Therapy duration and improvement of ventricular function in de novo heart failure: the Heart Failure Optimization study.

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.

A 57-Year-Old Female Presenting With Cardiopulmonary Arrest Secondary to Severe Hypokalemia From a Fanconi-Like Syndrome: A Case Report.

Fanconi syndrome is a multi-factorial disorder that involves diffuse malfunction of the proximal convoluted tubule in the kidney. Renal wasting of potassium, glucose, bicarbonate, amino acids, and phosphorus characterize the condition. We report a case of a 57-year-old female who presented to our emergency department with cardiopulmonary arrest. After successful resuscitation, she had extensive workup to uncover the cause of her cardiac arrest. She had extensive negative workup but was found to have severely low potassium, prompting further evaluation. She was noted to have elevated urine potassium, with a trans-tubular potassium gradient of 9. She was also found to have severe glycosuria, hypophosphatemia, proteinuria, and an elevated urine anion gap, suggesting proximal convoluted tubular dysfunction. The hypokalemia noted on admission was thought to have been the causative factor for the cardiopulmonary arrest and was thought to be due to proximal tubule dysfunction, with the major suspected diagnosis being a Fanconi-like syndrome. This report highlights the diagnosis and treatment of hypokalemia, the broad differential involved with hypokalemia, and the syndromes involved with renal potassium wasting. This report also seeks to raise awareness of the association of renal potassium wasting with cardiopulmonary arrest.

Reflective Engagement With a Digital Physical Activity Intervention Among People Living With and Beyond Breast Cancer: Mixed Methods Study.

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.

Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor.

The calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor1 (GPCR) that has a central role in regulating systemic calcium homeostasis2,3. 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 Gi versus Gq proteins in the presence and absence of the calcimimetic drug cinacalcet. High-resolution structures show that both Gi and Gq 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 Gi and Gq 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.

Using the R = MC2 heuristic to understand barriers to and facilitators of implementing school-based physical activity opportunities: a qualitative study.

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 = MC2 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 = MC2 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 = MC2 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.

Comparing the performance of 2 human papillomavirus assays for a new use indication: a real-world evidence-based evaluation in the United States.

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.

Risk factors for failure of manipulation under anesthesia in posttraumatic knee stiffness.

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.

Elementary school staff perspectives on the implementation of physical activity approaches in practice: an exploratory sequential mixed methods study.

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.

Observed and perceived benefits of providing physical activity opportunities in elementary schools: a qualitative study.

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.

Timing of venous thromboemboli in patients with acetabular and pelvic ring fractures.

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.

Hexahydroquinoline Derivatives Are Selective Agonists for the Adhesion G Protein-Coupled Receptor ADGRG1/GPR56.

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 CF3 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.

Social and Leisure Activities Predict Transitions in Cognitive Functioning in Older Mexican Adults: A Latent Transition Analysis of the Mexican Health and Aging Study.

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.

Healthier Energy Balance Behaviors Most Important for Health-Related Quality of Life in Rural Cancer Survivors in Central Pennsylvania.

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.

Structural basis for activation of CB1 by an endocannabinoid analog.

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 F2003.36 and W3566.48. 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.

Post-transplant lymphoproliferative disorder: Update on treatment and novel therapies.

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.

Impact of HPV testing in opportunistic cervical screening: Support for primary HPV screening in the United States.

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.

Assessing the Suitability of a Virtual 'Pink Warrior' for Older Breast Cancer Survivors during COVID-19: A Pilot Study.

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.

Patterns of home cooking practices among participants in a behavioral weight loss program: A latent class analysis.

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.

Effectiveness of elbasvir/grazoprevir plus ribavirin for hepatitis C virus genotype 1a infection and baseline NS5A resistance.

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.

Exploring the Effects of Perceived Stress on the Within-Person Relationships Between Daily Activity Levels and Sleep in Women: An Ecological Momentary Assessment Study.

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.