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Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1–3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.

Background Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. Objectives The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). Study design ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to Clinical Trial Registration https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

IntroductionThe spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: ‘delayed death’ by inhibiting the bacterium-like ribosomes of the apicoplast, and ‘quick-killing’ that kills rapidly across the entire blood stage development.MethodsHere, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans).ResultsSeventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment.DiscussionThe azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

Background The interview process represents a necessary but potentially resource intensive process from applicant and program perspectives. This study aimed to identify opinions of the 2020 Fellowship Council (FC) application and match process and in-cycle transition to virtual interviews due to the COVID-19 pandemic. Methods Surveys were developed to assess the interview process and were distributed by the FC to all applicants and fellowship programs. Completion was voluntary and data (median [IQR] reported) were anonymous. Results Applicant response was 53%. Applicants submitted 27.5 (13.25–40) applications, were offered 10 (4–17) interviews, and ranked 10 (5–15) programs. Due to COVID-19, 74% of interview plans changed. Applicants completed 30% of their planned in-person interviews. For decision-making, 90% felt that in-person and 81% virtual interviews were sufficiently informative. Expected cost was $4750 ($2000–$6000) vs. actual cost $1000 ($250–$2250), (p

Background and Aims: HEV infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, crosstalk with antiviral interferon response, and the potential of therapeutic targeting. Approach and Results: We measured IL-1β secretion, the hallmark of inflammasome activation, in serum of HEV-infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte-derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL-1β production. A profound increase of IL-1β secretion was further observed in HEV-infected patients (1,733 ± 1,234 pg/mL; n = 70) compared to healthy persons (731 ± 701 pg/mL; n = 70). Given that macrophages are the drivers of inflammatory response, we found that inoculation with infectious HEV particles robustly triggered NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF-κB signaling activation as a key upstream event of HEV-induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibits HEV and inflammasome response without cross-interference. Conclusions: HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting of NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.

Background Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well‐recognised problem but other allergic conditions are less well documented in CF. Objective To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. Methods A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. Results The cohort included 37 children with median age of 9 years (interquartile range: 6‐12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross‐sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection., “Example allergic timelines for children with CF”

IntroductionThis study aimed to develop and test novel self-administered measures (Absorptive capacity, Adaptive capacity, and Transformative capacity) of three aspects of a household's resilience to financial shocks (e.g., job loss) that can increase food insecurity risk.MethodsMeasures were piloted in a convenience sample of households at risk for food insecurity in the United States. The survey included the new measures, validation variables (financial shock, household food security, general health, personal resilience to challenges, and financial wellbeing), and demographic questions. Exploratory factor analysis was used to assess dimensionality, internal consistency was assessed [Cronbach's alpha (CA)], and construct validity was assessed (Spearman's correlation). Also, brief screener versions of the full measures were created.ResultsParticipants in the analytic samples (n = 220-394) averaged 44 years old, 67% experienced food insecurity, 47% had a high school diploma or less, 72% were women, and the sample was racially/ethnically diverse. Scores for Absorptive capacity [one factor; CA = 0.70; Mean = 1.32 (SD = 0.54)], Adaptive capacity [three factors; CAs 0.83-0.90; Mean = 2.63 (SD = 0.85)], and Transformative capacity [three factors; CAs 0.87-0.95; Mean = 2.70 (SD = 1.10)] were negatively associated with financial shocks (−0.221 to −0.307) and positively associated with food insecurity (0.310-0.550) general health (0.255-0.320), personal resilience (0.231-0.384), and financial wellbeing (0.401-0.474).DiscussionThese findings are encouraging and support reliability and validity of these new measures within this sample. Following further testing, such as Confirmatory Factor Analysis in future samples, these measures may prove useful for needs assessments, program evaluation, intake screening, and research/surveillance. Widespread adoption in the future may promote a more comprehensive understanding of the food insecurity experience and facilitate development of tailored interventions on upstream causes of food insecurity.

During the last decade, endemic swine H1 influenza A viruses (IAV) from six different genetic clades of the hemagglutinin gene caused zoonotic infections in humans. The majority of zoonotic events with swine IAV were restricted to a single case with no subsequent transmission. However, repeated introduction of human-seasonal H1N1, continual reassortment between endemic swine IAV, and subsequent drift in the swine host resulted in highly diverse swine IAV with human-origin genes that may become a risk to the human population. To prepare for the potential of a future swine-origin IAV pandemic in humans, public health laboratories selected candidate vaccine viruses (CVV) for use as vaccine seed strains. To assess the pandemic risk of contemporary US swine H1N1 or H1N2 strains, we quantified the genetic diversity of swine H1 HA genes, and identified representative strains from each circulating clade. We then characterized the representative swine IAV against human seasonal vaccine and CVV strains using ferret antisera in hemagglutination inhibition assays (HI). HI assays revealed that 1A.3.3.2 (pdm09) and 1B.2.1 (delta-2) demonstrated strong cross reactivity to human seasonal vaccines or CVVs. However, swine IAV from three clades that represent more than 50% of the detected swine IAVs in the USA showed significant reduction in cross-reactivity compared to the closest CVV virus: 1A.1.1.3 (alpha-deletion), 1A.3.3.3-clade 3 (gamma), and 1B.2.2.1 (delta-1a). Representative viruses from these three clades were further characterized in a pig-to-ferret transmission model and shown to exhibit variable transmission efficiency. Our data prioritize specific genotypes of swine H1N1 and H1N2 to further investigate in the risk they pose to the human population.

Neonates born to mothers taking opioids during pregnancy are at risk for neonatal opioid withdrawal syndrome (NOWS), for which there is no recognized standard approach to care. Nonpharmacologic treatment is typically used as a first-line approach for management, and pharmacologic treatment is added when clinical signs are not responding to nonpharmacologic measures alone. Although morphine and methadone are the most commonly used pharmacotherapies for NOWS, buprenorphine has emerged as a treatment option based on its pharmacologic profile and results from initial single site clinical trials. The objective of this report is to provide an overview of NOWS including a summary of ongoing work in the field and to review the state of the science, knowledge gaps, and practical considerations specific to the use of buprenorphine for the treatment of NOWS as discussed by a panel of experts during a virtual workshop hosted by the National Institutes of Health.

The current study examined (1) changes in psychosocial adjustment among adolescents completing two surveys before COVID-19 and those completing the final survey during COVID-19 and (2) related risk/protective factors. Participants were 208 US adolescents (Mage = 15.09, SD = 0.50, 48.8% female, 86.1% White; 40.9% COVID group) who completed longitudinal surveys assessing psychosocial adjustment and related risk/protective factors (e.g., emotion regulation, well-being pursuits). Only adolescents completing Wave 3 during COVID-19 experienced increases in depressive symptoms, negative affect, and isolation and decreases in positive affect and friendship. Several variables served as risk (i.e., dampening) and protective (i.e., eudaimonic and hedonic motives) factors of these changes. Findings highlight the range of factors that are distinctly associated with negative changes in adolescent adjustment during COVID-19.

The COVID-19 pandemic has demonstrated the need for real-time, open-access epidemiological information to inform public health decision-making and outbreak control efforts. In Canada, authority for healthcare delivery primarily lies at the provincial and territorial level; however, at the outset of the pandemic no definitive pan-Canadian COVID-19 datasets were available. The COVID-19 Canada Open Data Working Group was created to fill this crucial data gap. As a team of volunteer contributors, we collect daily COVID-19 data from a variety of governmental and non-governmental sources and curate a line-list of cases and mortality for all provinces and territories of Canada, including information on location, age, sex, travel history, and exposure, where available. We also curate time series of COVID-19 recoveries, testing, and vaccine doses administered and distributed. Data are recorded systematically at a fine sub-national scale, which can be used to support robust understanding of COVID-19 hotspots. We continue to maintain this dataset, and an accompanying online dashboard, to provide a reliable pan-Canadian COVID-19 resource to researchers, journalists, and the general public., Measurement(s) COVID-19 Cases • COVID-19 Mortalities • COVID-19 vaccination Technology Type(s) digital curation Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location Canada Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14331311

Alterations in maternal physiological adaptation during pregnancy lead to complications, including abnormal birthweight and gestational diabetes. Maternal adaptations are driven by placental hormones, although the full identity of these is lacking. This study unbiasedly characterized the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed on cultured primary trophoblast and fluorescence-activated sorted endocrine trophoblasts from mice and a placental secretome map was generated. Proteins secreted from the placenta were detectable in the circulation of mice and showed a higher relative abundance in pregnancy. Bioinformatic analyses showed that placental secretome proteins are involved in metabolic, immune and growth modulation, are largely expressed by human placenta and several are dysregulated in pregnancy complications. Moreover, proof-of-concept studies found that secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) were increased in women prior to diagnosis of gestational diabetes. Thus, placental secretome analysis could lead to the identification of new placental biomarkers of pregnancy complications., This work was supported by a Royal Society Dorothy Hodgkin Research Fellowship, Academy of Medical of Sciences Springboard Grant, Isaac Newton Trust Grant and Lister Institute Research Prize grant to ANSP (grant numbers DH130036 / RG74249, SBF002/1028 / RG88501, RG97390 and RG93692, respectively). TN was supported by an EU Marie Skłodowska-Curie Fellowship (PlaEndo/703160) and an Early Career Grant from the Society for Endocrinology. CLM is supported by the Diabetes UK Harry Keen Intermediate Clinical Fellowship (DUK-HKF 17/0005712) and the EFSD-Novo Nordisk Foundation Future Leader’s Award (NNF19SA058974). Work in the FR/FMG laboratory was supported by the Wellcome Trust (106262/Z/14/Z,106263/Z/14/Z), the MRC (MRC_MC_UU_12012/3 and MRC -Enhancing UK clinical research grant MR/M009041/1) and the Cambridge Biomedical Research Centre (NIHR-BRC Gastrointestinal Diseases theme).

Background Young mothers are more likely to provide a suboptimal early language environment for their children who in turn show impairments in their language development, yet few studies have used observational methods to assess the effectiveness of home-visiting programmes in improving the language outcomes of young mothers and their children. The Family Nurse Partnership (FNP) is a licensed home-visiting intervention developed in the USA and introduced into practice in England. The intervention involves up to 64 structured home visits from early pregnancy until the child's second birthday by specially recruited and trained Family Nurses. We assessed the effectiveness of FNP in improving the language outcomes of first-time teenage mothers and their infants. Method We conducted a pragmatic, non-blinded, randomised controlled trial to test whether the FNP programme improved mothers’ and children’s language production at 24 months postpartum. Eligible participants were nulliparous, aged 19 years or younger, and were recruited at less than 25 weeks’ gestation from community midwifery settings (Country). Pregnant young mothers were randomly assigned to FNP plus usual care (n = 243) or usual care alone (n = 233). At 24 months postpartum, mother–child dyads were observed during a standardised free-play task with their first-born child and features of their language production was coded. Data was analysed using multi-level modelling; linear or poisson/negative binomial regression models were used as appropriate. Results A small effect of FNP on mothers’ productive language was detected, where mothers in the FNP group demonstrated higher mean length of utterances than mothers who received usual care alone, mean difference (adjusted by minimisation variables and by site, linear regression) = 0.10, p Conclusion This observational study conducted within the context of a randomised-controlled trial suggests that the FNP home-visiting programme may have a small, but potentially important impact on young mothers’ speech to their toddlers. Exploratory analyses identified family environment, maternal, and child related predictors of the language outcomes of young mothers and their offspring. Trial registration This trial is registered with ISRCTN, number ISRCTN23019866, 20/04/2009.

BACKGROUND: Increased weight-related stigma during the COVID-19 pandemic has amplified the need to minimise the impacts on mental wellbeing. We investigated the relationship between the perceived changes in the representation of obesity in the media and mental wellbeing during the pandemic in a sample of people with obesity across 10 European countries. We also investigated the potential moderating effect of loneliness. METHODS: Between September to December 2020 during the COVID-19 pandemic, participants reported data on demographics, mental wellbeing (measured by World Health Organisation Five Wellbeing Index and Patient Health Questionaire-4), loneliness (measured by De Jong Gierveld short scale), and perceived change in the representation of obesity in media (measured by a study-specific question) using the online, cross-sectional EURopean Obesity PatiEnt pANdemic Survey (EUROPEANS). Data were analysed using linear mixed-effects models, controlling for age, gender, body mass index, and shielding status, with random incept for country. RESULTS: The survey was completed by 2882 respondents. Most identified as female (56%) and reported their ethnicity as White or White-mix (92%). The total sample had a mean age of 41 years and a BMI of 35.4 kg/m2. During the peak of the pandemic, compared to pre-pandemic, perceiving more negative representation of people with obesity on social media was associated with worse psychological distress, depression, and wellbeing. Perceiving more positive representation, compared to no change in representation, of people with obesity on television was associated with greater wellbeing, yet also higher psychological distress and anxiety. Loneliness, as a moderator, explained ≤0.3% of the variance in outcomes in any of the models. CONCLUSIONS: Perceiving negative representation of obesity on social media was associated with poorer mental wellbeing outcomes during the pandemic; positive representation on television was associated with both positive and negative mental wellbeing outcomes. We encourage greater media accountability when representing people with obesity., The EUROPEANS study was funded by the European Association for the Study of Obesity (EASO) and the European Coalition for People with obesity (EPCO). RAJ and ALA are supported by the Medical Research Council (MRC) (Grant MC_UU_00006/6). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.

This qualitative study aimed to understand the actions, challenges, and lessons learned for addressing the food and water needs of flood survivors, with a special focus on vulnerable populations and the implications for food security, to inform future disaster response efforts in the U.S. Semi-structured in-depth interviews were conducted from January to August 2020 with the local, state, and national stakeholders (n = 27) involved in the disaster response to the 2019 Nebraska floods, particularly those involved in providing mass care, such as food, water, and shelter, for the flood survivors. The challenge themes were related to limited risk awareness and apathy, the large scope of the impact, the difficulty with coordination and communication, the challenges in risk communication, the limited local-level capacity, and the perceived stigma and fear limiting the utilization of governmental assistance. The mitigation recommendations included the need to consider zoning and infrastructure updates, the implementation of efficient systems that leverage technology for coordination and communication, and guidance on how to address certain human factors. This study reinforces previous findings related to flood disasters and adds to our understanding of disaster response and food insecurity. The practical takeaways from this study can inform future flood-related disaster mitigation approaches in Nebraska and other rural areas.

Elevated prostate-specific antigen (PSA) levels often lead to unnecessary and possibly harmful transrectal ultrasound guided biopsy, e.g. when the biopsy is negative or contains only low-grade insignificant cancer, unlikely to become symptomatic in the man’s normal lifespan. A model based on four-kallikrein markers in blood (commercialized as 4Kscore) predicts risk of Grade group 2 or higher prostate cancer at biopsy, reducing unnecessary biopsies. We assessed whether these results extend to a single institution prostate biopsy cohort of Danish men and are enhanced by three microRNAs from urine (referred to as uCaP). The 4Kscore measured in cryopreserved blood from 234 men referred for 10+ core biopsy to Aarhus University Hospital, 29 with PSA > 25 ng/ml. We explored uCaP in urine from 157 of these men. Combined with age and DRE findings, both 4Kscore and uCaP could accurately predict Grade group 2 or higher prostate cancer (all patients: AUC = 0.802 and 0.797; PSA ≤ 25: AUC = 0.763 and 0.759). There was no additive effect when combining the 4Kscore and uCaP. Limitations include a study cohort with higher risk than commonly reported for biopsy cohorts. Our findings further support the clinical use of the 4Kscore to predict Grade group 2 or higher cancers in men being considered for biopsy.

Debate continues regarding the possible role of the hippocampus across short-term and working memory tasks. The current study examined the possibility of a hippocampal contribution to precise, high-resolution cognition and conjunctive memory. We administered visual working memory tasks featuring a continuous response component to a well-established developmental amnesic patient with relatively selective bilateral hippocampal damage (Jon) and healthy controls. The patient was able to produce highly accurate response judgments regarding conjunctions of color and orientation or color and location, using simultaneous or sequential presentation of stimuli, with no evidence of any impairment in working memory binding, categorical accuracy, or continuous precision. These findings indicate that hippocampal damage does not necessarily lead to deficits in high-resolution cognitive performance, even when the damage is severe and bilateral.

Background:There is evidence that commercially available behavioural weight management programmes can lead to short-term weight loss and reductions in glycaemia. Here, we aimed to provide the 5-year impact and cost-effectiveness of these interventions compared with a brief intervention. Methods:WRAP was a non-blinded, parallel-group randomised controlled trial (RCT). We recruited from primary care practices in England and randomly assigned participants to one of three interventions (brief intervention, 12-week open-group behavioural programme [WW, formerly Weight Watchers], or a 52-week open-group WW behavioural programme) in an uneven (2:5:5) allocation. Participants were followed up 5 years after randomisation using data from measurement visits at primary care practices or a research centre, review of primary care electronic medical notes, and self-report questionnaires. The primary outcome was change in weight at 5 years follow-up, assessed using analysis of covariance. We also estimated cost-effectiveness of the intervention. This study is registered at Current Controlled Trials, ISRCTN64986150. Findings:Between Oct 18, 2012, and Feb 10, 2014, we recruited 1269 eligible participants (two participants were randomly assigned but not eligible and therefore excluded) and 1040 (82%) consented to be approached about additional follow-up and to have their medical notes reviewed at 5 years. The primary outcome (weight) was ascertained for 871 (69%) of 1267 eligible participants. Mean duration of follow-up was 5·1 (SD 0·3) years. Mean weight change from baseline to 5 years was −0·46 (SD 8·31) kg in the brief intervention group, −1·95 (9·55) kg in the 12-week programme group, and −2·67 (9·81) kg in the 52-week programme. The adjusted difference in weight change was –1·76 (95% CI –3·68 to 0·17) kg between the 52-week programme and the brief intervention; –0·80 (–2·13 to 0·54) kg between the 52-week and the 12-week programme; and –0·96 (–2·90 to 0·97) kg between the 12-week programme and the brief intervention. During the trial, the 12-week programme incurred the lowest cost and produced the highest quality-adjusted life-years (QALY). Simulations beyond 5 years suggested that the 52-week programme would deliver the highest QALYs at the lowest cost and would be the most cost-effective. No participants reported adverse events related to the intervention. Interpretation:Although the difference in weight change between groups was not statistically significant, some weight loss was maintained at 5 years after an open-group behavioural weight management programme. Health economic modelling suggests that this could have important implications to reduce the incidence of weight-related disease and these interventions might be cost-saving.

Advanced maternal age (≥35 years) is associated with pregnancy complications. Aging impairs vascular reactivity and increases vascular stiffness. We hypothesized that uterine artery adaptations to pregnancy are impaired with advanced age. Uterine arteries of nonpregnant and pregnant (gestational day 20) young (4 months) and aged (9 months; ~35 years in humans) Sprague-Dawley rats were isolated. Functional (myogenic tone, n = 6–10/group) and mechanical (circumferential stress-strain, n = 10–24/group) properties were assessed using pressure myography and further assessment of elastin and collagen (histology, n = 4–6/group), and matrix metalloproteinase-2 (MMP-2, zymography, n = 6/group). Aged dams had worse pregnancy outcomes, including smaller litters and fetal weights (both p < 0.0001). Only in arteries of pregnant young dams did higher pressures (>100 mmHg) cause forced vasodilation. Across the whole pressure range (4–160 mmHg), myogenic behavior was enhanced in aged vs. young pregnant dams (p = 0.0010). Circumferential stress and strain increased with pregnancy in young and aged dams (p < 0.0001), but strain remained lower in aged vs. young dams (p < 0.05). Arteries from young nonpregnant rats had greater collagen:elastin ratios than the other groups (p < 0.05). In aged rats only, pregnancy increased MMP-2 active capacity. Altered functional and structural vascular adaptations to pregnancy may impair fetal growth and development with advanced maternal age.

Population genetic analyses of local ancestry tracts routinely assume that the ancestral admixture process is identical for both parents of an individual, an assumption that may be invalid when considering recent admixture. Here we present Parental Admixture Proportion Inference (PAPI), a Bayesian tool for inferring the admixture proportions and admixture times for each parent of a single admixed individual. PAPI analyzes unphased local ancestry tracts and has two components models: a binomial model that exploits the informativeness of homozygous ancestry regions to infer parental admixture proportions, and a hidden Markov model (HMM) that infers admixture times from tract lengths. Crucially, the HMM employs an approximation to the pedigree crossover dynamics that accounts for unobserved within-ancestry recombination, enabling inference of parental admixture times. We compared the accuracy of PAPI’s admixture proportion estimates with those of ANCESTOR in simulated admixed individuals and found that PAPI outperforms ANCESTOR by an average of 46% in a representative set of simulation scenarios, with PAPI’s estimates deviating from the ground truth by 0.047 on average. Moreover, PAPI’s admixture time estimates were strongly correlated with the ground truth in these simulations (R = 0.76), but have an average downward bias of 1.01 generations that is partly attributable to inaccuracies in local ancestry inference. As an illustration of its utility, we ran PAPI on real African Americans from the PAGE study (N = 5, 786) and found strong evidence of assortative mating by ancestry proportion: couples’ ancestry proportions are closer to each other than expected by chance (P < 10−6), and are highly correlated (R = 0.87). We anticipate that PAPI will be useful in studying the population dynamics of admixture and will also be of interest to individuals seeking to learn about their personal genealogies.

ObjectiveRacial/ethnic disparities in menopause symptoms and hormone therapy management remain understudied among women served by the Veteran's Health Administration, despite the unique racial/ethnic diversity of this population. Thus, we determined racial/ethnic disparities in medical record-documented menopause symptoms and prescribed menopausal hormone therapy among women veterans.MethodsWe conducted cross-sectional analyses of national Veteran's Health Administration electronic health record data from 2014 to 2015. We used logistic regression models to compare medical-record documented menopause symptoms and treatment (eg, vaginal estrogen or systemic hormone therapy) by self-identified race/ethnicity, adjusting for age, body mass index, and depression. Models examining hormone treatment were adjusted for menopause symptoms.ResultsAmong 200,901 women veterans (mean age 54.3, SD 5.4 y; 58% non-Hispanic/Latinx White, 33% non-Hispanic/Latinx Black, 4% Hispanic/Latinx, and 4% other), 5% had documented menopause symptoms, 5% were prescribed vaginal estrogen, and 5% were prescribed systemic hormone therapy. In fully adjusted multivariable models, non-Hispanic/Latinx Black women veterans had lower odds of documented menopause symptoms relative to non-Hispanic/Latinx White women (OR 0.82, 95% CI: 0.78-0.86). Moreover, non-Hispanic/Latinx Black women (OR 0.74, 95% CI: 0.70-0.77), as well as Hispanic/Latinx women (OR 0.68, 95% CI: 0.61-0.77), had lower likelihood of systemic hormone therapy prescription. Hispanic/Latinx women had higher odds of vaginal estrogen prescription (OR 1.12 95% CI: 1.02-1.24) than non-Hispanic/Latinx White women. Non-Hispanic/Latinx Black women had lower likelihood of estrogen use (OR 0.78 95% CI: 0.74-0.81) than non-Hispanic/Latinx White women.ConclusionDespite evidence suggesting higher menopause symptom burden among Black women in community samples, documented menopause symptoms and hormone therapy were less common among Black, compared with White, women veterans. Additionally, Hispanic/Latinx women veterans had lower odds of prescribed systemic menopause therapy and yet higher odds of prescribed vaginal estrogen, despite no difference in documented symptoms. These findings may signal important disparities in symptom reporting, documentation, and/or treatment for minority women veterans.

Background Despite the ongoing promotion of physical activity, the rates of physical inactivity remain high. Drawing on established methods of analysing consumer behaviour, this study seeks to understand how physical activity competes for finite time in a day – how Exercise and Sport compete with other everyday behaviours, and how engagement in physical activity is shared across Exercise and Sport activities. As targeted efforts are common in physical activity intervention and promotion, the existence of segmentation is also explored. Methods Time-use recall data (n = 2307 adults) is analysed using the Duplication of Behaviour Law, and tested against expected values, to document what proportion of the population that engage in one activity, also engage in another competing activity. Additionally, a Mean Absolute Deviation approach is used to test for segmentation. Results The Duplication of Behaviour Law is evident for everyday activities, and Exercise and Sport activities – all activities ‘compete’ with each other, and the prevalence of the competing activity determines the extent of competition. However, some activities compete more or less than expected, suggesting the combinations of activities that should be used or avoided in promotion efforts. Competition between everyday activities is predictable, and there are no specific activities that are sacrificed to engage in Exercise and Sport. How people share their physical activity across different Exercise and Sport activities is less predictable – Males and younger people (under 20 years) are more likely to engage in Exercise and Sport, and those who engage in Exercise and Sport are slightly more likely to Work and Study. High competition between Team Sports and Non-Team Sports suggests strong preferences for sports of different varieties. Finally, gender and age-based segmentation does not exist for Exercise and Sport relative to other everyday activities; however, segmentation does exist for Team Sports, Games, Active Play and Dance. Conclusions The Duplication of Behaviour Law demonstrates that population-level patterns of behaviour can yield insight into the competition between different activities, and how engagement in physical activity is shared across different Exercise and Sport activities. Such insights can be used to describe and predict physical activity behaviour and may be used to inform and evaluate promotion and intervention.

RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket. Competitive NanoBRET between the RAS-binding Affimers and known RAS binding small-molecules demonstrates the potential to use Affimers as tools to identify pharmacophores. This work highlights the potential of using biologics with small interface surfaces to select unseen, druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins., Oncogenic RAS mutants remain difficult to target with small molecules. Here, the authors show that RAS-binding Affimer proteins inhibit RAS signaling while binding diverse regions on the RAS surface, suggesting the potential to use Affimers as tools to identify new binding pockets and pharmacophores.

Background Lipoleiomyoma is a rare, benign variant of the commonplace uterine leiomyoma. Unlike leiomyoma, these tumors are composed of smooth muscle cells admixed with mature adipose tissue. While rare, they are most frequently identified in the uterus, but even more infrequently have been described in extrauterine locations. Case presentation We describe a case report of a 45-year-old woman with a history of in vitro fertilization pregnancy presenting 6 years later with abdominal distention and weight loss found to have a 30-cm intra-abdominal lipoleiomyoma. While cross-sectional imaging can narrow the differential diagnosis, histopathological analysis with stains positive for smooth muscle actin, desmin, and estrogen receptor, but negative for HMB-45 confirms the diagnosis of lipoleiomyoma. The large encapsulated tumor was resected en bloc. The patients post-operative course was uneventful and her symptoms resolved. Conclusions Lipoleiomyoma should be considered on the differential diagnosis in a woman with a large intra-abdominal mass. While considered benign, resection should be considered if the mass is symptomatic, and the diagnosis is unclear or there is a concern for malignancy.

Background Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy. Methods We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics. Results Among 888 infants, 49% (n = 431) were HEU and 51% (n = 457) HU. Of 431 HEU infants, 62% (n = 268) were exposed to HIV and antiretrovirals (ARVs) from conception and 38% (n = 163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17–26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [β = − 0.15 (95% Confidence Interval (CI): − 0.28, − 0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted β − 0.14 (95%CI: − 0.28, − 0.01]. Similar differences were noted for mean LAZ in univariable [β − 0.20 (95%CI: − 0.42, − 0.01] but not multivariable analyses [adjusted β − 0.18 (95%CI: − 0.41, + 0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU. Conclusion In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

Historically, conventional radiographs have been the primary tool to morphometrically evaluate the talocrural joint, which is comprised of the distal tibia, distal fibula, and proximal talus. More recently, high-resolution volumetric imaging, including computed tomography (CT), has enabled the generation of three-dimensional (3D) reconstructions of the talocrural joint. Weightbearing cone-beam CT (WBCT) technology provides additional benefit to assess 3D spatial relationships and joint congruency while the patient is load bearing. In this study we applied statistical shape modeling, a computational morphometrics technique, to objectively quantify anatomical variation, joint level coverage, joint space distance, and congruency at the talocrural joint. Shape models were developed from segmented WBCT images and included the distal tibia, distal fibula, and full talus. Key anatomical variation across subjects included the fibular notch on the tibia, talar trochlea sagittal plane rate of curvature, tibial plafond curvature with medial malleolus prominence, and changes in the fibular shaft diameter. The shape analysis also revealed a highly congruent talocrural joint with minimal inter-individual morphometric differences at the articular regions. These data are helpful to improve understanding of ankle joint pathologies and to guide refinement of operative treatments.

Internal consistency, construct, and criterion validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) v1.2 were evaluated in patients with early-stage carpometacarpal (CMC) osteoarthritis (OA). We hypothesized that in patients with early CMC OA, PROMIS UE scores would: (1) be lower than those in asymptomatic controls; (2) correlate with established patient-reported outcomes; (3) correlate with pinch and grip strengths; and (4) not correlate with radiographic disease progression.Patients with early CMC OA (modified Eaton stage 0 or 1) and matched asymptomatic control patients completed the PROMIS UE, Australian and Canadian Osteoarthritis Hand Index, and Patient-Rated Wrist-Hand Evaluation at 2 time points. The PROMIS UE's internal consistency was evaluated by Cronbach's alpha, construct validity by Spearman correlation coefficients among the patient-reported outcome measures, and criterion validity using measures of strength. A floor or ceiling effect was indicated if more than 15% of patients achieved the lowest or highest possible score.The PROMIS UE had high internal consistency. Patients with early CMC OA had a lower score than healthy controls (average, 42 vs 54, respectively). We observed moderate to high correlations between the PROMIS UEv1.2, Australian and Canadian Osteoarthritis Hand Index, and Patient-Rated Wrist-Hand Evaluation and good criterion validity when compared to key pinch and grip strengths. The PROMIS UE did not correlate to radiographic disease severity.The PROMIS UE had a high correlation with Australian and Canadian Osteoarthritis Hand Index and a moderate correlation with Patient-Rated Wrist-Hand Evaluation. The PROMIS UE had high internal consistency and good criterion validity.The PROMIS UE is a valid assessment for disability in patients with early CMC OA and can serve as a clinical adjunct to an outcome assessment.

Age and gender differences are prominent in the temperament literature, with the former particularly salient in infancy and the latter noted as early as the first year of life. This study represents a meta-analysis utilizing Infant Behavior Questionnaire-Revised (IBQ-R) data collected across multiple laboratories (N = 4438) to overcome limitations of smaller samples in elucidating links among temperament, age, and gender in early childhood. Algorithmic modeling techniques were leveraged to discern the extent to which the 14 IBQ-R subscale scores accurately classified participating children as boys (n = 2,298) and girls (n = 2,093), and into three age groups: youngest (< 24 weeks; n = 1,102), mid-range (24 to 48 weeks; n = 2,557), and oldest (> 48 weeks; n = 779). Additionally, simultaneous classification into age and gender categories was performed, providing an opportunity to consider the extent to which gender differences in temperament are informed by infant age. Results indicated that overall age group classification was more accurate than child gender models, suggesting that age-related changes are more salient than gender differences in early childhood with respect to temperament attributes. However, gender-based classification was superior in the oldest age group, suggesting temperament differences between boys and girls are accentuated with development. Fear emerged as the subscale contributing to accurate classifications most notably overall. This study leads infancy research and meta-analytic investigations more broadly in a new direction as a methodological demonstration, and also provides most optimal comparative data for the IBQ-R based on the largest and most representative dataset to date. National Institutes of Health [R01HL095606, R01HD082078, NIH R01 MH109692, R21 MH103627, R01 HD049878, R03 HD043057, 1P50 MH58922-01A1, 1P50 MH077928-01A1, 5R01HD080851-05, R01MH78033, 8P0GM103436, P20GM103436, 8P20GM103436, DK72996, M01RR10732]; Western Washington University [MFS 901, MFS 907] Published version MBE: R01HL095606, R01HD082078; National Institutes of Health https://www.nih.gov KPE, KB, & VL: NIH R01 MH109692; R21 MH103627 National Institutes of Health https://www.nih.gov MAB: R01 HD049878; R03 HD043057 National Institutes of Health https://www.nih.gov SG: 1P50 MH58922-01A1; 1P50 MH077928-01A1 National Institutes of Health https://www.nih.gov SS: 5R01HD080851-05 National Institutes of Health https://www.nih.gov AS: R01MH78033 National Institutes of Health https://www.nih.gov DL: 8P0GM103436; P20GM103436; 8P20GM103436 National Institutes of Health https://www.nih.gov TDRS: MFS 901; MFS 907 Western Washington University https://www.wwu.edu SAF: DK72996; M01RR10732 National Institutes of Health https://www.nih.gov None of the funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Objective Serous endometrial cancer (USC) is a challenging malignancy associated with metastasis, recurrence and poor outcome. To identify clinically relevant prognostic biomarkers, we focused on a panel of proteins selected after a comprehensive literature review, for tumour profiling of a homogeneous cohort of USC patients. Methods Protein levels and localization were assessed by immunohistochemistry analysis in 36 hysterectomy samples. Tissue sections were stained with the following antibodies: Aurora A, phospho (T288) Aurora A, BRCA1, CHK1, CIP2A, Cyclin B1, Cyclin E, E2F-1, phospho (S364) E2F-1, FBXW7, FOXM1, phospho (S9) GSK3Beta, PLK1, phospho (T210) PLK1, PPP2R1B, p73, RAD51. Each marker was evaluated as a continuously-scaled variable for association with disease progression and death, using Cox proportional hazards models. The sample consisted of 36 patients with USC, half with stage III or IV disease. Results Results showed that higher CHK1 (Checkpoint kinase 1) expression was associated with a decreased risk of progression and death, after adjusting for stage. Interestingly, analysis of a TCGA data set of 109 USC patients corroborates our results showing a favourable prognostic role of CHEK1 after adjusting for stage. Higher FBXW7 (F-box and WD repeat domain containing 7) expression and higher cytoplasmic expression of PPP2R1B (Protein Phosphatase 2 A, Scaffold Subunit Abeta) were each associated with a decreased risk of progression, after adjusting for stage. Conclusions In conclusion, results from the present study identify new clinically relevant biomarkers and potential drug targets for uterine serous endometrial cancer.

Doll play provides opportunities for children to practice social skills by creating imaginary worlds, taking others' perspectives, and talking about others' internal states. Previous research using functional near-infrared spectroscopy (fNIRS) found a region over the posterior superior temporal sulcus (pSTS) was more active during solo doll play than solo tablet play, implying that doll play might present opportunities for rehearsing theory of mind and empathy skills, even when playing alone. In this research, we addressed this more directly by investigating 4-8-year-old children's (N = 33) use of internal state language (ISL; i.e., references to emotions, desires, and cognitions) when playing with dolls and on tablets, both by themselves and with a social partner, and their associated brain activity in the pSTS using fNIRS. We found that children used more ISL about others when playing with dolls than when playing on tablets, particularly when they were playing alone. This mirrored the patterns seen in pSTS activity in previous research. When individual variability in ISL about others was considered, more ISL about others was linked to stronger pSTS activation. Thus, variability in pSTS activity during play is not about the perceptual or physical differences between toys (e.g., dolls are more human-like) but about what children think about when they engage in different kinds of play. This is the first research to investigate brain activity during spontaneously occurring ISL and indicates that children have a tendency to take and discuss others' perspectives during doll play, with implications for social processing in the brain. A video abstract of this article can be viewed at https://youtu.be/58HgxbuhBzU.

Background and ObjectivesPathogenic variants in the neuronal sodium channel α1 subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies.MethodsWe performed a retrospective multicenter cohort study comprising data from patients with SCN1A-positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001–June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes.ResultsA total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; p < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; p < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86–0.92]) and outperformed all other models (AUC 0.79–0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91–0.97]) and 2 (AUC 0.92 [95% CI 0.82–1.00]).DiscussionThe prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/).Classification of EvidenceThis study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.

In recent decades, genetic genealogy has become popular as a result of direct-to-consumer (DTC) genetic testing. Some DTC genetic testing companies offer genetic relative-finder (GRF) services that compare the DNA of consenting participants to identify genetic relatives among them and provide each participant a list of their relative matches. We surveyed a convenience sample of GRF service participants to understand the prevalence of discoveries and associated experiences. Almost half (46%) of the 23,196 respondents had participated in GRF services only for non-specific reasons that included interest in building family trees and general curiosity. However, most (82%) also learned the identity of at least one genetic relative. Separately, most respondents (61%) reported learning something new about themselves or their relatives, including potentially disruptive information such as that a person they believed to be their biological parent is in fact not or that they have a sibling they had not known about. Respondents generally reported that discovering this new information had a neutral or positive impact on their lives, and most had low regret regarding their decision to participate in GRF services. Yet some reported making life changes as a result of their discoveries. Compared to respondents making other types of discoveries, those who learned that they were donor conceived reported the highest decisional regret and represented the largest proportion reporting net-negative consequences for themselves. Our findings indicate that discoveries from GRF services may be common and that the consequences for individuals, while generally positive, can be far-reaching and complex.

[Figure: see text].

The incidence and mortality of early onset colorectal cancer (EOCRC) is rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (non-Hispanic Asian, non-Hispanic Black, non-Hispanic White, White Hispanic) using data from the American Association for Cancer Research Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1752 EOCRC patients, non-Hispanic Black patients had higher rates of KRAS mutations (60.9%; P = .001, q = 0.015), and non-Hispanic White and non-Hispanic Black patients had higher rates of APC mutations (77.1% and 76.6% among non-Hispanic White and non-Hispanic Black patients, respectively; P = .001, q = 0.015) via the Fisher exact test with Benjamini-Hochberg correction. Using R packages DESeq2 and clusterProfiler, we found that White Hispanic patients had increased expression of genes involved in oxidative phosphorylation (P

OBJECTIVE The parent-proxy Preschool HEAR-QL (Hearing Environments And Reflections on Quality of Life) is a quality of life (QOL) measure for 2 to 6-year-old children with hearing loss (HL). We compared Preschool HEAR-QL scores for children with HL and children with normal hearing (NH) to examine the measure's discriminant validity. STUDY DESIGN Cross-sectional study. SETTING Three tertiary care pediatric otolaryngology clinics. PATIENTS Two hundred forty-eight parents of children 2 to 6 years old with NH or HL participated. INTERVENTIONS None. MAIN OUTCOME MEASURE The Preschool HEAR-QL has five domains: Behavior and Attention, Hearing Environments, New Social Situations, Social Interactions, and Communications. Scores range from 0 to 100; higher scores indicate higher QOL. Scores for children with NH and with HL were compared using analysis of variance (ANOVA) and area under the receiver operating characteristic (AUROC) curves. RESULTS Total HEAR-QL mean (SD) scores were higher for children with NH compared to children with HL (75.7 [10.5] vs. 67.5 [15.5], p

The plasma levels of tissue-specific microRNAs can be used as diagnostic, disease severity and prognostic biomarkers for chronic and acute diseases and drug-induced injury. Thereby, the combination of diverse microRNAs into biomarker signatures using multivariate statistics seems especially powerful from the perspective of tissue and condition specific microRNA shedding into the plasma. Although next-generation sequencing (NGS) technology enables one to analyse circulating microRNAs on a genome-scale level, it suffers from potential biases (e.g., adapter ligation bias) and lacks absolute transcript quantitation as well as tailor-made quality controls. In order to develop a robust NGS discovery assay for genome-scale quantitation of circulating microRNAs, we first evaluated the sensitivity, repeatability and ligation bias of four commercially available small RNA library preparation protocols. The protocol from RealSeq Biosciences was selected based on its performance and usability and coupled with a novel panel of exogenous small RNA spike-in controls to enable quality control and absolute quantitation, thus ensuring comparability of data across independent NGS experiments. The established microRNA Next-Generation-Sequencing Discovery Assay (miND) was validated for its relative accuracy, precision, analytical measurement range and sequencing bias and was considered fit-for-purpose for microRNA biomarker discovery. Summarized, all these criteria were met, and thus, our analytical platform is considered fit-for-purpose for microRNA biomarker discovery from biofluids in the setting of any diagnostic, prognostic or patient stratification need. The established miND assay was tested on serum, cerebrospinal fluid (CSF), synovial fluid (SF) and extracellular vesicles (EV) extracted from cell culture medium of primary cells and proved its potential to be used across different sample types.

Background Infants born HIV-exposed yet remain uninfected (HEU) are at increased risk of poorer growth and health compared to infants born HIV-unexposed (HU). Whether maternal antiretroviral treatment (ART) in pregnancy ameliorates this risk of poorer growth is not well understood. Furthermore, whether risks are similar across high burden HIV settings has not been extensively explored. Methods We harmonized data from two prospective observational studies conducted in Cape Town, South Africa, and Lusaka, Zambia, to compare weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) Z-scores between infants who were HEU and HU, converting infant anthropometric measures using World Health Organisation Growth Standards adjusted for age and sex. Linear mixed effects models were fit to identify risk factors for differences in anthropometrics at 6–10 weeks and 6 months by infant HIV exposures status and by timing of exposure to maternal ART, either from conception or later in gestation. Results Overall 773 mother-infant pairs were included across two countries: women living with HIV (WLHIV), 51% (n = 395) with 65% on ART at conception and 35% initiating treatment in pregnancy. In linear mixed effects models, WAZ and WLZ at 6–10 weeks were lower among infants who were HEU vs HU [β = − 0.29 (95% CI: − 0.46, − 0.12) and [β = − 0.42 (95% CI: − 0.68, − 0.16)] respectively after adjusting for maternal characteristics and infant feeding with a random intercept for country. At 6 months, LAZ was lower [β = − 0.28 CI: − 0.50, − 0.06)] among infants who were HEU, adjusting for the same variables, with no differences in WAZ and WLZ. Within cohort evaluations identified different results with higher LAZ among infants who were HEU from Zambia at 6–10 weeks, [β = + 0.34 CI: + 0.01, + 0.68)] and lower LAZ among infants who were HEU from South Africa [β = − 0.30 CI: − 0.59, − 0.01)] at 6 months, without other anthropometric differences at either site. Conclusion Infant growth trajectories differed by country, highlighting the importance of studying contextual influences on outcomes of infants who were HEU.

Background: The COVID-19 pandemic has triggered stress, anxiety, and disruption to many individuals’ daily lives, which might impact eating habits. Objective: To examine changes in eating habits related to less healthy foods and beverages during the early phase of the COVID-19 pandemic among US adults. Design: Cross-sectional study. Participants/setting: Authors used SummerStyles data gathered in June 2020 among 3916 US adults (≥18 years). Main outcome measures: The outcome of interest was the reported frequency of consuming more (1) unhealthy snacks and desserts including chips, cookies, and ice cream and (2) sugar-sweetened beverages (SSBs) like regular soda, fruit drinks, sports/energy drinks, sweetened coffee/teas during the COVID-19 pandemic. Responses were categorized as Never/Rarely, Sometimes, or Often/Always. Explanatory variables were sociodemographics, weight status, and census regions. Statistical analyses performed: We used multinomial regressions to calculate adjusted odds ratios (AOR) for Sometimes or Often/Always consuming more unhealthy snacks/desserts (vs. Never/Rarely); and Sometimes or Often/Always more SSBs (vs. Never/Rarely). Results: Overall, 36% of adults reported sometimes consuming more unhealthy snacks/desserts; 16% did so often/always. Twenty-two percent of adults reported sometimes drinking more SSBs; 10% did so often/always. Factors significantly associated with higher odds of reporting often/always consuming more unhealthy snacks/desserts were younger adults (AOR range = 1.51–2.86 vs. adults ≥65 years), females (AOR = 1.58 vs. males), non-Hispanic Black (AOR = 1.89 vs. non-Hispanic White), lower household income (AOR = 2.01 for

To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC).We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors.Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with2 factors among grade 3, LVSI, or stage IB had a 3-year CSS95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology.Observation or VB only may be sufficient in stage I endometrioid HIR ECs with2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.

Adverse childhood experiences (ACEs) are a well-documented HIV-risk factor, but less is known about the relationship between ACEs and different HIV testing strategies. This study used data from an LGBTQ + community health assessment, that was part of a multi-staged community-based participatory research project in San Antonio, Texas. Overall, 464 young men who have sex with men (YMSM; 36-years-old) completed an online, cross-sectional survey that included questions about ACEs and HIV testing behavior. An association between increased ACEs exposure and the odds of clinic-based testing and HIVST HIV significantly decreased relative to never testing for HIV. Additionally, greater ACEs exposure was significantly associated with increased odds of reporting community-based testing (AOR = 1.09, 95% CI = 1.00, 1.20) and significantly reduced odds of HIV self-testing (AOR = 0.72, 95% CI = 0.63, 0.82) compared to clinic-based testing. Cumulative ACEs exposure is important in understanding HIV testing behaviors in YMSM and should be considered when developing HIV testing programs.

BACKGROUND AND OBJECTIVE. Low-income populations are more likely to experience food and nutrition insecurity and suffer a greater burden of non-communicable disease than the general population. The UnProcessed Pantry Project (UP3) is an intervention aimed to reduce ultra-processed food availability and consumption of food pantry clients accessing the emergency food system. METHODS. The pilot study included nutrition education, food boxes, and social support for 16-weeks at two food pantries. Data collection included the ASA24 dietary recall to calculate Healthy Eating Index-2015 (HEI-2015) scores, biomarkers (hemoglobin A1C, total cholesterol, blood pressure, waist circumference, BMI), and a demographic and psychosocial survey. RESULTS. Dietary quality among 43 participants significantly (p

The COVID-19 pandemic has brought enormous hardships to our country and healthcare system. We present our experience navigating through this pandemic with emphasis on reactivating our practice while keeping patients and staff safe. It is hoped that the methods and thought processes provided in this manuscript will help those who are in various stages of managing their practice or provide lessons learned as our country eventually moves beyond this pandemic. Lastly, we aspire to provide a guide for those who are in a position to prepare for the next pandemic.

Background: There is considerable heterogeneity in long-term weight loss among people referred to obesity treatment programmes. It is unclear whether attendance at face-to-face sessions in the early weeks of the programme is an independent predictor of long-term success. Objective: To investigate whether frequency of attendance at a community weight loss programme over the first 12 weeks is associated with long-term weight change. Methods: Participants were randomised to receive brief support only (control, n = 211), or a weight loss programme for 12 weeks (n = 530) or 52 weeks (n = 528). This study included participants with data on session attendance over the first 12 weeks (n = 889) compared to the control group. The association between attendance (continuously) and weight loss was explored using a linear model. A multi-level mixed-effects linear model was used to investigate whether attendance (categorised as 0, 1, 2–5, 6—9, and 10–12 sessions) was associated with weight loss at 3, 12, and 24 months compared to the control. Results: For every session attended in the first 12 weeks, the average weight loss was –0.259 kg/session at 24 months (p = 0.005). Analysis by attendance group found only those attending 10–12 sessions had significantly greater weight loss (–7.5 kg [95% CI –8.1 to –6.9] at 12 months; –4.7 kg [95% CI –5.3 to –4.1] at 24 months) compared to the control group (–3.4 [95% CI –4.5 to –2.4] at 12 months, –2.5 [95% CI –3.5 to –1.5] at 24 months). Early attendance was higher for people ≥70 years, but there was no evidence of a difference by gender, ethnicity, education, or income. Conclusions: Greater attendance at a community weight loss programme in the first 12 weeks is associated with enhanced weight loss up to 24 months. Regular attendance at a programme could be used as a criterion for continued provision of weight loss services to maximise the cost-effectiveness of interventions.