Emergent Pulmonary Embolectomy and Advanced Glioblastoma Multiforme

Pulmonary emboli are frequent causes of morbidity and mortality in patients with brain tumors. Treatment options are limited in these complex patients. We report a case of successful acute pulmonary embolectomy in a patient with an advanced brain cancer

Genetic epidemiology of motor neuron disease-associated variants in the Scottish population

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population

Tsx Produces a Long Noncoding RNA and Has General Functions in the Germline, Stem Cells, and Brain

The Tsx gene resides at the X-inactivation center and is thought to encode a protein expressed in testis, but its function has remained mysterious. Given its proximity to noncoding genes that regulate X-inactivation, here we characterize Tsx and determine its function in mice. We find that Tsx is actually noncoding and the long transcript is expressed robustly in meiotic germ cells, embryonic stem cells, and brain. Targeted deletion of Tsx generates viable offspring and X-inactivation is only mildly affected in embryonic stem cells. However, mutant embryonic stem cells are severely growth-retarded, differentiate poorly, and show elevated cell death. Furthermore, male mice have smaller testes resulting from pachytene-specific apoptosis and a maternal-specific effect results in slightly smaller litters. Intriguingly, male mice lacking Tsx are less fearful and have measurably enhanced hippocampal short-term memory. Combined, our study indicates that Tsx performs general functions in multiple cell types and links the noncoding locus to stem and germ cell development, learning, and behavior in mammals

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Quality versus Quantity: Determining Real-world Social Functioning Deficits in Schizophrenia

Social dysfunction is a hallmark of schizophrenia that is associated with emotional disturbances. Researchers have employed ecological momentary assessment (EMA) to measure social and emotional functioning in people with schizophrenia. Yet, few studies have evaluated quality of real-world social interactions, and it is unclear how interactions impact emotional experiences in this population. Using novel EMA that passively collects audio data, we examined daily social behavior and emotion in schizophrenia (n=38) and control (n=36) groups. Contrary to hypotheses, both groups interacted with others at the same rate and exhibited similar levels of positive emotion. However, as expected, the schizophrenia group exhibited significantly less high-quality interactions and reported more negative emotion than controls. Social versus non-social context did not influence experienced emotion in either group. This is the first real-world study to passively assess quality of social interactions in schizophrenia. Although those with schizophrenia did not differ in their number of interactions, they were less likely to engage in substantive, personal conversations. Because high-quality interactions are linked with better social outcomes, this finding has important potential treatment implications. Future research should investigate quality of interactions across different types of social activities to gain a more nuanced understanding of social dysfunction in schizophrenia

Do People With Schizophrenia Enjoy Social Activities as Much as Everyone Else? A Meta-analysis of Consummatory Social Pleasure

Background: The "emotion paradox" of schizophrenia suggests people with schizophrenia demonstrate deficits when reporting anticipated and retrospective pleasure; yet, in-the-moment, consummatory pleasure is largely intact. It is uncertain how these findings extend to social situations. This meta-analysis aimed to (1) determine the mean difference in consummatory social pleasure between people with schizophrenia and healthy controls, and (2) examine moderators of this effect, including study design and clinical characteristics of participants. Design: A literature search using PsycINFO, Web of Science, Pubmed, and EMBASE databases was conducted. Studies measuring consummatory social pleasure using experience sampling methods and laboratory social simulations were included. Random effects meta-analyses were conducted using Hedge's g. Results: Meta-analysis of 26 studies suggests people with schizophrenia exhibited a small, significant deficit in consummatory social pleasure (g = -0.38, 90% CI [-0.53, -0.22]). There was significant heterogeneity in effect sizes; magnitude was moderated by study design and type of measure used to assess social pleasure. Conclusions: Overall, people with schizophrenia seem to exhibit less consummatory social pleasure than controls. However, this deficit is smaller than in studies of anticipated and retrospective pleasure. Thus, consummatory social pleasure may not be quite as impaired in people with schizophrenia as traditional anhedonia research suggests. Moreover, pleasure deficits observed in people with schizophrenia may result from differences in the quality of their daily social experiences rather than differences in their capacity for social pleasure. Results have important implications for clinical interventions that address barriers to social engagement, low-pleasure beliefs, and cognitive remediation to treat schizophrenia

Social Activity in Schizotypy: Measuring Frequency and Enjoyment of Social Events

Improving social functioning deficits—a core characteristic of schizophrenia-spectrum disorders—is often listed by patients as a key recovery goal. Evidence suggests that social deficits also extend to people with schizotypy, a group at heightened risk for psychotic and other psychopathological disorders. One challenge of social functioning research in schizotypy is understanding whether social deficits arise from receiving less pleasure from social activities or from participating less in high-pleasure activities. However, limited information exists on what constitutes highly pleasurable, common social activities. In this study, 357 college students rated the frequency and enjoyment of 38 social activities. Our aims were to categorize activities based on their frequency and enjoyment, and whether these correlated with validated social functioning and schizotypy measures. We found that social activities could be characterized based on their frequency and enjoyment and created a frequency–enjoyment matrix that could be useful for future studies. Activities were correlated with social functioning, generally reaching a small effect size level, with increasing frequency and enjoyment showing associations with greater social functioning. Further, negative and disorganized—but not positive—traits were associated with less engagement and pleasure. Although follow-up studies in community samples are needed, our findings have the potential to help researchers and clinicians better understand which activities participants are more likely to engage in and derive pleasure from. The findings may also illustrate the extent to which social deficits may be due to less engagement or less pleasure from social activities, as well as which aspects of schizophrenia-spectrum disorders are associated with these facets of social functioning