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Many mammals have been reported to significantly bias their offspring sex ratios, but these deviations from equality have been difficult to understand and are often inconsistent even within the same species. Evolutionary theory predicts a number of scenarios where females should bias their investment to one sex over the other; when fitness returns are sex specific, selection favors the facultative adjustment of offspring sex ratios to the sex with the highest inclusive fitness return. Interpreting sex allocation in mammals within the framework of classic sex allocation theory is challenging given the complex life histories and social interactions of species, hence it is likely that there are multiple mechanisms and selective forces dependent upon maternal and environmental drivers. Here, we show the previously demonstrated condition-dependent sex allocation in bridled nailtail wallabies (Onychogalea fraenata), where females in better condition were more likely to have sons, was reversed under high population densities and elevated maternal stress. In this solitary species, an elevated glucocorticoid stress response under unnaturally high densities likely influences adaptive sex allocation to the dispersive sex, consistent with the local resource competition theory. Managing factors such as population density, maternal stress, and food resources may be used to adjust offspring sex ratios in this endangered species.

In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone.

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections. Programmed death-ligand 1 (PD-L1) is involved in the inhibition of antigen specific T cells via ligation of programmed death 1 (PD-1). Here, the authors show checkpoint inhibition by use of small molecule inhibition of PD-L1 which in a humanised mouse model was shown to restore T cell responses and reduced tumour burden.

Estimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030. Using the PEARL model-an agent-based simulation of PWH who have initiated ART in the US-the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART-reaching 908,000 individuals by 2030-PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts. The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV.

The 2019 Fire Influence on Regional to Global Environments and Air Quality (FIREX-AQ) field experiment obtained a diverse set of in situ and remotely sensed measurements before and during a pyrocumulonimbus (pyroCb) event over the Williams Flats fire in Washington State. This unique dataset confirms that pyroCb activity is an efficient vertical smoke transport pathway into the upper troposphere and lower stratosphere (UTLS). The magnitude of smoke plumes observed in the UTLS has increased significantly in recent years, following unprecedented wildfire and pyroCb activity observed worldwide. The FIREX-AQ pyroCb dataset is therefore extremely relevant to a broad community, providing the first measurements of fresh smoke exhaust in the upper troposphere, including from within active pyroCb cloud tops. High-resolution remote sensing reveals that three plume cores linked to localized fire fronts, burning primarily in dense forest fuels, contributed to four total pyroCb “pulses.” Rapid changes in fire geometry and spatial extent dramatically influenced the magnitude, behavior, and duration of pyroCb activity. Cloud probe measurements and weather radar identify the presence of large ice particles within the pyroCb and hydrometers below cloud base, indicating precipitation development. The resulting feedbacks suggest that vertical smoke transport efficiency was reduced slightly when compared with intense pyroCb events reaching the lower stratosphere. Physical and optical aerosol property measurements in pyroCb exhaust are compared with previous assumptions. A large suite of aerosol and gas-phase chemistry measurements sets a foundation for future studies aimed at understanding the composition of smoke plumes lifted by pyroconvection into the UTLS and their role in the climate system.

IntroductionA substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring.Methods and analysisThe DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants.Ethics and disseminationMultisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment.Trial registration numberACTRN12622001458729.

Nipah virus causes highly lethal disease, with case-fatality rates ranging from 40% to 100% in recognised outbreaks. No treatments or licensed vaccines are currently available for the prevention and control of Nipah virus infection. In 2019, WHO published an advanced draft of a research and development roadmap for accelerating development of medical countermeasures, including diagnostics, therapeutics, and vaccines, to enable effective and timely emergency response to Nipah virus outbreaks. This Personal View provides an update to the WHO roadmap by defining current research priorities for development of Nipah virus medical countermeasures, based primarily on literature published in the last 5 years and consensus opinion of 15 subject matter experts with broad experience in development of medical countermeasures for Nipah virus or experience in the epidemiology, ecology, or public health control of outbreaks of Nipah virus. The research priorities are organised into four main sections: cross-cutting issues (for those that apply to more than one category of medical countermeasures), diagnostics, therapeutics, and vaccines. The strategic goals and milestones identified in each section focus on key achievements that are needed over the next 6 years to ensure that the necessary tools are available for rapid response to future outbreaks of Nipah virus or related henipaviruses.

Background Sleep in childhood is affected by behavioral, environmental, and parental factors. We propose that these factors were altered during the COVID-19 pandemic. This study investigates sleep habit changes during the pandemic in 528 children 4–12 years old in the US, leveraging data from the Environmental Influences on Child Health Outcomes (ECHO) Program. Methods Data collection occurred in July 2019–March 2020 (pre-pandemic) and two pandemic periods: December 2020–April 2021 and May–August 2021. Qualitative interviews were performed in 38 participants. Results We found no changes in sleep duration, but a shift to later sleep midpoint during the pandemic periods. There was an increase in latency at the first pandemic collection period but no increase in the frequency of bedtime resistance, and a reduced frequency of naps during the pandemic. Qualitative interviews revealed that parents prioritized routines to maintain sleep duration but were more flexible regarding timing. Children from racial/ethnic minoritized communities slept less at night, had later sleep midpoint, and napped more frequently across all collection periods, warranting in-depth investigation to examine and address root causes. Conclusions The COVID-19 pandemic significantly impacted children sleep, but parental knowledge of the importance of sleep might have played a significant protective role. Impact During the COVID-19 pandemic, US children changed their sleep habits, going to bed and waking up later, but their sleep duration did not change. Sleep latency was longer. Parental knowledge of sleep importance might have played a protective role. Regardless of data collection periods, children from racial/ethnic minoritized communities slept less and went to bed later. This is one of the first study on this topic in the US, including prospective pre-pandemic qualitative and quantitative data on sleep habits. Our findings highlight the pandemic long-term impact on childhood sleep. Results warrants further investigations on implications for overall childhood health.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Monoclonal antibodies that recognize conformational epitopes in protein aggregates are important for research, diagnostic, and therapeutic applications related to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Unfortunately, it remains challenging to discover and engineer high-quality conformational antibodies that are specific for protein aggregates and possess optimal combinations of three key binding properties, namely high affinity, high conformational specificity, and low off-target binding. Here we report a directed evolution approach for generating high-quality conformational antibodies against Alzheimer’s Aβ fibrils in the native IgG format. Our directed evolution approach uses targeted mutagenesis, yeast surface display, cell sorting, and deep sequencing to identify antibody candidates with optimized binding properties. Notably, we find that this approach yields robust isolation of IgGs with higher affinity, higher conformational specificity, and lower off-target binding than multiple clinical-stage Aβ antibodies, including aducanumab and crenezumab. This antibody engineering platform can be readily applied to generate conformational antibodies against diverse types of peptide and protein aggregates linked to human diseases.