Genetic diversity and candidate genes for transient waterlogging tolerance in mungbean at the germination and seedling stages.

Mungbean [Vigna radiata var. radiata (L.) Wilczek] production in Asia is detrimentally affected by transient soil waterlogging caused by unseasonal and increasingly frequent extreme precipitation events. While mungbean exhibits sensitivity to waterlogging, there has been insufficient exploration of germplasm for waterlogging tolerance, as well as limited investigation into the genetic basis for tolerance to identify valuable loci. This research investigated the diversity of transient waterlogging tolerance in a mini-core germplasm collection of mungbean and identified candidate genes for adaptive traits of interest using genome-wide association studies (GWAS) at two critical stages of growth: germination and seedling stage (i.e., once the first trifoliate leaf had fully-expanded). In a temperature-controlled glasshouse, 292 genotypes were screened for tolerance after (i) 4 days of waterlogging followed by 7 days of recovery at the germination stage and (ii) 8 days of waterlogging followed by 7 days of recovery at the seedling stage. Tolerance was measured against drained controls. GWAS was conducted using 3,522 high-quality DArTseq-derived SNPs, revealing five significant associations with five phenotypic traits indicating improved tolerance. Waterlogging tolerance was positively correlated with the formation of adventitious roots and higher dry masses. FGGY carbohydrate kinase domain-containing protein was identified as a candidate gene for adventitious rooting and mRNA-uncharacterized LOC111241851, Caffeoyl-CoA O-methyltransferase At4g26220 and MORC family CW-type zinc finger protein 3 and zinc finger protein 2B genes for shoot, root, and total dry matter production. Moderate to high broad-sense heritability was exhibited for all phenotypic traits, including seed emergence (81%), adventitious rooting (56%), shoot dry mass (81%), root dry mass (79%) and SPAD chlorophyll content (70%). The heritability estimates, marker-trait associations, and identification of sources of waterlogging tolerant germplasm from this study demonstrate high potential for marker-assisted selection of tolerance traits to accelerate breeding of climate-resilient mungbean varieties.

Expansion of the immature B lymphocyte compartment in Graves' disease.

OBJECTIVE: The specific mechanisms driving autoimmunity in Graves' disease (GD) remain largely unknown. Kappa-deleting recombination excision circles (KRECs) are circular DNA molecules generated during B cell maturation in the bone marrow which provide a measure of B cell production and proliferation. We aimed to investigate the association between KRECs and B cell subpopulations, with thyroid status and clinical outcome in GD patients. METHODS: Kappa-deleting recombination excision circles were measured by quantitative real-time PCR using a triple-insert plasmid control in 132 GD patients and 140 healthy controls. In addition, KRECs in GD patients on withdrawal of antithyroid drug (ATD) and 6-10 weeks later were analysed according to a clinical outcome at 1 year. Flow cytometry was performed on isolated CD19+ B cells to quantitate 7 B lymphocyte subpopulations in 65 GD patients. RESULTS: Circulating KRECs were higher in GD vs. controls (P = 1.5 × 10-9) and demonstrated a positive correlation to thyroid hormones and autoantibodies (free thyroxine: P = 2.14 × 10-5, rho = .30; free triiodothyronine: P = 1.99 × 10-7, rho = .37; thyroid stimulating hormone receptor autoantibodies: P = 1.36 × 10-5, rho = .23). Higher KRECs in GD patients 6-10 weeks after ATD withdrawal were associated with relapse of hyperthyroidism at 1 year (P = .04). The KRECs were positively correlated to the total CD19+ B cell count (P = 3.2 × 10-7). CONCLUSIONS: This study reports a robust association between KRECs and GD, highlighting the importance of B cells in the pathogenesis of GD and the influence of thyroid status on B cell activity. The findings indicate a potential role for KRECs as a marker of disease activity and outcome in GD.

Comparative transcriptome analysis reveals molecular regulation of salt tolerance in two contrasting chickpea genotypes.

Salinity is a major abiotic stress that causes substantial agricultural losses worldwide. Chickpea (Cicer arietinum L.) is an important legume crop but is salt-sensitive. Previous physiological and genetic studies revealed the contrasting response of two desi chickpea varieties, salt-sensitive Rupali and salt-tolerant Genesis836, to salt stress. To understand the complex molecular regulation of salt tolerance mechanisms in these two chickpea genotypes, we examined the leaf transcriptome repertoire of Rupali and Genesis836 in control and salt-stressed conditions. Using linear models, we identified categories of differentially expressed genes (DEGs) describing the genotypic differences: salt-responsive DEGs in Rupali (1,604) and Genesis836 (1,751) with 907 and 1,054 DEGs unique to Rupali and Genesis836, respectively, salt responsive DEGs (3,376), genotype-dependent DEGs (4,170), and genotype-dependent salt-responsive DEGs (122). Functional DEG annotation revealed that the salt treatment affected genes involved in ion transport, osmotic adjustment, photosynthesis, energy generation, stress and hormone signalling, and regulatory pathways. Our results showed that while Genesis836 and Rupali have similar primary salt response mechanisms (common salt-responsive DEGs), their contrasting salt response is attributed to the differential expression of genes primarily involved in ion transport and photosynthesis. Interestingly, variant calling between the two genotypes identified SNPs/InDels in 768 Genesis836 and 701 Rupali salt-responsive DEGs with 1,741 variants identified in Genesis836 and 1,449 variants identified in Rupali. In addition, the presence of premature stop codons was detected in 35 genes in Rupali. This study provides valuable insights into the molecular regulation underpinning the physiological basis of salt tolerance in two chickpea genotypes and offers potential candidate genes for the improvement of salt tolerance in chickpeas.

Estimation of cardiac QTc intervals in people prescribed antipsychotics: a comparison of correction factors.

Background: A prolonged electrocardiogram (ECG) QT interval is associated with cardiac events and increased mortality. Antipsychotics can prolong the QT interval. The QT interval requires correction (QTc) for heart rate using a formula or QT-nomogram. The QT and QTc can be calculated automatically by the ECG machine or manually; however, machine-measured QT(c) intervals may be inaccurate. Objective: We aimed to investigate the mean QTc and proportion of prolonged QTc intervals in people taking antipsychotic medicines. Methods: We conducted an observational retrospective chart review and data analysis of all consecutive patients taking antipsychotics, with an ECG record, admitted to the psychiatric unit of a large tertiary hospital in Brisbane, Australia, between 1 January 2017 and 30 January 2019. We investigated the mean QTc of people taking antipsychotics to determine differences using (a) machine versus manual QT interval measurement and (b) QTc correction formulae (Bazett, Fridericia, Framingham, Hodges and Rautaharju) and the QT-nomogram. We also determined the number of people with a prolonged QTc using different methods and compared rates of prolonged QTc with antipsychotic monotherapy and polypharmacy. Results: Of 920 included people, the mean (±SD) machine-measured, Bazett-corrected QT interval (recorded from the ECG) was 435 ms (±27), significantly longer (p < 0.001) than the mean manually measured corrected QT intervals with Fridericia 394 ms (±24), Framingham 395 ms (±22), Hodges 398 ms (±22) and Rautaharju 400 ms (±24) formulae. There were significantly more people with a prolonged QTc using machine-measured QT and the Bazett formula (12.0%, 110/920) when compared with manually measured QT and the Fridericia formula (2.2%, 20/920) or QT-nomogram (0.7%, 6/920). Rates of QTc prolongation did not differ between people taking antipsychotic polypharmacy compared with monotherapy. Conclusion: Machine-measured QTc using the Bazett formula overestimates the QTc interval length and number of people with a prolonged QTc, compared with other formulae and the QT-nomogram. We recommend manually measuring the QT and correcting with the Fridericia formula or QT-nomogram prior to modifying antipsychotic therapies.

Treatment strategies for clozapine-induced hypotension: a systematic review.

Background: Clozapine is the most effective medication for treatment-refractory schizophrenia but is associated with significant adverse drug effects, including hypotension and dizziness, which have a negative impact on quality of life and treatment compliance. Available evidence for the management of clozapine-induced hypotension is scant. Objectives: Due to limited guidance on the safety and efficacy of pharmacological treatments for clozapine-induced hypotension, we set out to systematically review and assess the evidence for the management of clozapine-induced hypotension and provide guidance to clinicians, patients, and carers. Design: We undertook a systematic review of the safety and efficacy of interventions for clozapine-induced hypotension given the limited available evidence. Data Sources and Methods: PubMed, Embase, PsycINFO, CINAHL, and the Cochrane trial Registry were searched from inception to November 2021 for literature on the treatment strategies for clozapine-induced hypotension and dizziness using a PROSPERO pre-registered search strategy. For orthostatic hypotension, we developed a management framework to assist in the choice of intervention. Results: We identified nine case studies and four case series describing interventions in 15 patients. Hypotension interventions included temporary clozapine dose reduction, non-pharmacological treatments, and pharmacological treatments. Midodrine, fludrocortisone, moclobemide and Bovril® combination, and etilefrine were associated with improvement in symptoms or reduction in orthostatic hypotension. Angiotensin II, arginine vasopressin, and noradrenaline successfully restored and maintained mean arterial pressure in critical care situations. A paradoxical reaction of severe hypotension was reported with adrenaline use. Conclusion: Orthostatic hypotension is a common side effect during clozapine titration. Following an assessment of the titration schedule, salt and fluid intake, and review of hypertensive and nonselective α1-adrenergic agents, first-line treatment should be a temporary reduction in clozapine dose or non-pharmacological interventions. If orthostatic hypotension persists, fludrocortisone should be trialled with monitoring of potassium levels and sodium and fluid intake. Midodrine may be considered second-line or where fludrocortisone is contraindicated or poorly tolerated. For patients on clozapine with hypotension in critical care settings, the use of adrenaline to maintain mean arterial pressure should be avoided. Registration: PROSPERO (Registration No. CRD42020191530).

What Is the Evidence That Dietary Macronutrient Composition Influences Exercise Performance? A Narrative Review.

The introduction of the needle muscle biopsy technique in the 1960s allowed muscle tissue to be sampled from exercising humans for the first time. The finding that muscle glycogen content reached low levels at exhaustion suggested that the metabolic cause of fatigue during prolonged exercise had been discovered. A special pre-exercise diet that maximized pre-exercise muscle glycogen storage also increased time to fatigue during prolonged exercise. The logical conclusion was that the athlete's pre-exercise muscle glycogen content is the single most important acutely modifiable determinant of endurance capacity. Muscle biochemists proposed that skeletal muscle has an obligatory dependence on high rates of muscle glycogen/carbohydrate oxidation, especially during high intensity or prolonged exercise. Without this obligatory carbohydrate oxidation from muscle glycogen, optimum muscle metabolism cannot be sustained; fatigue develops and exercise performance is impaired. As plausible as this explanation may appear, it has never been proven. Here, I propose an alternate explanation. All the original studies overlooked one crucial finding, specifically that not only were muscle glycogen concentrations low at exhaustion in all trials, but hypoglycemia was also always present. Here, I provide the historical and modern evidence showing that the blood glucose concentration-reflecting the liver glycogen rather than the muscle glycogen content-is the homeostatically-regulated (protected) variable that drives the metabolic response to prolonged exercise. If this is so, nutritional interventions that enhance exercise performance, especially during prolonged exercise, will be those that assist the body in its efforts to maintain the blood glucose concentration within the normal range.

Serotonin-Affecting Antidepressant Use in Relation to Platelet Reactivity.

Depression is an independent risk factor of cardiovascular disease morbidity. Serotonin is a key neurotransmitter in depressive pathology, contained within platelets, and is a weak activator of platelets. Our study assessed the link between platelet reactivity traits, depression, and antidepressant (AD) use in a large population sample. Our study was conducted in the Framingham Heart Study (n = 3,140), and AD use (n = 563) and aspirin use (n = 681) were noted. Depression was measured using the Center for Epidemiological Studies-Depression (CES-D) survey. Platelet reactivity traits were measured across multiple agonists using five distinct assays. We utilized a linear mixed effects model to test associations between platelet traits and depression, adjusting for age, sex, aspirin use, and AD use. Similarly, we analyzed trait associations with any AD use, serotonin-affecting ADs, and norepinephrine-affecting ADs, respectively. There were strong associations with reduced platelet function and AD use, particularly with serotonin-affecting medications. This included lower Optimul epinephrine maximal aggregation (P = 4.87E-13), higher U46619 half maximal effective concentration (P = 9.09E-11), lower light transmission aggregometry (LTA) adenosine diphosphate (ADP) final aggregation (P = 1.03E-05), and higher LTA ADP disaggregation (P = 2.28E-05). We found similar associations with serotonin-affecting ADs in an aspirin-taking subset of our sample. There were no significant associations between platelet traits and depression. In the largest study yet of AD use and platelet function we show that antidepressants, particularly serotonin-affecting ADs, inhibit platelets. We did not find evidence that depressive symptomatology in the absence of medication is associated with altered platelet function. Our results are consistent with AD use leading to platelet serotonin depletions, decreased stability of platelet aggregates, and overall decreased aggregation to multiple agonists, which may be a mechanism by which ADs increase risk of bleeding and decrease risk of thrombosis.

Tolerance of four grain legume species to waterlogging, hypoxia and anoxia at germination and recovery.

Legume seeds, when relay sown following rice, may suffer from soil waterlogging and the associated hypoxia or even anoxia. This study evaluated the tolerance of grain legume species, grass pea (three genotypes), lentil (two genotypes), faba bean (two genotypes) and field pea (one genotype), to soil waterlogging in a glasshouse, to anoxia and hypoxia in temperature-controlled room at germination and seedling stages. Changes in oxygen in the surface layers of soil, with time after waterlogging, were measured by microelectrode profiling. The soil profiling showed that soil oxygen declined and then stabilized by the fourth day after waterlogging and oxygen was not detected at 8 mm below the soil surface. Germination of seeds under waterlogging for up to 12 days and seedling survival after the soil was drained for up to 36 days were measured in pot experiments. Seed germination and/or survival in anoxia (N2-flushed solutions) and hypoxia (1.0 and 2.5 kPa oxygen) were evaluated, and so were post-anoxia or post-hypoxia recoveries, all in comparison with aerated controls. Lentil had higher seedling emergence (55 %) than the other species during soil waterlogging. However, lentil had lower seedling survival (9 %) than grass pea (28 %) during recovery following soil drainage. Grass pea seeds were more tolerant of anoxia and of hypoxia than the seeds of the three other species. In conclusion, grass pea, with higher percent germination and seedling survival during recovery, is more tolerant to waterlogging and subsequent soil drainage than the three other grain legume species. Grass pea was also more tolerant of hypoxia and of anoxia at the seed germination stage. These findings demonstrate the superior waterlogging tolerance of grass pea in relay sowing, as compared with the other grain legumes.

Response of Mungbean (cvs. Celera II-AU and Jade-AU) and Blackgram (cv. Onyx-AU) to Transient Waterlogging.

Mungbean [Vigna radiata (L.) Wilczek] and blackgram [Vigna mungo (L.) Hepper] are important crops for smallholder farmers in tropical and subtropical regions. Production of both crops is affected by unexpected and increasingly frequent extreme precipitation events, which result in transient soil waterlogging. This study aimed to compare the waterlogging tolerance of mungbean and blackgram genotypes under the varying duration of waterlogging stress at germination and seedling stages. We evaluated the responses to different durations of transient waterlogging in a sandy clay loam under temperature-controlled glasshouse conditions. Waterlogging durations were 0, 1, 2, 3, 4, 5, 6, 7, and 8 days during germination and 0, 2, 4, 8, and 16 days during the seedling stage. We used two mungbean genotypes (green testa), Celera II-AU (small-seeded), and Jade-AU (large-seeded), contrasting in seed size and hypocotyl pigmentation, and a blackgram genotype (black testa), Onyx-AU. Waterlogging reduced soil redox potential, delayed or even prevented germination, decreased seedling establishment, and affected shoot and root development. In the seedlings waterlogged (WL) at 15 days after sowing (DAS), adventitious root formation and crown nodulation varied between the genotypes, and 16 days of waterlogging substantially reduced growth but did not result in plant death. Plants in soil with waterlogging for 8-16 days followed by drainage and sampling at 39 DAS had reduced shoot and root dry mass by 60-65% in mungbean and 40% in blackgram compared with continuously drained controls, due at least in part to fewer lateral roots. Soil plant analysis development (SPAD) chlorophyll content was also reduced. Onyx-AU, a blackgram genotype, was more tolerant to transient waterlogging than Jade-AU and Celera II-AU in both growth stages. Of the two mungbean genotypes, Celera II-AU had a greater seedling establishment than Jade-AU post waterlogging imposed at sowing. In contrast, Jade-AU had more plant biomass and greater recovery growth than Celera II-AU after waterlogging and recovery during the seedling stage. Both species were delayed in emergence in response to the shorter periods of transient waterlogging at germination, and with the longer waterlogging germination and emergence failed, whereas at the seedling stage both showed adaptation by the formation of adventitious roots.

Prolonged tedizolid use in cutaneous non-tuberculous mycobacterial infection.

Cutaneous non-tuberculous mycobacterial (NTM) infections are an emerging infectious disease and require a protracted course of combination antibiotics. Antimicrobial choice is limited by resistance and toxicity. Tedizolid is a new oxazolidinone antibiotic with in vitro activity against some NTM, but its use in the management of extrapulmonary NTM has not been described. We report on the utility of prolonged tedizolid use (8 months), after linezolid intolerance, in combination therapy in a case of difficult Mycobacterium chelonae cutaneous infection. Although tedizolid contributed to clinical remission, it may have also contributed to a multifocal peripheral neuropathy. Its efficacy may also have been limited by continued immunosuppression, with evidence to suggest disease relapse or treatment failure after completion of combination therapy. Tedizolid can be considered, with caution, in combination therapy for difficult cases of cutaneous NTM infection.

Hiding unhealthy heart outcomes in a low-fat diet trial: the Women's Health Initiative Randomized Controlled Dietary Modification Trial finds that postmenopausal women with established coronary heart disease were at increased risk of an adverse outcome if they consumed a low-fat 'heart-healthy' diet.

The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.

Regulation of root adaptive anatomical and morphological traits during low soil oxygen.

Flooding causes oxygen deprivation in soils. Plants adapt to low soil oxygen availability by changes in root morphology, anatomy, and architecture to maintain root system functioning. Essential traits include aerenchyma formation, a barrier to radial oxygen loss, and outgrowth of adventitious roots into the soil or the floodwater. We highlight recent findings of mechanisms of constitutive aerenchyma formation and of changes in root architecture. Moreover, we use modelling of internal aeration to demonstrate the beneficial effect of increasing cortex-to-stele ratio on sustaining root growth in waterlogged soils. We know the genes for some of the beneficial traits, and the next step is to manipulate these genes in breeding in order to enhance the flood tolerance of our crops.

Root O2 consumption, CO2 production and tissue concentration profiles in chickpea, as influenced by environmental hypoxia.

Roots in flooded soils experience hypoxia, with the least O2 in the vascular cylinder. Gradients in CO2 across roots had not previously been measured. The respiratory quotient (RQ; CO2 produced : O2 consumed) is expected to increase as O2 availability declines. A new CO2 microsensor and an O2 microsensor were used to measure profiles across roots of chickpea seedlings in aerated or hypoxic conditions. Simultaneous, nondestructive flux measurements of O2 consumption, CO2 production, and thus RQ, were taken for roots with declining O2 . Radial profiling revealed severe hypoxia and c. 0.8 kPa CO2 within the root vascular cylinder. The distance penetrated by O2 into the roots was shorter at lower O2 . The gradient in CO2 was in the opposite direction to that of O2 , across the roots and diffusive boundary layer. RQ increased as external O2 was lowered. For chickpea roots in solution at air equilibrium, O2 was very low and CO2 was elevated within the vascular cylinder; the extent of the severely hypoxic core increased as external O2 was reduced. The increased RQ in roots in response to declining external O2 highlighted the shift from respiration to ethanolic fermentation as the severely hypoxic/anoxic core became a progressively greater proportion of the root tissues.

Proximal deep vein thrombosis among hospitalised medical and obstetric patients in Rwandan university teaching hospitals: prevalence and associated risk factors: a cross-sectional study.

OBJECTIVES: To determine the prevalence of proximal deep vein thrombosis (DVT) by ultrasound scanning, as well as associated clinical features and known risk factors, among medical and obstetrics-gynaecology inpatients in two Rwandan tertiary hospitals. DESIGN: Cross-sectional study. SETTINGS: Rwanda teaching hospitals: Kigali and Butare University Teaching Hospitals. PARTICIPANTS: 901 adult patients admitted to the Departments of Internal Medicine and Obstetrics-Gynecology (O&G) who were at least 21 years of age and willing to provide a consent. OUTCOMES: Prevalence of proximal DVT, clinical features and known risk factors associated with DVT. METHODS: Between August 2015 and August 2016, participants were screened for DVT by compressive ultrasound of femoral and popliteal veins, conducted as a monthly cross-sectional survey of all consenting eligible inpatients. Patients completed a self-report survey on DVT risk factors. Prevalence of proximal DVT by compression ultrasonography was the primary endpoint, with univariate and multivariate regression analyses performed to assess associated clinical features and risk factors. RESULTS: Proximal DVT was found in 5.5% of the study population, with similar rates in medical and O&G inpatients. The mean age was 41±16 SD (range, 21-91), 70% were female and 7% were pregnant. Univariate analysis showed active malignancy, immobilisation, prolonged recent travel and history of DVT to be significant risk factors for proximal DVT (all p values <0.05); while only active malignancy was an independent risk factor on multivariate regression (OR 5.2; 95% CI 2.0 to 13). Leg pain or tenderness, increased calf circumference, unilateral limb swelling or pitting oedema were predictive clinical features of DVT on both univariate analysis and multivariate regression (all p values <0.05). CONCLUSION: Proximal DVT prevalence is high among hospitalised medical and O&G patients in two tertiary hospitals in Rwanda. For reducing morbidity and mortality, research to develop Africa-specific clinical prediction tools for DVT and interventions to increase thromboprophylaxis use in the region are urgently needed.

Better evidence: prospective cohort study assessing the utility of an evidence-based clinical resource at the University of Rwanda.

OBJECTIVE: Evidence-based clinical resources (EBCRs) have the potential to improve diagnostic and therapeutic accuracy. The majority of US teaching medical institutions have incorporated them into clinical training. Many EBCRs are subscription based, and their cost is prohibitive for most clinicians and trainees in low-income and middle-income countries. We sought to determine the utility of EBCRs in an East African medical school. SETTING: The University of Rwanda (UR), a medical school located in East Africa. PARTICIPANTS: Medical students and faculty members at UR. INTERVENTIONS: We offered medical students and faculty at UR free access to UpToDate, a leading EBCR and conducted a cohort study to assess its uptake and usage. Students completed two surveys on their study habits and gave us permission to access their activity on UpToDate and their grades. RESULTS: Of the 980 medical students invited to enrol over 2 years, 547 did (56%). Of eligible final year students, 88% enrolled. At baseline, 92% of students reported ownership of an internet-capable device, and the majority indicated using free online resources frequently for medical education. Enrolled final year students viewed, on average, 1.24 topics per day and continued to use UpToDate frequently after graduation from medical school. Graduating class exam performance was better after introduction of UpToDate than in previous years. CONCLUSIONS: Removal of the cost barrier was sufficient to generate high uptake of a leading EBCR by senior medical students and habituate them to continued usage after graduation.

Independent prescribing by advanced physiotherapists for patients with low back pain in primary care: protocol for a feasibility trial with an embedded qualitative component.

INTRODUCTION: Low back pain (LBP) is the most prevalent musculoskeletal condition in the UK. Guidelines advocate a multimodal approach, including prescription of medications. Advanced physiotherapy practitioners (APPs) are well placed to provide this care in primary care. Physiotherapist independent prescribing remains novel, with the first prescribers qualifying in 2014. This feasibility trial aims to evaluate the feasibility, suitability and acceptability of assessing the effectiveness of independent prescribing by APPs for patients with LBP in primary care, to inform the design of a future definitive stepped-wedged cluster trial. METHOD AND ANALYSIS: (1) Trial component. An APP (registered prescriber) will complete the initial participant consultation. If prescription drugs are required within the multimodal physiotherapeutic context, these will be prescribed. Patient-reported outcome measures will be completed prior to initial assessment and at 6 and 12 weeks to assess feasibility of follow-up and data collection procedures. Accelerometers will be fitted for 7 days to assess physical activity, sedentary behaviour and feasibility of use. (2) Embedded qualitative component. A focus group and semistructured interviews will be used to evaluate the views and experiences of the participants and APPs respectively, about the feasibility, suitability and acceptability of the proposed full trial. A Consolidated Standards of Reporting Trials diagram will be used to analyse feasible eligibility, recruitment and follow-up rates. Descriptive analysis of the data will be completed to evaluate procedures. Thematic analysis will be used to analyse and synthesise the qualitative data. ETHICS AND DISSEMINATION: This feasibility trial is approved by the Health Research Authority (HRA). Ethical approval was sought and granted via the Integrated Research Application System (IRAS) ID 250734.Data will be disseminated via publication in peer reviewed journal and conference presentation. It is anticipated that the results of this study will be used in conjunction with ethical evaluation, economic and risk analyses, as well as consultation with key stakeholders including the British health consumer when contemplating change, enhancement or redesign of the essential full randomised controlled trial. TRIAL REGISTRATION NUMBER: ISRCTN15516596, Pre-results.