Social experimentation in the face of formidable fables

Public welfare

A touchdown nucleic acid amplification protocol as an alternative to culture backup for immunofluorescence in the routine diagnosis of acute viral respiratory tract infections

BACKGROUND: Immunofluorescence and virus culture are the main methods used to diagnose acute respiratory virus infections. Diagnosing these infections using nucleic acid amplification presents technical challenges, one of which is facilitating the different optimal annealing temperatures needed for each virus. To overcome this problem we developed a diagnostic molecular strip which combined a generic nested touchdown protocol with in-house primer master-mixes that could recognise 12 common respiratory viruses. RESULTS: Over an 18 month period a total of 222 specimens were tested by both immunofluorescence and the molecular strip. The specimens came from 103 males (median age 3.5 y), 80 females (median age 9 y) and 5 quality assurance scheme specimens. Viruses were recovered from a number of specimen types including broncho-alveolar lavage, nasopharyngeal secretions, sputa, post-mortem lung tissue and combined throat and nasal swabs. Viral detection by IF was poor in sputa and respiratory swabs. A total of 99 viruses were detected in the study from 79 patients and 4 quality control specimens: 31 by immunofluorescence and 99 using the molecular strip. The strip consistently out-performed immunofluorescence with no loss of diagnostic specificity. CONCLUSIONS: The touchdown protocol with pre-dispensed primer master-mixes was suitable for replacing virus culture for the diagnosis of respiratory viruses which were negative by immunofluorescence. Results by immunofluorescence were available after an average of 4–12 hours while molecular strip results were available within 24 hours, considerably faster than viral culture. The combined strip and touchdown protocol proved to be a convenient and reliable method of testing for multiple viruses in a routine setting

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.Sally Hunter and Carol Brayne are supported by funding from the National Institute for Health Research, Senior Investigator Award, awarded to Carol Brayne. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Sally Hunter is supported by the Addenbrooke’s Charitable Trust, the Paul G. Allen Family Foundation and Alzheimer’s Research, UK. Suvi Hokkanen was supported by Alzheimer’s Research, UK

Building the nation's body:The contested role of abortion and family planning in post-war South Sudan

: This paper offers an ethnographic analysis of public health policies and interventions targeting unwanted pregnancy (family planning and abortion) in contemporary South Sudan as part of wider 'nation-building' after war, understood as a process of collective identity formation which projects a meaningful future by redefining existing institutions and customs as national characteristics. The paper shows how the expansion of post-conflict family planning and abortion policy and services are particularly poignant sites for the enactment of reproductive identity negotiation, policing and conflict. In addition to customary norms, these processes are shaped by two powerful institutions - ethnic movements and global humanitarian actors - who tend to take opposing stances on reproductive health. Drawing on document review, observations of the media and policy environment and interviews conducted with 54 key informants between 2013 and 2015, the paper shows that during the civil war, the Sudan People's Liberation Army and Movement mobilised customary pro-natalist ideals for military gain by entreating women to amplify reproduction to replace those lost to war and rejecting family planning and abortion. International donors and the Ministry of Health have re-conceptualised such services as among other modern developments denied by war. The tensions between these competing discourses have given rise to a range of societal responses, including disagreements that erupt in legal battles, heated debate and even violence towards women and health workers. In United Nations camps established recently as parts of South Sudan have returned to war, social groups exert a form of reproductive surveillance, policing reproductive health practices and contributing to intra-communal violence when clandestine use of contraception or abortion is discovered. In a context where modern contraceptives and abortion services are largely unfamiliar, conflict around South Sudan's nation-building project is partially manifest through tensions and violence in the domain of reproduction.<br/

Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE): Consensus Working Group Report

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer’s disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials

Evidence for perinatal and child health care guidelines in crisis settings: can Cochrane help?

<p>Abstract</p> <p>Background</p> <p>It is important that healthcare provided in crisis settings is based on the best available research evidence. We reviewed guidelines for child and perinatal health care in crisis situations to determine whether they were based on research evidence, whether Cochrane systematic reviews were available in the clinical areas addressed by these guidelines and whether summaries of these reviews were provided in Evidence Aid.</p> <p>Methods</p> <p>Broad internet searches were undertaken to identify relevant guidelines. Guidelines were appraised using AGREE and the clinical areas that were relevant to perinatal or child health were extracted. We searched The Cochrane Database of Systematic Reviews to identify potentially relevant reviews. For each review we determined how many trials were included, and how many were conducted in resource-limited settings.</p> <p>Results</p> <p>Six guidelines met selection criteria. None of the included guidelines were clearly based on research evidence. 198 Cochrane reviews were potentially relevant to the guidelines. These reviews predominantly addressed nutrient supplementation, breastfeeding, malaria, maternal hypertension, premature labour and prevention of HIV transmission. Most reviews included studies from developing settings. However for large portions of the guidelines, particularly health services delivery, there were no relevant reviews. Only 18 (9.1%) reviews have summaries in Evidence Aid.</p> <p>Conclusions</p> <p>We did not identify any evidence-based guidelines for perinatal and child health care in disaster settings. We found many Cochrane reviews that could contribute to the evidence-base supporting future guidelines. However there are important issues to be addressed in terms of the relevance of the available reviews and increasing the number of reviews addressing health care delivery.</p

Will a Good Citizen Actively Support Organizational Change? Investigation of Psychological Processes Underlying Active Change Support

The present study investigated motivational factors of employees active change support (ACS). It also investigated good citizens response to the change by highlighting convergence and divergence of motivational factors between ACS and traditional extra-role behavior. The findings based on 166 staff responses and 346 supervisor assessments in a hospital that recently implemented a sharedgovernance structure suggest that active change support is a result of an active thinking process that involves perception of potential benefit from change but not necessarily the consequence of conventional predictors of extra-role behaviors (i.e., positive attitudes). The findings also suggest that good citizens are not necessarily the supporters of organizational change and that in actuality they confront motivational dilemma especially when they hold high quality relationship with their employer because they are reluctant to challenge the status quo

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio