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.

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 social media game to increase physical activity among older adult women: protocol of a randomized controlled trial to evaluate CHALLENGE.

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.

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.

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.

Autologous stem cell transplantation in adults with atypical teratoid rhabdoid tumor: a case report and review.

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.

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