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Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

Respiratory function has become a global health priority. Not only is chronic respiratory disease a leading cause of worldwide morbidity and mortality, but the COVID-19 pandemic has heightened attention on respiratory health and the means of enhancing it. Subsequently, and inevitably, the respiratory system has become a target of the multi-trillion-dollar health and wellness industry. Numerous commercial, respiratory-related interventions are now coupled to therapeutic and/or ergogenic claims that vary in their plausibility: from the reasonable to the absurd. Moreover, legitimate and illegitimate claims are often conflated in a wellness space that lacks regulation. The abundance of interventions, the range of potential therapeutic targets in the respiratory system, and the wealth of research that varies in quality, all confound the ability for health and exercise professionals to make informed risk-to-benefit assessments with their patients and clients. This review focuses on numerous commercial interventions that purport to improve respiratory health, including nasal dilators, nasal breathing, and systematized breathing interventions (such as pursed-lips breathing), respiratory muscle training, canned oxygen, nutritional supplements, and inhaled L-menthol. For each intervention we describe the premise, examine the plausibility, and systematically contrast commercial claims against the published literature. The overarching aim is to assist health and exercise professionals to distinguish science from pseudoscience and make pragmatic and safe risk-to-benefit decisions.

IntroductionSeveral studies report that pulmonary oxygen uptake (V̇O 2 ) at the respiratory compensation point (RCP) is equivalent to the V̇O 2 at critical power (CP), suggesting that the variables can be used interchangeably to demarcate the threshold between heavy and severe intensity domains. However, if RCP is a valid surrogate for CP, their values should correspond even when assessed in patients with chronic obstructive pulmonary disease (COPD) in whom the "normal" mechanisms linking CP and RCP are impeded. The aim of this study was to compare V̇O 2 at CP with V̇O 2 at RCP in patients with COPD.MethodsTwenty-two COPD patients (14 male/8 female; forced expiratory volume in 1 s, 46% ± 17% pred) performed ramp-incremental cycle ergometry to intolerance (5-10 W·min -1 ) for the determination of gas exchange threshold (GET) and RCP. CP was calculated from the asymptote of the hyperbolic power-duration relationship from 3-5 constant-power exercise tests to intolerance. CP was validated with a 20-min constant-power ride.ResultsGET was identified in 20 of 22 patients at a V̇O 2 of 0.93 ± 0.18 L·min -1 (75% ± 13% V̇O 2peak ), whereas RCP was identified in just 3 of 22 patients at a V̇O 2 of 1.40 ± 0.39 L·min -1 (85% ± 2% V̇O 2peak ). All patients completed constant-power trials with no difference in peak physiological responses relative to ramp-incremental exercise ( P > 0.05). CP was 46 ± 22 W, which elicited a V̇O 2 of 1.04 ± 0.29 L·min -1 (90% ± 9% V̇O 2peak ) during the validation ride. The difference in V̇O 2 at 15 and 20 min of the validation ride was 0.00 ± 0.04 L, which was not different from a hypothesized mean of 0 ( P = 0.856), thereby indicating a V̇O 2 steady state.ConclusionsIn COPD patients, who present with cardiopulmonary and/or respiratory-mechanical dysfunction, CP can be determined in the absence of RCP. Accordingly, CP and RCP are not equivalent in this group.

Per- and polyfluoroalkyl substances (PFAS) are forever chemicals that have been used for their heat, grease, and water-resistant properties on disposable dinnerware. However, PFAS pose risks to human health and the environment and alternative treatments are currently being implemented in the disposable dinnerware industry, including bio- or plant-based treatments. To date, consumer perceptions of the practical usage and environment-related attributes of PFAS versus plant-based alternative treatments have not been addressed. An online survey elicited 1304 U S. consumers' perceptions of the attributes from each treatment and factors impacting those perceptions. On average, participants purchased disposable plates 13 times per year with 50 % ± 50 purchasing them for everyday use. Approximately 20 % ± 40 of the sample had heard of PFAS prior to the study while 62 % ± 49 had heard of bio-based products. In general, PFAS treatments were perceived as performing slightly better in the practical usage attributes (i.e., grease resistant, water resistant, durable); however, the plant-based alternative treatments were perceived as more environmentally friendly (i.e., better for the environment, better for personal health, recyclable, compostable). Older participants viewing plant-based treatments as better at grease resistance, water resistance, durability, and microwavable relative to younger participants. Conversely, people with higher education levels viewed plant-based treatments as less resistant to grease but more durable. Interestingly, participants’ perceptions and existing knowledge of PFAS and bio-based products influenced their perceptions of plant-based treatments being more environmentally friendly. Results provide insights for industry stakeholders as they move forward in implementing PFAS alternative treatments.

The COVID-19 pandemic is a public health crisis that continues to impact individuals worldwide. While children may be less susceptible to severe medical complications, they are nonetheless vulnerable to stress and anxiety associated with the pandemic. However, current understanding of psychological functioning and potential strategies to mitigate distress amid a pandemic is naturally limited. Consequently, this article is an attempt to fill that gap. Existing literature on pandemics, health-related anxieties, intolerance of uncertainty, and psychopathological sequelae is summarized within the context of the COVID-19 outbreak. Conclusions from the empirical data and emerging theoretical models are reviewed and synthesized. Finally, several potentially engaging and effective examples of developmentally appropriate interventions targeting intolerance of uncertainty and health-related anxieties in pediatric patients during the peri- and post-pandemic periods are described.

Abstract Introduction Older carers or ‘care partners’ of older people experiencing care needs often provide essential support, at times while neglecting their own health and well‐being. This is an increasingly frequent scenario due to both demographic changes and policy shifts towards ageing in place. Multiple community stakeholders within the care and support ecosystem hold valuable expertise about the needs of older care partners, and the programme and policy responses that may better support their health and well‐being. The aim of this study was to identify the perspectives of stakeholders obtained through the codesign phase of a multicomponent research project investigating new models of care and support for older care partners suitable for the Australian context. Methods Principles of codesign were used to engage a purposeful sample of older care partners, health professionals, researchers, policy makers and health service administrators. Participants took part in a series of three codesign workshops conducted remotely via video conferencing. The workshops were supported with briefing material and generated consensus‐based summaries, arriving at a preferred service model. Findings This paper reports the research design and structure of the codesign panels, the range of findings identified as important to support the health and well‐being of older carers of older people, and the resulting service model principles. The codesigned and preferred model of care is currently being prepared for implementation and evaluation in Australia. Public Contribution This study was conducted using codesign methodology, whereby stakeholders including older care partners and others involved in supporting older carers, were integrally involved with design, development, results and conclusions.

In this qualitative study, we focused on a two-way model of engagement, utilizing observational and individual interview data to examine community members' perceptions of their participation in a statewide initiative to increase leadership capacity at the community level. We review barriers to engagement recognized in the literature. Our study builds upon evolving definitions and models of community engagement, and furthers our understanding of community members' own perceptions of the definition and process involved in successful two-way community engagement. Our findings suggest three emergent themes for community participants: (1) trust, (2) relationships, and (3) priceless value of the engagement. Involving the community members in the design, implementation, and evaluation of the initiative was a unique approach to scaling up a statewide leadership development engagement effort, and the inclusive nature of this process enabled us to examine perceptions of engagement efforts in a single initiative across communities throughout the state of Georgia.

BackgroundLower heart rate (HR) increases during exercise and slower HR recovery (HRR) after exercise are markers of worse autonomic function that may be associated with risk of acute respiratory events (ARE).MethodsData from 6-min walk testing (6MWT) in COPDGene were used to calculate the chronotropic index (CI) [(HR immediately post 6MWT - resting HR)/((220 - age) - resting HR)] and HRR at 1 min after 6MWT completion. We used zero-inflated negative binomial regression to test associations of CI and HRR with rates of any ARE (requiring steroids and/or antibiotics) and severe ARE (requiring emergency department visit or hospitalization), among all participants and in spirometry subgroups (normal, chronic obstructive pulmonary disease [COPD], and preserved ratio with impaired spirometry).ResultsAmong 4,484 participants, mean follow-up time was 4.1 years, and 1,966 had COPD. Among all participants, CI-6MWT was not associated with rate of any ARE [adjusted incidence rate ratio (aIRR) 0.98 (0.95-1.01)], but higher CI-6MWT was associated with lower rate of severe ARE [0.95 (0.92-0.99)]. Higher HRR was associated with a lower rate of both any ARE [0.97 (0.95-0.99)] and severe ARE [0.95 (0.92-0.98)]. Results were similar in the COPD spirometry subgroup.ConclusionHeart rate measures derived from 6MWT tests may have utility in predicting risk of acute respiratory events and COPD exacerbations.

IntroductionSevere chronic obstructive pulmonary disease (COPD) is partly characterized by diminished skeletal muscle oxidative capacity and concurrent dyslipidemia. It is unknown whether such metabolic derangements increase the risk of cardiovascular disease. This study explored associations among physical activity (PA), muscle oxidative capacity, and coronary artery calcium (CAC) in COPDGene participants.MethodsData from current and former smokers with COPD (n = 75) and normal spirometry (n = 70) were retrospectively analyzed. Physical activity was measured for seven days using triaxial accelerometry (steps/day and vector magnitude units [VMU]) along with the aggregate of self-reported PA amount and PA difficulty using the PROactive D-PPAC instrument. Muscle oxidative capacity (k) was assessed via near-infrared spectroscopy, and CAC was assessed via chest computerized tomography.ResultsRelative to controls, COPD patients exhibited higher CAC (median [IQR], 31 [0-431] vs 264 [40-799] HU; p = 0.003), lower k (mean ± SD = 1.66 ± 0.48 vs 1.25 ± 0.37 min-1; p < 0.001), and lower D-PPAC total score (65.2 ± 9.9 vs 58.8 ± 13.2; p = 0.003). Multivariate analysis-adjusting for age, sex, race, diabetes, disease severity, hyperlipidemia, smoking status, and hypertension-revealed a significant negative association between CAC and D-PPAC total score (β, -0.05; p = 0.013), driven primarily by D-PPAC difficulty score (β, -0.03; p = 0.026). A 1 unit increase in D-PPAC total score was associated with a 5% lower CAC (p = 0.013). There was no association between CAC and either k, steps/day, VMU, or D-PPAC amount.ConclusionPatients with COPD and concomitantly elevated CAC exhibit greater perceptions of difficulty when performing daily activities. This may have implications for exercise adherence and risk of overall physical decline.

The COVID-19 pandemic is a public health crisis that continues to impact individuals worldwide. While children may be less susceptible to severe medical complications, they are nonetheless vulnerable to stress and anxiety associated with the pandemic. However, current understanding of psychological functioning and potential strategies to mitigate distress amid a pandemic is naturally limited. Consequently, this article is an attempt to fill that gap. Existing literature on pandemics, health-related anxieties, intolerance of uncertainty, and psychopathological sequelae is summarized within the context of the COVID-19 outbreak. Conclusions from the empirical data and emerging theoretical models are reviewed and synthesized. Finally, several potentially engaging and effective examples of developmentally appropriate interventions targeting intolerance of uncertainty and health-related anxieties in pediatric patients during the peri- and post-pandemic periods are described.

Abstract While 9-valent human papillomavirus (HPV) vaccination is approved by the US Food and Drug Administration for use in adolescents as young as age 9, providers typically recommend it at ages 11–12. Studies suggest that recommending HPV vaccination at 9 or 10 years of age could increase up-to-date vaccination by age 13, which could especially benefit rural populations with reduced access to primary health care and lower HPV vaccination coverage than urban areas. This study aimed to assess the feasibility of the age-9 recommendation of HPV vaccination in rural clinics. We conducted in-depth interviews with providers and staff from two primary care clinics in central North Carolina to understand attitudes toward recommending HPV vaccination to 9- and 10-year-olds. All interviewees agreed that HPV vaccination was important for cancer prevention and should be recommended before the onset of sexual activity, agreeing that HPV vaccination could be initiated before age 11 to improve timeliness and completion of the vaccination series. However, opinions were mixed on whether HPV vaccination should be initiated as young as 9 years old. Two key informants recruited from two university-affiliated clinics described their experiences recommending HPV vaccination to 9- and 10-year-olds, including a modified vaccination schedule that promotes HPV vaccination during routine well-child visits, prior to pubertal onset, and alongside other recommended adolescent vaccines. Age-9 recommendation and administration of HPV vaccination is possible with minimal changes to current clinical practices and could increase the convenience and acceptability of HPV vaccination in under-vaccinated settings.

Background Microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH) are well‐established imaging biomarkers of failed myocardial tissue reperfusion in patients with ST‐segment elevation–myocardial infarction treated with percutaneous coronary intervention. MVO and IMH are associated with an increased risk of adverse outcome independent of infarct size, but whether the size of the culprit lesion vessel plays a role in the occurrence and severity of reperfusion injury is currently unknown. This study aimed to evaluate the association between culprit lesion vessel size and the occurrence and severity of reperfusion injury as determined by cardiac magnetic resonance imaging. Methods and Results Patients (n=516) with first‐time ST‐segment–elevation myocardial infarction underwent evaluation with cardiac magnetic resonance at 4 (3–5) days after infarction. MVO was assessed with late gadolinium enhancement imaging and IMH with T2* mapping. Vessel dimensions were determined using catheter‐based reference. Median culprit lesion vessel size was 3.1 (2.7–3.6) mm. MVO and IMH were found in 299 (58%) and 182 (35%) patients. Culprit lesion vessel size was associated with body surface area, diabetes, total ischemic time, postinterventional thrombolysis in myocardial infarction flow, and infarct size. There was no association between vessel size and MVO or IMH in univariable and multivariable analysis (P>0.05). These findings were consistent across patient subgroups with left anterior descending artery and non–left anterior descending artery infarctions and those with thrombolysis in myocardial infarction 3 flow post–percutaneous coronary intervention. Conclusions Comprehensive characterization of myocardial tissue reperfusion injury by cardiac magnetic resonance revealed no association between culprit lesion vessel size and the occurrence of MVO and IMH in patients treated with primary percutaneous coronary intervention for ST‐segment–elevation myocardial infarction.

Background: Dysglycaemia increases the risk of myocardial infarction and subsequent recurrent cardiovascular events. However, the role of dysglycaemia in ischemia/reperfusion injury with development of irreversible myocardial tissue alterations remains poorly understood.In this study we aimed to investigate the association of ongoing dysglycaemia with persistence of infarct core iron and their longitudinal changes over time in patients undergoing primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI). Methods: We analyzed 348 STEMI patients treated with primary PCI between 2016 and 2021 that were included in the prospective MARINA-STEMI study (NCT04113356). Peripheral venous blood samples for glucose and glycated hemoglobin (HbA1c) measurements were drawn on admission and 4 months after STEMI. Cardiac magnetic resonance (CMR) imaging including T2 * mapping for infarct core iron assessment was performed at both time points. Associations of dysglycaemia with persistent infarct core iron and iron resolution at 4 months were calculated using multivariable regression analysis. Results: Intramyocardial hemorrhage was observed in 147 (42%) patients at baseline. Of these, 89 (61%) had persistent infarct core iron 4 months after infarction with increasing rates across HbA1c levels (

Background Although hemorrhage remains the leading cause of survivable death in casualties, modern conflicts are becoming more austere limiting available resources to include resuscitation products. With limited resources also comes prolonged evacuation time, leaving suboptimal prehospital field care conditions. When blood products are limited or unavailable, crystalloid becomes the resuscitation fluid of choice. However, there is concern of continuous crystalloid infusion during a prolonged period to achieve hemodynamic stability for a patient. This study evaluates the effect of hemodilution from a 6-hour prehospital hypotensive phase on coagulation in a porcine model of severe hemorrhagic shock.Methods Adult male swine (n=5/group) were randomized into three experimental groups. Non-shock (NS)/normotensive did not undergo injury and were controls. NS/permissive hypotensive (PH) was bled to the PH target of systolic blood pressure (SBP) 85±5 mm Hg for 6 hours of prolonged field care (PFC) with SBP maintained via crystalloid, then recovered. Experimental group underwent controlled hemorrhage to mean arterial pressure 30 mm Hg until decompensation (Decomp/PH), followed by PH resuscitation with crystalloid for 6 hours. Hemorrhaged animals were then resuscitated with whole blood and recovered. Blood samples were collected at certain time points for analysis of complete blood counts, coagulation function, and inflammation.Results Throughout the 6-hour PFC, hematocrit, hemoglobin, and platelets showed significant decreases over time in the Decomp/PH group, indicating hemodilution, compared with the other groups. However, this was corrected with whole blood resuscitation. Despite the appearance of hemodilution, coagulation and perfusion parameters were not severely compromised.Conclusions Although significant hemodilution occurred, there was minimal impact on coagulation and endothelial function. This suggests that it is possible to maintain the SBP target to preserve perfusion of vital organs at a hemodilution threshold in resource-constrained environments. Future studies should address therapeutics that can mitigate potential hemodilutional effects such as lack of fibrinogen or platelets.Level of evidence Not applicable—Basic Animal Research.

Assessing airway function during exercise provides useful information regarding mechanical properties of the airways and the extent of ventilatory limitation in COPD. The primary aim of this study was to use impulse oscillometry (IOS) to assess dynamic changes in airway impedance across a range of exercise intensities in patients with GOLD 1-4, before and after albuterol administration. A secondary aim was to assess the reproducibility of IOS measures during exercise. Fifteen patients with COPD (8 males/7 females; age = 66 ± 8 yr; prebronchodilator FEV1 = 54.3 ± 23.6%Pred) performed incremental cycle ergometry before and 90 min after inhaled albuterol. Pulmonary ventilation and gas exchange were measured continuously, and IOS-derived indices of airway impedance were measured every 2 min immediately preceding inspiratory capacity maneuvers. Test-retest reproducibility of exercise IOS was assessed as mean difference between replicate tests in five healthy subjects (3 males/2 females). At rest and during incremental exercise, albuterol significantly increased airway reactance (X5) and decreased airway resistance (R5, R5-R20), impedance (Z5), and end-expiratory lung volume (60% ± 12% vs. 58% ± 12% TLC, main effect P = 0.003). At peak exercise, there were moderate-to-strong associations between IOS variables and IC, and between IOS variables and concavity in the expiratory limb of the spontaneous flow-volume curve. Exercise IOS exhibited moderate reproducibility in healthy subjects which was strongest with R5 (mean diff. = -0.01 ± 0.05 kPa/L/s; ICC = 0.68), R5-R20 (mean diff. = -0.004 ± 0.028 kPa/L/s; ICC = 0.65), and Z5 (mean diff. = -0.006 ± 0.021 kPa/L/s; ICC = 0.69). In patients with COPD, exercise evoked increases in airway resistance and decreases in reactance that were ameliorated by inhaled bronchodilators. The technique of exercise IOS may aid in the clinical assessment of dynamic airway function during exercise.NEW & NOTEWORTHY This study provides a novel, mechanistic insight into dynamic airway function during exercise in COPD, before and after inhaled bronchodilators. The use of impulse oscillometry (IOS) to evaluate airway function is unique among exercise studies. We show strong correlations among IOS variables, dynamic hyperinflation, and shape-changes in the spontaneous expiratory flow-volume curve. This approach may aid in the clinical assessment of airway function during exercise.

This review article considers processes by which the main components of wood have been reported to arrange themselves into various kinds of organized structures, at least to a partial extent. The biosynthesis of wood provides the clearest examples of such self-organization. For example, even before a cellulose macromolecule has been completely synthesized in a plant organism, the leading parts of the polymer chains already will have assembled themselves into organized crystals, i.e., nano-fibrils. This review then considers a challenge that faces industrial engineers: how to emulate the great success of natural systems when attempting to achieve favorable materials properties, process efficiency, and environmental friendliness when developing new engineered wood structures, barrier films, and other desired products composed of lignocellulosic materials. Based on the reviewed literature, it appears that the main chemical components of wood, even after they have been isolated from each other, still have a remnant of their initial tendencies to come back together in a somewhat non-random fashion, following mechanisms that can be favorable for the production of engineered materials having potentially useful functions.

BackgroundSlow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.Study design and methodsA total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.ResultsHRR after 6MWT (bt/min) was categorized in quintiles: ≤5 (23.0% of participants), 6-10 (20.7%), 11-15 (18.9%), 16-22 (18.5%) and ≥23 (18.9%). Compared to HRR≤5, HRR≥11 was associated with (p

We analyse and self-reflect on an action research project conducted in a financial organisation twelve years ago. The research question was: What are the challenges of initiating an action research project in a financial organisation with top-down control that uses the Balanced Scorecard? The data came from action learning seminars with line managers, observations, interviews, and meetings in a Norwegian bank (Bank) with approximately 800 employees. The data were analysed using thematic analysis. This study's findings indicate that performance management and top-down senior management control may unintentionally hinder the possibilities for proceeding with action research projects. The researchers lacked open communication with senior management about the purpose of the project, and the managers who participated in the action learning found it difficult to explain to colleagues and senior management what they learned from the processes. Action research did not fit with the Bank's strategic use of performance management. The project may have increased the stress on the line managers as we identified problems without providing the opportunity to make real changes in their organisation. As a result, we determined that action researchers should be cautious in initiating action research without concrete support, active participation and 'common ground' dialogues with senior management.

Human trafficking is a human rights violation affecting millions worldwide. Victims may go unrecognized during their emergency department (ED) visit, and may lose the opportunity to address their complex needs. Using a published toolkit based on existing guidelines and recommendations from experts, and models from other centers, we describe the implementation of an ED response protocol. In following the recommendations of the toolkit, we began with attempts to fully understand the local human trafficking problem and then networked with those working in anti-trafficking efforts. Collaboration with other specialties is highlighted as a key part of this process. Building upon the knowledge gained from these steps, we were able to develop a concise protocol to guide members of our department in more effectively caring for known or suspected victims of human trafficking. The first section of the protocol addresses ways in which providers can identify at-risk patients through both screening questions and general observations. Interviewing techniques are outlined with an emphasis on patient-centered and trauma-informed care. Additionally, the protocol discusses physician responsibility in documenting encounters and legal reporting, which may vary depending on location. We stress the importance of meeting the needs of the patient while prioritizing the safety of all involved. Additionally, the protocol provides a list of resources for the patient beyond medical care such as emergency housing, legal assistance, and food pantries. The overall purpose of this protocol is to provide coordinated response so that all providers may be consistent in caring for this vulnerable population.

A routine clinical assessment in a 39-year-old male revealed liver function tests at 1.4–2.3 times the normal limit. He was asymptomatic, had no personal/family history of liver disease, and did not drink or use recreational drugs. He was in good physical condition and engaged in regular running and resistance exercise. Negative workup included tests for hepatitis A, B, and C, M-proteins, and antimitochondrial antibodies. Abdominal ultrasound was unremarkable. The patient was referred to a gastroenterologist who ordered repeat liver function tests (LFTs) and a liver biopsy. Before his follow-up assessment the patient abstained from exercise for seven days, after which all LFTs had normalized. The abnormal liver panel was thus likely due to exercise-induced muscle damage and/or changes in hepatocyte membrane permeability. Importantly, the diagnostic pathway did not include any assessment of muscle biomarkers (e.g., creatine kinase) or the patient's exercise training habits. This case highlights a knowledge gap in primary care regarding the possible causes of LFT abnormalities in young adults.

Abstract Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.

Nicholas B Tiller,1 April Kinninger,2 Asghar Abbasi,1 Richard Casaburi,1 Harry B Rossiter,1 Matthew J Budoff,2 Alessandra Adami3 1Institute of Respiratory Medicine and Exercise Physiology, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA; 2Division of Cardiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA; 3Department of Kinesiology, University of Rhode Island, Kingston, RI, USACorrespondence: Harry B Rossiter, Institute of Respiratory Medicine and Exercise Physiology, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, 1124 W. Carson Street, CDCRC Building, Torrance, CA, 90502, USA, Tel +1 310-222-8200, Email hrossiter@lundquist.orgIntroduction: Severe chronic obstructive pulmonary disease (COPD) is partly characterized by diminished skeletal muscle oxidative capacity and concurrent dyslipidemia. It is unknown whether such metabolic derangements increase the risk of cardiovascular disease. This study explored associations among physical activity (PA), muscle oxidative capacity, and coronary artery calcium (CAC) in COPDGene participants.Methods: Data from current and former smokers with COPD (n = 75) and normal spirometry (n = 70) were retrospectively analyzed. Physical activity was measured for seven days using triaxial accelerometry (steps/day and vector magnitude units [VMU]) along with the aggregate of self-reported PA amount and PA difficulty using the PROactive D-PPAC instrument. Muscle oxidative capacity (k) was assessed via near-infrared spectroscopy, and CAC was assessed via chest computerized tomography.Results: Relative to controls, COPD patients exhibited higher CAC (median [IQR], 31 [0– 431] vs 264 [40– 799] HU; p = 0.003), lower k (mean ± SD = 1.66 ± 0.48 vs 1.25 ± 0.37 min− 1; p < 0.001), and lower D-PPAC total score (65.2 ± 9.9 vs 58.8 ± 13.2; p = 0.003). Multivariate analysis—adjusting for age, sex, race, diabetes, disease severity, hyperlipidemia, smoking status, and hypertension—revealed a significant negative association between CAC and D-PPAC total score (β, − 0.05; p = 0.013), driven primarily by D-PPAC difficulty score (β, − 0.03; p = 0.026). A 1 unit increase in D-PPAC total score was associated with a 5% lower CAC (p = 0.013). There was no association between CAC and either k, steps/day, VMU, or D-PPAC amount.Conclusion: Patients with COPD and concomitantly elevated CAC exhibit greater perceptions of difficulty when performing daily activities. This may have implications for exercise adherence and risk of overall physical decline.Keywords: coronary artery calcium, COPD, muscle, oxidative capacity, physical activity, respiratory

Den-Ching A Lee,1,2 Elissa Burton,3,4 Susan Slatyer,5 Alessandro Jacinto,6 Déborah Oliveira,7 Christina Bryant,8 Anjali Khushu,9 Elizabeth Tiller,9 Aislinn Lalor,2,10 Moira Watson,5 Natasha Layton,2 Natasha Brusco,2 Keith D Hill2,11 1School of Primary and Allied Health Care, Faculty of Medicine, Nursing and Health Sciences, Monash University, Frankston, Victoria, 3199, Australia; 2Rehabilitation, Ageing and Independent Living (RAIL) Research Centre, Monash University, Frankston, Victoria, 3199, Australia; 3Curtin School of Allied Health, Faculty of Health Sciences, Curtin University, Bentley, Western Australia, 6102, Australia; 4enAble Institute, Faculty of Health Sciences, Curtin University, Bentley, Western Australia, 6102, Australia; 5Centre for Healthy Ageing, Murdoch University, Murdoch, Western Australia, 6150, Australia; 6Faculty of Geriatric Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil; 7Medical School, Faculty Postgraduate Department of Psychiatry, Federal University of Sao Paulo – UNIFESP, Sao Paulo-SP, Brazil; 8Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Victoria, 3010, Australia; 9Department of Geriatrics (Falls Prevention Service), Peninsula Health, Frankston, Victoria, 3199, Australia; 10Department of Occupational Therapy, Monash University, Melbourne, Victoria, 3199, Australia; 11National Centre for Healthy Ageing, Monash University and Peninsula Health, Frankston, Victoria, 3199, AustraliaCorrespondence: Den-Ching A Lee, School of Primary and Allied Health Care, Faculty of Medicine, Nursing and Health Sciences, Monash University, Moorooduc Highway, Frankston, Victoria, 3199, Australia, Tel +613 9904 4662, Email angel.lee@monash.eduIntroduction: Carers play a critical role in supporting older people with health problems to remain living at home. This study aimed to understand the role and quality of life of older carers of older people and identify strategies used to manage their own health and well-being.Methods: Older carers (aged ≥ 50 years) of older people (aged ≥ 65 years) in Australia participated in a cross-sectional survey focused on carer roles, self-rated health, information and activities used to maintain their carer role and health, barriers to accessing health care, and assessment of quality of life (QoL) using the Dementia Quality of Life Scale for Older Family Carers. Multiple regression analysis examined relationships between variables and the QoL outcome.Results: The survey was completed by 189 older carers (mean age: 68 years; SD = 9.3). Most were female (83.5%), 80.2% providing care daily and 47.8% provided ≥six hours care daily. Almost half (45.1%) self-reported their health as average or below. Despite rating ensuring personal health as very important (mean importance 8/10), only 46.3% reported receiving support from their general practitioner for their carer role. The most common barrier to accessing care for themselves was “not having enough time”. Factors independently associated with poorer carer QoL were living with the care-recipient, caring for someone with depression/anxiety and poor care-recipient health. Factors independently associated with higher carer QoL were placing high importance on personal health, receiving assistance from a specialist clinic as a carer, and older age.Conclusion: Older carers of older people provide high levels of care and experience reduced quality of life. Innovative approaches that provide integrated care and support for older carers to promote their QoL are urgently needed.Keywords: carers, older, health, dementia, quality of life, barriers