GP interest in teaching junior doctors: does practice location, size and infrastructure matter?

BACKGROUND: With the influx of Australian medical graduates into the workforce, new clinical prevocational training rotations within general practice need to be developed. This study describes the relationship between general practitioner teachers' interest in hosting junior doctor rotations, and general practice characteristics including rural location, size and infrastructure. METHOD: All GP teachers of registrars and medical students in the Australian Capital Territory and southeast New South Wales were sent a survey. The features of rural location, size and infrastructure of these teachers' general practices were analysed to determine their influence on teacher interest in hosting junior doctor rotations. RESULTS: Factors such as rural location and infrastructure did not influence willingness to host junior doctors significantly. However, those in medium sized practices were less interested than small or large practices. DISCUSSION: Rural location and teaching room infrastructure of practices need not be determinants in junior doctor teaching practice recruitment, while medium practice size is a significant determinant of lack of teacher interest in hosting junior doctors. This requires further investigation

Group Acupuncture Therapy With Yoga Therapy for Chronic Neck, Low Back, and Osteoarthritis Pain in Safety Net Setting for an Underserved Population: Design and Rationale for a Feasibility Pilot

Chronic pain is prevalent in the United States, with impact on physical and psychological functioning as well as lost work productivity. Minority and lower socioeconomic populations have increased prevalence of chronic pain with less access to pain care, poorer outcomes, and higher risk of fatal opioid overdose. Acupuncture therapy is effective in treating chronic pain conditions including chronic low back pain, neck pain, shoulder pain, and knee pain from osteoarthritis. Acupuncture therapy, including group acupuncture, is feasible and effective, and specifically so for underserved and diverse populations at risk for health outcome disparities. Acupuncture therapy also encourages patient engagement and activation. As chronic pain improves, there is a natural progression to want and need to increase activity and movement recovery. Diverse movement approaches are important for improving range of motion, maintaining gains, strengthening, and promoting patient engagement and activation. Yoga therapy is an active therapy with proven benefit in musculoskeletal pain disorders and pain associated disability. The aim of this quasi-experimental pilot feasibility trial is to test the bundling of these 2 effective care options for chronic pain, to inform both the design for a larger randomized pragmatic effectiveness trial as well as implementation strategies across underserved settings

Barriers and Facilitators to Implementing Bundled Acupuncture and Yoga Therapy to Treat Chronic Pain in Community Healthcare Settings: A Feasibility Pilot

Objective: To identify factors associated with implementing bundled group acupuncture and yoga therapy (YT) to treat underserved patients with chronic pain in community health center (CHC) settings. This is not an implementation science study, but rather an organized approach for identification of barriers and facilitators to implementing these therapies as a precursor to a future implementation science study. Design: This study was part of a single-arm feasibility trial, which aimed to test the feasibility of bundling GA and YT for chronic pain in CHCs. Treatment outcomes were measured before and after the 10-week intervention period. Implementation feasibility was assessed through weekly research team meetings, weekly yoga provider meetings, monthly acupuncture provider meetings, and weekly provider surveys. Settings: The study was conducted in New York City at two Montefiore Medical Group (MMG) sites in the Bronx, and one Institute for Family Health (IFH) site in Harlem. Subjects: Participants in the feasibility trial were recruited from IFH and MMG sites, and needed to have had lower back, neck, or osteoarthritis pain for \u3e 3 months. Implementation stakeholders included the research team, providers of acupuncture and YT, referring providers, and CHC staff. Results: Implementation of these therapies was assessed using the Consolidated Framework for Implementation Research. We identified issues associated with scheduling, treatment fidelity, communication, the three-way disciplinary interaction of acupuncture, yoga, and biomedicine, space adaptation, site-specific logistical and operational requirements, and patient-provider language barriers. Issues varied as to their frequency and resolution difficulty. Conclusions: This feasibility trial identified implementation issues and resolution strategies that could be further explored in future implementation studies. Clinical Trial Registration No.: NCT04296344

Individual vs. Group Delivery of Acupuncture Therapy for Chronic Musculoskeletal Pain in Urban Primary Care-a Randomized Trial

BACKGROUND: Acupuncture has been shown to be effective for the treatment of chronic musculoskeletal back, neck, and osteoarthritis pain. However, access to acupuncture treatment has been limited in medically underserved and low-income populations. OBJECTIVE: Acupuncture therapy delivered in groups could reduce cost and expand access. We compared the effectiveness of group versus individual acupuncture for pain and function among ethnically diverse, low-income primary care patients with chronic musculoskeletal pain. DESIGN: This was a randomized comparative effectiveness non-inferiority trial in 6 Bronx primary care community health centers. Participants with chronic ( \u3e 3 months) back, neck, or osteoarthritis pain were randomly assigned to individual or group acupuncture therapy for 12 weeks. PARTICIPANTS: Seven hundred seventy-nine participants were randomized. Mean age was 54.8 years. 35.3% of participants identified as black and 56.9% identified as Latino. Seventy-six percent were Medicaid insured, 60% reported poor/fair health, and 37% were unable to work due to disability. INTERVENTIONS: Participants received weekly acupuncture treatment in either group or individual setting for 12 weeks. MAIN MEASURES: Primary outcome was pain interference on the Brief Pain Inventory at 12 weeks; secondary outcomes were pain severity (BPI), physical and mental well-being (PROMIS-10), and opiate use. Outcome measures were collected at baseline, 12 and 24 weeks. KEY RESULTS: 37.5% of individual arm and 30.3% in group had \u3e 30% improvement in pain interference (d = 7.2%, 95% CI - 0.6%, 15.1%). Non-inferiority of group acupuncture was not demonstrated for the primary outcome assuming a margin of 10%. In the responder analysis of physical well-being, 63.1% of individual participants and 59.5% of group had clinically important improvement at 12 weeks (d = 3.6%, 95% CI - 4.2%, 11.4%). CONCLUSIONS: Both individual and group acupuncture therapy delivered in primary care settings reduced chronic pain and improved physical function at 12 weeks; non-inferiority of group was not shown. TRIAL REGISTRATION: Clinicaltrials.gov # NCT02456727

Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin\u27s I-band: the cardiomyopathy-linked mutation T2580I

Missense single-nucleotide polymorphisms (mSNPs) in titin are emerging as a main causative factor of heart failure. However, distinguishing between benign and disease-causing mSNPs is a substantial challenge. Here, we research the question of whether a single mSNP in a generic domain of titin can affect heart function as a whole and, if so, how. For this, we studied the mSNP T2850I, seemingly linked to arrhythmogenic right ventricular cardiomyopathy (ARVC). We used structural biology, computational simulations and transgenic muscle in vivo methods to track the effect of the mutation from the molecular to the organismal level. The data show that the T2850I exchange is compatible with the domain three-dimensional fold, but that it strongly destabilizes it. Further, it induces a change in the conformational dynamics of the titin chain that alters its reactivity, causing the formation of aberrant interactions in the sarcomere. Echocardiography of knock-in mice indicated a mild diastolic dysfunction arising from increased myocardial stiffness. In conclusion, our data provide evidence that single mSNPs in titin\u27s I-band can alter overall muscle behaviour. Our suggested mechanisms of disease are the development of non-native sarcomeric interactions and titin instability leading to a reduced I-band compliance. However, understanding the T2850I-induced ARVC pathology mechanistically remains a complex problem and will require a deeper understanding of the sarcomeric context of the titin region affected

Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F

The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplas mic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a molecular tool and a therapeutic lead is hampered by its limited production scale, largely caused by intramolecular assembly of the macrocyclic ring. Here, using in vitro and/or in cellula biological assays to explore the first series of ring-opened analogues for the ipomoeassins, and indeed all resin glycosides, we provide clear evidence that macrocyclic integrity is not required for the cytotoxic inhibition of Sec61-dependent protein translocation by Ipom-F. Furthermore, our modeling suggests that open-chain analogues of Ipom-F can interact with multiple sites on the Sec61α subunit, most likely located at a previously identified binding site for mycolactone and/or the so-called lateral gate. Subsequent in silico-aided design led to the discovery of the stereochemically simplified analogue 3 as a potent, alternative lead compound that could be synthesized much more efficiently than Ipom-F and will accelerate future ipomoeassin research in chemical biology and drug discovery. Our work may also inspire further exploration of ring-opened analogues of other resin glycosides

Synthesis, Biological Evaluation and Docking Studies of Ring-Opened Analogues of Ipomoeassin F

The plant-derived macrocyclic resin glycoside ipomoeassin F (Ipom-F) binds to Sec61α and significantly disrupts multiple aspects of Sec61-mediated protein biogenesis at the endoplasmic reticulum, ultimately leading to cell death. However, extensive assessment of Ipom-F as a molecular tool and a therapeutic lead is hampered by its limited production scale, largely caused by intramolecular assembly of the macrocyclic ring. Here, using in vitro and/or in cellula biological assays to explore the first series of ring-opened analogues for the ipomoeassins, and indeed all resin glycosides, we provide clear evidence that macrocyclic integrity is not required for the cytotoxic inhibition of Sec61-dependent protein translocation by Ipom-F. Furthermore, our modeling suggests that open-chain analogues of Ipom-F can interact with multiple sites on the Sec61α subunit, most likely located at a previously identified binding site for mycolactone and/or the so-called lateral gate. Subsequent in silico-aided design led to the discovery of the stereochemically simplified analogue 3 as a potent, alternative lead compound that could be synthesized much more efficiently than Ipom-F and will accelerate future ipomoeassin research in chemical biology and drug discovery. Our work may also inspire further exploration of ring-opened analogues of other resin glycosides

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Delineating the autistic phenotype in children with neurofibromatosis type 1

Background Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. Methods Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. Results The study cohort comprised 68 children (3–15 years). Sixty-three per cent met the ADOS-2 ‘autism spectrum’ cut-off, and 34% exceeded the more stringent threshold for ‘autistic disorder’ on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by ‘insistence on sameness’ (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. Limitations Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. Conclusions Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management