Palaeo-Eskimo genetic ancestry and the peopling of Chukotka and North America.

Much of the American Arctic was first settled 5,000 years ago, by groups of people known as Palaeo-Eskimos. They were subsequently joined and largely displaced around 1,000 years ago by ancestors of the present-day Inuit and Yup'ik1-3. The genetic relationship between Palaeo-Eskimos and Native American, Inuit, Yup'ik and Aleut populations remains uncertain4-6. Here we present genomic data for 48 ancient individuals from Chukotka, East Siberia, the Aleutian Islands, Alaska, and the Canadian Arctic. We co-analyse these data with data from present-day Alaskan Iñupiat and West Siberian populations and published genomes. Using methods based on rare-allele and haplotype sharing, as well as established techniques4,7-9, we show that Palaeo-Eskimo-related ancestry is ubiquitous among people who speak Na-Dene and Eskimo-Aleut languages. We develop a comprehensive model for the Holocene peopling events of Chukotka and North America, and show that Na-Dene-speaking peoples, people of the Aleutian Islands, and Yup'ik and Inuit across the Arctic region all share ancestry from a single Palaeo-Eskimo-related Siberian source.

Genetics of glucose homeostasis in pregnancy and postpartum.

AIMS/HYPOTHESIS: Pregnancy is accompanied by maternal metabolic adaptations to ensure fetal growth and development, including insulin resistance, which occurs primarily during the second and third trimesters of pregnancy, and a decrease in fasting blood sugar levels over the course of pregnancy. Glucose-related traits are regulated by genetic and environmental factors and modulated by physiological variations throughout the life course. We addressed the hypothesis that there are both overlaps and differences between genetic variants associated with glycaemia-related traits during and outside of pregnancy. METHODS: Genome-wide SNP data were used to identify genetic variations associated with glycaemia-related traits measured during an OGTT performed at ~28 weeks' gestation in 8067 participants in the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study. Associations outside of pregnancy were determined in 3977 individuals who also participated in the HAPO Follow-Up Study at 11-14 years postpartum. A Bayesian classification algorithm was used to determine whether SNPs associated with fasting and 2 h glucose and fasting C-peptide during pregnancy had a pregnancy-predominant effect vs a similar effect during pregnancy and postpartum. RESULTS: SNPs in six loci (GCKR, G6PC2, GCK, PPP1R3B, PCSK1 and MTNR1B) were significantly associated with fasting glucose during pregnancy, while SNPs in CDKAL1 and MTNR1B were associated with 1 h glucose and SNPs in MTNR1B and HKDC1 were associated with 2 h glucose. Variants in CDKAL1 and MTNR1B were associated with insulin secretion during pregnancy. Variants in multiple loci were associated with fasting C-peptide during pregnancy, including GCKR, IQSEC1, PPP1R3B, IGF1 and BACE2. GCKR and BACE2 were associated with 1 h C-peptide and GCKR, IQSEC1 and BACE2 with insulin sensitivity during pregnancy. The associations of MTNR1B with 2 h glucose, BACE2 with fasting and 1 h C-peptide and insulin sensitivity, and IQSEC1 with fasting C-peptide and insulin sensitivity that we identified during pregnancy have not been previously reported in non-pregnancy cohorts. The Bayesian classification algorithm demonstrated that the magnitude of effect of the lead SNP was greater during pregnancy compared with 11-14 years postpartum in PCSK1 and PPP1R3B with fasting glucose, in three loci, including MTNR1B, with 2 h glucose, and in six loci, including IGF1, with fasting C-peptide. CONCLUSIONS/INTERPRETATION: Our findings support the hypothesis that there are both overlaps and differences between the genetic architecture of glycaemia-related traits during and outside of pregnancy. Genetic variants at several loci, including PCSK1, PPP1R3B, MTNR1B and IGF1, appear to influence glycaemic regulation in a unique fashion during pregnancy. Future studies in larger cohorts will be needed to replicate the present findings, fully characterise the genetics of maternal glycaemia during pregnancy and determine similarities to and differences from the non-gravid state.

Metabolomic and genetic architecture of gestational diabetes subtypes.

AIMS/HYPOTHESIS: Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. METHODS: This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1 h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). RESULTS: Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1 h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1 h metabolites that were associated with insulin-resistant GDM. CONCLUSIONS/INTERPRETATION: This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.

BACKGROUND: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. METHODS: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. RESULTS: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. CONCLUSIONS: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. FUNDING: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.

Regional differences in thermoregulation between two European butterfly communities.

Understanding how different organisms cope with changing temperatures is vital for predicting future species' distributions and highlighting those at risk from climate change. As ectotherms, butterflies are sensitive to temperature changes, but the factors affecting butterfly thermoregulation are not fully understood. We investigated which factors influence thermoregulatory ability in a subset of the Mediterranean butterfly community. We measured adult thoracic temperature and environmental temperature (787 butterflies; 23 species) and compared buffering ability (defined as the ability to maintain a consistent body temperature across a range of air temperatures) and buffering mechanisms to previously published results from Great Britain. Finally, we tested whether thermoregulatory ability could explain species' demographic trends in Catalonia. The sampled sites in each region differ climatically, with higher temperatures and solar radiation but lower wind speeds in the Catalan sites. Both butterfly communities show nonlinear responses to temperature, suggesting a change in behaviour from heat-seeking to heat avoidance at approximately 22°C. However, the communities differ in the use of buffering mechanisms, with British populations depending more on microclimates for thermoregulation compared to Catalan populations. Contrary to the results from British populations, we did not find a relationship between region-wide demographic trends and butterfly thermoregulation, which may be due to the interplay between thermoregulation and the habitat changes occurring in each region. Thus, although Catalan butterfly populations seem to be able to thermoregulate successfully at present, evidence of heat avoidance suggests this situation may change in the future.

Adding a sustained attention task to a physically demanding cycling exercise exacerbates neuromuscular fatigue and impairs cognitive performance in both normoxia and hypoxia.

PURPOSE: Both cognitive motor dual-tasks (CMDT) protocols and hypoxic environments have been associated with significant impairments in cognitive and physical performance. We aimed to determine the effects of hypoxia on cognitive performance and neuromuscular fatigue during a highly physically demanding CMDT. METHODS: Fifteen young adults completed a first session involving a cognitive task (CTLCOG) followed by cycling exercise (CTLEX) in normoxia. After that, they randomly participated in CMDT sessions in normoxia (DTNOR) and hypoxia (DTHYP). The physical exercise consisted of 20 min cycling at a "hard" perceived effort, and the cognitive task consisted of 15 min sustained attention to response time task (SART). Concurrent psycho-physiological measurements included: quadriceps neuromuscular fatigue (peripheral/central components from femoral nerve electrostimulation), prefrontal cortex (PFC) oxygenation by near-infrared spectroscopy, and perception of effort. RESULTS: SART performance significantly decreased in DTNOR (-15.7 ± 15.6%, P < 0.01) and DTHYP (-26.2 ± 16.0%, P < 0.01) compared to CTLCOG (-1.0 ± 17.7%, P = 0.61). Peripheral fatigue similarly increased across conditions, whereas the ability of the central nervous system to activate the working muscles was impaired similarly in DTNOR (-6.1 ± 5.9%, P < 0.001) and DTHYP (-5.4 ± 7.3%, P < 0.001) compared to CTLEX (-1.1 ± 0.2%, P = 0.52). Exercise-induced perception of effort was higher in DTHYP vs. DTNOR and in DTNOR vs. CTLEX. This was correlated with cognitive impairments in both normoxia and hypoxia. PFC deoxygenation was more pronounced in DTHYP compared to DTNOR and CTLEX. CONCLUSION: In conclusion, performing a sustained attention task together with physically challenging cycling exercise promotes central neuromuscular fatigue and impairs cognitive accuracy; the latter is particularly noticeable when the CMDT is performed in hypoxia.

The reliability of a portable steam sauna pod for the whole-body passive heating of humans.

INTRODUCTION: Passive heating is receiving increasing attention within human performance and health contexts. A low-cost, portable steam sauna pod may offer an additional tool for those seeking to manipulate physiological (cardiovascular, thermoregulatory and sudomotor) and perceptual responses for improving sporting or health profiles. This study aimed to 1) report the different levels of heat stress and determine the pods' inter-unit reliability, and 2) quantify the reliability of physiological and perceptual responses to passive heating. METHOD: In part 1, five pods were assessed for temperature and relative humidity (RH) every 5 min across 70 min of heating for each of the 9 settings. In part 2, twelve males (age: 24 ± 4 years) completed two 60 min trials of passive heating (3 × 20 min at 44 °C/99% RH, separated by 1 week). Heart rate (HR), rectal (Trectal) and tympanic temperature (Ttympanic) were recorded every 5 min, thermal comfort (Tcomfort) and sensation (Tsensation) every 10 min, mean arterial pressure (MAP) at each break period and sweat rate (SR) after exiting the pod. RESULTS: In part 1, setting 9 provided the highest temperature (44.3 ± 0.2 °C) and longest time RH remained stable at 99% (51±7 min). Inter-unit reliability data demonstrated agreement between pods for settings 5-9 (intra-class correlation [ICC] >0.9), but not for settings 1-4 (ICC <0.9). In part 2, between-visits, high correlations, and low typical error of measurement (TEM) and coefficient of variation (CV) were found for Trectal, HR, MAP, SR, and Tcomfort, but not for Ttympanic or Tsensation. A peak Trectal of 38.09 ± 0.30 °C, HR of 124 ± 15 b min-1 and a sweat loss of 0.73 ± 0.33 L were reported. No between-visit differences (p > 0.05) were observed for Trectal, Ttympanic, Tsensation or Tcomfort, however HR (+3 b.min-1) and MAP (+4 mmHg) were greater in visit 1 vs. 2 (p < 0.05). CONCLUSION: Portable steam sauna pods generate reliable heat stress between-units. The highest setting (44 °C/99% RH) also provides reliable but modest adjustments in physiological and perceptual responses.

Studying the aging of Laponite suspensions using extensional rheology.

The effect of aging on the break-up dynamics of Laponite suspensions was studied in an extensional geometry. It was found that samples of increased age undergo stronger necking at the midpoint. The thinning of samples, driven purely by motion of the plates, was compared with standard shear rheology to understand how the dynamics are related to the sample properties. The Laponite suspensions exhibit a growing stress overshoot with monotonically decreasing yield strain as they age. However, it is shown that the thinning curves in extension are only a good indicator of the sample's static yield stress, being insensitive to its yield strain. These measurements suggest that following an initial linear visco-elastic regime, samples accumulate significant plastic deformations prior to the complete yielding of the sample. The implications of this for the importance of assessing changes to the ductile-brittle nature of samples are also discussed.

Neuromuscular fatigability during repeated sprints assessed with an innovative cycle ergometer.

PURPOSE: Repeated sprint ability is an integral component of team sports. This study aimed to evaluate fatigability development and its aetiology during and immediately after a cycle repeated sprint exercise performed until a given fatigability threshold. METHODS: On an innovative cycle ergometer, 16 healthy males completed an RSE (10-s sprint/28-s recovery) until task failure (TF): a 30% decrease in sprint mean power (Pmean). Isometric maximum voluntary contraction of the quadriceps (IMVC), central alterations [voluntary activation (VA)], and peripheral alterations [twitch (Pt)] were evaluated before (pre), immediately after each sprint (post), at TF and 3 min after. Sprints were expressed as a percentage of the total number of sprints to TF (TSTF). Individual data were extrapolated at 20, 40, 60, and 80% TSTF. RESULTS: Participants completed 9.7 ± 4.2 sprints before reaching a 30% decrease in Pmean. Post-sprint IMVCs were decreased from pre to 60% TSTF and then plateaued (pre: 345 ± 56 N, 60% 247 ± 55 N, TF: 233 ± 57 N, p < 0.001). Pt decreased from 20% and plateaued after 40% TSTF (p < 0.001, pre-TF = - 45 ± 13%). VA was not significantly affected by repeated sprints until 60% TSTF (pre-TF = - 6.5 ± 8.2%, p = 0.036). Unlike peripheral parameters, VA recovered within 3 min (p = 0.042). CONCLUSION: During an RSE, Pmean and IMVC decreases were first concomitant to peripheral alterations up to 40% TSTF and central alterations was only observed in the second part of the test, while peripheral alterations plateaued. The distinct recovery kinetics in central versus peripheral components of fatigability further confirm the necessity to reduce traditional delays in neuromuscular fatigue assessment post-exercise.

Comparing signals of natural selection between three Indigenous North American populations.

While many studies have highlighted human adaptations to diverse environments worldwide, genomic studies of natural selection in Indigenous populations in the Americas have been absent from this literature until very recently. Since humans first entered the Americas some 20,000 years ago, they have settled in many new environments across the continent. This diversity of environments has placed variable selective pressures on the populations living in each region, but the effects of these pressures have not been extensively studied to date. To help fill this gap, we collected genome-wide data from three Indigenous North American populations from different geographic regions of the continent (Alaska, southeastern United States, and central Mexico). We identified signals of natural selection in each population and compared signals across populations to explore the differences in selective pressures among the three regions sampled. We find evidence of adaptation to cold and high-latitude environments in Alaska, while in the southeastern United States and central Mexico, pathogenic environments seem to have created important selective pressures. This study lays the foundation for additional functional and phenotypic work on possible adaptations to varied environments during the history of population diversification in the Americas.

Correction: Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

Exploring the career experiences of Australian oral health therapists in different practice settings.

OBJECTIVE: To examine the reasons behind Australian oral health therapists (OHTs) pursuing different career pathways. BASIC RESEARCH DESIGN: Qualitative study with thematic analysis within an inductive realist approach. METHODS: A convenience sample of OHTs completed semi-structured interviews on Zoom. Participants discussed their experiences working as OHTs and commented on the future directions for the profession in Australia. RESULTS: Participants (n=21) chose clinical practice due to excellent job availability, good remuneration, and the opportunity to use their knowledge. Many indicated that non-clinical careers helped relieve the stress and fatigue of clinical practice. Some also enjoyed the variety that non-clinical jobs brought and viewed them as a means to advance their career. Participants indicated the need to better communicate the professional role and scope of practice of the OHT profession to other healthcare providers such as dentists and the general public. Some viewed independent practice as a way to serve the community. Others did not feel that they had the knowledge and skills to do so. CONCLUSION: These findings may help individual OHTs in career decision-making. OHTs could assume a major role in addressing oral healthcare inequality in Australia.

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I.

BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

Bayesian estimation of genetic regulatory effects in high-throughput reporter assays.

MOTIVATION: High-throughput reporter assays dramatically improve our ability to assign function to noncoding genetic variants, by measuring allelic effects on gene expression in the controlled setting of a reporter gene. Unlike genetic association tests, such assays are not confounded by linkage disequilibrium when loci are independently assayed. These methods can thus improve the identification of causal disease mutations. While work continues on improving experimental aspects of these assays, less effort has gone into developing methods for assessing the statistical significance of assay results, particularly in the case of rare variants captured from patient DNA. RESULTS: We describe a Bayesian hierarchical model, called Bayesian Inference of Regulatory Differences, which integrates prior information and explicitly accounts for variability between experimental replicates. The model produces substantially more accurate predictions than existing methods when allele frequencies are low, which is of clear advantage in the search for disease-causing variants in DNA captured from patient cohorts. Using the model, we demonstrate a clear tradeoff between variant sequencing coverage and numbers of biological replicates, and we show that the use of additional biological replicates decreases variance in estimates of effect size, due to the properties of the Poisson-binomial distribution. We also provide a power and sample size calculator, which facilitates decision making in experimental design parameters. AVAILABILITY AND IMPLEMENTATION: The software is freely available from www.geneprediction.org/bird. The experimental design web tool can be accessed at http://67.159.92.22:8080. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Slip in adhesion tests of a Kaolin clay.

Adhesion tests were performed on concentrated suspensions of Kaolin clay. At low concentrations samples formed conical deposits on both the top and bottom plates with the central region narrowing to a filament before undergoing breakup. In contrast high concentration samples deformed as a cylinder before apparently fracturing into two pieces. As the concentration of the samples was increased the samples underwent quite different forms of slip which it is shown can be deduced from their respective force distance curves. The type of slip behaviour for a given concentration of clay could be modified with changes to surface roughness, the initial compressive load prior to an experiment and with the separation velocity of the plates. The different slip characteristics appear to arise from the concentration dependent way in which particles interact with the rough surface topography.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

The elderly's physiological and perceptual responses to cooling during simulated activities of daily living in UK summer climatic conditions.

OBJECTIVES: The elderly are the most at-risk population for heat-related illness and mortality during the periods of hot weather. However, evidence-based elderly-specific cooling strategies to prevent heat-illness are limited. The aim of this investigation was to quantify the elderly's physiological and perceptual responses to cooling through cold water ingestion (COLD) or an L-menthol mouth rinse (MENT) during simulated activities of daily living in UK summer climatic conditions. STUDY DESIGN: Randomised, controlled repeated measures research design. METHODS: A total of ten participants (men n = 7, women n = 3: age; 69 ± 3 yrs, height; 168 ± 10 cm, body mass; 68.88 ± 13.72 kg) completed one preliminary and three experimental trials; control (CON), COLD and MENT. Experimental trials consisted of 40 min rest followed by 30 min of cycling exercise at 6 metabolic equivalents and a 6-min walk test (6MWT), within a 35 °C, 50% relative humidity environment. Experimental interventions (every 10 min); cold water (4 °C) ingestion (total of 1.5L) or menthol (5 ml mouth swill for 5 s, menthol concentration of 0.01%). RESULTS: Peak rectal temperature (Tre) was significantly (P < 0.05) lower in COLD compared with CON (-0.34 ± 0.16 °C) and MENT (-0.36 ± 0.20 °C). End exercise heart rate (HR) decreased in COLD compared with CON (-7 ± 9 b min-1) and MENT (-6 ± 7 b min-1). There was no difference in end exercise thermal sensation (TS) (CON; 6.1 ± 0.4, COLD; 6.0 ± 0.4, MENT; 6.4 ± 0.6) or thermal comfort (TC) (CON; 4 ± 1, COLD; 4 ± 1, MENT; 4 ± 1) between trials. The participants walked significantly further during the COLD 6MWT compared with CON (40 m ± 40 m) and MENT (40 m ± 30 m). There was reduced physiological strain in the COLD 6MWT compared with CON (Tre; -0.21 ± 0.24 °C, HR; -7 ± 8 b min-1) and MENT (Tre; -0.23 ± 0.24 °C, HR; -4 ± 7 b min-1). CONCLUSION: The elderly have reduced physiological strain (Tre and HR) during activities of daily living and a 6MWT in hot UK climatic conditions, when they drink cold water. Furthermore, the elderly's perception (TS and TC) of the hot environment did not differ from CON at the end of exercise with COLD or MENT interventions. Menthol provided neither perceptual benefit to exercise in the heat nor functional gain. The TS data indicate that elderly may be at increased risk of heat illness, due to not feeling hot and uncomfortable enough to implement physiological strain reducing strategies such as cold-water ingestion.

Interaction and influence of child and family characteristics upon success of weight management treatment.

PURPOSE: Interventions to address childhood obesity demonstrate moderate effects at best. Previous research has focused on factors of the intervention that influence success. Yet, effective overweight and obesity interventions require an interaction between family and individual factors. It is vital to characterize those who are successful vs. those who are not within treatment based on these factors. METHODS: This study utilized data from an existing multidisciplinary (i.e., nutrition, physical therapy, psychology, and medicine) group treatment for children with overweight and obesity. Children (N = 113) were given the Behavior Assessment System for Children, the Pediatric Quality of Life Inventory, and completed an interview at baseline, then height and weight were measured at 6 months and 12 months post-intervention. Latent class analysis was used to determine how family and individual characteristics and behavior interact and group together to characterize individuals who lose weight vs. do not lose weight during treatment. RESULTS: The four-cluster model was the best fit for the data. The four identified groups delineated one for whom treatment was successful, and three for whom treatment was not successful. Those three were differentiated by families who appeared to have inconsistent engagement with treatment, families who appeared to not be engaged with treatment, and families who had baseline risk factors that likely require a significantly higher level of treatment. CONCLUSION: Characterizing the differences between those who successfully respond to this treatment from those who were unsuccessful can help identify those most likely to benefit from treatment. Future research and treatment considerations should include treatment modifications for nonresponders. LEVEL OF EVIDENCE: Level III, longitudinal cohort study.

Metabolomic and genetic associations with insulin resistance in pregnancy.

AIMS/HYPOTHESIS: Our study aimed to integrate maternal metabolic and genetic data related to insulin sensitivity during pregnancy to provide novel insights into mechanisms underlying pregnancy-induced insulin resistance. METHODS: Fasting and 1 h serum samples were collected from women in the Hyperglycemia and Adverse Pregnancy Outcome study who underwent an OGTT at ∼28 weeks' gestation. We obtained targeted and non-targeted metabolomics and genome-wide association data from 1600 and 4528 mothers, respectively, in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai); 1412 of the women had both metabolomics and genome-wide association data. Insulin sensitivity was calculated using a modified insulin sensitivity index that included fasting and 1 h glucose and C-peptide levels after a 75 g glucose load. RESULTS: Per-metabolite and network analyses across the four ancestries identified numerous metabolites associated with maternal insulin sensitivity before and 1 h after a glucose load, ranging from amino acids and carbohydrates to fatty acids and lipids. Genome-wide association analyses identified 12 genetic variants in the glucokinase regulatory protein gene locus that were significantly associated with maternal insulin sensitivity, including a common functional missense mutation, rs1260326 (ß = -0.2004, p = 4.67 × 10-12 in a meta-analysis across the four ancestries). This SNP was also significantly associated with multiple fasting and 1 h metabolites during pregnancy, including fasting and 1 h triacylglycerols and 2-hydroxybutyrate and 1 h lactate, 2-ketoleucine/ketoisoleucine and palmitoleic acid. Mediation analysis suggested that 1 h palmitoleic acid contributes, in part, to the association of rs1260326 with maternal insulin sensitivity, explaining 13.7% (95% CI 4.0%, 23.3%) of the total effect. CONCLUSIONS/INTERPRETATION: The present study demonstrates commonalities between metabolites and genetic variants associated with insulin sensitivity in the gravid and non-gravid states and provides insights into mechanisms underlying pregnancy-induced insulin resistance. Graphical abstract.

The eMERGE genotype set of 83,717 subjects imputed to ~40 million variants genome wide and association with the herpes zoster medical record phenotype.

The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).