An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Head Position in Stroke Trial (HeadPoST)- sitting-up vs lying-flat positioning of patients with acute stroke: study protocol for a cluster randomised controlled trial

Background Positioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0°) compared with sitting-up (≥30°) head positioning in the first 24 hours of hospital admission for patients with acute stroke. Methods/Design We plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0°) or sitting-up (≥30°) head position as a ‘business as usual’ stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (α 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period. Discussion HeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke. Trial registration ClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014

Best Practices for Virtual Care: A Consensus Statement From the Canadian Rheumatology Association

Objective. To develop best practice statements for the provision of virtual care in adult and pediatric rheumatology for the Canadian Rheumatology Association\u27s (CRA) Telehealth Working Group (TWG). Methods. Four members of the TWG representing adult, pediatric, university-based, and community rheumatology practices defined the scope of the project. A rapid literature review of existing systematic reviews, policy documents, and published literature and abstracts on the topic was conducted between April and May 2021. The review informed a candidate set of 7 statements and a supporting document. The statements were submitted to a 3-round (R) modified Delphi process with 22 panelists recruited through the CRA and patient advocacy organizations. Panelists rated the importance and feasibility of the statements on a Likert scale of 1-9. Statements with final median ratings between 7-9 with no disagreement were retained in the final set. Results. Twenty-one (95%) panelists participated in R1, 15 (71%) in R2, and 18 (82%) in R3. All but 1 statement met inclusion criteria during R1. Revisions were made to 5/7 statements following R2 and an additional statement was added. All statements met inclusion criteria following R3. The statements addressed the following themes in the provision of virtual care: adherence to existing standards and regulations, appropriateness, consent, physical examination, patient-reported outcomes, use in addition to in-person visits, and complex comanagement of disease. Conclusion. The best practice statements represent a starting point for advancing virtual care in rheumatology. Future educational efforts to help implement these best practices and research to address identified knowledge gaps are planned

Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing

$\textbf{Objective}$ Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture. $\textbf{Methods}$ Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons. $\textbf{Results}$ Of 163 neurons, 118 expressed high levels of $\textit{Pomc}$ with little/no Agrp expression and were considered “canonical” POMC neurons (P$^{+}$). The other 45/163 expressed low levels of $\textit{Pomc}$ and high levels of $\textit{Agrp}$ (A$^{+}$P$_{+}$). Unbiased clustering analysis of P$^{+}$ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P$^{+}$ neurons expressed the leptin receptor ($\textit{Lepr}$) compared with 58% (26/45) of A$^{+}$P$_{+}$ neurons. In contrast, the insulin receptor ($\textit{Insr}$) was expressed at similar frequency on P$^{+}$ and A$^{+}$P$_{+}$ neurons (64% and 55%, respectively). $\textbf{Conclusion}$ These data reveal arcuate POMC neurons to be a highly heterogeneous population. Accession Numbers: GSE92707.This work was supported by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1 & MRC_MC_UU_12012/5), a Wellcome Trust Strategic Award (100574/Z/12/Z), and the Helmholtz Alliance ICEMED

Estimated GFR and the Effect of Intensive Blood Pressure Lowering after Acute Intracerebral Hemorrhage

Background: The kidney-brain interaction has been a topic of growing interest. Past studies of the effect of kidney function on intracerebral hemorrhage (ICH) outcomes have yielded inconsistent findings. Although the second, main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) suggests the effectiveness of early intensive blood pressure (BP) lowering in improving functional recovery after ICH, the balance of potential benefits and harms of this treatment in those with decreased kidney function remains uncertain. Study Design: Secondary analysis of INTERACT2, which randomly assigned patients with ICH with elevated systolic BP (SBP) to intensive (target SBP 90, 60-90, and <60 mL/min/1.73 m2, respectively). Outcomes: The effect of admission eGFR on the primary outcome of death or major disability at 90 days (defined as modified Rankin Scale scores of 3-6) was analyzed using a multivariable logistic regression model. Potential effect modification of intensive BP lowering treatment by admission eGFR was assessed by interaction terms. Results: Of 2,623 included participants, 912 (35%) and 280 (11%) had mildly and moderately/severely decreased eGFRs, respectively. Patients with moderately/severely decreased eGFRs had the greatest risk for death or major disability at 90 days (adjusted OR, 1.82; 95% CI, 1.28-2.61). Effects of early intensive BP lowering were consistent across different eGFRs (P = 0.5 for homogeneity). Limitations: Generalizability issues arising from a clinical trial population. Conclusions: Decreased eGFR predicts poor outcome in acute ICH. Early intensive BP lowering provides similar treatment effects in patients with ICH with decreased eGFRs

Integration across time determines path deviation discrimination for moving objects.

YesBackground: Human vision is vital in determining our interaction with the outside world. In this study we characterize our ability to judge changes in the direction of motion of objects-a common task which can allow us either to intercept moving objects, or else avoid them if they pose a threat. Methodology/Principal Findings: Observers were presented with objects which moved across a computer monitor on a linear path until the midline, at which point they changed their direction of motion, and observers were required to judge the direction of change. In keeping with the variety of objects we encounter in the real world, we varied characteristics of the moving stimuli such as velocity, extent of motion path and the object size. Furthermore, we compared performance for moving objects with the ability of observers to detect a deviation in a line which formed the static trace of the motion path, since it has been suggested that a form of static memory trace may form the basis for these types of judgment. The static line judgments were well described by a 'scale invariant' model in which any two stimuli which possess the same two-dimensional geometry (length/width) result in the same level of performance. Performance for the moving objects was entirely different. Irrespective of the path length, object size or velocity of motion, path deviation thresholds depended simply upon the duration of the motion path in seconds. Conclusions/Significance: Human vision has long been known to integrate information across space in order to solve spatial tasks such as judgment of orientation or position. Here we demonstrate an intriguing mechanism which integrates direction information across time in order to optimize the judgment of path deviation for moving objects.Wellcome Trust, Leverhulme Trust, NI

Patient-reported GP health assessments rather than individual cardiovascular risk burden are associated with the engagement in lifestyle changes: Population-based survey in South Australia

© 2019 The Author(s). Background: Little is known about whether a more comprehensive health assessment, performed by a general practitioner (GP) during a clinical encounter, could influence patients' lifestyle. We aimed to investigate whether health assessments, performed by GPs, are more important than the presence of cardiovascular disease (CVD) or cardiometabolic risk factors (obesity, diabetes, hypertension, dyslipidaemia) for engagement in lifestyle change. Methods: Cross-sectional, population-based survey conducted in South Australia (September-December 2017) using face-To-face interviews and self-reported data of 2977 individuals aged 15+ years. The main outcome was engagement in four lifestyle changes: 1) increasing fruit/vegetable intake, 2) increasing physical activity level, 3) reducing alcohol consumption, and 4) attempts to stop smoking. Health assessments performed by a GP in the last 12 months included clinical/laboratory investigations (weight/waist circumference, blood pressure, glucose levels, lipid levels) and questions about lifestyle/wellbeing (current diet, physical activity, smoking status, alcohol intake, mental health, sleeping problems). Results were restricted to individuals aged 35+ years because of the low prevalence of CVD or their risk factors among younger participants. Logistic regression was used in all associations, adjusted for sociodemographic, lifestyle, mental health, and clinical variables. Results: Of the 2384 investigated adults (mean age 57.3 ± 13.9 years; 51.9% females), 10.2% had CVD and 49.1% at least one cardiometabolic risk factor. Clinical/laboratory assessments performed by the GP were 2-3 times more frequent than assessments of lifestyle, mental health status, or sleeping problems, especially among those with CVD. Individuals with CVD or a cardiometabolic risk factor were no more likely to be increasing their fruit/vegetable consumption (33.6%), physical activity level (40.9%), reducing alcohol consumption (31.1%), or trying to quit smoking (34.0%) than 'healthy' participants. However, lifestyle changes were between 30 and 100% more likely when GPs performed three or more health assessments (either clinical/laboratory or questions about lifestyle/wellbeing) than when individuals did not visit the GP or when GPs performed no any assessment during these clinical encounters (p < 0.05 in all cases). Conclusion: More frequent and comprehensive CVD-related assessments by GPs were more important in promoting a healthier lifestyle than the presence of CVD or cardiometabolic risk factors by themselves

Mechanical and kinetic effects of shortened tropomyosin reconstituted into myofibrils

The effects of tropomyosin on muscle mechanics and kinetics were examined in skeletal myofibrils using a novel method to remove tropomyosin (Tm) and troponin (Tn) and then replace these proteins with altered versions. Extraction employed a low ionic strength rigor solution, followed by sequential reconstitution at physiological ionic strength with Tm then Tn. SDS-PAGE analysis was consistent with full reconstitution, and fluorescence imaging after reconstitution using Oregon-green-labeled Tm indicated the expected localization. Myofibrils remained mechanically viable: maximum isometric forces of myofibrils after sTm/sTn reconstitution (control) were comparable (~84%) to the forces generated by non-reconstituted preparations, and the reconstitution minimally affected the rate of isometric activation (kact), calcium sensitivity (pCa50), and cooperativity (nH). Reconstitutions using various combinations of cardiac and skeletal Tm and Tn indicated that isoforms of both Tm and Tn influence calcium sensitivity of force development in opposite directions, but the isoforms do not otherwise alter cross-bridge kinetics. Myofibrils reconstituted with Δ23Tm, a deletion mutant lacking the second and third of Tm’s seven quasi-repeats, exhibited greatly depressed maximal force, moderately slower kact rates and reduced nH. Δ23Tm similarly decreased the cooperativity of calcium binding to the troponin regulatory sites of isolated thin filaments in solution. The mechanisms behind these effects of Δ23Tm also were investigated using Pi and ADP jumps. Pi and ADP kinetics were indistinguishable in Δ23Tm myofibrils compared to controls. The results suggest that the deleted region of tropomyosin is important for cooperative thin filament activation by calcium

Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing

$\textbf{Objective}$ Arcuate proopiomelanocortin (POMC) neurons are critical nodes in the control of body weight. Often characterized simply as direct targets for leptin, recent data suggest a more complex architecture. $\textbf{Methods}$ Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC neurons. $\textbf{Results}$ Of 163 neurons, 118 expressed high levels of $\textit{Pomc}$ with little/no Agrp expression and were considered “canonical” POMC neurons (P$^{+}$). The other 45/163 expressed low levels of $\textit{Pomc}$ and high levels of $\textit{Agrp}$ (A$^{+}$P$_{+}$). Unbiased clustering analysis of P$^{+}$ neurons revealed four different classes, each with distinct cell surface receptor gene expression profiles. Further, only 12% (14/118) of P$^{+}$ neurons expressed the leptin receptor ($\textit{Lepr}$) compared with 58% (26/45) of A$^{+}$P$_{+}$ neurons. In contrast, the insulin receptor ($\textit{Insr}$) was expressed at similar frequency on P$^{+}$ and A$^{+}$P$_{+}$ neurons (64% and 55%, respectively). $\textbf{Conclusion}$ These data reveal arcuate POMC neurons to be a highly heterogeneous population. Accession Numbers: GSE92707.This work was supported by the UK Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1 & MRC_MC_UU_12012/5), a Wellcome Trust Strategic Award (100574/Z/12/Z), and the Helmholtz Alliance ICEMED