A Conceptual Framework for Studying the Sources of Variation in Program Effects

Evaluations of public programs in many fields reveal that (1) different types of programs (or different versions of the same program) vary in their effectiveness, (2) a program that is effective for one group of people might not be effective for other groups of people, and (3) a program that is effective in one set of circumstances may not be effective in other circumstances. This paper presents a conceptual framework for research on such variation in program effects and the sources of this variation. The framework is intended to help researchers -- both those who focus mainly on studying program implementation and those who focus mainly on estimating program effects -- see how their respective pieces fit together in a way that helps to identify factors that explain variation in program effects and thereby support more systematic data collection on these factors. The ultimate goal of the framework is to enable researchers to offer better guidance to policymakers and program operators on the conditions and practices that are associated with larger and more positive effects

Why high-error-rate random mutagenesis libraries are enriched in functional and improved proteins

Recently, several groups have used error-prone polymerase chain reactions to construct mutant libraries containing up to 27 nucleotide mutations per gene on average, and reported a striking observation: although retention of protein function initially declines exponentially with mutations as has previously been observed, orders of magnitude more proteins remain viable at the highest mutation rates than this trend would predict. Mutant proteins having improved or novel activity were isolated disproportionately from these heavily mutated libraries, leading to the suggestion that distant regions of sequence space are enriched in useful cooperative mutations and that optimal mutagenesis should target these regions. If true, these claims have profound implications for laboratory evolution and for evolutionary theory. Here, we demonstrate that properties of the polymerase chain reaction can explain these results and, consequently, that average protein viability indeed decreases exponentially with mutational distance at all error rates. We show that high-error-rate mutagenesis may be useful in certain cases, though for very different reasons than originally proposed, and that optimal mutation rates are inherently protocol-dependent. Our results allow optimal mutation rates to be found given mutagenesis conditions and a protein of known mutational robustness.Comment: Optimality results improved. 26 pages, 4 figures, 3 table

EMBIO trial study protocol: left gastric artery embolisation for weight loss in patients living with obesity with a BMI 35–50 kg/m²

Introduction: Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities. / Methods and analysis: 76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18–70 with a body mass index 35–50 kg/m2 and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months. / Ethics and dissemination: This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and all subsequent revisions. Local research ethics approval was granted by London-Central Research Ethics Committee, (Reference 19/LO/0509) on 11 October 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) issued the Letter of No Objection on 8 April 2022 (Reference CI/2022/0008/GB). The trial’s development and progress are monitored by an independent trial steering committee and data monitoring and ethics committee. The researchers plan to disseminate results at conferences, in peer- reviewed journals as well as lay media and to patient organisations. / Trial registration number: ISRCTN16158402

Molecular and cellular biology of von Willebrand factor

Von Willebrand factor (vWF), a central protein in the regulation of blood coagulation, serves as a major adhesive link between platelets and the blood vessel wall and also functions as a carrier in plasma for factor VIII. Abnormalities of vWF result in von Willebrand disease (vWD), a common inherited human bleeding disorder. Deficient von Willebrand factor function has been proposed as potentially protective against the development of coronary vascular disease and several recent investigational therapies are directed at the vWF-platelet interaction. This review summarizes the current state of knowledge regarding the biosynthesis and processing of vWF and the relationship of vWF structure to function. Finally, recent progress in identifying specific genetic mutations responsible for the many variants of vWD is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31861/1/0000811.pd

Sarcolemma-localized nNOS is required to maintain activity after mild exercise

Many neuromuscular conditions are characterized by an exaggerated exercise- induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients(1), and some patients experience severe fatigue without any demonstrable somatic disease(2). Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown(2). With no treatment available, this form of inactivity is a major determinant of disability(3). Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase ( nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS- null mice do not have muscle pathology and have no loss of muscle- specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction- induced signalling from sarcolemma- localized nNOS, which decreases cGMP- mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise- induced signalling.Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant ; University of Iowa Cardiovascular Interdisciplinary Research ; National Research Service Award ; National Institute of Arthritis and Musculoskeletal and Skin Diseases ; National Institutes of Health ; Senator Paul D. Wellstone Fellowship ; Muscular Dystrophy Association Development Grant ; Howard Hughes Medical InstituteWe thank M. Anderson and M. Henry for comments, and M. M. Kilburg, K. Uppal, B. J. Steinmann and S. Watkins and members of the Campbell laboratory for scientific contributions. This work was supported in part by a Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant. Y.M.K. was supported by grants from the University of Iowa Cardiovascular Interdisciplinary Research/ National Research Service Award (NRSA) Fellowship, from an individual NRSA Fellowship from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, from the National Institutes of Health (NIH), and from a Senator Paul D. Wellstone Fellowship. E.P.R. was supported by a Muscular Dystrophy Association Development Grant. R.M.W. was supported by the NIH. K.P.C. is an investigator of the Howard Hughes Medical Institute.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62850/1/nature07414.pd

Social Tourism and Healthy Ageing

Recent research in social tourism notes possible links between tourism participation and improvements in health. However, there is a lack of quantitative evidence concerning the potential links between tourism participation and self-reported health amongst older people. An ageing society requires measures to promote independent living and enhance older people's quality of life. This paper provides evidence that older tourists are more active and healthy than non-tourists, from a study comparing health perceptions amongst Spanish older people. The results provide tentative conclusions of causal relationships between tourism and dimensions of physical and mental health through a Structural Equation Model

Quark-hadron duality in electron scattering

The duality between partonic and hadronic descriptions of physical phenomena is one of the most remarkable features of strong interaction physics. A classic example of this is in electron-nucleon scattering, in which low-energy cross sections, when averaged over appropriate energy intervals, are found to exhibit the scaling behavior expected from perturbative QCD. We present a comprehensive review of data on structure functions in the resonance region, from which the global and local aspects of duality are quantified, including its flavor, spin and nuclear medium dependence. To interpret the experimental findings, we discuss various theoretical approaches which have been developed to understand the microscopic origins of quark-hadron duality in QCD. Examples from other reactions are used to place duality in a broader context, and future experimental and theoretical challenges are identified.Comment: 198 pages, 80 figures, to appear in Physics Report