Pharmacological Management of Lewy Body Dementia: A Systematic Review and Meta-Analysis.

OBJECTIVE: The authors examined research on effects, costs, and patient and caregiver views of pharmacological management strategies for Lewy body dementia. METHOD: Studies were identified through bibliographic databases, trials registers, gray literature, reference lists, and experts. The authors used the search terms "Lewy or parkinson" and "dementia" through March 2015 and used the following inclusion criteria: participants with diagnoses of Lewy body dementia, dementia with Lewy bodies, or Parkinson's disease dementia (or participants' caregivers); investigation of pharmacological management strategies; outcome measures and test scores reported. Data extraction and quality assessment were conducted by at least two authors. Meta-analyses were conducted, and when studies could not be combined, summaries were provided. RESULTS: Forty-four studies examining 22 strategies were included in the review. Meta-analysis indicated beneficial effects of donepezil and rivastigmine for cognitive and psychiatric symptoms. Rivastigmine, but not donepezil, was associated with greater risk of adverse events. Meta-analysis of memantine suggested that it is well tolerated but with few benefits. Descriptive summaries provide some evidence of benefits for galantamine, modafinil, levodopa, rotigotine, clozapine, duloxetine, clonazepam, ramelteon, gabapentin, zonisamide, and yokukansan. Piracetam, amantadine, selegiline, olanzapine, quetiapine, risperidone, and citalopram do not appear to be effective. CONCLUSIONS: High-level evidence related to pharmacological strategies for managing Lewy body dementia is rare. Strategies for important areas of need in Lewy body dementia, such as autonomic symptoms and caregiver burden, have not been investigated, nor have the views of patients and caregivers about pharmacological strategies.Supported by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research program (DTC-RP-PG-0311-12001); the NIHR Biomedical Research Unit in Dementia and the Biomedical Research Centre awarded to Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge; and the NIHR Biomedical Research Unit in Lewy Body Dementia and Biomedical Research Centre awarded to Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University.This is the author accepted manuscript. The final version is available from the American Psychiatric Association via http://dx.doi.org/10.1176/appi.ajp.2015.1412158

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

Peer reviewed: TrueBACKGROUND: National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. METHODS: In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). RESULTS: Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. CONCLUSION: The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation

Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records.

Peer reviewed: TrueOBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry

Dung beetle brood balls from Pleistocene highland palaeosols of Andean Ecuador: A reassessment of Sauer's Coprinisphaera and their palaeoenvironments

Independently, Roselli (1939) and Sauer (1955) described and named similar fossil brood balls from the Paleogene of Uruguay (Devincenzia murguiai) and from the Quaternary of Ecuador (Coprinisphaera ecuadoriensis), respective- ly. In their contributions, they illustrated and described fossil brood balls characterized by the presence of a medium-sized hole piercing the wall of spherical to sub-spherical chambers. Newly collected brood balls from palaeosols of the Cangahua Formation (Ecuador), and other previously deposited in ichnological collections from Ecuador, Uruguay, and Argentina, including type material, were revised to update Coprinisphaera ichnotaxonomy. Coprinisphaera ecuadoriensis Sauer (1955) is a subjective junior synonym of Coprinisphaera murguiai (Roselli, 1939). Coprinisphaera murguiai sensu Laza, 2006 (non Roselli, 1939) is in turn a new ichnospecies named herein Coprinisphaera lazai isp. n. Additionally, a new ichnospecies, named herein as Coprinisphaera kitu isp. n.., was found in the Cangahua Formation. It is represented by a spherical to sub-spherical chamber having a discrete wall, with a crown composed of a hemispherical structure on one pole. The statistical analysis of the size of the two ichnospecies found in the Cangahua Formation suggests that C. kitu and C. murguiai may represent two stages (closed and emerged balls, respectively) of a unique original morphology (C. kitu) and producer. There are no extant dung beetle species that construct brood balls with a morphology similar to that of C. kitu. The producer of C. kitu would be the recently described fossil Phanaeini, Phanaeus violetae. Phytoliths extracted from infillings of closed C. kitu revealed that Poaceae were mostly included in the diet of the herbivores that produced the dung. Considering the vertebate fossil record for the Pleistocene Cangahua Formation, ground sloths, mastodons, and horses could have been the dung providers. The record of Tombownichnus plenus, Lazaichnus fistulosus, and Castrichnus incolumis suggests the presence of cleptoparasites and detritivores in the dung community. Cangahua sediments accumulated in a volcaniclastic, intermontane setting located at 2500–2900 m.a.s.l. and under fluctuat- ing syneruptive conditions. Changes in facies associations and palaeosol types enable to distinguish three stages in evolution of sedimentation and landscapes. Calcic Andisols, andic Aridisols, and andic Mollisols, in the upper section, are the pedotypes that more commonly include Coprinisphaera. The intravolcanic environments where dung beetles, and probably large herbivores, better developed were temperate, seasonal, semiarid to subhumid, grasslands and wooded grasslands. They were covered by ashfalls reworked by wind and minor volcaniclastic flows.Fil: Sánchez, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales; ArgentinaFil: Genise, Jorge Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales; ArgentinaFil: Bellosi, Eduardo Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales; ArgentinaFil: Román Carrión, Jose Luis. Museo de Historia Natural "Gustavo Orcés V."; EcuadorFil: Cantil, Liliana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales; Argentin