A survey of UK medical schools' arrangements for early patient contact

Background: Many U.K. medical schools have patient contact in the first two years of the undergraduate course. Aim: To compare the purposes and organization of early patient contact in UK medical schools and to relate these arrangements to the schools' curricular objectives. Methods: A telephone survey of lead educators in UK medicals schools. Categories of contact were plotted against phases of the course to discern patterns of organisation. Results: The quantity of contact varies considerably (four to 65 days). There is a pattern, with learning objectives around the social context of health and illness preceding skills based work and integrated clinical knowledge for practice coming later. Schools fall into three categories: close adherence to the preclinical/clinical split, with limited early contact acting as an introduction to social aspects of health; provision of substantial patient contact to maximize the integration of knowledge and skills; and transitional, with limited clinical goals. General practice provides between one third and one half of early patient contact. Conclusions: Arrangements meet the objectives set by each school and reflect differing educational philosophies. Change is toward more early contact. There appears to be no national guidance which supports a minimum quantity of patient contact or specific educational purpose in the early years of U.K. basic medical training

Lentiviral vectors can be used for full-length dystrophin gene therapy

Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. In our work, we have demonstrated that lentiviral vectors can package and deliver inserts of a similar size to dystrophin. We report a novel approach for delivering large transgenes in lentiviruses, in which we demonstrate proof-of-concept for a 'template-switching' lentiviral vector that harnesses recombination events during reverse-transcription. During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD

Explicit BCJ Numerators from Pure Spinors

We derive local kinematic numerators for gauge theory tree amplitudes which manifestly satisfy Jacobi identities analogous to color factors. They naturally emerge from the low energy limit of superstring amplitudes computed with the pure spinor formalism. The manifestation of the color--kinematics duality is a consequence of the superstring computation involving no more than (n-2)! kinematic factors for the full color dressed n-point amplitude. The bosonic part of these results describe gluon scattering independent on the number of supersymmetries and captures any N^kMHV helicity configuration after dimensional reduction to D=4 dimensions.Comment: 32 pages, harvma

Simple rules for evidence translation in complex systems: a qualitative study

Background Ensuring patients benefit from the latest medical and technical advances remains a major challenge, with rational-linear and reductionist approaches to translating evidence into practice proving inefficient and ineffective. Complexity thinking, which emphasises interconnectedness and unpredictability, offers insights to inform evidence translation theories and strategies. Drawing on detailed insights into complex micro-systems, this research aimed to advance empirical and theoretical understanding of the reality of making and sustaining improvements in complex healthcare systems. Methods Using analytical auto-ethnography, including documentary analysis and literature review, we assimilated learning from 5 years of observation of 22 evidence translation projects (UK). We used a grounded theory approach to develop substantive theory and a conceptual framework. Results were interpreted using complexity theory and ‘simple rules’ were identified reflecting the practical strategies that enhanced project progress. Results The framework for Successful Healthcare Improvement From Translating Evidence in complex systems (SHIFT-Evidence) positions the challenge of evidence translation within the dynamic context of the health system. SHIFT-Evidence is summarised by three strategic principles, namely (1) ‘act scientifically and pragmatically’ – knowledge of existing evidence needs to be combined with knowledge of the unique initial conditions of a system, and interventions need to adapt as the complex system responds and learning emerges about unpredictable effects; (2) ‘embrace complexity’ – evidence-based interventions only work if related practices and processes of care within the complex system are functional, and evidence-translation efforts need to identify and address any problems with usual care, recognising that this typically includes a range of interdependent parts of the system; and (3) ‘engage and empower’ – evidence translation and system navigation requires commitment and insights from staff and patients with experience of the local system, and changes need to align with their motivations and concerns. Twelve associated ‘simple rules’ are presented to provide actionable guidance to support evidence translation and improvement in complex systems. Conclusion By recognising how agency, interconnectedness and unpredictability influences evidence translation in complex systems, SHIFT-Evidence provides a tool to guide practice and research. The ‘simple rules’ have potential to provide a common platform for academics, practitioners, patients and policymakers to collaborate when intervening to achieve improvements in healthcare

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

A survey of 557 GHz water vapor emission in the NGC 1333 molecular cloud

Using NASA\u27s Submillimeter Wave Astronomy Satellite (SWAS), we have examined the production of water in quiescent and shocked molecular gas through a survey of the 556.936 GHz 110-101 transition of ortho-H2O in the NGC 1333 molecular core. These observations reveal broad emission lines associated with the IRAS 2, IRAS 4, IRAS 7, and HH 7-11 outflows. Toward three positions we detect narrow (Δv ~ 2-3 km s-1) emission lines clearly associated with the ambient gas. The SWAS observations, with a resolution of ~4\u27, are supplemented with observations from the Infrared Space Observatory (ISO) and by an unbiased survey of a ~17\u27 × 15\u27 area, with ~50\u27\u27 resolution, in the low-J transitions of CO, 13CO, C18O, N2H+, CH3OH, and SiO. Using these combined data sets, with consistent assumptions, we find beam-averaged ortho-H2O abundances of greater than 10-6 relative to H2 for all four outflows. A comparison of SWAS and ISO water data is consistent with nondissociative shock models, provided the majority of the ortho-H2O (110-101) emission arises from cool postshock material with enhanced abundances. In the ambient gas the ortho-H2O abundance is found to lie between 0.1 × 10-7 and 1 × 10-7 relative to H2 and is enhanced when compared to cold prestellar molecular cores. A comparison of the water emission with tracers of dense condensations and shock chemistry finds no clear correlation. However, the water emission appears to be associated with the presence of luminous external heating sources that power the reflection nebula and the photodissociation region (PDR). Simple PDR models are capable of reproducing the water and high-J 13CO emission, suggesting that a PDR may account for the excitation of water in low-density undepleted gas, as suggested by Spaans & van Dishoeck

Cardiorespiratory fitness, fatness, and the acute blood pressure response to exercise in adolescence

OBJECTIVE: Exaggerated exercise blood pressure (BP) is associated with cardiovascular risk factors in adolescence. Cardiorespiratory fitness and adiposity (fatness) are independent contributors to cardiovascular risk, but their interrelated associations with exercise BP are unknown. This study aimed to determine the relationships between fitness, fatness and the acute BP response to exercise in a large birth cohort of adolescents. METHODS: 2292 adolescents from the Avon Longitudinal Study of Parents and Children (aged 17.8±0.4 years, 38.5% male) completed a submaximal exercise step-test that allowed fitness (VO2 max ) to be determined from workload and heart rate using a validated equation. Exercise BP was measured immediately on test cessation and fatness calculated as the ratio of total fat mass to total body mass measured by DXA. RESULTS: Post-exercise systolic BP decreased stepwise with tertile of fitness (146 (18); 142 (17); 141 (16) mmHg) but increased with tertile of fatness (138 (15); 142 (16); 149 (18) mmHg). In separate models, fitness and fatness were associated with post-exercise systolic BP adjusted for sex, age, height, smoking and socioeconomic status (standardized β: -1.80, 95%CI: -2.64, -0.95 mmHg/SD and 4.31, 95%CI: 3.49, 5.13 mmHg/SD). However, when fitness and fatness were included in the same model, only fatness remained associated with exercise BP (4.65, 95%CI: 3.69, 5.61 mmHg/SD). CONCLUSION: Both fitness and fatness are associated with the acute BP response to exercise in adolescence. The fitness-exercise BP association was not independent of fatness, implying the cardiovascular protective effects of cardiorespiratory fitness may only be realised with more-favourable body composition