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PURPOSE: There are significant racial/ethnic disparities in youth access to and use of appropriate depression treatment. Although there is a growing literature on racial/ethnic differences in treatment preference among adults, we know very little about whether these differences persist for adolescents and whether parents have an influence on their teens' treatment perspectives. METHODS: Teens and parents from a sample of primary care settings were interviewed at baseline and 6 months. We used bivarate and regression analyses to describe racial/ethnic differences in teen and parent depression knowledge and treatment preference and to assess the impact of parental views on teen perspectives. RESULTS: Latino and African American teens had lower average scores on antidepressant knowledge (p < .01) and counseling knowledge than white teens (p < .01). These racial/ethnic differences were greater among parents (p < .001). Parent antidepressant knowledge had an impact on teen knowledge when teens reported turning to them for advice (beta = 0.20, p < .05). Teen knowledge about medication (odds ratio [OR] = 1.16, p < .01) and counseling (OR = 1.26, p < .001) were associated with a willingness to seek active treatment. CONCLUSIONS: Racial/ethnic differences in depression treatment knowledge persist, but are more pronounced for parents than teens. Talking to parents who have more knowledge about depression treatment is associated with more teen knowledge and that knowledge is associated with greater willingness to seek depression treatment. Research is needed on the content and type of conversations that parents and teens have about depression treatment, and if there are differences by race/ethnicity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the clinical management of heart disease and determine whether there was age- and sex-related bias in the use of investigations and interventions. DESIGN: Retrospective analysis of individual patient records against criteria of appropriateness based on published guidelines, clinical practice and literature relevant to the 1996-7 study period. SETTING: A single, district general hospital in London, serving a population of 185,000 people. SUBJECTS: General medical, elderly medical, and cardiology inpatients and patients attending elderly medical and cardiology outpatient clinics as new referrals between 1 April 1996 and 31 March 1997. RESULTS: We located case notes of 1790 of the 1975 subjects eligible for the study: 911 (51%) were outpatients and 51% were men. Patients aged <75 were significantly more likely than patients aged >or=75 years to be given thrombolysis after an acute myocardial infarction, to be given secondary prevention with aspirin and beta-blockers, to undergo exercise testing and coronary angiography, and to receive an echocardiogram. Men were also significantly more likely than women to have these investigations and interventions as well as to receive an angiotensin-converting enzyme inhibitor when left ventricular dysfunction was identified. Investigations and interventions were underused at all ages. CONCLUSION: As well as identifying age and sex bias, we found the underuse of investigations and interventions in all age groups in this district general hospital. Should similar patterns of care be found elsewhere, the delivery of high-quality care in an equitable manner (as identified by the National Service Framework for coronary heart disease) may require considerably more resources than have been allocated. [ABSTRACT FROM AUTHOR]

Objectives: Our primary objective was to determine if more comprehensive advance care planning (ACP) documentation was associated with fewer transfers to hospital in the last year of life. Our secondary objective was to determine the impact of ACP processes and practices on hospital transfers in the last year of life., Design: Retrospective cohort study., Setting and Participants: Long-term care (LTC) residents in Ontario, Canada, 65 years and older who died between January 1, 2017, and May 30, 2018, and resided in a participating LTC home., Methods: We administered a survey to directors of care at LTC homes inquiring about ACP practices. Our exposure of interest was living in a home with comprehensive ACP documentation that includes information beyond preferences for cardiopulmonary resuscitation and hospital transfer. Our primary outcome was the number of transfers to hospital in the last year of life. We fit negative binomial regression models to determine the independent effect of comprehensive ACP and other indicators of ACP quality., Results: A total of 157 LTC homes with 6637 decedent residents were included in our study; 2942 lived in homes with comprehensive ACP documentation and 3695 had non-comprehensive ACP documents. Comprehensive documentation was not associated with fewer hospital transfers in the final year of life [incidence rat ratio (IRR), 1.00; 95% CI, 0.91-1.09]. ACP documentation update frequency, availability of ACP documents in the electronic medical record, referring to ACP documents during a health crisis, inclusion of resident values in ACP documents, and involvement of a multidisciplinary team were all associated with fewer transfers to hospital during follow-up in the last year of life., Conclusions and Implications: ACP documents that contain information beyond preferences for cardiopulmonary resuscitation and hospital transfer had no association with transfers to hospital, but high-quality ACP practices and processes were associated with fewer transfers., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Study Design: Systematic review., Objectives: Intraoperative neuromonitoring (IOMN) has become a standard practice in the detection and prevention of nerve damage and postoperative deficit. While multicenter studies have addressed this inquiry, there have been no systematic reviews to date. This systematic review identifies the leading causes of IONM alerts during adult spinal deformity (ASD) surgeries., Methods: Following PRISMA guidelines, a literature search was performed in PubMed and Embase. IONM alert causes were grouped by equivalent terms used across different studies and binned into larger categories, including surgical maneuver, Changes in blood pressure/temperature, Oxygenation, Anesthesia, Patient position, and Unknown., Results: Inclusion criteria were studies on adult patients receiving ASD correction surgery using IONM with documented alert causes. 1544 references were included in abstract review, 128 in full text review, and 16 studies qualified for data extraction. From those studies, there was a total of 3945 adult patients with 299 IONM alerts. Surgical maneuver led the alert causes (258 alerts/86.3%), with signal loss most commonly occurring at correction or osteotomy (101/33.8% and 95/31.8% respectively). Pedicle screw placement caused 35 alerts (11.7%). Changes in temperature and blood pressure were the third largest category (34/11.4%)., Conclusions: The most frequent causes of IONM alerts in ASD surgery were surgical maneuvers such as correction, osteotomy, and pedicle screw placement. This information provides spine surgeons with a quantitative perspective on the causes of IONM changes and show that most occur at predictable times during ASD surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Pedicle subtraction osteotomy (PSO) is a complex surgical procedure that provides correction of moderate sagittal imbalance. Surgical complications have adverse effects on patient outcomes and healthcare costs, making it imperative for clinical researchers to focus on minimizing complications. However, when it comes to risk modeling of PSO surgery, there is currently no consensus on which patient characteristics or measures should be used. This study aimed to describe complications and compare the performance of various sociodemographic characteristics, surgical variables, and established risk indices in predicting postoperative complications, infections, and readmissions after lumbar PSO surgeries., Methods: A review was conducted on 191 patients who underwent PSO surgery at a single institution by a single fellowship-trained orthopaedic spine surgeon between January 1, 2018, and December 31, 2021. Demographic, intraoperative, and postoperative data within 30 days, 1 year, and 2 years of the index procedure were evaluated. Descriptive statistics, t -test, chi-squared analysis, and logistic regression models were used., Results: Intraoperative complications were significantly associated with coronary artery disease (odds ratios [OR] 3.95, P = 0.03) and operating room time (OR 1.01, P = 0.006). 30-day complications were significantly cardiovascular disease (OR 2.68, P = 0.04) and levels fused (OR 1.10, P = 0.04). 2-year complications were significantly associated with cardiovascular disease (OR 2.85, P = 0.02). 30-day readmissions were significantly associated with sex (4.47, 0.04) and length of hospital stay (χ 2 = 0.07, P = 0.04). 2-year readmissions were significantly associated with age (χ 2 = 0.50, P = 0.03), hypertension (χ 2 = 4.64, P = 0.03), revision surgeries (χ 2 = 5.46, P = 0.02), and length of hospital stay (χ 2 = 0.07, P = 0.03)., Discussion: This study found that patients with coronary vascular disease and longer fusions were at higher risk of postoperative complications and patients with notable intraoperative blood loss were at higher risk of postoperative infections. In addition, physicians should closely follow patients with extended postoperative hospital stays, with advanced age, and undergoing revision surgery because these patients were more likely to be readmitted to the hospital., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Study Design: Retrospective Study., Objective: At the North American Spine Society (NASS) conference, participants may influence spine surgery practices and patient care through their contributions. Therefore, their financial conflicts of interest are of notable interest. This study aims to compare the demographics and payments made to participating surgeons., Methods: A list of 151 spine surgeons was created based on those who participated in the 2022 NASS conference. Demographic information was obtained from public physician profiles. General payments, research payments, associated research funding, and ownership interest were collected for each physician. Descriptive statistics and two-tailed t-tests were used., Results: In 2021, 151 spine surgeon participants received industry payments, totaling USD 48 294 115. The top 10% of orthopedic surgeons receiving payments accounted for 58.7% of total orthopedic general value, while the top 10% of neurosurgeons accounted for 70.1%. There was no significant difference between these groups' general payment amounts. Surgeons with 21-30 years of experience received the most general funding. There was no difference in funding between surgeons in academic or private settings. For all surgeons, royalties accounted for the largest percentage of the general value exchanged, while food/beverage accounted for the largest percentage of transactions., Conclusion: Our study found that only years of experience had a positive association with general payments, and most monetary value belonged to a small handful of surgeons. These participants receiving significant money may promote techniques requiring products of companies providing their compensation. Future conferences may require disclosure policy changes so attendees understand the degree of funding participants receive., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Long-term care (LTC) residents are susceptible to falling and the risk of subsequent morbidity and mortality may be compounded with concurrent anticoagulation use. Uncertainty exists around the benefit and harm of anticoagulation use for residents with a high risk for falls because of concerns of major bleeding complications. We aimed to examine if anticoagulant use increases mortality risk among LTC residents who fall., Design: A retrospective cohort study., Setting and Participants: Older adults (≥65 years) admitted to a LTC facility in Ontario, Canada between January 1, 2010, and December 1, 2019, who were transferred to emergency departments for fall-related injuries., Methods: The exposure was the use of an oral anticoagulant (OAC). The primary outcome was mortality within 30 days of transfer. Secondary outcomes were major hemorrhage and care utilization. We used hierarchical logistic regression models to examine the association between the use of OAC and 30-day mortality., Results: There were 56,419 residents transferred to the hospital for a fall, of whom 9611 (17.0%) were on an OAC. At 30 days, 5794 (10.3%) of the cohort had died: 12.0% (1151) on an OAC and 9.90% (4643) not on an OAC [risk difference (RD), 2.1%; 95% CI, 1.40%-2.82%]. There were 485 major hemorrhage cases: 1.3% (125) on an OAC and 0.8% (360) not on an OAC (RD, 0.5%; 95% CI, 0.26%-0.74%). Multivariable analysis found no significant association between OAC use and 30-day mortality [odds ratio (OR), 0.98; 95% CI, 0.90-1.06], but an increased risk of major hemorrhage (OR, 1.31; 95% CI, 1.04-1.66). Both groups had similar health system and neurosurgical care utilization., Conclusions and Implications: Among LTC residents transferred to the emergency department for fall-related injuries, OACs did not increase the risk of post-fall mortality. OAC prescribing for frail older adults who experience falls should consider their individual risk profile., Competing Interests: Disclosures The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by promoting guanine nucleotide exchange. Here, we investigate the coupling of G proteins with GPCRs and describe the events that ultimately lead to the ejection of GDP from its binding pocket in the Gα subunit, the rate-limiting step during G-protein activation. Using molecular dynamics simulations, we investigate the temporal progression of structural rearrangements of GDP-bound G s protein (G s ·GDP; hereafter G s GDP ) upon coupling to the β 2 -adrenergic receptor (β 2 AR) in atomic detail. The binding of G s GDP to the β 2 AR is followed by long-range allosteric effects that significantly reduce the energy needed for GDP release: the opening of α1-αF helices, the displacement of the αG helix and the opening of the α-helical domain. Signal propagation to the G s occurs through an extended receptor interface, including a lysine-rich motif at the intracellular end of a kinked transmembrane helix 6, which was confirmed by site-directed mutagenesis and functional assays. From this β 2 AR-G s GDP intermediate, G s undergoes an in-plane rotation along the receptor axis to approach the β 2 AR-G s empty state. The simulations shed light on how the structural elements at the receptor-G-protein interface may interact to transmit the signal over 30 Å to the nucleotide-binding site. Our analysis extends the current limited view of nucleotide-free snapshots to include additional states and structural features responsible for signaling and G-protein coupling specificity., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

G-protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by stimulating guanine nucleotide exchange in the Gα subunit 1 . To visualize this mechanism, we developed a time-resolved cryo-EM approach that examines the progression of ensembles of pre-steady-state intermediates of a GPCR-G-protein complex. By monitoring the transitions of the stimulatory G s protein in complex with the β 2 -adrenergic receptor at short sequential time points after GTP addition, we identified the conformational trajectory underlying G-protein activation and functional dissociation from the receptor. Twenty structures generated from sequential overlapping particle subsets along this trajectory, compared to control structures, provide a high-resolution description of the order of main events driving G-protein activation in response to GTP binding. Structural changes propagate from the nucleotide-binding pocket and extend through the GTPase domain, enacting alterations to Gα switch regions and the α5 helix that weaken the G-protein-receptor interface. Molecular dynamics simulations with late structures in the cryo-EM trajectory support that enhanced ordering of GTP on closure of the α-helical domain against the nucleotide-bound Ras-homology domain correlates with α5 helix destabilization and eventual dissociation of the G protein from the GPCR. These findings also highlight the potential of time-resolved cryo-EM as a tool for mechanistic dissection of GPCR signalling events., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: People with opioid use disorder (OUD) are at risk of premature death and can benefit from palliative care. We sought to compare palliative care provision for decedents with and without OUD., Methods: We conducted a cohort study using health administrative databases in Ontario, Canada, to identify people who died between July 1, 2015, and Dec. 31, 2021. The exposure was OUD, defined as having emergency department visits, hospital admissions, or pharmacologic treatments suggestive of OUD within 3 years of death. Our primary outcome was receipt of 1 or more palliative care services during the last 90 days before death. Secondary outcomes included setting, initiation, and intensity of palliative care. We conducted a secondary analysis excluding sudden deaths (e.g., opioid toxicity, injury)., Results: Of 679 840 decedents, 11 200 (1.6%) had OUD. Compared with people without OUD, those with OUD died at a younger age and were more likely to live in neighbourhoods with high marginalization indices. We found people with OUD were less likely to receive palliative care at the end of their lives (adjusted relative risk [RR] 0.84, 95% confidence interval [CI] 0.82-0.86), but this difference did not exist after excluding people who died suddenly (adjusted RR 0.99, 95% CI 0.96-1.01). People with OUD were less likely to receive palliative care in clinics and their homes regardless of cause of death., Interpretation: Opioid use disorder can be a chronic, life-limiting illness, and people with OUD are less likely to receive palliative care in communities during the 90 days before death. Health care providers should receive training in palliative care and addiction medicine to support people with OUD., Competing Interests: Competing interests:: Jenny Lau reports honoraria from the University of Toronto and travel funding from the Canadian Institutes of Health Research and Health Canada. She is a member of the Global Institute of Psychosocial, Palliative and End-of-Life Care Operations Committee and medical director of the Harold and Shirley Lederman Palliative Care Centre. Tara Gomes reports research funding from the Ontario Ministry of Health, the Ontario College of Pharmacists, and the Canadian Agency for Drugs and Technologies in Health; consulting fees from the Auditor General of British Columbia; payment for expert testimony from the Office of the Chief Coroner of Ontario; and travel support from Indigenous Services Canada. She is a Tier 2 Canada Research Chair in Drug Policy Research & Evaluation. Sarina Isenberg reports travel funding from the American Association of Hospice Palliative Medicine. She is director of the St. Joseph’s Villa Foundation Board of Directors and a member of the Temple Anshe Sholom Succession Planning Committee. No other competing interests were declared., (© 2024 CMA Impact Inc. or its licensors.)

Study Design: A single-institution, retrospective cohort study., Objective: The objective was to present demographic characteristics, mechanism of injuries, lengths of stay, intensive care unit (ICU) days, discharge locations, and causes of 90-day readmission for patients with subaxial spinal cord injuries resulting in paraplegia or tetraplegia., Summary of Background Data: Spinal cord injuries resulting in paraplegia or tetraplegia are rare injuries with debilitating outcomes. Numerous advances have occurred in caring for these patients, but patients still experience multiple complications. The severity of these injuries and numerous complications result in prolonged hospital stays and the need for extensive rehabilitation., Methods: Twelve patients with subaxial spinal cord injury resulting in paraplegia or tetraplegia from a level 1 adult trauma center were reviewed. The primary outcomes included hospital length of stay, ICU days, intrahospital complications, 90-day readmission rates, and discharge location. We reviewed the literature for these outcomes in spinal cord injuries., Results: For patients with subaxial spinal cord injuries resulting in paraplegia and tetraplegia, the average age was 36.0 years, and most were male [91.7% (11/12)]. The most common mechanism of injury was gunshot wounds[41.7% (5/12)]. Patients spent an average of 46.3 days in the hospital and 30.7 days in the ICU. Respiratory complications were the most common (9 patients). Fifty percent of patients (6/12) were discharged to the inpatient spinal cord rehab center, and 16.7% (2/12) expired while in the hospital. Two patients (20.0%) were readmitted within 90 days of discharge., Conclusions: Most patients with subaxial spinal cord injuries resulting in paraplegia or tetraplegia were young males with high-energy traumas. Many patients had intrahospital complications, and most were discharged to the hospital spinal rehab center. These findings likely stem from the severity of paraplegia and tetraplegia injuries and the need for rehabilitation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advancing health equity requires more contextualised evidence., Objectives: To synthesise published evidence using an existing framework on the origins of health disparities and determine care-related outcome disparities for residents of long-term care, comparing minoritised populations to the context-specific dominant population., Design: Systematic review., Subjects: Residents of 24-hour long-term care homes., Methods: The protocol was registered a priori with PROSPERO (CRD42021269489). Literature published between 1 January 2000 and 26 September 2021, was searched, including studies comparing baseline characteristics and outcomes in minoritised versus dominant populations. Dual screening, two-reviewer verification for extraction, and risk of bias assessments were conducted to ensure rigour. Studies were synthesized using a conceptual framework to contextualise evidence according to multi-level factors contributing to the development of care disparities., Results: Twenty-one of 34 included studies demonstrated disparities in care outcomes for minoritised groups compared to majority groups. Thirty-one studies observed differences in individual-level characteristics (e.g. age, education, underlying conditions) upon entry to homes, with several outcome disparities (e.g. restraint use, number of medications) present at baseline and remaining or worsening over time. Significant gaps in evidence were identified, particularly an absence of literature on provider information and evidence on the experience of intersecting minority identities that contribute to care-related outcome disparities in long-term care., Conclusion: This review found differences in minoritised populations' care-related outcomes. The findings provide guidance for future health equity policy and research-supporting diverse and intersectional capacity building in long-term care., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

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.)

Study Design: Retrospective Cohort Analysis., Objectives: Extended hospital length of stay (LOS) poses a significant cost burden to patients undergoing adult spinal deformity (ASD) surgery. The purpose of this study is to investigate the relationship between late-week surgery and LOS in patients undergoing ASD surgery., Methods: 256 patients who underwent ASD surgery between January 2018 and December 2021 by a single fellowship-trained orthopedic spine surgeon comprised the patient sample. Demographics, intraoperative, and perioperative data were collected for the 256 patients who underwent ASD surgery. Patients were divided into two groups based on surgical day of the week: (1) Early-week (Monday/Tuesday) n = 126 and (2) Late-week (Thursday/Friday) n = 130. Descriptive statistics, T-tests, and linear and logistic regression models were used to analyze the data., Results: Surgical details and sociodemographic characteristics did not differ between the groups. When controlling for TLIF/DLIF status and PSO status there was no difference in mean length of stay between the groups. The late-week group was associated with a greater risk of 30-day readmission, but there was no difference in complications, infections, or intraoperative complications., Conclusions: We found no difference in mean length of stay between surgeries performed early in the week vs late in the week. Although late-week surgeries had higher 30-day readmission risk, all other outcomes, including complication rates, showed no significant differences. When adequate weekend post-operative care is available, we do not advise restricting ASD surgeries to specific weekdays., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Pedicle subtraction osteotomies (PSOs) are complex spinal deformity surgeries that are associated with high complication rates. They are typically done by an experienced spine surgeon with another attending, resident, or physician assistant serving as the first assistant. The purpose of this study was to determine whether selecting a surgical team for single-level PSO based on case difficulty and fusion length could equalize intraoperative and perioperative outcomes among three groups: dual-attending (DA), attending and orthopaedic resident (RS), and attending and physician assistant (PA)., Methods: This study was a retrospective cohort analysis of 312 patients undergoing single-level thoracic or lumbar PSO from January 2007 to December 2020 by a fellowship-trained orthopaedic spine surgeon. Demographic, intraoperative, and perioperative data within 30 days and 2 years of the index procedure were analyzed., Results: Patient demographics did not markedly differ between surgical groups. The mean cohort age was 64.5 years with BMI 31.9 kg/m 2 . Patients with the DA approach had a significantly longer surgical time (DA = 412 min vs. resident = 372 min vs. physician assistant = 323 min; P < 0.001). Patients within the DA group experienced a significantly lower rate of infection (DA = 2.1% [3/140] vs. RS = 7.9% [9/114] vs. PA = 1.7% [1/58], P = 0.043), surgical complication rate (DA = 26% [37/140] vs. RS = 41% [47/114] vs. PA = 33% [19/58], P < 0 .001), and readmission rate (DA = 6.4% [9/140] vs. RS = 12.3% [14/114] vs. PA = 19% [11/58] P = 0.030) within 30 days of surgery. No notable differences were observed among groups in 2-year complication, infection, readmission, or revision surgery rates., Conclusions: These study results support the DA surgeon approach. Resident involvement, even in less complex cases, can still negatively affect perioperative outcomes. Additional selection criteria development is needed., Competing Interests: All authors state that they have no conflicts of interest that are relevant to this project to disclose. No funding was obtained for this study., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

Objectives: Because of an increasing need to build capacity for end-of-life care, improving access to palliative care is a priority. Where a physician practices (eg, hospital, outpatient clinic, home) directly relates to the type of service and the stage of illness at which care is provided. In this study, we describe the physician palliative care specialist workforce and the settings of care within which they practice., Design: A retrospective cohort., Setting and Participants: All physicians with palliative care billing codes who were practicing between April 1, 2018, and March 31, 2019, in Ontario, Canada., Methods: Descriptive statistics of physician billing location and frequency using linked population-based health administrative data., Results: We identified 8883 physicians who provided palliative care during the study period. Of those, 723 (8.1%) were classified as palliative care specialists (>10% of their billings encounters were palliative care). The majority (57.4%) of palliative care specialists worked in 1 setting more than 90% of their time, across home visits (27.1%), indirect care (22.4%), and office (7.9%). There were 61 palliative care specialists practicing in mixed locations who provided home visits, meaning 310 (42.9%) of the palliative care specialists delivered some home-based care., Conclusions and Implications: This research provides a comprehensive description of the current palliative care specialist physician workforce that can support efforts to build capacity for high-quality end-of-life care., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Physicians and nurse practitioners (NPs) play critical roles in supporting palliative and end-of-life care in the community. We examined healthcare outcomes among patients who received home visits from physicians and NPs in the 90 days before death., Methods: We conducted a retrospective cohort study using linked data of adult home care users in Ontario, Canada, who died between 1 January 2018 and 31 December 2019. Healthcare outcomes included medications for pain and symptom management, emergency department (ED) visits, hospitalisations and a community-based death. We compared the characteristics of and outcomes in decedents who received a home visit from an NP, physician and both to those who did not receive a home visit., Results: Half (56.9%) of adult decedents in Ontario did not receive a home visit from a provider in the last 90 days of life; 34.5% received at least one visit from a physician, 3.8% from an NP and 4.9% from both. Compared with those without any visits, having at least one home visit reduced the odds of hospitalisation and ED visits, and increased the odds of receiving medications for pain and symptom management and achieving a community-based death. Observed effects were larger in patients who received at least one visit from both., Conclusions: Beyond home care, receiving home visits from primary care providers near the end of life may be associated with better outcomes that are aligned with patients' preferences-emphasising the importance of NPs and physicians' role in supporting people near the end of life., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: With the increasing use of the internet for health information, it is essential to prioritize resources that match the reading level of patients and parents. Limited health literacy is a notable issue in the United States, creating a financial burden and negatively affecting patient outcomes. This study aimed to assess the availability and readability of pediatric hospital web pages concerning two prevalent spine conditions in children, spondylolisthesis and spondylolysis, specifically examining whether the available resources meet the recommended sixth grade reading level., Methods: A total of 179 pediatric hospital web pages were assessed for their availability and readability of spondylolisthesis and spondylolysis patient information. The web pages' readability was assessed using five readability formulae. Descriptive statistics and Student t-tests were performed on the collected scores with significance set at P < 0.05., Results: Among the analyzed hospitals, 40.2% had no information on spondylolisthesis or spondylolysis, 20.1% mentioned treating these conditions, 7.8% had < 100 dedicated words, and only 31.8% had dedicated web pages with more than 100 words on these conditions. The average reading grade level for the evaluated web pages was 12.0, indicating a high school education level is required for comprehension. None of the web pages were written below the recommended sixth grade reading level., Discussion: The readability of the limited resources was markedly higher than the recommended reading level. In addition, this study emphasizes the need for enhanced accessibility and readability of online patient information from pediatric hospitals to improve parental comprehension and informed decision-making. Physicians should consider identifying online resources that they consider of high quality and acceptable readability to support better patient understanding and outcomes., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Objective: To describe the timing of involvement of various physician specialties over the last year of life across different levels of primary care physician continuity for differing causes of death., Methods: We conducted a retrospective cohort study of adults who died in Ontario, Canada, between 1 January 2013 and 31 December 2018, using linked population level health administrative data. Outcomes were median days between death and first and last outpatient palliative care specialist encounter, last outpatient encounter with other specialists and with the usual primary care physician. These were calculated by tertile of score on the Usual Provider Continuity Index, defined as the proportion of outpatient physician encounters with the patient's primary care physician., Results: Patients' (n=395 839) mean age at death was 76 years. With increasing category of usual primary care physician continuity, a larger proportion were palliative care generalists, palliative care specialist involvement decreased in duration and was concentrated closer to death, the primary care physician was involved closer to death, and other specialist physicians ceased involvement earlier. For patients with cancer, palliative care specialist involvement was longer than for other patients., Conclusions: Compared with patients with lower continuity, those with higher usual provider continuity were more likely to have a primary care physician involved closer to death providing generalist palliative care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To describe variations in the receipt of potentially inappropriate interventions in the last 100 days of life of patients with cancer according to patient characteristics and cancer site., Methods: We conducted a population-based retrospective cohort study of cancer decedents in Ontario, Canada who died between 1 January 2013 and 31 December 2018. Potentially inappropriate interventions, including chemotherapy, major surgery, intensive care unit admission, cardiopulmonary resuscitation, defibrillation, dialysis, percutaneous coronary intervention, mechanical ventilation, feeding tube placement, blood transfusion and bronchoscopy, were captured via hospital discharge records. We used Poisson regression to examine associations between interventions and decedent age, sex, rurality, income and cancer site., Results: Among 151 618 decedents, 81.3% received at least one intervention, and 21.4% received 3+ different interventions. Older patients (age 95-105 years vs 19-44 years, rate ratio (RR) 0.36, 95% CI 0.34 to 0.38) and women (RR 0.94, 95% CI 0.93 to 0.94) had lower intervention rates. Rural patients (RR 1.09, 95% CI 1.08 to 1.10), individuals in the highest area-level income quintile (vs lowest income quintile RR 1.02, 95% CI 1.01 to 1.04), and patients with pancreatic cancer (vs colorectal cancer RR 1.10, 95% CI 1.07 to 1.12) had higher intervention rates., Conclusions: Potentially inappropriate interventions were common in the last 100 days of life of cancer decedents. Variations in interventions may reflect differences in prognostic awareness, healthcare access, and care preferences and quality. Earlier identification of patients' palliative care needs and involvement of palliative care specialists may help reduce the use of these interventions at the end of life., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Physician home visits are associated with better health outcomes, yet most patients near the end of life never receive such a visit. Our objectives were to describe the receipt of physician home visits during the last year of life after a referral to home care - an indication that the patient can no longer live independently - and to measure associations between patient characteristics and receipt of a home visit., Methods: We conducted a retrospective cohort study using linked population-based health administrative databases housed at ICES. We identified adult (aged ≥ 18 yr) decedents in Ontario who died between Mar. 31, 2013, and Mar. 31, 2018, who were receiving primary care and were referred to publicly funded home care services. We described the provision of physician home visits, office visits and telephone management. We used multinomial logistic regression to calculate the odds of receiving home visits from a rostered primary care physician, controlling for referral during the last year of life, age, sex, income quintile, rurality, recent immigrant status, referral by rostered physician, referral during hospital stay, number of chronic conditions and disease trajectory based on the cause of death., Results: Of the 58 753 decedents referred in their last year of life, 3125 (5.3%) received a home visit from their family physician. Patient characteristics associated with higher odds of receiving home visits compared to office-based or telephone-based care were being female (adjusted odds ratio [OR] 1.28, 95% confidence interval [CI] 1.21-1.35), being 85 years of age or older (adjusted OR 2.42, 95% CI 1.80-3.26) and living in a rural area (adjusted OR 1.09, 95% CI 1.00-1.18). Increased odds were associated with home care referrals by the patient's primary care physician (adjusted OR 1.49, 95% CI 1.39-1.58) and referrals occurring during a hospital stay (adjusted OR 1.20, 95% CI 1.13-1.28)., Interpretation: A small proportion of patients near the end of life received home-based physician care, and patient characteristics did not explain the low visit rates. Future work on system- and provider-level factors may be critical to improve access to home-based end-of-life primary care., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

It has been well-established that novelty-seeking and impulsivity are significant risk factors for the development of psychological disorders, including substance use disorder and behavioral addictions. While dysfunction in the prefrontal cortex is at the crux of these disorders, little is known at the cellular level about how alterations in neuron activity can drive changes in impulsivity and novelty seeking. We harnessed a cre-dependent caspase-3 ablation in both male and female mice to selectively ablate vasoactive intestinal peptide (VIP)-expressing interneurons in the prefrontal cortex to better explore how this microcircuit functions during specific behavioral tasks. Caspase-ablated animals had no changes in anxiety-like behaviors or hedonic food intake but had a specific increase in impulsive responding during longer trials in the three-choice serial reaction time test. Together, these data suggest a circuit-level mechanism in which VIP interneurons function as a gate to selectively respond during periods of high expectation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hatter, Scott. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mammalian Ric-8 proteins act as chaperones to regulate the cellular abundance of heterotrimeric G protein α subunits. The Ric-8A isoform chaperones Gαi/o, Gα12/13, and Gαq/11 subunits, while Ric-8B acts on Gαs/olf subunits. Here, we determined cryoelectron microscopy (cryo-EM) structures of Ric-8B in complex with Gαs and Gαolf, revealing isoform differences in the relative positioning and contacts between the C-terminal α5 helix of Gα within the concave pocket formed by Ric-8 α-helical repeat elements. Despite the overall architectural similarity with our earlier structures of Ric-8A complexed to Gαq and Gαi1, Ric-8B distinctly accommodates an extended loop found only in Gαs/olf proteins. The structures, along with results from Ric-8 protein thermal stability assays and cell-based Gαolf folding assays, support a requirement for the Gα C-terminal region for binding specificity, and highlight that multiple structural elements impart specificity for Ric-8/G protein binding., Competing Interests: Declaration of interests G.S. is a co-founder of and consultant for Deep Apple Therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Thoracolumbar fractures (TLFs) are the most common spinal fractures seen in patients with trauma. The Thoracolumbar Injury Classification and Severity (TLICS) classification system is commonly used to help clinicians make more consistent and objective decisions in assessing the indications for surgical intervention in patients with thoracolumbar fractures. Patients with TLICS scores <4 are treated conservatively, but a percentage of them will have failed conservative treatment and require surgery at a later date., Methods: All patients who received an orthopaedic consult between January 2016 and December 2020 were screened for inclusion and exclusion criteria. For patients meeting the study requirements, deidentified data were collected including demographics, diagnostics workup, and hospital course. Data analysis was conducted comparing length of stay, time between first consult and surgery, and time between surgery and discharge among each group., Results: 1.4% of patients with a TLICS score <4 not treated surgically at initial hospital stay required surgery at a later date. Patients with a TLICS score <4 treated conservatively had a statistically significant shorter hospital stay compared with those treated surgically. However, when time between initial consult and surgery was factored into the total duration of hospital stay for those treated surgically, the duration was statistically equivalent to those treated nonsurgically., Conclusion: For patients with a TLICS score <4 with delayed mobilization after 3 days in the hospital or polytraumatic injuries, surgical stabilization at initial presentation can decrease the percentage of patients who fail conservative care and require delayed surgery. Patients treated surgically have a longer length of stay than those treated conservatively, but there is no difference in stay when time between consult and surgery was accounted for. In addition, initial surgery in patients with delayed mobilization can prevent long waits to surgery, while conservative measures are exhausted., Level Iii Evidence: Retrospective cohort study., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

It has been shown that there is disparity in access to long-term care and other services for minority populations. This study assessed long-term care access among older individuals belonging to minority populations including visible, ethnocultural, linguistic, and sexual minorities. Barriers and facilitators influencing admission were identified and evaluated.A search for articles from 10 databases published between January 2000 and January 2021 was conducted. Included studies evaluated factors affecting minority populations' admission to long-term care, and non-residents' perceptions of future admission. This review was registered with PROSPERO: CRD42018038662. Sixty included quantitative and qualitative studies, ranging in quality from fair to excellent. Findings suggest minority status is associated with reduced admission to long-term care, controlling for confounding variables. Barriers identified include discordant language, fear of discrimination, lack of information, and family obligations. Findings suggest that minority populations experienced barriers accessing long-term care and had unmet cultural and language needs while receiving care in this setting.

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.)

Inhibitor-2 (I-2) is a prototypic inhibitor of protein phosphatase-1 (PP1), a major serine-threonine phosphatase that regulates synaptic plasticity and learning and memory. Although I-2 is a potent inhibitor of PP1 in vitro , our previous work has elucidated that, in vivo , I-2 may act as a positive regulator of PP1. Here we show that I-2 and PP1 γ , but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhanced PP1 γ interaction with its major synaptic scaffold, neurabin, by Förster resonance energy transfer (FRET)/Fluorescence lifetime imaging microscopy (FLIM) studies, while having a limited effect on PP1 auto-inhibitory phosphorylation. Furthermore, our study indicates that the effect of I-2 on PP1 activity in vivo is dictated by I-2 threonine-72 phosphorylation. Our work thus demonstrates a molecular mechanism by which I-2 positively regulates PP1 function in synaptic transmission., 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 Foley, Altimimi, Hou, Zhang, McKee, Papasergi-Scott, Yang, Mayer, Ward, MacLean, Nairn, Stellwagen and Xia.)

Interleukin (IL)-33 is highly expressed in the nucleus of cells present at barrier sites and signals via the ST2 receptor. IL-33 signalling via ST2 is essential for return to tissue homeostasis after acute inflammation, promoting fibrinogenesis and wound healing at injury sites. However, this wound-healing response becomes aberrant during chronic or sustained inflammation, leading to transforming growth factor beta (TGF-β) release, excessive extracellular matrix deposition, and fibrosis. This review addresses the role of the IL-33 pathway in fibrotic diseases of the lung, liver, gastrointestinal tract, skin, kidney and heart. In the lung and liver, IL-33 release leads to the activation of pro-fibrotic TGF-β, and in these sites, IL-33 has clear pro-fibrotic roles. In the gastrointestinal tract, skin, and kidney, the role of IL-33 is more complex, being both pro-fibrotic and tissue protective. Finally, in the heart, IL-33 serves cardioprotective functions by favouring tissue healing and preventing cardiomyocyte death. Altogether, this review indicates the presence of an unclear and delicate balance between resolving and pro-fibrotic capabilities of IL-33, which has a central role in the modulation of type 2 inflammation and fibrosis in response to tissue injury., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Oxidized phosphatidylcholines (OxPCs) are implicated in chronic tissue damage. Hyperlipidemic LDL-R--deficient mice transgenic for an OxPC-recognizing IgM fragment (scFv-E06) are protected against nonalcoholic fatty liver disease (NAFLD). To examine the effect of OxPC elimination at different stages of NAFLD progression, we used cre-dependent, adeno-associated virus serotype 8-mediated expression of the single-chain variable fragment of E06 (AAV8-scFv-E06) in hepatocytes of albumin-cre mice. AAV8-induced expression of scFv-E06 at the start of FPC diet protected mice from developing hepatic steatosis. Independently, expression of scFv-E06 in mice with established steatosis prevented the progression to hepatic fibrosis. Mass spectrometry-based oxophospho-lipidomics identified individual OxPC species that were reduced by scFv-E06 expression. In vitro, identified OxPC species dysregulated mitochondrial metabolism and gene expression in hepatocytes and hepatic stellate cells. We demonstrate that individual OxPC species independently affect disease initiation and progression from hepatic steatosis to steatohepatitis, and that AAV-mediated expression of scFv-E06 is an effective therapeutic intervention.

Glucagon-like peptide-1 (GLP-1) regulates energy homeostasis via activation of the GLP-1 receptors (GLP-1Rs) in the central nervous system. However, the mechanism by which the central GLP-1 signal controls blood glucose levels, especially in different nutrient states, remains unclear. Here, we defined a population of glucose-sensing GLP-1R neurons in the dorsomedial hypothalamic nucleus (DMH), by which endogenous GLP-1 decreases glucose levels via the cross-talk between the hypothalamus and pancreas. Specifically, we illustrated the sufficiency and necessity of DMH GLP-1R in glucose regulation. The activation of the DMH GLP-1R neurons is mediated by a cAMP-PKA-dependent inhibition of a delayed rectifier potassium current. We also dissected a descending control of DMH GLP-1R -dorsal motor nucleus of the vagus nerve (DMV)-pancreas activity that can regulate glucose levels by increasing insulin release. Thus, our results illustrate how central GLP-1 action in the DMH can induce a nutrient state-dependent reduction in blood glucose level.

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.)

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism 1 . Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G i . Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G i can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Infections in elderly patients can prove diagnostically challenging. Age-related factors affecting the immune system in older individuals contribute to nonspecific presentations. Other age-related factors and chronic conditions have symptoms that may or may not point to an infectious diagnosis. Delay in administration of antimicrobials can lead to poor outcomes; however, unnecessary administration of antimicrobials can lead to increased morbidity and contribute to the emergence of multidrug-resistant organisms. Careful clinical assessment and consideration of patient history and risk factors is crucial. When necessary, antimicrobials should be chosen that are appropriate for the diagnosis and deescalated as soon as possible., Competing Interests: Disclosure MMS and SYL have no conflicts of interest to disclose. SYL received support through the Foundation for Barnes-Jewish Hospital and the Washington University Institute of Clinical and Translational Sciences which is, in part, supported by the NIH/National Center for Advancing Translational Sciences (NCATS), Clinical and Translational Science Award (CTSA) program (UL1TR002345)., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Kinesin family member 3A (KIF3A) is a molecular motor protein in the heterotrimeric kinesin-2 complex that drives anterograde intraflagellar transport. This process plays a pivotal role in both biogenesis and maintenance of the primary cilium that supports tissue development. Ciliogenesis associated kinase 1 (CILK1) phosphorylates human KIF3A at Thr672. CILK1 loss of function causes ciliopathies that manifest profound and multiplex developmental defects, including hydrocephalus, polydactyly, shortened and hypoplastic bones and alveoli airspace deficiency, leading to perinatal lethality. Prior studies have raised the hypothesis that CILK1 phosphorylation of KIF3A is critical for its regulation of organ development., Results: We produced a mouse model with phosphorylation site Thr674 in mouse Kif3a mutated to Ala. Kif3a T674A homozygotes are viable and exhibit no skeletal and brain abnormalities, and only mildly reduced airspace in alveoli. Mouse embryonic fibroblasts carrying Kif3a T674A mutation show a normal rate of ciliation and a moderate increase in cilia length., Conclusion: These results indicate that eliminating Kif3a Thr674 phosphorylation by Cilk1 is insufficient to reproduce the severe developmental defects in ciliopathies caused by Cilk1 loss of function. This suggests KIF3A-Thr672 phosphorylation by CILK1 is not essential for tissue development and other substrates are involved in CILK1 ciliopathies., (2020 Wiley Periodicals LLC.)

Glucagon-like peptide-1 (GLP-1) regulates reproduction centrally, although, the neuroanatomical basis of the process is unknown. Therefore, the putative networking of the central GLP-1 and gonadotropin-releasing hormone (GnRH) systems was addressed in male mice using whole mount immunocytochemistry and optogenetics. Enhanced antibody penetration and optical clearing procedures applied to 500-1000 µm thick basal forebrain slices allowed the simultaneous visualization of the two distinct systems in the basal forebrain. Beaded GLP-1-IR axons innervated about a quarter of GnRH neurons (23.2 ± 1.4%) forming either single or multiple contacts. GnRH dendrites received a more intense GLP-1 innervation (64.6 ± 0.03%) than perikarya (35.4 ± 0.03%). The physiological significance of the innervation was examined by optogenetic activation of channelrhodopsin-2 (ChR2)-expressing axons of preproglucagon (GCG) neurons upon the firing of GnRH neurons by patch clamp electrophysiology in acute brain slices of triple transgenic mice (Gcg-cre/ChR2/GFP-GnRH). High-frequency laser beam stimulation (20 Hz, 10 ms pulse width, 3 mW laser power) of ChR2-expressing GCG axons in the mPOA increased the firing rate of GnRH neurons (by 75 ± 17.3%, p = 0.0007). Application of the GLP-1 receptor antagonist, Exendin-3-(9-39) (1 μM), prior to the photo-stimulation, abolished the facilitatory effect. In contrast, low-frequency trains of laser pulses (0.2 Hz, 60 pulses) had no effect on the spontaneous postsynaptic currents of GnRH neurons. The findings indicate a direct wiring of GLP-1 neurons with GnRH cells which route is excitatory for the GnRH system. The pathway may relay metabolic signals to GnRH neurons and synchronize metabolism with reproduction.

The nucleus of the solitary tract (NTS) is critical for the central integration of signals from visceral organs and contains preproglucagon (PPG) neurons, which express leptin receptors in the mouse and send direct projections to the paraventricular nucleus of the hypothalamus (PVH). Here, we visualized projections of PPG neurons in leptin-deficient Lep ob/ob mice and found that projections from PPG neurons are elevated compared with controls, and PPG projections were normalized by targeted rescue of leptin receptors in LepRb TB/TB mice, which lack functional neuronal leptin receptors. Moreover, Lep ob/ob and LepRb TB/TB mice displayed increased levels of neuronal activation in the PVH following vagal stimulation, and whole-cell patch recordings of GLP-1 receptor-expressing PVH neurons revealed enhanced excitatory neurotransmission, suggesting that leptin acts cell autonomously to suppress representation of excitatory afferents from PPG neurons, thereby diminishing the impact of visceral sensory information on GLP-1 receptor-expressing neurons in the PVH., Competing Interests: JB, RL, MS, RS No competing interests declared, (© 2020, Biddinger et al.)

Stimulation of the metabotropic GABA B receptor by γ-aminobutyric acid (GABA) results in prolonged inhibition of neurotransmission, which is central to brain physiology 1 . GABA B belongs to family C of the G-protein-coupled receptors, which operate as dimers to transform synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins 2,3 . However, GABA B is unique in its function as an obligate heterodimer in which agonist binding and G-protein activation take place on distinct subunits 4,5 . Here we present cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABA B receptors. Complemented by cellular signalling assays and atomistic simulations, these structures reveal that extracellular loop 2 (ECL2) of GABA B has an essential role in relaying structural transitions by ordering the linker that connects the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of each of the subunits of GABA B caps and interacts with the hydrophilic head of a phospholipid that occupies the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G proteins. These results provide a starting framework through which to decipher the mechanistic modes of signal transduction mediated by GABA B dimers, and have important implications for rational drug design that targets these receptors.

Many chaperones promote nascent polypeptide folding followed by substrate release through ATP-dependent conformational changes. Here we show cryoEM structures of Gα subunit folding intermediates in complex with full-length Ric-8A, a unique chaperone-client system in which substrate release is facilitated by guanine nucleotide binding to the client G protein. The structures of Ric-8A-Gα i and Ric-8A-Gα q complexes reveal that the chaperone employs its extended C-terminal region to cradle the Ras-like domain of Gα, positioning the Ras core in contact with the Ric-8A core while engaging its switch2 nucleotide binding region. The C-terminal α5 helix of Gα is held away from the Ras-like domain through Ric-8A core domain interactions, which critically depend on recognition of the Gα C terminus by the chaperone. The structures, complemented with biochemical and cellular chaperoning data, support a folding quality control mechanism that ensures proper formation of the C-terminal α5 helix before allowing GTP-gated release of Gα from Ric-8A., Competing Interests: Declaration of Interests B.K.K. is a co-founder of and consultant for ConfometRx, Inc., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Smartphone apps and mobile devices are an emerging method of healthcare data collection. This study sought to understand how physicians currently view mobile health (mHealth) technologies and use them in patient care., Methods: A total of 186 physicians affiliated with Washington University School of Medicine in St. Louis, Missouri, USA completed a survey in 2016 regarding their current implementation of mHealth technologies for patient care and support for further development., Results: More than half of respondents were willing to discuss health apps and mobile devices with patients. However, most were not currently recommending them to patients. Apps/devices that encouraged a healthy diet and weight or tracked heart rate received the highest satisfaction ratings. Apps/devices that accessed the EMR (electronic medical record) remotely, provided medication reminders, or enrolled research subjects garnered the most interest despite respondents lacking prior experience. A majority agreed that collected biometrics are useful for promoting a healthy lifestyle (68%), tracking medical treatment (64%), or conducting research (56%); and agreed that proof of accuracy and precision (81%) and the efficient integration of collected data (68%) are necessary improvements. Uploading data automatically and updating physicians in real-time was the most preferred method of data integration into the EMR., Conclusions: Physicians show interest in using mHealth technologies for patient care but have limited experience, usually with those specific to their specialties. Proof of quality and a method to integrate data into the EMR are necessary for a mainstream role in healthcare., (© The Author(s) 2020.)

Introduction: One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption., Methods: Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined., Results: When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 ± 0.05 and 1.4 ± 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p < .05), respectively. The average nicotine intake in female rats was 0.6 ± 0.05 and 0.6 ± 0.03 mg/kg/day for nicotine and menthol-nicotine combination (p > .05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 ± 4.9, mentholated nicotine group: 31.9 ± 3.2 ng/mL) or female (nicotine group: 24.0 ± 3.3, mentholated nicotine group: 17.8 ± 2.9 ng/mL) rats (p > .05)., Conclusions: Menthol increases oral nicotine consumption in male, but not female, rats., Implications: This study may provide data on the co-use of menthol and nicotine in smokeless tobacco, particularly oral dissolvable tobacco products., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)