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Aim: Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive primary CNS neoplasm, predominantly observed in children. The use of autologous stem cell transplantation (ASCT) in pediatric ATRT has shown promise; however, its utility in adult ATRT remains unclear. Patients & methods: This study presents the case of an adult patient with ATRT who is in remission after ASCT and reviews the literature on ASCT in adults with ATRT. Four cases of ATRT in adults who underwent ASCT were identified, with pertinent data summarized. Results: All five patients survived longer than the historical average survival rate, four of whom had no clinical or radiographic evidence of disease at the final follow-up. Conclusion: Based on limited data, there may be a role for ASCT in the treatment of adults with ATRT.

Background: Various studies have reported on the impact of human papillomavirus (HPV) vaccines. Here we present the largest population-based investigation of genotype-specific distributions over the decade following implementation of the 4-valent HPV vaccine (HPV6/11/16/18) in the United States., Methods: Liquid-based cervical cytology samples from individuals aged 15-30 years undergoing cervical screening throughout New Mexico were tested by broad-spectrum HPV genotyping. Weighted relative differences in HPV type-specific prevalence (RDP) and 95% confidence intervals (95%CI) were calculated comparing individuals screened in 2007-2009 (n = 95,915) to those screened in 2013-2016 (n = 103,371). Weighted logistic regression was used to estimate relative risk of type-specific HPV infections. Tests of significance were 2-sided., Results: Genotype-specific prevalence reduced significantly for HPV16 (RDP=-52.6%, 95%CI -56.9 to -48.3), HPV18 (RDP=-62.1%, 95%CI -68.5 to -55.8), HPV31 (RDP=-34.2%, 95%CI -42.1 to -26.3) and HPV33 (RDP=-31.8%, 95%CI -48.4 to -15.1). The RDP increased for other carcinogenic HPV types by 19.5% (95%CI +14.3 to + 24.6) when excluding HPV16/18. Large reductions in HPV6/11 RDP were observed but overall, non-carcinogenic, non-vaccine types increased. Comparing females born in 1996 to those born in 1989, risk of infection with HPV6/11/16/18 decreased by 80.0% among individuals aged 21-25 years. High-grade squamous intraepithelial lesions or worse (HSIL+) decreased by 49.4% when extending the evaluation from 2007 to 2018., Conclusion(s): HSIL+ incidence is decreasing with large reductions in the prevalence of 4-valent HPV vaccine types and non-vaccine types HPV31 and 33, reflecting vaccine cross-protection. Increases in non-vaccine HPVs may attenuate anticipated reductions in HPV-related abnormalities including cancers however the benefits of HPV vaccination remain substantial., (© The Author(s) 2024. Published by Oxford University Press.)

Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests to declare: Forum for Collaborative Research, as an organization, receives grants from the pharmaceutical industry but these are unrestricted and not specific to the work described in this article. KHM has received unrestricted research grants from Gilead Sciences, Merck & Co., Inc., and ViiV Healthcare. JM is a paid consultant for both Gilead Sciences in the area of HIV prevention. BSP, as an inventor of the LAg-Avidity EIA at CDC, receives a portion of the royalties from the sale of the test kits, as per policy of the U.S. government. MNR received consulting fees from the Bill and Melinda Gates Foundation, Merck, the Forum for Collaborative research, and the International AIDS Vaccine Initiative in 2024. VV is a full-time employee of ViiV Healthcare and owns GSK stock. HYL received NIH NIAID grant support for genomic HIV incidence assay research. All other authors have declared that no competing interests exist.

Purpose: Explore the potential utility of a Cooperative Extension-specific program to support post-active treatment cancer survivors., Methods: A user-centered study was conducted to identify barriers to and facilitators of the implementation of a program for adult cancer survivors living post primary cancer treatment ("cancer survivors") via Cooperative Extension ("Extension"), including interviews analyzed using the Consolidated Framework for Implementation Research. Participants included Cooperative Extension Educators and adult cancer survivors in Oklahoma who completed data collection from July 2023 to September 2023., Results: N = 20 participants were enrolled. Cancer survivors indicated poor familiarity with Extension, or a primary association with agriculture. Some voiced surprise Extension was not already providing cancer-related programming. Many expressed poor support in their communities due to issues secondary to rurality, often relying on non-cancer programs. Educators voiced a strong capability to deliver cancer-related programming if intentionally designed, with many already providing education on relevant topics (e.g., finances, nutrition, physical activity). A salient barrier was poor connectivity with the healthcare system., Conclusions: There is an immense need for improved survivorship care in underserved communities due to poor social connectedness, support structures, and poor mental health. Cooperative Extension is well-poised to deliver cancer survivorship-specific programming., Implications for Cancer Survivors: Cooperative Extension provides an extensive network of professionals who can provide support to cancer survivors, particularly those post-active treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To determine the timing of symptomatic venous thromboemboli (VTE) in patients sustaining a pelvic and/or acetabular fracture. Secondly, to evaluate for any factors that may influence this timing., Methods: A retrospective cohort of 47 patients with acetabular and/or pelvic ring injuries who developed VTEs at a single academic level I trauma center were identified from 2012 to 2018. The chronology of VTE diagnosis in relation to date of injury, initial surgery, final surgery, and date of discharge was evaluated. Patients who developed VTEs were then evaluated based on known risk factors for VTE to determine if any of these affected timing., Results: Symptomatic VTEs were diagnosed in 3.8% of patients with pelvic and/or acetabular fractures. In patients who developed a thromboembolism, diagnosis occurred on average 21.5 (± 19.2), 20.7 (± 19.9), 9.8 (± 23.4), and 4.3 (± 27.6) days after injury, index procedure, final procedure, and date of discharge. 25% of patients developed VTE more than 4 weeks after their initial injury. No known risk factors effected the timing of VTE., Conclusion: The 2015 OTA expert panel recommends 4 weeks of anticoagulation for orthopedic trauma patients at high risk of VTE, which may be too short a duration. In our cohort, 25% of VTEs occurred greater than 4 weeks after injury. Additional research is needed to clarify the exact duration of anticoagulation after pelvic and acetabular fractures; however, surgeons may want to consider anticoagulating patients for greater than 4 weeks., Level of Evidence: Level III-retrospective cohort., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Older adult women often do not engage in sufficient physical activity (PA) and can encounter biological changes that exacerbate the negative effects of inadequate activity. Wearable activity monitors can facilitate PA initiation, but evidence of sustained behavior change is lacking. Supplementing wearable technologies with intervention content that evokes enjoyment, interest, meaning, and personal values associated with PA may support long term adherence. In this paper, we present the protocol of an NIA-funded study designed to evaluate the efficacy of CHALLENGE for increasing step count and motivation for PA in insufficiently active older women (Challenges for Healthy Aging: Leveraging Limits for Engaging Networked Game-based Exercise). CHALLENGE uses social media to supplement wearable activity monitors with the autonomy-supportive frame of a game. We hypothesize that CHALLENGE will engender playful experiences that will improve motivation for exercise and lead to sustained increases in step count., Methods: We will recruit 300 healthy, community dwelling older adult women on a rolling basis and randomize them to receive either the CHALLENGE intervention (experimental arm) or an activity monitor-only intervention (comparison arm). Participants in both groups will receive a wearable activity monitor and personalized weekly feedback emails. In the experimental group, participants will also be added to a private Facebook group, where study staff will post weekly challenges that are designed to elicit playful experiences while walking. Assessments at baseline and 6, 12, and 18 months will measure PA and motivation-related constructs. We will fit linear mixed-effects models to evaluate differences in step count and motivational constructs, and longitudinal mediation models to evaluate if interventional effects are mediated by changes in motivation. We will also conduct thematic content analysis of text and photos posted to Facebook and transcripts from individual interviews., Discussion: By taking part in a year-long intervention centered on imbuing walking behaviors with playful and celebratory experiences, participating older adult women may internalize changes to their identity and relationship with PA that facilitate sustained behavior change. Study results will have implications for how we can harness powerful and increasingly ubiquitous technologies for health promotion to the vast and growing population of older adults in the U.S. and abroad., Trial Registration: ClinicalTrials.gov Identifier NCT04095923. Registered September 17th, 2019., (© 2024. The Author(s).)

Background and Aims: In patients with de novo heart failure with reduced ejection fraction (HFrEF), improvement of left ventricular ejection fraction (LVEF) is expected to occur when started on guideline-recommended medical therapy. However, improvement may not be completed within 90 days., Methods: Patients with HFrEF and LVEF ≤ 35% prescribed a wearable cardioverter-defibrillator between 2017 and 2022 from 68 sites were enrolled, starting with a registry phase for 3 months and followed by a study phase up to 1 year. The primary endpoints were LVEF improvement > 35% between Days 90 and 180 following guideline-recommended medical therapy initiation and the percentage of target dose reached at Days 90 and 180., Results: A total of 598 patients with de novo HFrEF [59 years (interquartile range 51-68), 27% female] entered the study phase. During the first 180 days, a significant increase in dosage of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists was observed (P < .001). At Day 90, 46% [95% confidence interval (CI) 41%-50%] of study phase patients had LVEF improvement > 35%; 46% (95% CI 40%-52%) of those with persistently low LVEF at Day 90 had LVEF improvement > 35% by Day 180, increasing the total rate of improvement > 35% to 68% (95% CI 63%-72%). In 392 patients followed for 360 days, improvement > 35% was observed in 77% (95% CI 72%-81%) of the patients. Until Day 90, sustained ventricular tachyarrhythmias were observed in 24 wearable cardioverter-defibrillator carriers (1.8%). After 90 days, no sustained ventricular tachyarrhythmia occurred in wearable cardioverter-defibrillator carriers., Conclusions: Continuous optimization of guideline-recommended medical therapy for at least 180 days in HFrEF is associated with additional LVEF improvement > 35%, allowing for better decision-making regarding preventive implantable cardioverter-defibrillator therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: People living with and beyond breast cancer can face internal barriers to physical activity (eg, fatigue and pain). Digital interventions that promote psychological acceptance and motivation may help this population navigate these barriers. The degree to which individuals (1) adhere to intervention protocols and (2) reflect on and internalize intervention content may predict intervention efficacy., Objective: The objective of this study was to characterize the nature of reflective processes brought about by an 8-week acceptance- and mindfulness-based physical activity intervention for insufficiently active survivors of breast cancer (n=75). Furthermore, we explored the potential utility of a metric of reflective processes for predicting study outcomes., Methods: Of the intervention's 8 weekly modules, 7 (88%) included an item that asked participants to reflect on what they found to be most useful. Two coders conducted directed content analysis on participants' written responses. They assessed each comment's depth of reflection using an existing framework (ranging from 0 to 4, with 0=simple description and 4=fundamental change with consideration of social and ethical issues). The coders identified themes within the various levels of reflection. We fit multiple linear regression models to evaluate whether participants' (1) intervention adherence (ie, number of modules completed) and (2) the mean level of the depth of reflection predicted study outcomes., Results: Participants were aged on average 57.2 (SD 11.2) years, mostly non-Hispanic White (58/75, 77%), and mostly overweight or obese (54/75, 72%). Of the 407 responses to the item prompting personal reflection, 70 (17.2%) were rated as reflection level 0 (ie, description), 247 (60.7%) were level 1 (ie, reflective description), 74 (18.2%) were level 2 (ie, dialogic reflection), 14 (3.4%) were level 3 (ie, transformative reflection), and 2 (0.5%) were level 4 (ie, critical reflection). Lower levels of reflection were characterized by the acquisition of knowledge or expressing intentions. Higher levels were characterized by personal insight, commentary on behavior change processes, and a change of perspective. Intervention adherence was associated with increases in self-reported weekly bouts of muscle-strengthening exercise (B=0.26, SE 0.12, 95% CI 0.02-0.50) and decreases in sleep disturbance (B=-1.04, SE 0.50, 95% CI -0.06 to -2.02). The mean level of reflection was associated with increases in psychological acceptance (B=3.42, SE 1.70, 95% CI 0.09-6.75) and motivation for physical activity (ie, integrated regulation: B=0.55, SE 0.25, 95% CI 0.06-1.04)., Conclusions: We identified a useful method for understanding the reflective processes that can occur during digital behavior change interventions serving people living with and beyond breast cancer. Intervention adherence and the depth of reflection each predicted changes in study outcomes. Deeper reflection on intervention content was associated with beneficial changes in the determinants of sustained behavior change. More research is needed to investigate the relations among digital behavior change intervention use, psychological processes, and intervention efficacy., (©Michael C Robertson, Emily Cox-Martin, Karen Basen-Engquist, Elizabeth J Lyons. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 09.02.2024.)

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor 1 (GPCR) that has a central role in regulating systemic calcium homeostasis 2,3 . Here we use cryo-electron microscopy and functional assays to investigate the activation of human CaSR embedded in lipid nanodiscs and its coupling to functional G i versus G q proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both G i and G q drive additional conformational changes in the activated CaSR dimer to stabilize a more extensive asymmetric interface of the seven-transmembrane domain (7TM) that involves key protein-lipid interactions. Selective G i and G q coupling by the receptor is achieved through substantial rearrangements of intracellular loop 2 and the C terminus, which contribute differentially towards the binding of the two G-protein subtypes, resulting in distinct CaSR-G-protein interfaces. The structures also reveal that natural polyamines target multiple sites on CaSR to enhance receptor activation by zipping negatively charged regions between two protomers. Furthermore, we find that the amino acid L-tryptophan, a well-known ligand of CaSR extracellular domains, occupies the 7TM bundle of the G-protein-coupled protomer at the same location as cinacalcet and other allosteric modulators. Together, these results provide a framework for G-protein activation and selectivity by CaSR, as well as its allosteric modulation by endogenous and exogenous ligands., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The US Food and Drug Administration supports innovations to facilitate new indications for high-risk human papillomavirus testing. This report describes the retrospective testing of stored specimens and analysis of existing data to efficiently and cost-effectively support a new indication for the Onclarity human papillomavirus assay (Becton, Dickinson and Company, BD Life Sciences - Integrated Diagnostic Solutions, Sparks, MD). The performance of this index test was compared with that of a predicate test, the cobas human papillomavirus assay (Roche Diagnostics, Indianapolis, IN). Both human papillomavirus assays are based on real-time polymerase chain reaction platforms that detect the presence of 14 high-risk human papillomavirus genotypes. The predicate assay reports human papillomavirus types 16 and 18 as individual results and the other 12 human papillomavirus genotypes as 1 pooled result. The index assay reports 9 independent results (human papillomavirus types 16, 18, 31, 33/58, 35/39/68, 45, 51, 52, and 56/59/66). Both the index and predicate assays are approved by the Food and Drug Administration for cervical cancer screening, but at the time that this study was initiated, the index human papillomavirus assay was not approved for use with cervical specimens collected in PreservCyt (Hologic, Inc, San Diego, CA) liquid-based cytology media., Objective: The performance of the index human papillomavirus assay was compared with that of the predicate human papillomavirus assay for the detection of cervical intraepithelial neoplasia grades 2 or greater and 3 or greater (≥CIN2 or ≥CIN3) using PreservCyt liquid-based cytology specimens collected from women aged 21 to 65 years. In addition, the ability of the index test's extended genotyping to stratify ≥CIN2 and ≥CIN3 risks, using these specimens, was evaluated., Study Design: The New Mexico HPV Pap Registry was used to select an age- and cytology-stratified random sample of 19,879 women undergoing opportunistic cervical screening and follow-up in routine clinical practice across New Mexico. A subset (n = 4820) of PreservCyt specimens was selected from 19,879 women for paired testing by the index and predicate human papillomavirus assays within age and cytology strata and included women with or without cervical biopsy follow-up. Point estimate differences and ratios were calculated for cervical disease detection and positivity rates, respectively, with 95% confidence intervals to determine statistical significance. The cumulative risk of ≥CIN2 or ≥CIN3, with up to 5-year follow-up, was estimated for the index assay using Kaplan-Meier methods., Results: The 5-year cumulative ≥CIN3 detection rates were 5.6% for the index assay and 4.6% for the predicate assay (difference, 1.0%; 95% confidence interval, 0.5%-1.5%). The ≥CIN3 positivity rates within <1 year were 95.3% for the index assay and 94.5% for the predicate assay (ratio, 1.01; 95% confidence interval, 0.98-1.06). The ≥CIN3 cumulative positivity rates for the index and predicate assays were also similar at 5 years. Among cases of ≥CIN3, the positive agreement rates between the index and predicate assays for human papillomavirus types 16 and 18 were 100.0% (95% confidence interval, 95.0%-100.0%) and 90.9% (95% confidence interval, 62.3%-98.4%), respectively. Human papillomavirus type 16 carried the highest ≥CIN2 or ≥CIN3 risk, followed by human papillomavirus types 18/31/33/58/52/45 and human papillomavirus types 35/56/59/51/56/59/66., Conclusion: The index and predicate human papillomavirus assays demonstrated equivalent performance, and extended human papillomavirus genotyping, using the index assay, provided effective ≥CIN2 and ≥CIN3 risk stratification, supporting a new indication for use of the index assay with PreservCyt., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Schools are a key setting for supporting youth physical activity, given their broad reach and diverse student populations. Organizational readiness is a precursor to the successful implementation of school-based physical activity opportunities. The R = MC 2 heuristic (Readiness = Motivation x Innovation-Specific Capacity x General Capacity) describes readiness as a function of an organization's motivation and capacity to implement an innovation and can be applied to better understand the implementation process. The purpose of this study was to explore the barriers to and facilitators of implementing school-based physical activity opportunities in the context of organizational readiness., Methods: We analyzed interview data from 15 elementary school staff (principals, assistant principals, physical education teachers, and classroom teachers) from a school district in Texas. We focused on factors related to adopting, implementing, and sustaining a variety of school-based physical activity opportunities. We used the Framework Method to guide the analysis and coded data using deductive (informed by the R = MC 2 heuristic) and inductive approaches. Themes were generated using the frequency, depth, and richness of participant responses., Results: Four themes emerged from the data: (1) implementation is aided by the presence of internal and external relationships; (2) physical activity opportunities compete with other school priorities; (3) seeing the benefits of physical activity opportunities motivates school staff toward implementation; and (4) staff buy-in is critical to the implementation process. Themes 1-3 aligned with subcomponents of the R = MC 2 heuristic (intra- and inter-organizational relationships, priority, and observability), whereas Theme 4 (staff buy-in) related to multiple subcomponents within the Motivation component but was ultimately viewed as a distinct construct., Conclusion: Our results highlight and explain how key readiness constructs impact the implementation of school-based physical activity opportunities. They also highlight the importance of obtaining staff buy-in when implementing in the school setting. This information is critical to developing readiness-building strategies that help schools improve their capacity to deliver physical activity opportunities effectively., Trial Registration: Not applicable., (© 2024. The Author(s).)

Objectives: Mexico has a rapidly aging population at risk for cognitive impairment. Social and leisure activities may protect against cognitive decline in older adults. The benefits of these behaviors may vary by patterns of cognitive impairment. The objectives of this study were to identify latent states of cognitive functioning, model the incidence of transitions between these states, and investigate how social and leisure activities were associated with state transitions over a 6-year period in Mexican adults aged 60 and older., Methods: We performed latent transition analyses to identify distinct cognitive statuses in the 2012 and 2018 waves of the Mexican Health and Aging Study (N = 9,091). We examined the transition probabilities between these states and their associations with social and leisure activities., Results: We identified 4 cognitive statuses at baseline: normal cognition (43%), temporal disorientation (30%), perceptual-motor function impairment (7%), and learning and memory impairment (20%). Various social and leisure activities were associated with reduced odds of death and disadvantageous cognitive transitions, as well as increased odds of beneficial transitions., Discussion: Mapping the effects of popular social and leisure activities onto common patterns in cognitive functioning may inform the development of more enjoyable and effective health-protective behavioral interventions., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To determine the proportion of patients who fail manipulation under anesthesia (MUA) as a treatment for posttraumatic knee stiffness and determine the risk factors for MUA failure., Methods: A retrospective cohort study was performed at a level I trauma center. We identified 213 knees in 199 patients with arthrofibrosis treated by MUA within 1 year of injury from 2007 to 2020. The primary outcome was MUA failure as defined by need for repeat MUA or surgical release after MUA. Multivariable logistic regression was used to determine the association between MUA failure and potential risk factors., Results: Overall, 111 knees (52%) failed treatment with MUA. An association was demonstrated between MUA failure and delay in treatment >90 days after injury (OR 3.6, p < 0.01), neurologic injury (OR 2.2, p = 0.02), and pre-procedure knee flexion <45° (OR 1.9, p < 0.01). The rate of failure for knees with no risk factors was 0% (0 of 14), 37% for knees with one risk factor (27 of 73), and 67% (84 of 126) for knees with two or more risk factors., Conclusion: For patients whose MUA is delayed beyond 90 days postinjury, pre-manipulation knee flexion is <45°, or those with associated neurologic injury; odds of MUA failing to correct posttraumatic arthrofibrosis are significantly increased. The likelihood of obtaining adequate range of motion (ROM) with MUA alone is lower than reported in other populations, with a higher likelihood of being treated with surgical release or additional MUA to attempt to obtain adequate ROM., Competing Interests: Declaration of Competing Interest N. N. O'Hara receives stock options from Arbutus Medical, Inc. unrelated to this research. R. V. O'Toole is a paid consultant for Stryker, receives stock options from Imagen, and receives royalties from Lincotek, all unrelated to this research. The remaining authors report no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Schools play an important role in promoting physical activity for youth. However, school-based physical activity opportunities often compete with other academic priorities, limiting their implementation. The purpose of this study was to qualitatively explore elementary school teacher and staff perspectives on providing physical activity opportunities and how they impact students and learning., Methods: We partnered with a school district in Texas to conduct semi-structured individual interviews. We used a purposeful sampling approach to recruit elementary teachers and staff knowledgeable about the physical activity opportunities provided at their school. Interviews included questions about participant opinions of providing physical activity opportunities and the types of opportunities provided. We analyzed data using a directed content analysis and iterative categorization approach., Results: Fifteen participants (4 teachers, 4 physical education teachers, 3 assistant principals, and 4 principals) completed interviews from 10 elementary schools. Participants discussed observed and perceived benefits when providing physical activity opportunities, which emerged into four themes and subthemes: (1) academic benefits (learning readiness, learning engagement, and academic performance); (2) social-emotional benefits (behavior, interpersonal and social skills, and classroom culture); (3) physical benefits (brain health, skill development, physical health); and (4) instructional benefits (quality teaching time, helpful teaching tools, and teacher-student relationships)., Conclusions: Teachers and staff observed numerous benefits when students had opportunities to be physically active, including the positive impact on academic and social-emotional outcomes. Our findings highlight the alignment of physical activity with other school priorities. Physical activity programming can be used in ways to support academics, learning, behavior, and other important outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Walker, Craig, Pfledderer, Robertson, Cuccaro, Fumero and Bartholomew.)

Introduction: A whole-of-school approach is best to promote physical activity before, during, and after school. However, multicomponent programming is often complex and difficult to deliver in school settings. There is a need to better understand how components of a whole-of-school approach are implemented in practice. The objectives of this mixed methods study were to: (1) qualitatively explore physical activity approaches and their implementation in elementary schools, (2) quantitatively assess implementation levels, and (3) examine associations between school-level physical activity promotion and academic ratings., Methods: We used an exploratory sequential mixed methods design. We conducted semi-structured qualitative interviews with elementary school staff from a Texas school district and used a directed content analysis to explore physical activity approaches and their implementation. Using qualitative findings, we designed a survey to quantitatively examine the implementation of physical activity approaches, which we distributed to elementary staff district wide. We used Pearson correlation coefficients to examine the association between the amount of physical activity opportunities present in individual schools and school-level academic ratings., Results: We completed 15 interviews (7 principals/assistant principals, 4 physical educators, and 4 classroom teachers). Elementary school teachers and staff indicated PE and recess implementation was driven from the top-down by state and district policies, while implementation of classroom-based approaches, before and after school programming, and active transport were largely driven from the bottom-up by teachers and school leaders. Teachers and staff also discussed implementation challenges across approaches. Survey respondents ( n  = 247 from 22 schools) indicated 54.6% of schools were implementing ≥135 min/week of physical education and 72.7% were implementing 30 min/day of recess. Classroom-based approaches were less common. Twenty-four percent of schools reported accessible before school programs, 72.7% reported accessible after school programs, and 27% promoted active transport. There was a direct association between the number of physical activity opportunities provided and school-level academic ratings r (22) = 0.53, p  = 0.01., Conclusion: Schools provided physical activity opportunities consistent with a whole-of-school approach, although there was variability between schools and implementation challenges were present. Leveraging existing school assets while providing school-specific implementation strategies may be most beneficial for supporting successful physical activity promotion in elementary schools., Competing Interests: During the writing of this manuscript, Dr. Walker was supported by the National Heart, Lung, and Blood Institute (1K01HL151817-01A1). Data collection was supported by a research career development award for (K12HD052023): Building Interdisciplinary Research Career in Women’s Health Program-BIRCWH; Berenson, PI) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health and the University of Texas Health Science Center at Houston School of Public Health Cancer Education and Career Development Program grant from the National Cancer Institute (R25 CA057712). During the writing of this manuscript Dr. Craig was supported by the University of Texas Health Science Center at Houston School of Public Health Cancer Education and Career Development Program grant from the National Cancer Institute (T32/CA057712). This work is partially supported by the Center for Health Promotion and Prevention Research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agency., (Copyright © 2023 Walker, Pfledderer, Craig, Robertson, Heredia and Bartholomew.)

Background: Many studies show positive bidirectional associations between physical activity (PA) and sleep at the between-person level. There is an increased interest in investigating these associations at the within-person level. Few studies examined the effects of time-varying moderators on the within-person bidirectional associations between PA and sleep. This study aimed to examine the bidirectional within-person day-level associations between activity levels and self-reported sleep duration and explore the moderating effects of perceived stress on these day-level associations., Method: Data from 158 women that included 7-day free-living monitoring over 4 measurement periods was analyzed using multilevel modeling to explore the moderating effects of daily stress on the bidirectional, within-person associations between activity levels and self-reported sleep duration. Moderate-to-vigorous PA (MVPA) and sedentary behavior (SB) were estimated from a waist-worn accelerometer. Self-reported sleep duration and perceived stress were collected by ecological momentary assessment., Results: No significant within-person associations between MVPA minutes and self-reported sleep duration were found in either direction. However, engaging in more MVPA than one's usual level was associated with longer sleep later that night when perceived stress was higher than usual (p = .04). Bidirectional negative within-person association between SB minutes and self-reported sleep duration was found (ps < .01). The negative association between SB and sleep duration later that night was stronger when perceived stress was lower than usual (p = .01)., Conclusion: Daily stress played an important role in the day-to-day associations between activity levels and sleep., (© 2022. International Society of Behavioral Medicine.)

Human papillomavirus (HPV) testing for cervical screening increases diagnosis of precancer and reduces the incidence of cervical cancer more than cytology alone. However, real-world evidence from diverse practice settings is lacking for the United States (U.S.) to support clinician adoption of primary HPV screening. Using a population-based registry, which captures all cervical cytology (with or without HPV testing) and all cervical biopsies, we conducted a real-world evidence study of screening in women aged 30 to 64 years across the entire state of New Mexico. Negative cytology was used to distinguish cotests from reflex HPV tests. A total of 264 198 cervical screening tests (with exclusions based on clinical history) were recorded as the first screening test between 2014 and 2017. Diagnoses of cervical intraepithelial neoplasia grades 2 or 3 or greater (CIN2+, CIN3+) from 2014 to 2019 were the main outcomes. Of cytology-negative screens, 165 595 (67.1%) were cotests and 4.8% of these led to biopsy within 2 years vs 3.2% in the cytology-only group. Among cytology-negative, HPV tested women, 347 of 398 (87.2%) CIN2+ cases were diagnosed in HPV-positive women, as were 147 of 164 (89.6%) CIN3+ cases. Only 29/921 (3.2%) CIN3+ and 67/1964 (3.4%) CIN2+ cases were diagnosed in HPV-negative, cytology-positive women with biopsies. Under U.S. opportunistic screening, across a diversity of health care delivery practices, and in a population suffering multiple disparities, we show adding HPV testing to cytology substantially increased the yield of CIN2+ and CIN3+. CIN3+ was rarely diagnosed in HPV-negative women with abnormal cytology, supporting U.S. primary HPV-only screening., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

GPR56 is a widely expressed adhesion GPCR (AGPCR) that has pleotropic roles in brain development, platelet function, cancer, and more. Nearly all AGPCRs possess extracellular regions that bind protein ligands and conceal a cryptic tethered peptide agonist. AGPCR reception of mechanical or shear force is thought to release the tethered agonist permitting its binding to the AGPCR orthosteric site for consequent activation of G protein signaling. This multistep mechanism of AGPCR activation is difficult to target, emphasizing the need for tool compounds and potential therapeutics that modulate AGPCRs directly. We expanded our cell-based pilot screen for GPR56 small molecule activators to screen >200,000 compounds and identified two promising agonists: 2-(furan-2-yl)-1-[(4-phenylphenyl)carbonyl]pyrrolidine, or compound 4, and propan-2-yl-4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, or compound 36. Both compounds activated GPR56 receptors enginered to have impaired tethered agonists and/or be cleavage deficient. Compound 4 activated a subset of group VIII AGPCRs while compound 36 had exclusive specificity for GPR56 among the GPCRs tested. Compound 36 SAR analysis identified an analog with the isopropyl R group replaced with a cyclopentyl ring and the electrophilic bromine replaced with a CF 3 group. Analog 36.40 had 40% increased potency over compound 36 and was 20-fold more potent than synthetic peptidomimetics designed from the GPR56 tethered agonist. The new GPCR56 tool compounds discovered in this screen may be used to further advance understanding of GPR56 function and aid development of AGPCR-targeted therapeutics. SIGNIFICANCE STATEMENT: Adhesion G protein coupled receptors (AGPCRs) are a large, clinically relevant class of GPCRs with no available therapeutics, in part due to their unique mechanism of activation. GPR56 is a widely expressed model AGPCR involved in cancer metastasis, hemostasis, and neuron myelination. In the present study, we identified novel small molecule agonists for GPR56. These molecules are among the most potent identified thus far and may become useful leads in the development of a GPR56-targeted therapeutic., (Copyright © 2023 by The Author(s).)

Standard-of-care HIV pre-exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on-PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on-PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Rural cancer survivors face a greater number of health disparities, including poorer health-related quality of life (HRQoL), than urban cancer survivors. Engagement in healthy lifestyle behaviors also varies between rural and urban cancer survivors. Lifestyle behaviors can improve HRQoL; however, the combination of behaviors most important for HRQoL in rural survivors is unclear. This study examined clusters of lifestyle behaviors in rural cancer survivors, and differences in HRQoL between behavioral clusters., Methods: Rural cancer survivors in the United States (N = 219) completed a cross-sectional survey. Lifestyle behaviors were classified into unhealthy/healthy binary categories (inactive/active, longer/shorter sedentary time, excessive/acceptable fat intake, very low/higher fruit and vegetable intake, some/no alcohol consumption, and poor/good sleep quality). Behavioral clusters were identified by latent class analysis. HRQoL differences between behavioral clusters were assessed by ordinary least squares regression., Results: The 2-class model demonstrated the best fit and interpretability. The "mostly unhealthy behaviors" class (38.5% of sample) had higher probabilities of all unhealthy behaviors, except alcohol consumption. The "healthier energy balance" class (61.5% of sample) had higher probabilities of active, shorter sedentary, higher fruit and vegetable consumption, excessive fat intake, some alcohol consumption, and poor sleep categories, and reported better HRQoL., Conclusions: Healthier energy balance behaviors were particularly relevant for HRQoL in rural cancer survivors. Multiple behavior change interventions to improve HRQoL in rural cancer survivors should focus on supporting energy balance behaviors. Many rural cancer survivors may lead very unhealthy lifestyles, placing them at high risk of adverse outcomes. This subpopulation should be prioritized to help alleviate cancer health disparities.

Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the "toggle switch" residues F200 3.36 and W356 6.48 . Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator., (© 2023. The Author(s).)

Post-transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk-stratified sequential algorithm with rituximab +/- chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/- RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk-stratified sequential approach. We also discuss the role of EBV-cytotoxic T lymphocytes in treatment of EBV-driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors in this population., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Cooking education is a popular approach to health promotion; however, the relationship between specific cooking practices, diet and weight loss is not well understood. The goal of this study was to 1) evaluate the relationship between cooking practices, dietary behaviors, and weight loss after a weight loss intervention and 2) identify patterns of cooking practices and their implications on weight loss. Using a quasi-experimental, single-arm cohort study design, we analyzed data from 249 adults with overweight/obesity who were participating in a weight loss program. Participants self-reported demographics, height and weight, and diet and physical activity behaviors. The Health Cooking Questionnaire 2 (HCQ2) was used to collect information on cooking practices post intervention. The HCQ2 responses were used to generate Healthy Cooking Index (HCI) scores, a summative measure of cooking practices with the potential to influence health. Latent Class Analysis (LCA) was utilized to define distinct patterns of cooking behaviors. Cooking patterns and HCI scores were examined relative to participant demographics, dietary behaviors, and weight loss. HCI scores post-intervention were positively associated with age, weight loss, and favorable dietary behaviors in this study. The LCA revealed three distinct patterns of cooking behavior (Red Meat Simple, Vegetarian Simple, Health & Taste Enhancing). The Red Meat Simple cooking pattern was associated with less weight loss compared to other patterns. The findings of this study set the foundation for more research on cooking education as a method for improving weight loss outcomes in the context of behavioral interventions., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two μOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and β-arrestin recruitment. Cryo-EM structures of μOR-Gi1 complex with MP (2.5 Å) and LFT (3.2 Å) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and β-arrestins bind. These observations highlight how drugs engaging different parts of the μOR orthosteric pocket can lead to distinct signaling outcomes., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Islatravir (MK-8591) is a deoxyadenosine analog in development for the treatment and prevention of HIV-1 infection. An islatravir-eluting implant could provide an additional option for pre-exposure prophylaxis (PrEP)., Setting: Previous data support a threshold islatravir triphosphate concentration for PrEP of 0.05 pmol/10 6 cells in peripheral blood mononuclear cells. Prototype islatravir-eluting implants were previously studied to establish general tolerability and pharmacokinetics (PKs) of islatravir relative to the threshold level., Methods: In this randomized, double-blind, placebo-controlled, phase 1 trial, a next-generation radiopaque islatravir-eluting implant (48 mg, 52 mg, or 56 mg) or placebo implant was placed for a duration of 12 weeks in participants at low risk of HIV infection. Safety and tolerability, as well as PK for islatravir parent and islatravir triphosphate from plasma and peripheral blood mononuclear cells, were assessed throughout placement and 8 weeks after removal., Results: In total, 36 participants (8 active and 4 placebo per dose arm) were enrolled and completed this study. Implants were generally well tolerated, with no discontinuations due to an adverse event, and no clear dose-dependence in implant-related adverse events. No clinically meaningful relationships were observed for changes in laboratory values, vital signs, or electrocardiogram assessments. Mean islatravir triphosphate levels at day 85 (0.101-0.561 pmol/10 6  cells) were above the PK threshold for all dose levels., Conclusion: Islatravir administered using a subdermal implant has the potential to be an effective and well-tolerated method for administering PrEP to individuals at risk of acquiring HIV-1., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction and Objectives: In clinical trials, patients with hepatitis C virus (HCV) genotype (GT)1a infection and baseline resistance-associated substitutions (RASs) at amino acid positions 28, 30, 31, or 93 receiving elbasvir/grazoprevir for 12 weeks achieved lower rates of sustained virologic response (SVR) than those without baseline RASs. SVR rates in patients with RASs were improved when elbasvir/grazoprevir treatment duration was extended from 12 to 16 weeks and administered concomitantly with ribavirin., Materials and Methods: This was a retrospective, observational analysis using electronic health record abstraction. Patients with HCV GT1a infection and RASs at positions 28, 30, 31, or 93 who were prescribed 16 weeks of elbasvir/grazoprevir and ≥ 1 prescription for ribavirin were included. SVR was defined as HCV RNA below the lower limit of quantification ≥ 70 days after end of treatment., Results: The primary analysis included patients with baseline RASs at positions 30, 31, or 93 (n = 76); a secondary analysis included patients with RASs at positions 28, 30, 31, or 93 (n = 93). SVR was achieved by 77.6% (59/76) of patients in the primary analysis and 80.6% (75/93) of those in the secondary analysis. Of the 18 (19.4%) patients in the secondary cohort who failed to achieve SVR, 8 relapsed (4 with treatment-emergent NS5A substitutions) and 10 did not have viral sequencing to distinguish relapse from reinfection., Conclusions: This analysis highlights the opportunities in leveraging real-world data to further understand treatment outcomes in smaller, discrete subgroups of patients with HCV infection who cannot be thoroughly evaluated in clinical trials., Competing Interests: Declaration of interest DDH, MR, and BAH are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and shareholders of Merck & Co., Inc., Rahway, NJ, USA. TCM was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and a shareholder of Merck & Co., Inc., Rahway, NJ, USA, at the time this study was conducted. DDH, TCM, MR, and BAH conducted the study as part of their employment using company resources. JRK and FK are employees of the US Department of Veterans Affairs Center for Innovations in Quality, Effectiveness, and Safety, which received funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, for the conduct of this research. Ms. Chaffin was an employee of the US Department of Veterans Affairs Center for Innovations in Quality, Effectiveness, and Safety at the time this study was conducted., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

The COVID-19 pandemic impacted the conduct of in-person physical activity (PA) interventions among older survivors of BC, who need such interventions to stay active and prevent functional decline. We tested the feasibility of virtually delivering an exergame-based PA intervention to older BC survivors. We enrolled 20 female BC survivors ≥55 years and randomly assigned them to two groups. The intervention group (Pink Warrior 2) received 12 weekly virtual exergame sessions with behavioral coaching, survivorship navigation support, and a Fitbit for self-monitoring. The control group received 12 weekly phone-based survivorship discussion sessions and wore a Mi Band 3. Feasibility was evaluated by rates of recruitment (≥0.92 participants/center/month), retention (≥80%), and group attendance (≥10 sessions), percentage of completed virtual assessments, and number of technology-related issues and adverse events. Intervention acceptability was measured by participants' ratings on a scale of 1 (strongly disagree) to 5 (strongly agree). The recruitment rate was 1.93. The retention and attendance rates were 90% and 88% (≥10 sessions), respectively. Ninety-six percent completed virtual assessments without an adverse event. Acceptability was high (≥4). The intervention met benchmarks for feasibility. Additional research is needed to further understand the impact of virtually delivered PA interventions on older BC survivors., Competing Interests: The authors declare no conflict of interest.

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose 1 . Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site 2 found in µOR 3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp 2.50 residue in the Na + site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G i subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G z efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G i , G o and G z subtypes and arrestins, thus modulating their in vivo pharmacology., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The effects of Vibrant Lives, a 6-month worksite-weight-loss program, were examined in a cohort of school-district employees with overweight or obesity. The VL Basic (VLB) participants received materials and tailored text messages, the VL Plus (VLP) participants additionally received WIFI-enabled activity monitors and scales and participated in health challenges throughout the school year, and the VL Plus with Support (VLP + S) participants additionally received coaching support. The levels of program satisfaction and retention and changes in weight, physical activity (PA), and diet were compared across groups using Pearson chi-square tests, repeated-measure mixed models, and logistic regression. After the program, the VLB ( n = 131), VLP ( n = 87), and VLP + S ( n = 88) groups had average weight losses of 2.5, 2.5, and 3.4 kg, respectively, and average increases in weekly PA of 40.4, 35.8, and 65.7 min, respectively. The VLP + S participants were more likely than the other participants to have clinically significant weight loss (≥3%; p = 0.026). Compared with the VLB participants, the VLP participants were less likely to meet the recommendations for consuming fast food ( p = 0.022) and sugar-sweetened beverages ( p = 0.010). The VLP and VLP + S participants reported higher program satisfaction than the VLB participants. The VL program facilitates weight loss among school-district employees with overweight and obesity by increasing their PA and healthy diet.

Objective: The COVID-19 pandemic has been shown to be negatively associated with physical activity engagement, adherence to healthy diet, and weight management among people with obesity. The current study examined COVID-19-related changes in weight, physical activity (PA), and diet among employees with obesity or overweight who participated in Vibrant Lives (VL), a worksite weight loss program., Methods: School district employees participated in the 6-month VL weight loss program and were categorized into non-COVID-era participants and COVID-era participants. Participants completed questionnaires about PA and dietary intake at baseline and follow-up. COVID-era participants reported the effects of pandemic on their behaviors. Changes in weight, PA, and diet were compared between groups using multilevel linear mixed models and logistic regression models., Results: A total of 266 participants (non-COVID, n=173; COVID, n=93) were included. Significant weight loss (non-COVID, -2.3 kg vs. COVID, -1.3 kg) and increases in moderate-to-vigorous PA minutes (non-COVID, 48.7 min vs. COVID, 61.5 min) were observed associated with the program, but no significant differences in changes between the groups were found. Compared to non-COVID participants, COVID participants decreased fast food consumption ( P =.008) and increased sugar-sweetened beverage intake ( P =.016). Higher frequency of snacking and overeating were reported as barriers to a healthy diet., Conclusion: The COVID-19 pandemic was negatively associated with healthful dietary behaviors. The information obtained from participants regarding the reasons for their pandemic-related changes in diet may help identify strategies to encourage healthier behaviors and weight management among people who have been negatively affected by the COVID-19 pandemic.This article is protected by copyright. All rights reserved., (This article is protected by copyright. All rights reserved.)

Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. Despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained structures of neurotensin 1 receptor bound to antagonist SR48692, μ-opioid receptor bound to alvimopan, apo somatostatin receptor 2 and histamine receptor 2 bound to famotidine. We expect this rapid, straightforward approach to facilitate the broad exploration of GPCR inactive states without the need for extensive engineering and crystallization., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT 2A serotonin receptor (HTR2A), the 5-HT 2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs., Competing Interests: Declaration of interests The Krogan Laboratory has received research support from Vir Biotechnology, F. Hoffmann-La Roche, and Rezo Therapeutics. N.J.K. has financially compensated consulting agreements with the Icahn School of Medicine at Mount Sinai, New York; Maze Therapeutics; Interline Therapeutics; Rezo Therapeutics; GEn1E Life Sciences, Inc.; and Twist Bioscience Corp. N.J.K. is on the Board of Directors of Rezo Therapeutics and is a shareholder in Tenaya Therapeutics, Maze Therapeutics, Rezo Therapeutics, and Interline Therapeutics. G.S. is co-founder and consultant for Deep Apple Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally 1-4 . Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization 5-7 . Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT 2A receptor (5-HT 2A R) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT 2A or the 5-HT 2B receptors. Structure-based optimization led to the 5-HT 2A R agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT 2A R agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT 2A R. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT 2A R agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Methylation of host and viral genes is promising for triage of women with high-risk human papillomavirus infections (hrHPV). Using a population-based sample of hrHPV positive women with cervical biopsies within 12 months after cervical screening, the clinical value of the S5 methylation classifier (S5), HPV genotyping and cytology were compared as potential triage tests, for outcomes of cervical intraepithelial neoplasia (CIN) grade 3 or greater (CIN3+), CIN2+ and CIN2, and the area under the curve (AUC) calculated. S5 scores increased with histopathology severity (P trend  < .001). For CIN3+, the AUC was 0.780 suggesting S5 provides good discrimination between

The formyl peptide receptor 1 (FPR1) is primarily responsible for detection of short peptides bearing N-formylated methionine (fMet) that are characteristic of protein synthesis in bacteria and mitochondria. As a result, FPR1 is critical to phagocyte migration and activation in bacterial infection, tissue injury and inflammation. How FPR1 distinguishes between formyl peptides and non-formyl peptides remains elusive. Here we report cryo-EM structures of human FPR1-Gi protein complex bound to S. aureus-derived peptide fMet-Ile-Phe-Leu (fMIFL) and E. coli-derived peptide fMet-Leu-Phe (fMLF). Both structures of FPR1 adopt an active conformation and exhibit a binding pocket containing the R201 5.38 XXXR205 5.42 (RGIIR) motif for formyl group interaction and receptor activation. This motif works together with D106 3.33 for hydrogen bond formation with the N-formyl group and with fMet, a model supported by MD simulation and functional assays of mutant receptors with key residues for recognition substituted by alanine. The cryo-EM model of agonist-bound FPR1 provides a structural basis for recognition of bacteria-derived chemotactic peptides with potential applications in developing FPR1-targeting agents., (© 2022. The Author(s).)

Background: Hepatitis C virus (HCV) reinfection after successful treatment may reduce the benefits of cure among people who inject drugs., Objective: To evaluate the rate of HCV reinfection for 3 years after successful treatment among people receiving opioid agonist therapy (OAT)., Design: A 3-year, long-term, extension study of persons enrolled in the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) study (ClinicalTrials.gov: NCT02105688)., Setting: 55 clinical trial sites in 13 countries., Patients: Aged 18 years and older with chronic HCV infection with genotypes 1, 4, or 6 receiving stable OAT., Intervention: No treatments were administered., Measurements: Serum samples were assessed for HCV reinfection. Urine drug screening was performed., Results: Among 296 participants who received treatment, 286 were evaluable for reinfection and 199 were enrolled in the long-term extension study. The rate of HCV reinfection was 1.7 [95% CI, 0.8 to 3.0] per 100 person-years; 604 person-years of follow-up). A higher rate of reinfection was seen among people with recent injecting drug use (1.9 [95% CI, 0.5 to 4.8] per 100 person-years; 212 person-years). Ongoing drug use and injecting drug use were reported by 59% and 21% of participants, respectively, at the 6-month follow-up visit and remained stable during 3 years of follow-up., Limitations: Participants were required to be 80% adherent to OAT at baseline and may represent a population with higher stability and lower risk for HCV reinfection. Rate of reinfection may be underestimated because all participants did not continue in the long-term extension study; whether participants who discontinued were at higher risk for reinfection is unknown., Conclusion: Reinfection with HCV was low but was highest in the first 24 weeks after treatment completion and among people with ongoing injecting drug use and needle-syringe sharing., Primary Funding Source: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Background: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347)., Methods: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting., Results: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE., Conclusions: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Peripheral T cell lymphomas (PTCL) comprise a diverse group of aggressive T-cell and NK-cell lymphomas with many subtypes sharing same treatment algorithms despite having different pathobiology and responses to treatment. The molecular advances made in discovery of genetic mutations that disrupt epigenetic modulation in some subtypes of PTCL such as angioimmunoblastic T cell lymphoma and PTCL-not otherwise specified (NOS) may explain the poor outcomes and unsatisfactory responses to frontline line CHOP and CHOP-like therapy seen in this group of lymphomas. In this article, we address the main genetic mutations such as IDH2, TET2 and DNMT3A seen in PTCL and that disrupt the epigenetic modulation pathways, focusing on acetylation, deacetylation and methylation. Since therapeutic agents that target the disrupted epigenetic modulation pathways in PTCL may change treatment landscape in the near future, we will highlight the ones approved for treatment of refractory and/or relapsed PTCL and also the pivotal regimens being evaluated in clinical trials for treatment of frontline and refractory relapsed disease. We stress the importance of determining whether there is an association between the discussed genetic mutations and responses to the highlighted therapeutic agents such that treatments could be better tailored in patients with this kind of lymphoma with unmet needs., (Copyright © 2022. Published by Elsevier Inc.)

G protein-coupled receptors (GPCRs) and other membrane proteins are valuable drug targets, and their dynamic nature makes them attractive systems for study with molecular dynamics (MD) simulations and free energy approaches. Here, we report the development, implementation, and validation of OPLS-AA/M force field parameters to enable simulations of these systems. These efforts include the introduction of post-translational modifications including lipidations and phosphorylation. We also modify previously reported parameters for lipids to be more consistent with the OPLS-AA force field standard and extend their coverage. These new parameters are validated on a variety of test systems, with the results compared to high-level quantum mechanics calculations, experimental data, and simulations with other force fields. The results demonstrate that the new parameters reliably reproduce the behavior of membrane protein systems.

Prognosis for patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Immune-based therapeutic treatments such as CD19 Chimeric Antigen Receptor (CAR) T cell therapies have dramatically changed the treatment landscape for R/R DLBCL leading to durable remissions in ~ 50% of patients. However, there remains an unmet need for developing novel therapies to improve clinical outcomes of patients not responding or relapsing after CAR T cell therapies. Lack of suitable immunotherapeutic targets and disease heterogeneity represent the foremost challenges in this emerging field. In this review, we discuss the recently approved and emerging novel immunotherapies for patients with R/R DLBCL in the post-CAR T era and the cell surface targets currently used., Competing Interests: PG participated in advisory boards for Astra Zeneca, Daiichi Sanyo, Secura Bio and Kyowa Hakko Kirin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Atallah-Yunes, Robertson, Davé, Ghione and Perna.)

Background: Classroom-based physical activity approaches can improve children's physical activity levels during school. However, the implementation of these approaches remains a challenge. The purpose of this study was to examine implementation strategies to support the delivery of classroom-based physical activity approaches from the perspectives of elementary school staff., Methods: We conducted individual interviews with elementary school staff from a mid-sized school district in Texas. Interviews lasted approximately 60 min and were audio recorded and transcribed for analyses. We used directed content analysis and an iterative categorization approach to identify emerging themes related to implementation strategies., Results: We interviewed 15 participants (4 classroom teachers, 4 physical education teachers, 3 assistant principals, and 4 principals) about implementation strategies supporting classroom-based physical activity approaches. Four prominent themes related to implementation strategies emerged: 1) the role of program champions, 2) the use and function of staff training, 3) the importance of strategic planning, and 4) the use of positive reinforcements to support implementation., Conclusions: Results highlight the need for multiple implementation strategies to support the delivery of classroom-based physical activity approaches. Results also highlight potential mechanisms through which the implementation strategies operate. This information is valuable to future planning efforts for classroom-based physical activity approaches., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Survivors of breast cancer can face internal barriers to physical activity, such as uncertainty and frustration stemming from physical limitations, decreased physical functioning, fatigue, and pain. Interventions that draw from the principles of Acceptance and Commitment Therapy (ACT) may help survivors of breast cancer overcome some of the internal barriers associated with physical activity., Objective: The primary aim of this study was to investigate the acceptability of an electronically delivered physical activity intervention for survivors of breast cancer, centered on ACT processes., Methods: This study used a 1-group pretest-posttest design. We recruited 80 insufficiently active female survivors of breast cancer using a web-based recruitment strategy. The 8-week intervention consisted of weekly modules that featured didactic lessons and experiential exercises targeting key ACT processes in the context of physical activity promotion (namely, values, committed action, acceptance, defusion, and contacting the present moment). We determined intervention acceptability according to study retention (≥70%), adherence rates (≥75% of the participants completing ≥50% of the modules), and posttest survey scores reflecting the perceived ease of use, perceived usefulness, and interest and enjoyment of the intervention (≥5 on a 7-point Likert-type scale). We also evaluated changes in self-reported aerobic and muscle strengthening-physical activity, physical activity acceptance, physical activity regulation, and health-related outcomes., Results: The retention rate (61/80, 76%), adherence rate (60/80, 75%), average perceived ease of use (6.17, SD 1.17), perceived usefulness (5.59, SD 1.40), and interest and enjoyment scores (5.43, SD 1.40) met the acceptability criteria. Participants increased their self-reported aerobic physical activity (Cohen d=1.04), muscle strengthening-physical activity (Cohen d=1.02), physical activity acceptance (cognitive acceptance: Cohen d=0.35; behavioral commitment: Cohen d=0.51), physical activity regulation (identified regulation: Cohen d=0.37; integrated regulation: Cohen d=0.66), increased their ability to participate in social roles and activities (Cohen d=0.18), and reported less fatigue (Cohen d=0.33) and sleep disturbance (Cohen d=0.53)., Conclusions: Electronically delivered acceptance- and mindfulness-based interventions may be useful for promoting physical activity in survivors of breast cancer. Further research is needed to refine these approaches and evaluate their effectiveness., (©Michael C Robertson, Emily Cox-Martin, Ross Shegog, Christine M Markham, Kayo Fujimoto, Casey P Durand, Abenaa Brewster, Elizabeth J Lyons, Yue Liao, Sara A Flores, Karen M Basen-Engquist. Originally published in JMIR Cancer (https://cancer.jmir.org), 29.04.2022.)

The improvement in outcomes seen with the introduction of rituximab, a CD20 monoclonal antibody in combination with chemotherapy or as a single agent in the treatment of indolent non-Hodgkin lymphomas has paved the way for development of various forms of monoclonal antibodies that act in different ways against non-Hodgkin lymphoma tumor cells. These could directly target a single surface antigen resulting in various ways of tumor cells toxicity and killing. Other forms of monoclonal antibodies include antibody-drug conjugates and bispecific antibodies. The role of therapeutic monoclonal antibodies in the treatment of lymphoma will be reviewed, highlighting their mode of action, clinical efficacy, and side effects., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Published by Elsevier Ltd.)

Cytokines regulate both the innate and adaptive immune responses to cancer. Although antitumor activity has been seen for several cytokines in preclinical models, they have had limited success as single therapeutic agents in clinical trials of cancer immunotherapy. However, the possible combinations of cytokines with other immune therapeutics and the advancement in genetic engineering, synthetic biology and cellular and immune therapy has led to the revival of interest in cytokines as anticancer agents. This article will review several immunostimulatory cytokines with anticancer activity, focusing on the those that have been studied in treatment of lymphoma and highlighting recent advances of potential clinical relevance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Atallah-Yunes and Robertson.)

Background: Older adult women are at risk for negative health outcomes that engaging in sustained physical activity can help prevent. However, promoting long-term maintenance of physical activity in this population has proven to be a challenge. Increasing autonomous motivations (ie, intrinsic, integrated, and identified regulations) for physical activity may facilitate enduring behavior change. Digitally delivered games for health that take a celebratory technology approach, that is, using technology to create new ways to experience valued behaviors and express valued beliefs, may be a useful way to target autonomous motivations for physical activity. Formative research with the target population is needed to design compelling intervention content., Objective: The objective of this study is to investigate older adult women's reactions to and thoughts about a photography-based, social media walking game targeting autonomous motivations for physical activity., Methods: During an individual semistructured interview, a moderator solicited feedback from 20 older adult women (age range 65-74 years) as part of formative research to develop a social media game featuring weekly walking challenges. The challenges were designed to target autonomous motivations for physical activity. Interviews were audio-recorded and transcribed verbatim. Two reviewers conducted thematic content analysis on interview transcripts., Results: We identified 3 overarching themes in qualitative data analysis. These reflected the playful experiences, value, and acceptability associated with the intervention challenges. Generally, participants understood what the challenges were asking them to do, proffered appropriate example responses, and indicated that the challenges would be enjoyable. Participants reported that the intervention content afforded many and varied playful experiences (eg, competition, discovery, exploration, expression, fellowship, humor, nurture, sensation). Further, participants indicated that the intervention increased their motivation for physical activity, occasioned meaningful shifts in perspective, increased their knowledge of various topics of interest, provided an opportunity to create valued connection with others, and provided health-related benefits. Participants suggested the intervention emphasize local history, nature, and cultural events., Conclusions: The photography-based, social media walking game with relatively simple game mechanics was well received and judged to be apt to bring about a wide variety of emotive experiences. A clear, geographically specific identity emerged as a key driver of interest for intervention content. Taking a celebratory technology approach holds promise for targeting autonomous motivations for physical activity in older adult women., (©Michael C Robertson, Maria Chang Swartz, Ursela Christopherson, Jason R Bentley, Karen M Basen-Engquist, Debbe Thompson, Elena Volpi, Elizabeth J Lyons. Originally published in JMIR Serious Games (https://games.jmir.org), 14.04.2022.)

Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions 1 . Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface 1 . Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood 2-5 . Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The objective of this study was to investigate changes in physical activity patterns associated with the COVID-19 pandemic in individuals with overweight and obesity who were participating in a school district worksite weight loss program. We conducted comparative design interrupted time series analyses on physical activity device (Fitbit) data from the 2018-2019 and 2019-2020 school years (N = 211). We administered a questionnaire in 2020 to supplement device data. After the stay-at-home orders in 2020, participants tended to decrease their weekly step count (B = -1315.7, SE = 627.7, p = .045), decrease their weekly "Lightly active minutes" (B = -39.1, SE = 12.6, p = .007), and increase their weekly "Very active minutes" compared to their counterparts from the year before (B = 7.6, SE = 3.2, p = .020). Decreased motivation, gym closures, and safety concerns were cited as barriers to physical activity. Having more time and health consciousness were cited as facilitators of physical activity. The COVID-19 pandemic was related to changes in physical activity in both positive and negative ways, revealing opportunities to promote healthy lifestyle behaviors in this population. More research is needed to determine optimal approaches to health promotion in the post-COVID-19 era., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Somatostatin is a signaling peptide that plays a pivotal role in physiologic processes relating to metabolism and growth through its actions at somatostatin receptors (SSTRs). Members of the SSTR subfamily, particularly SSTR2, are key drug targets for neuroendocrine neoplasms, with synthetic peptide agonists currently in clinical use. Here, we show the cryogenic-electron microscopy structures of active-state SSTR2 in complex with heterotrimeric G i3 and either the endogenous ligand SST14 or the FDA-approved drug octreotide. Complemented by biochemical assays and molecular dynamics simulations, these structures reveal key details of ligand recognition and receptor activation at SSTRs. We find that SSTR ligand recognition is highly diverse, as demonstrated by ligand-induced conformational changes in ECL2 and substantial sequence divergence across subtypes in extracellular regions. Despite this complexity, we rationalize several known sources of SSTR subtype selectivity and identify an additional interaction for specific binding. These results provide valuable insights for structure-based drug discovery at SSTRs., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)