Research priorities in advanced heart failure: James Lind alliance priority setting partnership.

OBJECTIVE: To determine research priorities in advanced heart failure (HF) for patients, carers and healthcare professionals. METHODS: Priority setting partnership using the systematic James Lind Alliance method for ranking and setting research priorities. An initial open survey of patients, carers and healthcare professionals identified respondents' questions, which were categorised to produce a list of summary research questions; questions already answered in existing literature were removed. In a second survey of patients, carers and healthcare professionals, respondents ranked the summary research questions in order of priority. The top 25 unanswered research priorities were then considered at a face-to-face workshop using nominal group technique to agree on a 'top 10'. RESULTS: 192 respondents submitted 489 responses each containing one or more research uncertainty. Out-of-scope questions (35) were removed, and collating the responses produced 80 summary questions. Questions already answered in the literature (15) were removed. In the second survey, 65 questions were ranked by 128 respondents. The top 10 priorities were developed at a consensus meeting of stakeholders and included a focus on quality of life, psychological support, the impact on carers, role of the charity sector and managing prognostic uncertainty. Ranked priorities by physicians and patients were remarkably divergent. CONCLUSIONS: Engaging stakeholders in setting research priorities led to a novel set of research questions that might not have otherwise been considered. These priorities can be used by researchers and funders to direct future research towards the areas which matter most to people living with advanced HF

Biodiversity, drug discovery, and the future of global health:Introducing the biodiversity to biomedicine consortium, a call to action

First paragraph: Looking to nature for medicine is nothing new – we have been doing it for tens of thousands of years and although modern pharmaceutical science has come a long way from those ancient roots, nature is and will always be an important source of useful compounds and inspiration. Dismissing nature in this regard is a huge mistake as evolution is the greatest problem solver and the myriad compounds produced by the immense variety of species we share the planet with have been honed by three billion years of trial and error. However, with every bit of habitat that disappears under the plough or concrete we impoverish nature and deprive ourselves of potential medicines.Additional co-authors: Uttam Babu Shrestha, Milica Pešić, Alexander Kagansk

Biodiversity, drug discovery, and the future of global health: Introducing the biodiversity to biomedicine consortium, a call to action

Looking to nature for medicine is nothing new – we have been doing it for tens of thousands of years and although modern pharmaceutical science has come a long way from those ancient roots, nature is and will always be an important source of useful compounds and inspiration. Dismissing nature in this regard is a huge mistake as evolution is the greatest problem solver and the myriad compounds produced by the immense variety of species we share the planet with have been honed by three billion years of trial and error. However, with every bit of habitat that disappears under the plough or concrete we impoverish nature and deprive ourselves of potential medicines

Slow-wave sleep dysfunction in mild parkinsonism is associated with excessive beta and reduced delta oscillations in motor cortex

Increasing evidence suggests slow-wave sleep (SWS) dysfunction in Parkinson’s disease (PD) is associated with faster disease progression, cognitive impairment, and excessive daytime sleepiness. Beta oscillations (8–35 Hz) in the basal ganglia thalamocortical (BGTC) network are thought to play a role in the development of cardinal motor signs of PD. The role cortical beta oscillations play in SWS dysfunction in the early stage of parkinsonism is not understood, however. To address this question, we used a within-subject design in a nonhuman primate (NHP) model of PD to record local field potentials from the primary motor cortex (MC) during sleep across normal and mild parkinsonian states. The MC is a critical node in the BGTC network, exhibits pathological oscillations with depletion in dopamine tone, and displays high amplitude slow oscillations during SWS. The MC is therefore an appropriate recording site to understand the neurophysiology of SWS dysfunction in parkinsonism. We observed a reduction in SWS quantity (p = 0.027) in the parkinsonian state compared to normal. The cortical delta (0.5–3 Hz) power was reduced (p = 0.038) whereas beta (8–35 Hz) power was elevated (p = 0.001) during SWS in the parkinsonian state compared to normal. Furthermore, SWS quantity positively correlated with delta power (r = 0.43, p = 0.037) and negatively correlated with beta power (r = −0.65, p < 0.001). Our findings support excessive beta oscillations as a mechanism for SWS dysfunction in mild parkinsonism and could inform the development of neuromodulation therapies for enhancing SWS in people with PD

Disentangling the stigma of HIV/AIDS from the stigmas of drugs use, commercial sex and commercial blood donation – a factorial survey of medical students in China

BackgroundHIV/AIDS related stigma interferes with the provision of appropriate care and support for people living with HIV/AIDS. Currently, programs to address the stigma approach it as if it occurs in isolation, separate from the co-stigmas related to the various modes of disease transmission including injection drug use (IDU) and commercial sex (CS). In order to develop better programs to address HIV/AIDS related stigma, the inter-relationship (or \u27layering\u27) between HIV/AIDS stigma and the co-stigmas needs to be better understood. This paper describes an experimental study for disentangling the layering of HIV/AIDS related stigmas.MethodsThe study used a factorial survey design. 352 medical students from Guangzhou were presented with four random vignettes each describing a hypothetical male. The vignettes were identical except for the presence of a disease diagnosis (AIDS, leukaemia, or no disease) and a co-characteristic (IDU, CS, commercial blood donation (CBD), blood transfusion or no co-characteristic). After reading each vignette, participants completed a measure of social distance that assessed the level of stigmatising attitudes.ResultsBivariate and multivariable analyses revealed statistically significant levels of stigma associated with AIDS, IDU, CS and CBD. The layering of stigma was explored using a recently developed technique. Strong interactions between the stigmas of AIDS and the co-characteristics were also found. AIDS was significantly less stigmatising than IDU or CS. Critically, the stigma of AIDS in combination with either the stigmas of IDU or CS was significantly less than the stigma of IDU alone or CS alone.ConclusionThe findings pose several surprising challenges to conventional beliefs about HIV/AIDS related stigma and stigma interventions that have focused exclusively on the disease stigma. Contrary to the belief that having a co-stigma would add to the intensity of stigma attached to people with HIV/AIDS, the findings indicate the presence of an illness might have a moderating effect on the stigma of certain co-characteristics like IDU. The strong interdependence between the stigmas of HIV/AIDS and the co-stigmas of IDU and CS suggest that reducing the co-stigmas should be an integral part of HIV/AIDS stigma intervention within this context.<br /

Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2

We have used whole exome sequencing to identify biallelic missense mutations in the nuclearencoded mitochondrial inorganic pyrophosphatase (PPA2) in ten individuals from four unrelated pedigrees that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis and cardiac arrhythmia and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutated PPA2 containing mitochondria from fibroblasts showed the activity of inorganic pyrophosphatase significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations, and suggest that PPA2 is a new cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized

Crowdsourcing hypothesis tests: Making transparent how design choices shape research results

To what extent are research results influenced by subjective decisions that scientists make as they design studies? Fifteen research teams independently designed studies to answer fiveoriginal research questions related to moral judgments, negotiations, and implicit cognition. Participants from two separate large samples (total N > 15,000) were then randomly assigned to complete one version of each study. Effect sizes varied dramatically across different sets of materials designed to test the same hypothesis: materials from different teams renderedstatistically significant effects in opposite directions for four out of five hypotheses, with the narrowest range in estimates being d = -0.37 to +0.26. Meta-analysis and a Bayesian perspective on the results revealed overall support for two hypotheses, and a lack of support for three hypotheses. Overall, practically none of the variability in effect sizes was attributable to the skill of the research team in designing materials, while considerable variability was attributable to the hypothesis being tested. In a forecasting survey, predictions of other scientists were significantly correlated with study results, both across and within hypotheses. Crowdsourced testing of research hypotheses helps reveal the true consistency of empirical support for a scientific claim.</div

The Effectiveness of Incarceration-Based Drug Treatment on Criminal Behavior: A Systematic Review

Many, if not most, incarcerated offenders have substance abuse problems. Without effective treatment, these substance-abusing offenders are likely to persist in non-drug offending. The period of incarceration offers an opportunity to intervene in the cycle of drug abuse and crime. Although many types of incarceration-based drug treatment programs are available (e.g., therapeutic communities and group counseling), the effectiveness of these programs is unclear. The objective of this research synthesis is to systematically review quasi-experimental and experimental (RCT) evaluations of the effectiveness of incarceration-based drug treatment programs in reducing post-release recidivism and drug relapse. A secondary objective of this synthesis is to examine variation in effectiveness by programmatic, sample, and methodological features. In this update of the original 2006 review (see Mitchell, Wilson, and MacKenzie, 2006), studies made available since the original review were included in an effort to keep current with emerging research. This synthesis of evaluations of incarceration-based drug treatment programs found that such programs are modestly effective in reducing recidivism. These findings most strongly support the effectiveness of therapeutic communities, as these programs produced relatively consistent reductions in recidivism and drug use. Both counseling and incarceration-based narcotic maintenance programs had mixed effects. Counseling programs were associated with reductions in recidivism but not drug use; whereas, incarceration-based narcotic maintenance programs were associated with reductions in drug use but not recidivism. Note that our findings regarding the effectiveness of incarceration-based narcotic maintenance programs differ from a larger review of community-based narcotic maintenance programs (see Egli, Pina, Christensen, Aebi, and Killias, 2009). Finally, boot camp programs for drug offenders had negligible effects on both recidivism and drug use

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants