is a novel, noninvasive way of measuring impaired gas exchange for clinically important endpoints in COVID-19.

The Association Between Adverse and Positive Childhood Experiences and Marijuana Use During Lactation.

Background: Adverse childhood experiences (ACEs) are associated with substance use later in life, including marijuana use. It is unknown whether these behaviors extend to lactating women. Our objective was to examine the association between childhood ACE and marijuana use in lactating individuals and determine whether positive childhood experiences (PCEs) modified this association. Methods: This study included 617 lactating individuals from the UC San Diego Human Milk Research Biorepository enrolled from 2015 to 2020. ACE and PCE histories were assessed by the Positive and Adverse Childhood Experiences questionnaire. Past 2-week marijuana use was self-reported at enrollment. Multivariable log-linear regressions were used to calculate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for ACE history and marijuana use, and to assess modification by PCE. Results: Marijuana use during lactation was higher among individuals who reported three or more ACEs (aRR = 2.58, 95% CI = 1.23-5.44), household dysfunction (aRR = 3.08, 95% CI = 1.17-8.10), sexual abuse (aRR = 2.25, 95% CI = 1.08-4.68), or physical abuse (aRR = 2.10, 95% CI = 1.02-4.13). There was no association between emotional abuse and marijuana use during lactation. There was no effect modification by PCEs. Conclusion: Higher ACE frequency, and specifically history of household dysfunction, physical abuse, or sexual abuse increased risk for marijuana use during lactation. Because of marijuana's potential adverse effects on the infant through human milk, postpartum ACE screening is warranted.

Implementing Holistic Review Practices in a Pulmonary and Critical Care Fellowship.

Background: Medical schools have used holistic review in admissions to increase mission-aligned enrollment of students from backgrounds underrepresented in medicine. Graduate medical education programs have increasingly followed suit. However, there is a paucity of literature regarding holistic review at the fellowship level. Objective: Here, we share our experience implementing the Association of American Medical Colleges core principles of holistic review during the 2021 recruitment cycle. Methods: We used a partially asynchronous and online learning strategy to train division members on the principles of holistic review. Following the match, we conducted a survey of faculty members and fellows to understand their opinions on our holistic review training and implementation. Results: Although few of our colleagues clearly understood holistic review before the training, they were able to identify broad-based criteria that aligned with our division's mission and balanced applicants' experiences, attributes, competencies, and metrics. These were viewed as better selection criteria than traditional measures and were incorporated into the individualized consideration of applicants. Our survey had a 41.5% response rate, with 10 of 22 fellows and 24 of 60 faculty members responding. Most faculty members and fellows agreed that holistic review decreases socioeconomic disparities in fellowship recruitment (79.2% and 80.0%, respectively) and promotes inclusion and diversity (83.3% and 90.0%, respectively). Faculty members appeared more confident than fellows that our training efforts had influenced recruitment. All respondents agreed that it would be critical for such training to be repeated yearly. Conclusion: Although this was a single-institution experience, implementing holistic review was feasible and well received by faculty and fellows.

Management of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Onboard a U.S. Navy Hospital Ship Amid a Global Omicron Surge.

INTRODUCTION: We present a real-world experience of a U.S. Navy Hospital Ship deployed amid a global Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surge and the challenges of navigating policy while maintaining a mission-focused itinerary in an operational environment. MATERIALS AND METHODS: We performed a chart review of SARS-CoV-2 cases from April 18 to September 20, 2022, within a closed population of fully vaccinated adults onboard the USNS Mercy (T-AH 19) during the 5-month 2022 Pacific Partnership mission to Guam, Vietnam, Palau, Philippines, and the Solomon Islands. RESULTS: There were 123 total SARS-CoV-2 cases over the course of the mission, constituting 16.6% of the total crew (123/741). No more than 14 service members were actively infected at a given time (1.9%, 14/741). The average number of active cases at any given time was 0.8 (1.9 SD, 0.1% [0.8/741]), and just 14 of these were shipboard secondary cases. No significant operational requirements of the ship were impacted by infection-related manning shortages, there were no hospitalizations, and all infected members experienced full recovery. CONCLUSIONS: Despite ongoing cases throughout the majority of the mission, a healthy immunized crew experienced no serious cases and minimal impact on operational effectiveness.

Genetic regulation of RNA splicing in human pancreatic islets.

BACKGROUND: Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes (T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown. RESULTS: We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3. CONCLUSIONS: These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.

Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach.

The rising prevalence of childhood obesity has been postulated as an explanation for the increasing rate of individuals diagnosed with type 1 diabetes (T1D). In this study, we use Mendelian randomization (MR) to provide evidence that childhood body size has an effect on T1D risk (OR = 2.05 per change in body size category, 95% CI = 1.20 to 3.50, P = 0.008), which remains after accounting for body size at birth and during adulthood using multivariable MR (OR = 2.32, 95% CI = 1.21 to 4.42, P = 0.013). We validate this direct effect of childhood body size using data from a large-scale T1D meta-analysis based on n = 15,573 cases and n = 158,408 controls (OR = 1.94, 95% CI = 1.21 to 3.12, P = 0.006). We also provide evidence that childhood body size influences risk of asthma, eczema and hypothyroidism, although multivariable MR suggested that these effects are mediated by body size in later life. Our findings support a causal role for higher childhood body size on risk of being diagnosed with T1D, whereas its influence on the other immune-associated diseases is likely explained by a long-term effect of remaining overweight for many years over the lifecourse.

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10-8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

Symptom profiles following combat injury and long-term quality of life: a latent class analysis.

PURPOSE: The purpose of this study was to identify symptom profiles among U.S. military personnel within 1 year after combat injury and assess the relationship between the symptom profiles and long-term quality of life (QoL). METHODS: The study sample consisted of 885 military personnel from the Expeditionary Medical Encounter Database who completed (1) a Post-Deployment Health Assessment (PDHA) within 1 year following combat injury in Iraq or Afghanistan, and (2) a survey for the Wounded Warrior Recovery Project (WWRP), a longitudinal study tracking patient-reported outcomes (e.g., QoL) in injured military personnel. Fifteen self-reported symptoms from the PDHA were assessed using latent class analysis to develop symptom profiles. Multivariable linear regression assessed the predictive effect of symptom profiles on QoL using the physical (PCS) and mental (MCS) component summary scores from the 36-Item Short Form Survey included in the WWRP. Time between PDHA and WWRP survey ranged from 4.3 to 10.5 years (M = 6.6, SD = 1.3). RESULTS: Five distinct symptom profiles were identified: low morbidity (50.4%), multimorbidity (15.6%), musculoskeletal (14.0%), psycho-cognitive (11.1%), and auditory (8.9%). Relative to low morbidity, the multimorbidity (ß = - 5.45, p < 0.001) and musculoskeletal (ß = - 4.23, p < 0.001) profiles were associated with lower PCS, while the multimorbidity (ß = - 4.25, p = 0.002) and psycho-cognitive (ß = - 3.02, p = 0.042) profiles were associated with lower MCS. CONCLUSION: Multimorbidity, musculoskeletal, and psycho-cognitive symptom profiles were the strongest predictors of lower QoL. These profiles can be employed during screening to identify at-risk service members and assist with long-term clinical planning, while factoring in patient-specific impairments and preferences.

Analysis of overlapping genetic association in type 1 and type 2 diabetes.

AIMS/HYPOTHESIS: Given the potential shared aetiology between type 1 and type 2 diabetes, we aimed to identify any genetic regions associated with both diseases. For associations where there is a shared signal and the allele that increases risk to one disease also increases risk to the other, inference about shared aetiology could be made, with the potential to develop therapeutic strategies to treat or prevent both diseases simultaneously. Alternatively, if a genetic signal co-localises with divergent effect directions, it could provide valuable biological insight into how the association affects the two diseases differently. METHODS: Using publicly available type 2 diabetes summary statistics from a genome-wide association study (GWAS) meta-analysis of European ancestry individuals (74,124 cases and 824,006 controls) and type 1 diabetes GWAS summary statistics from a meta-analysis of studies on individuals from the UK and Sardinia (7467 cases and 10,218 controls), we identified all regions of 0.5 Mb that contained variants associated with both diseases (false discovery rate <0.01). In each region, we performed forward stepwise logistic regression to identify independent association signals, then examined co-localisation of each type 1 diabetes signal with each type 2 diabetes signal using coloc. Any association with a co-localisation posterior probability of ≥0.9 was considered a genuine shared association with both diseases. RESULTS: Of the 81 association signals from 42 genetic regions that showed association with both type 1 and type 2 diabetes, four association signals co-localised between both diseases (posterior probability ≥0.9): (1) chromosome 16q23.1, near CTRB1/BCAR1, which has been previously identified; (2) chromosome 11p15.5, near the INS gene; (3) chromosome 4p16.3, near TMEM129 and (4) chromosome 1p31.3, near PGM1. In each of these regions, the effect of genetic variants on type 1 diabetes was in the opposite direction to the effect on type 2 diabetes. Use of additional datasets also supported the previously identified co-localisation on chromosome 9p24.2, near the GLIS3 gene, in this case with a concordant direction of effect. CONCLUSIONS/INTERPRETATION: Four of five association signals that co-localise between type 1 diabetes and type 2 diabetes are in opposite directions, suggesting a complex genetic relationship between the two diseases.

Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants.

The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher's infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.

Somatic selection of poorly differentiating variant stem cell clones could be a key to human ageing.

Any replicating system in which heritable variants with differing replicative potentials can arise is subject to a Darwinian evolutionary process. The continually replicating adult tissue stem cells that control the integrity of many tissues of long-lived, multicellular, complex vertebrate organisms, including humans, constitute such a replicating system. Our suggestion is that somatic selection for mutations (or stable epigenetic changes) that cause an increased rate of adult tissue stem cell proliferation, and their long-term persistence, at the expense of normal differentiation, is a major key to the ageing process. Once an organism has passed the reproductive age, there is no longer any significant counterselection at the organismal level to this inevitable cellular level Darwinian process.

Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic ß-Cells.

OBJECTIVE: Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet ß-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ≥13 years (≥13 group), with both B- and T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ≥13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology of the most aggressive form of type 1 diabetes that initiates in the first years of life. RESEARCH DESIGN AND METHODS: Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the <7 group compared with the ≥13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7-13 years, and 1,708 at ≥13 years). RESULTS: Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in ß-cells (GLIS3) and the other five likely affecting key T-cell (IL2RA, IL10, IKZF3, and THEMIS), thymus (THEMIS), and B-cell development/functions (IKZF3 and IL10) or in both immune and ß-cells (CTSH), showed evidence for stronger effects in the <7 group. CONCLUSIONS: A subset of type 1 diabetes-associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic ß- and immune cells.

Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression.

In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.

Noninvasive measurement of pulmonary gas exchange: comparison with data from arterial blood gases.

A new noninvasive method was used to measure the impairment of pulmonary gas exchange in 34 patients with lung disease, and the results were compared with the traditional ideal alveolar-arterial Po2 difference (AaDO2) calculated from arterial blood gases. The end-tidal Po2 was measured from the expired gas during steady-state breathing, the arterial Po2 was derived from a pulse oximeter if the SpO2 was 95% or less, which was the case for 23 patients. The difference between the end-tidal and the calculated Po2 was defined as the oxygen deficit. Oxygen deficit was 42.7 mmHg (SE 4.0) in this group of patients, much higher than the means previously found in 20 young normal subjects measured under hypoxic conditions (2.0 mmHg, SE 0.8) and 11 older normal subjects (7.5 mmHg, SE 1.6) and emphasizes the sensitivity of the new method for detecting the presence of abnormal gas exchange. The oxygen deficit was correlated with AaDO2 ( R2 0.72). The arterial Po2 that was calculated from the noninvasive technique was correlated with the results from the arterial blood gases ( R2 0.76) and with a mean bias of +2.7 mmHg. The Pco2 was correlated with the results from the arterial blood gases (R2 0.67) with a mean bias of -3.6 mmHg. We conclude that the oxygen deficit as obtained from the noninvasive method is a very sensitive indicator of impaired pulmonary gas exchange. It has the advantage that it can be obtained within a few minutes by having the patient simply breathe through a tube.

A New, Noninvasive Method of Measuring Impaired Pulmonary Gas Exchange in Lung Disease: An Outpatient Study.

BACKGROUND: It would be valuable to have a noninvasive method of measuring impaired pulmonary gas exchange in patients with lung disease and thus reduce the need for repeated arterial punctures. This study reports the results of using a new test in a group of outpatients attending a pulmonary clinic. METHODS: Inspired and expired partial pressure of oxygen (PO2) and Pco2 are continually measured by small, rapidly responding analyzers. The arterial PO2 is calculated from the oximeter blood oxygen saturation level and the oxygen dissociation curve. The PO2 difference between the end-tidal gas and the calculated arterial value is called the oxygen deficit. RESULTS: Studies on 17 patients with a variety of pulmonary diseases are reported. The mean ± SE oxygen deficit was 48.7 ± 3.1 mm Hg. This finding can be contrasted with a mean oxygen deficit of 4.0 ± 0.88 mm Hg in a group of 31 normal subjects who were previously studied (P < .0001). The analysis emphasizes the value of measuring the composition of alveolar gas in determining ventilation-perfusion ratio inequality. This factor is largely ignored in the classic index of impaired pulmonary gas exchange using the ideal alveolar PO2 to calculate the alveolar-arterial oxygen gradient. CONCLUSIONS: The results previously reported in normal subjects and the present studies suggest that this new noninvasive test will be valuable in assessing abnormal gas exchange in the clinical setting.

Genetics of the human face: Identification of large-effect single gene variants.

To discover specific variants with relatively large effects on the human face, we have devised an approach to identifying facial features with high heritability. This is based on using twin data to estimate the additive genetic value of each point on a face, as provided by a 3D camera system. In addition, we have used the ethnic difference between East Asian and European faces as a further source of face genetic variation. We use principal components (PCs) analysis to provide a fine definition of the surface features of human faces around the eyes and of the profile, and chose upper and lower 10% extremes of the most heritable PCs for looking for genetic associations. Using this strategy for the analysis of 3D images of 1,832 unique volunteers from the well-characterized People of the British Isles study and 1,567 unique twin images from the TwinsUK cohort, together with genetic data for 500,000 SNPs, we have identified three specific genetic variants with notable effects on facial profiles and eyes.

Statistical aspects of evolution under natural selection, with implications for the advantage of sexual reproduction.

The prevalence of sexual reproduction remains mysterious, as it poses clear evolutionary drawbacks compared to reproducing asexually. Several possible explanations exist, with one of the most likely being that finite population size causes linkage disequilibria to randomly generate and impede the progress of natural selection, and that these are eroded by recombination via sexual reproduction. Previous investigations have either analysed this phenomenon in detail for small numbers of loci, or performed population simulations for many loci. Here we present a quantitative genetic model for fitness, based on the Price Equation, in order to examine the theoretical consequences of randomly generated linkage disequilibria when there are many loci. In addition, most previous work has been concerned with the long-term consequences of deleterious linkage disequilibria for population fitness. The expected change in mean fitness between consecutive generations, a measure of short-term evolutionary success, is shown under random environmental influences to be related to the autocovariance in mean fitness between the generations, capturing the effects of stochastic forces such as genetic drift. Interaction between genetic drift and natural selection, due to randomly generated linkage disequilibria, is demonstrated to be one possible source of mean fitness autocovariance. This suggests a possible role for sexual reproduction in reducing the negative effects of genetic drift, thereby improving the short-term efficacy of natural selection.