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Leftover pills from postoperative opioid prescriptions place patients and members of their communities at risk for opioid misuse. We aimed to better understand patients’ post-discharge opioid consumption patterns to inform new methods of postoperative opioid prescribing. We assessed post-discharge opioid consumption of general surgery patients and assessed the adequacy of discharge opioid prescriptions. We then compared patient opioid consumption to a number of theoretical discharge prescriptions based on different opioid prescribing guidelines and a proposed discharge prescription based on the metric 24-h pre-discharge opioid consumption (PDOC). 62/99 patients (62.6%) returned an opioid log book. Median 24-h PDOC was 22.5 MME (IQR 5.0–45.0) and median discharge prescription size was 15 pills (IQR:10–20). Prescriptions were adequate for 83.7% of patients. The median number of pills used was 3 (IQR:0–11) and median time to opioid cessation was 3 days (IQR:0–5). Actual prescriptions were consistent with national opioid prescribing guidelines. Prescriptions based on the formula 2 × 24-h PDOC would have decreased the number of leftover pills by 7.5 per patient. Despite prescribing opioids consistent with national opioid prescribing guidelines, patients still receive too many pills. Improved opioid prescribing could be accomplished by use of the formula 2 × 24-h PDOC. •General surgery patients use very few opioids following hospital discharge.•Current prescribing guidelines recommend higher amounts of opioids than needed.•The metric 24-h pre-discharge opioid consumption could be used to help improve opioid stewardship.

Background Simian immunodeficiency virus (SIV) infection of nonhuman primates is the predominant model for preclinical evaluation of human immunodeficiency virus (HIV) vaccines. These studies frequently utilize high-doses of SIV that ensure infection after a single challenge but do not recapitulate critical facets of sexual HIV transmission. Investigators are increasingly using low-dose challenges in which animals are challenged once every week or every two weeks in order to better replicate sexual HIV transmission. Using this protocol, some animals require over ten challenges before SIV infection is detectable, potentially inducing localized immunity. Moreover, the lack of certainty over which challenge will lead to productive infection prevents tissue sampling immediately surrounding the time of infection. Findings Here we challenged Mauritian cynomolgus macaques with 100 50% tissue culture infectious doses (TCID 50 ) of SIVmac239 intrarectally three times a day for three consecutive days. Ten of twelve animals had positive plasma viral loads after this challenge regimen. Conclusions This approach represents a straightforward advance in SIV challenge protocols that may avoid induction of local immunity, avoid inconsistent timing between last immunization and infection, and allow sampling immediately after infection using low-dose challenge protocols.

Background CD8+ T cell responses, restricted by major histocompatibility complex (MHC) class I molecules, are critical to controlling human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) replication. Previous studies have used MHC-matched siblings and monozygotic twins to evaluate genetic and stochastic influences on HIV-specific T cell responses and viral evolution. Here we used a genetically restricted population of Mauritian cynomolgus macaques (MCM) to characterize T cell responses within nine pairs of MHC-matched animals. Findings In MHC-matched animals, there was considerable heterogeneity in the specificity and magnitude of T cell responses detected via individual peptide gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assays. These findings were further supported by full proteome pooled peptide matrix ELISPOT data collected from this cohort at 52 weeks post-infection. Interestingly, peptide regions that elicited dominant T cell responses were more commonly shared between MHC-matched MCM than peptide regions that elicited non-dominant T cell responses. Conclusions Our findings suggest that, while some T cell responses mounted during chronic infection by MHC-matched MCM are similar, the majority of responses are highly variable. Shared responses detected in this study between MHC-matched MCM were directed against epitopes that had previously elicited relatively dominant responses in MCM with the same MHC class I haplotype, suggesting that the factors that influence dominance may influence the reproducibility of responses as well. This may be an important consideration for future T cell-based vaccines aiming to consistently and reproducibly elicit protective T cell responses.

Despite litter size and kitten survival in mountain lions (Puma concolor) being well‐documented, there is a critical gap in the literature regarding the time that elapses between litter mortality and subsequent rebreeding in females. Here, we present observations from seven female mountain lions from two distinct study locations—the Black Hills of South Dakota and the Jemez Mountains of north‐central New Mexico—where female mountain lions lost litters and rebred shortly afterward. Our findings contribute novel data to the understanding of reproduction in mountain lions, including the shortest documented interval between litter loss and rebreeding (range: ≤ 4–94 days; mean: 46 days). These observations underscore the evolutionary pressures shaping sexual selection in mountain lions and highlight the significant physiological toll females endure as a consequence of infanticide and intraguild competition, with implications for population dynamics and fitness. We documented rapid rebreeding by female mountain lions (Puma concolor) following litter loss, including the shortest known rebreeding interval to date. These observations highlight the importance of infanticide and intraguild competition in shaping female fitness and population dynamics.

Background Children in households of lower socioeconomic status (SES) are more likely to be overweight/obese. We aimed to determine if home physical activity (PA) environments differed by SES and to explore home environment mediators of the relation of family SES to children’s PA and sedentary behavior. Methods Participants were 715 children aged 6 to 11 from the Neighborhood Impact on Kids (NIK) Study. Household SES was examined using highest educational attainment and income. Home environment was measured by parent report on a survey. Outcomes were child’s accelerometer-measured PA and parent-reported screen time. Mediation analyses were conducted for home environment factors that varied by SES. Results Children from lower income households had greater media access in their bedrooms (TV 52% vs. 14%, DVD player 39% vs. 14%, video games 21% vs. 9%) but lower access to portable play equipment (bikes 85% vs. 98%, jump ropes 69% vs. 83%) compared to higher income children. Lower SES families had more restrictive rules about PA (2.5 vs. 2.0). Across SES, children watched TV/DVDs with parents/siblings more often than they engaged in PA with them. Parents of lower SES watched TV/DVDs with their children more often (3.1 vs. 2.5 days/week). Neither total daily and home-based MVPA nor sedentary time differed by SES. Children’s daily screen time varied from 1.7 hours/day in high SES to 2.4 in low SES families. Media in the bedroom was related to screen time, and screen time with parents was a mediator of the SES--screen time relationship. Conclusions Lower SES home environments provided more opportunities for sedentary behavior and fewer for PA. Removing electronic media from children’s bedrooms has the potential to reduce disparities in chronic disease risk.

Background Studies identifying correlates of physical activity (PA) at all levels of the ecological model can provide an empirical basis for designing interventions to increase older adults’ PA. Purpose Applying ecological model principles, this study concurrently examined individual, psychosocial, and environmental correlates of older adults’ PA to determine whether built environment factors contribute to PA over and above individual/demographic and psychosocial variables. Methods Using a cross-sectional observational design, 726 adults, aged ≥66 years, were recruited from two US regions. Explanatory variables included demographics, self-efficacy, social support, barriers, and environmental variables measured by using geographic information systems (GIS) and self-report. Outcomes included reported walking for errands and leisure/exercise and accelerometer-measured daily moderate to vigorous PA (MVPA). Analyses employed mixed-model regressions with backward elimination. Results For daily MVPA, the only significant environmental variable was GIS-based proximity to a park ( p  < 0.001) after controlling for individual/demographic and psychosocial factors. Walking for errands was positively related to four environmental variables: reported walking/cycling facilities ( p  < 0.05), GIS-based intersection density ( p  < 0.01), mixed land use ( p  < 0.01), and private recreation facilities ( p  < 0.01). Walking for leisure/exercise was negatively related to GIS-based mixed land use ( p  < 0.05). Non-Hispanic white race/ethnicity, self-efficacy, and social support positively related to all three PA outcomes ( p  < 0.05). Conclusions Correlates of older adults’ PA were found at all ecological levels, supporting multiple levels of influence and need for multilevel interventions. Environmental correlates varied by PA outcome. Walking for errands exhibited the most environmental associations.

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination. Newly made proteins must be folded into specific three-dimensional shapes before they can perform their roles in cells. Many proteins are folded in a cell compartment called the endoplasmic reticulum. The cell closely monitors the quality of the work done by this compartment. If the endoplasmic reticulum has more proteins to fold than it can handle, unfolded or misfolded proteins accumulate and trigger a stress response called the unfolded protein response. This increases the capacity of the endoplasmic reticulum to fold proteins to match the demand. However, if the stress persists, then the unfolded protein response instructs the cell to die to protect the rest of the body. A protein called ATF6α is one of three branches of the unfolded protein response. This protein is found in the endoplasmic reticulum where it is inactive. Endoplasmic stress causes ATF6α to move from the endoplasmic reticulum to another compartment called the Golgi apparatus. There, two enzymes cut ATF6α to release a fragment of the protein that then moves to the nucleus to increase the production of the machinery needed to fold proteins in the endoplasmic reticulum. Errors in protein folding can cause serious diseases in humans and other animals. Drugs that target ATF6α might be able to regulate part of the unfolded protein response to treat these diseases. However, no drugs that act on ATF6α had been identified. Now, two groups of researchers have independently identified small molecules that specifically target ATF6α. Gallagher et al. screened over 100,000 compounds for their ability to reduce the activity of ATF6α-regulated genes. The experiments reveal that a class of small molecules termed Ceapins can selectively block the activity of ATF6α during endoplasmic reticulum stress, but had no effect on other proteins involved in the unfolded protein response. Furthermore, when human cells experiencing stress were treated with Ceapins, a greater number of cells died in comparison to cells that had not received Ceapins. An accompanying study by Gallagher and Walter reports on the mechanism by which Ceapins act on ATF6α. Independently, Plate et al. identified a type of small molecule that can activate ATF6. Together, the findings of Gallagher et al. and Plate et al. may lead to the development of new drugs for treating diseases associated with incorrect protein folding in the endoplasmic reticulum.

A highly effective HIV vaccine has been the goal of vaccinologists for nearly 35 years. A successful vaccine would need to induce broadly neutralizing antibodies (bnAbs) that are capable of neutralizing multiple HIV strains (see the Perspective by Agazio and Torres). Steichen et al. report a strategy in which the first vaccine shot can lead to immune responses that generate desired bnAbs. By combining knowledge of human antibody repertoires and structure to guide design, they validated candidate immunogens through functional preclinical testing. Saunders et al. designed immunogens with differences in binding strength for bnAb precursors, which enabled selection of rare mutations after immunization. The immunogens promoted bnAb precursor maturation in humanized mice and macaques. Science , this issue p. eaax4380 , p. eaay7199 ; see also p. 1197 Engineering antibodies against rare HIV mutations is required for HIV neutralizing antibody development.

Background Though park presence and access disparities are well studied for their associations with physical activity (PA), disparities in the availability and quality of amenities and facilities within parks have been infrequently examined. Methods Five hundred forty-three parks from 472 block groups in the Seattle, WA and Baltimore, MD regions were audited using the Environmental Assessment of Public Recreation Spaces (EAPRS) to assess presence and quality (e.g., condition, cleanliness) of amenities (e.g., restrooms, seating) and facilities (e.g., fields, courts). General linear model regressions investigated Census 2000-derived neighborhood race/ethnicity and income main effect and interactive relationships with 7 park quality summary scores: 1) trails, 2) open space, 3) sports facilities, 4) PA facilities count, 5) PA facilities quality, 6) aesthetics, and 7) overall amenities, controlling for park size. The regions were analyzed separately due to differing race/ethnicity distributions. Results In the Seattle region, neighborhood income was significantly negatively associated with sports quality score ( p  < .043), PA facilities total count ( p  < .015) and the overall amenities quality score ( p  < .004) (unexpected direction). In the Baltimore region, neighborhood race/ethnicity (percent White/non-Hispanic) was significantly positively related to the open spaces quality score ( p  < .011) (expected direction). A significant income-by-race/ethnicity interaction was found for PA facilities quality ( p  = .014), with high-percent minority neighborhoods having higher quality parks in high- vs. low-income neighborhoods, yet was opposite in mostly White/non-Hispanic neighborhoods. The other income-by-race/ethnicity interaction was for overall amenities quality score ( p  = .043), where scores in high-percent minority neighborhoods were best in high- vs. low-income neighborhoods. There was little difference in scores within mostly White or mixed neighborhoods by income. Conclusions Patterns of association of neighborhood race/ethnicity and income with park qualities differed between regions. In the Seattle region, “equitable differences” were found, where lower income neighborhoods had better park quality on average. In the Baltimore region, park quality was more consistently negatively associated with income and race/ethnic diversity, and complex interactions of race/ethnicity by income were detected. These findings emphasize the need to explore other factors that may explain variations in park quality, like local policy, citizen involvement in park decision-making, park funding and allocation, sources of funding and park priorities.

How homeodomain proteins gain sufficient DNA binding specificity to regulate diverse processes is a long-standing question. Here, we determine how the ALX4 Paired-like protein achieves DNA binding specificity for a TAAT–NNN–ATTA dimer site. We first show that ALX4 binds this motif independently of its co-factor, TWIST1, in cranial neural crest cells. Structural analysis identifies seven ALX4 residues that participate in dimer binding, many of which are conserved across the Paired-like family, but not other homeodomain proteins. Unexpectedly, the two ALX4 proteins within the dimer use distinct residues to form asymmetric protein-protein and protein-DNA interactions and mediate cooperativity. Moreover, we find that ALX4 cooperativity is required for transcriptional activation and that ALX4 disease variants cause distinct molecular defects that include loss of cooperativity. These findings provide insights into how Paired-like factors gain DNA specificity and show how disease variants can be stratified based on their molecular defects. How homeodomain proteins achieve sufficient DNA binding specificity is poorly understood. Here, the authors use a structural approach to show that the ALX4 homeodomain achieves DNA binding specificity using asymmetric protein and DNA interactions.