bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological Assessment of Delirium Severity: The Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S)
Authors: van Sleuwen Meike , Sun Haoqi , Eckhardt Christine , Neelagiri Anudeepthi , Tesh Ryan A. , Westmeijer Mike , Paixao Luis , Rajan Subapriya , Velpula Krishnamurthy Parimala , Sikka Pooja , Leone Michael J. , Panneerselvam Ezhil , Quadri Syed A. , Akeju Oluwaseun , Kimchi Eyal Y. , Westover M. Brandon
Published: September 2021

OBJECTIVES:

Delirium is a common and frequently underdiagnosed complication in acutely hospitalized patients, and its severity is associated with worse clinical outcomes. We propose a physiologically based method to quantify delirium severity as a tool that can help close this diagnostic gap: the Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S).

DESIGN:

Retrospective cohort study.

SETTING:

Single-center tertiary academic medical center.

PATIENTS:

Three-hundred seventy-three adult patients undergoing electroencephalography to evaluate altered mental status between August 2015 and December 2019.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We developed the E-CAM-S based on a learning-to-rank machine learning model of forehead electroencephalography signals. Clinical delirium severity was assessed using the Confusion Assessment Method Severity (CAM-S). We compared associations of E-CAM-S and CAM-S with hospital length of stay and inhospital mortality. E-CAM-S correlated with clinical CAM-S (R = 0.67; p < 0.0001). For the overall cohort, E-CAM-S and CAM-S were similar in their strength of association with hospital length of stay (correlation = 0.31 vs 0.41, respectively; p = 0.082) and inhospital mortality (area under the curve = 0.77 vs 0.81; p = 0.310). Even when restricted to noncomatose patients, E-CAM-S remained statistically similar to CAM-S in its association with length of stay (correlation = 0.37 vs 0.42, respectively; p = 0.188) and inhospital mortality (area under the curve = 0.83 vs 0.74; p = 0.112). In addition to previously appreciated spectral features, the machine learning framework identified variability in multiple measures over time as important features in electroencephalography-based prediction of delirium severity.

CONCLUSIONS:

The E-CAM-S is an automated, physiologic measure of delirium severity that predicts clinical outcomes with a level of performance comparable to conventional interview-based clinical assessment.
Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia
Authors: Verma Vivek , Drury Gillian L. , Parisien Marc , Özdağ Acarli Ayşe N. , Al-Aubodah Tho-Alfakar , Nijnik Anastasia , wen Xia , Tugarinov Nicol , Verner Maria , Klares Richie , Linton Alexander , Krock Emerson , Morado Urbina Carlos E. , Winsvold Bendik , Fritsche Lars G. , Fors Egil A. ,   HUNT-All In Pain, Piccirillo Ciriaco , Khoutorsky Arkady , Svensson Camilla I. , Fitzcharles Mary A. , Ingelmo Pablo M. , Bernard Nicole F. , Dupuy Franck P. , Üçeyler Nurcan , Sommer Claudia , King Irah L. , Meloto Carolina B. , Diatchenko Luda
Published: September 2021

The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16–binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.
ANGPTL3 as therapeutic target
Authors: Kersten Sander
Published: September 2021

Purpose of review

Elevated LDL-C and triglycerides are important risk factors for the development of atherosclerotic cardiovascular disease. Although effective therapies for lipid lowering exist, many people do not reach their treatment targets. In the last two decades, ANGPTL3 has emerged as a novel therapeutic target for lowering plasma LDL-C and triglycerides. Here, an overview of the recent literature on ANGPTL3 is provided, focusing on the therapeutic benefits of inactivation of ANGPTL3 via monoclonal antibodies, antisense oligonucleotides, and other more nascent approaches. In addition, the potential mechanisms by which ANGPTL3 inactivation lowers plasma LDL-C are discussed.

Recent findings

ANGPTL3 is a factor secreted by the liver that inhibits lipoprotein lipase and other lipases via the formation of a complex with the related protein ANGPTL8. Large-scale genetic studies in humans have shown that carriers of loss-of-function variants in ANGPTL3 have lower plasma LDL-C and triglyceride levels, and are at reduced risk of atherosclerotic cardiovascular disease. Clinical studies in patients with different forms of dyslipidemia have demonstrated that inactivation of ANGPTL3 using monoclonal antibodies or antisense oligonucleotides markedly lowers plasma LDL-C and triglyceride levels.

Anti-ANGPTL3 therapies hold considerable promise for reducing plasma LDL-C and triglycerides in selected patient groups.
Genetic association of LPL rs326 with BMI among the Kuwaiti population
Authors: Malek Sara H. , Al-Serri Ahmad E. , Al-Bustan Suzanne A.
Published: September 2021

Lipoprotein lipase is a key enzyme in lipid metabolism with reported variants associated with obesity, hypertension, type 2 diabetes, and coronary heart disease. This study was performed to investigate the association between common lipoprotein lipase single nucleotide polymorphisms and metabolic disorders in a sample of Kuwaiti cohort (n = 494). Five lipoprotein lipase variants (rs1801177, rs295, rs326, ss2137497749, and ss2137497750) across the lipoprotein lipase gene were genotyped by real-time PCR employing the TaqMan allele discrimination assay. Genotype, allelic frequencies, and Hardy-Weinberg Equilibrium were determined for each variant in the cohort followed by multivariate and logistic regression analysis. A novel finding was observed for the G allele of single nucleotide polymorphism rs326 which was associated with increased BMI after adjusting for age and sex (β = 1.04; 95% confidence interval = 0.15–1.94; P = 0.02). Moreover, a significant difference in the distribution of the minor C allele of rs295 among coronary heart disease subjects compared with noncoronary heart disease, however, this significance was diminished after controlling for age, sex, and BMI. This study demonstrated that lipoprotein lipase rs326 may be indicative for the increased risk of obesity and possibly rs295 for coronary heart disease. The findings are also in agreement with other reports suggesting that intronic variants are important genetic markers in association studies. The findings warrant further studies in a large cohort to confirm and validate the results presented.
Host and brood parasite coevolutionary interactions covary with comparative patterns of the avian visual system
Authors: Ausprey Ian J. , Hauber Mark E.
Published: September 2021

In coevolutionary arms-races, reciprocal ecological interactions and their fitness impacts shape the course of phenotypic evolution. The classic example of avian host–brood parasite interactions selects for host recognition and rejection of increasingly mimetic foreign eggs. An essential component of perceptual mimicry is that parasitic eggs escape detection by host sensory systems, yet there is no direct evidence that the avian visual system covaries with parasitic egg recognition or mimicry. Here, we used eye size measurements collected from preserved museum specimens as a metric of the avian visual system for species involved in host–brood parasite interactions. We discovered that (i) hosts had smaller eyes compared with non-hosts, (ii) parasites had larger eyes compared with hosts before but not after phylogenetic corrections, perhaps owing to the limited number of independent evolutionary origins of obligate brood parasitism, (iii) egg rejection in hosts with non-mimetic parasitic eggs positively correlated with eye size, and (iv) eye size was positively associated with increased avian-perceived host–parasite eggshell similarity. These results imply that both host-use by parasites and anti-parasitic responses by hosts covary with a metric of the visual system across relevant bird species, providing comparative evidence for coevolutionary patterns of host and brood parasite sensory systems.
Human voice pitch measures are robust across a variety of speech recordings: methodological and theoretical implications
Authors: Pisanski Katarzyna , Groyecka-Bernard Agata , Sorokowski Piotr
Published: September 2021

Fundamental frequency (
f
o
), perceived as voice pitch, is the most sexually dimorphic, perceptually salient and intensively studied voice parameter in human nonverbal communication. Thousands of studies have linked human
f
o
to biological and social speaker traits and life outcomes, from reproductive to economic. Critically, researchers have used myriad speech stimuli to measure
f
o
and infer its functional relevance, from individual vowels to longer bouts of spontaneous speech. Here, we acoustically analysed
f
o
in nearly 1000 affectively neutral speech utterances (vowels, words, counting, greetings, read paragraphs and free spontaneous speech) produced by the same 154 men and women, aged 18–67, with two aims: first, to test the methodological validity of comparing
f
o
measures from diverse speech stimuli, and second, to test the prediction that the vast inter-individual differences in habitual
f
o
found between same-sex adults are preserved across speech types. Indeed, despite differences in linguistic content, duration, scripted or spontan­­eous production and within-individual variability, we show that 42–81% of inter-individual differences in
f
o
can be explained between any two speech types. Beyond methodological implications, together with recent evidence that inter-individual differences in
f
o
are remarkably stable across the lifespan and generalize to emotional speech and nonverbal vocalizations, our results further substantiate voice pitch as a robust and reliable biomarker in human communication.
Genome organization and evolution of a eukaryotic nicotinate co-inducible pathway
Authors: Bokor Eszter , Flipphi Michel , Kocsubé Sándor , Ámon Judit , Vágvölgyi Csaba , Scazzocchio Claudio , Hamari Zsuzsanna
Published: September 2021

In
Aspergillus nidulans
a regulon including 11
hxn
genes (
hxnS
,
T
,
R
,
P
,
Y
,
Z
,
X
,
W
,
V
,
M
and
N
) is inducible by a nicotinate metabolic derivative, repressible by ammonium and under stringent control of the nitrogen-state-sensitive GATA factor AreA and the specific transcription factor HxnR. This is the first report in a eukaryote of the genomic organization of a possibly complete pathway of nicotinate utilization. In
A. nidulans
the regulon is organized in three distinct clusters, this organization is variable in the
Ascomycota
. In some
Pezizomycotina
species all 11 genes map in a single cluster; in others they map in two clusters. This variable organization sheds light on cluster evolution. Instances of gene duplication followed by or simultaneous with integration in the cluster, partial or total cluster loss, and horizontal gene transfer of several genes (including an example of whole cluster re-acquisition in
Aspergillus
of section
Flavi
) were detected, together with the incorporation in some clusters of genes not found in the
A. nidulans
co-regulated regulon, which underlie both the plasticity and the reticulate character of metabolic cluster evolution. This study provides a comprehensive phylogeny of six members of the cluster across representatives of all
Ascomycota
classes.
The multifaceted role of lemur tyrosine kinase 3 in health and disease
Authors: Ditsiou Angeliki , Gagliano Teresa , Samuels Mark , Vella Viviana , Tolias Christos , Giamas Georgios
Published: September 2021

In the last decade, LMTK3 (lemur tyrosine kinase 3) has emerged as an important player in breast cancer, contributing to the advancement of disease and the acquisition of resistance to therapy through a strikingly complex set of mechanisms. Although the knowledge of its physiological function is largely limited to receptor trafficking in neurons, there is mounting evidence that LMTK3 promotes oncogenesis in a wide variety of cancers. Recent studies have broadened our understanding of LMTK3 and demonstrated its importance in numerous signalling pathways, culminating in the identification of a potent and selective LMTK3 inhibitor. Here, we review the roles of LMTK3 in health and disease and discuss how this research may be used to develop novel therapeutics to advance cancer treatment.
FastMix: A Versatile Multi-Omics Data Integration Pipeline for Cell Type-Specific Biomarker Inference
Authors: Zhang Yun , Sun Hao , Mandava Aishwarya , Aevermann Brian D. , Kollmann Tobias R. , Scheuermann Richard H. , Qiu Xing , Qian Yu
Published: September 2021

We developed a novel analytic pipeline -FastMix- to integrate flow cytometry, bulk transcriptomics, and clinical covariates for statistical inference of cell type-specific gene expression signatures.FastMixaddresses the “largep, smalln” problem via a carefully designed linear mixed effects model (LMER), which is applicable for both cross-sectional and longitudinal studies. With a novel moment-based estimator,FastMixruns and converges much faster than competing methods for big data analytics. The pipeline also includes a cutting-edge flow cytometry data analysis method for identifying cell population proportions. Simulation studies showed thatFastMixproduced smaller type I/II errors with more accurate parameter estimation than competing methods. When applied to real transcriptomics and flow cytometry data in two vaccine studies,FastMix-identified cell type-specific signatures were largely consistent with those obtained from the single cell RNA-seq data, with some unique interesting findings.
New insights from GWAS on longitudinal and cross-sectional BMI and related phenotypes in admixed children with Native American and European ancestries
Authors: Vicuña Lucas , Barrientos Esteban , Norambuena Tomás , Alvares Danilo , Gana Juan Cristobal , Leiva Valeria , Mericq Veronica , Meza Cristian , Pereira Ana , Santos José L. , Eyheramendy Susana
Published: September 2021

Body-mass index (BMI) is a well-known marker of adiposity across all ages. The genetic architecture of BMI has been thoroughly studied among adults. In contrast, there are a few genome-wide association studies (GWAS) on children. Further, GWAS on children have been performed almost exclusively in Europeans at single ages. We aimed to better understand the genetic architecture of BMI trajectory across ages and how BMI is affected by Native American genetic ancestry. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed Chilean children with mostly European and Mapuche Native American genetic ancestry. We focused on BMI and two traits that occur at the minimum of the childhood BMI growth trajectory, namely, age at adiposity rebound (Age-AR) and BMI at adiposity rebound (BMI-AR). We found several variants in the immune geneHLA-DQB3that are strongly associated with BMI at ages 1.5-2.5 years old, but not at other ages. We also identified a variant in the sex-determining geneDMRT1significantly associated with Age-AR (P= 9.8 × 10−9). Further, BMI was significantly higher in Mapuche than in European children at all ages between 5.5 and 16.5 years old, but not before. Finally, Age-AR was significantly lower (P= 0.013) by 1.64 years in the Mapuche children compared with Europeans.
Acquired peripheral nerve injuries associated with severe COVID-19
Authors: Franz Colin K. , Murthy Nikhil K. , Malik George R. , Kwak Jean W. , D’Andrea Dom , Wolfe Alexis R. , Farr Ellen , Stearns Melanie A. , Deshmukh Swati , Tavee Jinny O. , Sun Fang , Swong Kevin N. , Rydberg Leslie , Cotton R. James , Wolfe Lisa F. , Walter James M. , Coleman John M. , Rogers John A.
Published: September 2021

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe COVID-19. We combine our latest data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.
Diagnostic surveillance of high-grade gliomas: towards automated change detection using radiology report classification
Authors: Noto Tommaso Di , Atat Chirine , Teiga Eduardo Gamito , Hegi Monika , Hottinger Andreas , Cuadra Meritxell Bach , Hagmann Patric , Richiardi Jonas
Published: September 2021

Natural Language Processing (NLP) on electronic health records (EHRs) can be used to monitor the evolution of pathologies over time to facilitate diagnosis and improve decision-making. In this study, we designed an NLP pipeline to classify Magnetic Resonance Imaging (MRI) radiology reports of patients with high-grade gliomas. Specifically, we aimed to distinguish reports indicating changes in tumors between one examination and the follow-up examination (treatment response/tumor progression versus stability). A total of 164 patients with 361 associated reports were retrieved from routine imaging, and reports were labeled by one radiologist. First, we assessed which embedding is more suitable when working with limited data, in French, from a specific domain. To do so, we compared a classic embedding techniques, TF-IDF, to a neural embedding technique, Doc2Vec, after hyperparameter optimization for both. A random forest classifier was used to classify the reports into stable (unchanged tumor) or unstable (changed tumor). Second, we applied the post-hoc LIME explainability tool to understand the decisions taken by the model. Overall, classification results obtained in repeated 5-fold cross-validation with TF-IDF reached around 89% AUC and were significantly better than those achieved with Doc2Vec (Wilcoxon signed-rank test,P= 0.009). The explainability toolkit run on TF-IDF revealed some interesting patterns: first, words indicating change such asprogressionwere rightfully frequent for reports classified as unstable; similarly, words indicating no change such asnotwere frequent for reports classified as stable. Lastly, the toolkit discovered misleading words such asT2which are clearly not directly relevant for the task. All the code used for this study is made available.
Reddit discussions about buprenorphine associated precipitated withdrawal in the era of fentanyl
Authors: Spadaro Anthony , Sarker Abeed , Hogg-Bremer Whitney , Love Jennifer S , O’Donnell Nicole , Nelson Lewis S. , Perrone Jeanmarie
Published: September 2021

Background

Buprenorphine is an evidence-based treatment for Opioid Use Disorder (OUD). Standard buprenorphine induction requires a period of opioid abstinence to minimize risk of precipitated opioid withdrawal (POW). Our objective was to study the impact of the increasing presence of fentanyl and its analogs in the opioid supply of the United States, on buprenorphine induction and POW, using social media data from Reddit.

Methods

This is a data-driven, mixed methods study of opioid-related forums, called subreddits, on Reddit to analyze posts related to fentanyl, POW, and buprenorphine induction. The posts were collected from seven subreddits using an application programming interface for Reddit. We applied natural language processing to identify subsets of salient posts relevant to buprenorphine induction, and performed manual, qualitative, thematic analyses of them.

Results

267,136 posts were retrieved from seven subreddits. Fentanyl mentions increased from 3 in 2013 to 3870 in 2020, and POW mentions increased from 2 (2012) to 332 (2020). Manual review of 384 POW-mentioning posts and 106 ‘Bernese method’ (a microdosing induction strategy) mentioning posts revealed common themes and peoples’ experiences. Specifically, presence of fentanyl caused POWs despite long abstinence durations, and alternative induction via microdosing were frequently recommended in peer-to-peer discussions.

Conclusions

This study found that increased social media chatter on Reddit about POW correlated with fentanyl mentions. A subset of posts described microdosing as a self-management strategy to avoid POW. Reddit posts suggest that people are utilizing these strategies to initiate buprenorphine due to challenges arising from fentanyl prevalence in the opioid supply.

Highlights

Increase in mentions of precipitated opioid withdrawal (POW) on Reddit from 2012 to 2021 was closely correlated with the increase in fentanyl mentions.

Experiences of precipitated opioid withdrawal (POW) were described by individuals who reported sufficient periods of abstinence by standard buprenorphine induction protocols.

People with Opioid Use Disorder (OUD) on Reddit are using and recommending microdosing strategies with buprenorphine to avoid POW.

People who used fentanyl report experiencing POW following statistically longer periods of abstinence than people who use heroin.
Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program
Authors: Pagadala Meghana S. , Lynch Julie , Karunamuni Roshan , Alba Patrick R. , Lee Kyung Min , Agiri Fatai Y. , Anglin Tori , Carter Hannah , Gaziano J. Michael , Jasuja Guneet Kaur , Deka Rishi , Rose Brent S. , Panizzon Matthew S. , Hauger Richard L. , Seibert Tyler M.
Published: September 2021

Background

Genetic scores may provide an objective measure of a man’s risk of prostate cancer and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of prostate cancer in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneous, high-risk group

Methods

This was a retrospective analysis of Million Veteran Program (MVP), a national, population-based cohort study of United States military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race/ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.

Results

590,750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial/ethnic group (p<10−10). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for fatal prostate cancer was 4.42 [95% CI: 3.91-5.02]. When accounting for guideline-recommended risk factors (family history, race/ethnicity), PHS290 remained the strongest independent predictor of any, metastatic, and fatal prostate cancer.

Conclusions

PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.
Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data
Authors: Zhang Martin Jinye , Hou Kangcheng , Dey Kushal K. , Sakaue Saori , Jagadeesh Karthik A. , Weinand Kathryn , Taychameekiatchai Aris , Rao Poorvi , Pisco Angela Oliveira , Zou James , Wang Bruce , Gandal Michael , Raychaudhuri Soumya , Pasaniuc Bogdan , Price Alkes L.
Published: September 2021

Gene expression at the individual cell-level resolution, as quantified by single-cell RNA-sequencing (scRNA-seq), can provide unique insights into the pathology and cellular origin of diseases and complex traits. Here, we introduce single-cell Disease Relevance Score (scDRS), an approach that links scRNA-seq with polygenic risk of disease at individual cell resolution without the need for annotation of individual cells to cell types; scDRS identifies individual cells that show excess expression levels for genes in a disease-specific gene set constructed from GWAS data. We determined via simulations that scDRS is well-calibrated and powerful in identifying individual cells associated to disease. We applied scDRS to GWAS data from 74 diseases and complex traits (average N =346K) in conjunction with 16 scRNA-seq data sets spanning 1.3 million cells from 31 tissues and organs. At the cell type level, scDRS broadly recapitulated known links between classical cell types and disease, and also produced novel biologically plausible findings. At the individual cell level, scDRS identified subpopulations of disease-associated cells that are not captured by existing cell type labels, including subpopulations of CD4+ T cells associated with inflammatory bowel disease, partially characterized by their effector-like states; subpopulations of hippocampal CA1 pyramidal neurons associated with schizophrenia, partially characterized by their spatial location at the proximal part of the hippocampal CA1 region; and subpopulations of hepatocytes associated with triglyceride levels, partially characterized by their higher ploidy levels. At the gene level, we determined that genes whose expression across individual cells was correlated with the scDRS score (thus reflecting co-expression with GWAS disease genes) were strongly enriched for gold-standard drug target and Mendelian disease genes.
Identification of Common genes and proteins in Alzheimer’s Disease, Multiple Sclerosis and Duchenne Muscular Dystrophy using in-silico methods
Authors: Singh Subhankar Kumar , Chakraborty Souvik , Maiti Tarasankar , Chakraborty Anuska
Published: September 2021

Alzheimer’s is a type of dementia symptom that slowly worsens over some time. In its early stages, memory loss is mild, but with late-stage Alzheimer’s, the patient loses the ability to carry on a conversation and respond to their environment. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, gliosis, and neuronal loss. Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. It is the most common hereditary neuromuscular disease and does not exhibit a predilection for any race or ethnic group. In this study, several gene expression study data were analyzed and there were 557 Differentially Expressed Genes (DEGs) in all three chosen Datasets. A protein-protein interaction network was created using STRING and CytoHubba plug-in was used to identify the top ten genes which are POLR2A, SETD2, EFTUD2, RBM25, PRPF40A, CDK13, BPTF, THOC2, SNRNP70, and SCAF11. Online software Enrichr was used for Gene Ontology and KEGG pathway enrichment analysis to find out the biological process, molecular function, cellular component, and the pathways that are commonly affected in these diseases.
Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain
Authors: Neuser Sonja , Krey Ilona , Schwan Annemarie , Jamra Rami Abou , Bartolomaeus Tobias , Döring Jan , Syrbe Steffen , Plassmann Margit , Rohde Stefan , Roth Christian , Rehder Helga , Radtke Maximilian , Le Duc Diana , Schubert Susanna , Bermúdez-Guzmán Luis , Leal Alejandro , Schoner Katharina , Popp Bernt
Published: September 2021

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist.

We present the first prenatal diagnosis of PNKP-related primary microcephaly. Detailed pathological examination of a male fetus revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities in a sibling fetus. Prenatal trio exome sequencing identified compound-heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sibling fetus. Through RNA analyses, we characterized skipping of exon 4 affecting the PNKP Forkhead-associated (FHA) and Phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the same splice-donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro) and c.151G>C, p.(Val51Leu), respectively). RNA-seq showed complex splicing events for c.1029+2T>C and c.151G>C. Computational modelling and structural analysis revealed significant clustering of missense variants in the FHA domain, with some variants potentially generating structural damage.

Our detailed clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modelling, we highlight the mutational complexity and exemplify a framework for variant characterization in this multi-domain protein.
Donor clonal hematopoiesis and recipient outcomes after transplantation
Authors: Gibson Christopher J. , Kim Haesook T. , Zhao Lin , Murdock H. Moses , Hambley Bryan , Ogata Alana , Madero-Marroquin Rafael , Wang Shiyu , Green Lisa , Fleharty Mark , Dougan Tyler , Cheng Chi-An , Blumenstiel Brendan , Cibulskis Carrie , Tsuji Junko , Duran Madeleine , Gocke Christopher D. , Antin Joseph H. , Nikiforow Sarah , DeZern Amy E. , Chen Yi-Bin , Ho Vincent T. , Jones Richard J. , Lennon Niall J. , Walt David R. , Ritz Jerome , Soiffer Robert J. , Gondek Lukasz P. , Lindsley R. Coleman
Published: September 2021

Background

Clonal hematopoiesis (CH) can be transmitted from donor to recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.

Methods

We performed targeted error-corrected sequencing on samples from 1727 donors aged 40 or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.

Results

CH was present in 22.5% of donors, withDNMT3A(14.6%) andTET2(5.2%)mutations being most common; 85% of donor clones showed engraftment in recipients after transplantation, including clones with variant allele fraction (VAF)<0.01.DNMT3A-CH with VAF≥0.01, but not smaller clones, was associated with improved recipient overall (HR 0.79, P=0.042) and progression-free survival (HR 0.72, P=0.003) after adjustment for significant clinical variables. In patients receiving calcineurin-based GVHD prophylaxis, donorDNMT3A-CH was associated with reduced relapse (sHR 0.59, P=0.014), increased chronic GVHD (sHR 1.36, P=0.042), and higher IL-12p70 levels in recipients. No recipient of sole DNMT3A orTET2-CH developed donor cell leukemia (DCL). In 7 of 8 cases, DCL evolved from donor CH with rareTP53or splicing factor mutations or from donors carrying germlineDDX41mutations.

Conclusion

Donor CH is associated with clinical outcomes in transplant recipients, with differential impact on alloimmune function and potential for leukemic transformation related to mutated gene and clonal abundance.DNMT3A-CH is associated with improved recipient survival due to reduced relapse risk and an augmented network of inflammatory cytokines in recipients. Risk of DCL is driven by pre-existing somatic MDS-associated mutations or germline predisposition in donors.
CD14 Positive Extracellular Vesicles in Broncho-Alveolar Lavage Fluid as a New Biomarker of Acute Respiratory Distress Syndrome
Authors: Mahida Rahul Y. , Price Joshua , Lugg Sebastian T. , Li Hui , Parekh Dhruv , Scott Aaron , Harrison Paul , Matthay Michael A. , Thickett David R.
Published: September 2021

Recent studies have indicated that extracellular vesicles (EV) may play a role in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS). EV have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within ARDS patient broncho-alveolar lavage fluid (BAL), and to determine whether BAL EV could be utilized as a potential biomarker in ARDS. BAL was collected from sepsis patients with and without ARDS, and from esophagectomy patients post-operatively (of whom a subset later developed ARDS during hospital admission). BAL EV were characterized with regards to size, number and cell of origin. Sepsis patients with ARDS had significantly higher numbers of CD14+/CD81+ monocyte-derived BAL EV than sepsis patients without ARDS (p=0.015). However, the converse was observed in esophagectomy patients who later developed ARDS (p=0.003). Esophagectomy patients who developed ARDS also had elevated CD31+/CD63+ and CD31+/CD81+ endothelial-derived BAL EV (p≤0.02) compared to esophagectomy patients who did not develop ARDS. Further studies are required to determine whether CD31+ BAL EV may be a predictive biomarker for ARDS in esophagectomy patients. CD14+/CD81+ BAL EV numbers were significantly higher in those patients with sepsis-related ARDS who died during the 30 days following ICU admission (p=0.027). Thus, CD14+/CD81+ BAL EV are a potential biomarker for disease severity and mortality in sepsis-related ARDS. These findings provide the impetus to further elucidate the contribution of these EV to ARDS pathogenesis.
A prevaccination validated network that drives the breadth of the protective neutralizing antibody response following Dengue Vaccine TV003 immunization
Authors: Pelletier Adam Nicolas , Sanchez Gabriela , Watson Mark , Izmirly Abdullah , Di Pucchio Tiziana , Haddad Elias , Paramithiotis Eustache , Khalil Jorge , Diamond Michael , Kallas Esper , Sekaly Rafick Pierre
Published: September 2021

Development of fully protective dengue virus (DV) vaccines has been problematic as infection with DV requires a broad antibody immune response that targets all 4 possible serotypes. Herein, we used an integrated systems vaccinology approach to identify prevaccination features that allow the development of fully protective DV-specific antibody responses. This approach allowed us to identify a transcription network in a subset of monocytes defined by the expression of CD68 and downstream of specific pro- and anti-inflammatory cytokines. Moreover, we identified metabolites as drivers of an immune response that induced neutralizing antibodies to the 4 DV serotypes. Specifically, PC/PE drove the production of TGF-B in CD68 low monocytes, which was a positive correlate of the protective antibody response. In contrast, primary and secondary bile acids triggered a proinflammatory response downstream of TGR5 signaling and inflammasome activation in CD68 high monocytes, which was associated to a non-protective antibody response. These features were validated in vitro in primary myeloid cells. Our results highlight the role of cell and systemic metabolism as regulators of protective immune responses to vaccination, and that systems vaccinology is a key tool to identify such mechanisms.
Practices for Measuring 3D Organelle Morphology and Generating Surfaces with Amira
Authors: Lopez Edgar Garza , Vue Zer , Katti Prasanna , Neikirk Kit , Biete Michelle , Lam Jacob , Beasley Heather K. , Marshall Andrea G. , Rodman Taylor , Christensen Trace , Salisbury Jeffrey , Vang Larry , Mungai Margaret , AshShareef Salma , Murray Sandra , Shao Jianqiang , Streeter Jennifer , Glancy Brian , Pereira Renata O. , Abel E. Dale , Hinton Antentor
Published: September 2021

Analysis of 3D structures is of paramount importance in cellular biology. Although light microscopy and transmission electron microscopy (TEM) have remained staples for imaging cellular structures, they lack the ability to image in 3D. However, recent technological advances, such as serial block-face scanning electron microscopy (SBF-SEM) and focused ion beam scanning electron microscopy (FIB-SEM), have allowed researchers to observe cellular ultrastructure in 3D. Here, we propose a standardized protocol using the visualization software Amira to quantify organelle morphologies in 3D; this method allows researchers to produce accurate and reproducible measurements of cellular structure characteristics. We demonstrate this applicability by utilizing SBF-SEM and Amira to quantify mitochondria and endoplasmic reticulum (ER) structures.

GRAPHICAL ABSTRACT
CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis
Authors: Baker David , MacDougall Amy , Kang Angray S. , Schmierer Klaus , Giovannoni Gavin , Dobson Ruth
Published: September 2021

Background

CD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown.

Methods

Relapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via theclinicalstudydatarequest.comportal.

Results

Only 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab.

Conclusions

Few people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.
Bayesian approach to comparing the left ventricular volume in myocardial infarction and in normal cases
Authors: Hernowo A.T.
Published: September 2021

Introduction

Post-contrast delayed-enhancement MRI helps to show the extent of myocardial infarction (MI), as well as allowing the morphometric analysis of the heart structure, e.g., left ventricular volume (LVV). Here the author deployed Bayesian implementation of statistical inference to determine the difference between the LVV in MI cases and in normal controls.

Methods

Sixty-seven MI patients and thirty-three controls from the EMIDEC dataset challenge were used. These were acquired at the University Hospital of Dijon (France). A cardiologist with 10 years of experience in cardiology and MRI and a biophysicist with 20 years of experience of cardiovascular MRI supervised the acquisition and annotated the images. ITK-Snap was used to extract the LVV and Bayesian inference were used to investigate the data.

Results

Patients with MI were younger than the controls (58.3 ± 11.5 vs. 66.5 ± 12.9 years; BF10 = 17.9). With age taken into consideration, the patients showed larger LVV relative to the controls (128.1 ± 46.3 vs. 83.4 ± 24.4 cm3; post-hoc BF10 = 12663.8).

Using Bayesian approach, we can conclude decisively that there is volumetric difference or remodeling in individuals with MI.
Effectiveness of the mRNA BNT162b2 vaccine against SARS-CoV-2 severe infections in the Israeli over 60 population: a temporal analysis done by using the national surveillance data
Authors: De Leo Stefano
Published: September 2021

Last August, when the delta variant became the dominant infection strain, Israel, one of the countries with the highest levels of vaccination in the world, faced a scary pandemic wave. The frighteningly increasing number of infections was seen as the perfect storm to test the effectiveness of the mRNA BNT162b2 vaccine. The new surge forced the government to use a booster shot to protect the most vulnerable age groups. Starting from the August national surveillance data, we analysed the temporal effectiveness of vaccination against severe infections in the Israeli over 60 population. The study shows that the two-dose vaccine still works in preventing people from getting seriously sick but not with the same effectiveness observed in the first months of 2021. However, the observed temporal increase of the vaccine effectiveness in Israel, during August, suggests a correlation with the increase of the population protected by the booster shot.
Bayesian Inference of State-Level COVID-19 Basic Reproduction Numbers across the United States
Authors: Mallela Abhishek , Neumann Jacob , Miller Ely F. , Chen Ye , Posner Richard G. , Lin Yen Ting , Hlavacek William S.
Published: September 2021

Although many persons in the United States have acquired immunity to COVID-19, either through vaccination or infection with SARS-CoV-2, COVID-19 will pose an ongoing threat to non-immune persons so long as disease transmission continues. We can estimate when sustained disease transmission will end in a population by calculating the population-specific basic reproduction number ℛ0, the expected number of secondary cases generated by an infected person in the absence of any interventions. The value of ℛ0 relates to a herd immunity threshold (HIT), which is given by 1 − 1/ℛ0. When the immune fraction of a population exceeds this threshold, sustained disease transmission becomes exponentially unlikely (barring mutations allowing SARS-CoV-2 to escape immunity). Here, we report state-level ℛ0 estimates obtained using Bayesian inference. Maximum a posteriori estimates range from 7.1 for New Jersey to 2.3 for Wyoming, indicating that disease transmission varies considerably across states and that reaching herd immunity will be more difficult in some states than others. ℛ0 estimates were obtained from compartmental models via the next-generation matrix approach after each model was parameterized using regional daily confirmed case reports of COVID-19 from 21-January-2020 to 21-June-2020. Our ℛ0 estimates characterize infectiousness of ancestral strains, but they can be used to determine HITs for a distinct, currently dominant circulating strain, such as SARS-CoV-2 variant Delta (lineage B.1.617.2), if the relative infectiousness of the strain can be ascertained. On the basis of Delta-adjusted HITs, vaccination data, and seroprevalence survey data, we find that no state has achieved herd immunity as of 20-September-2021.

Significance Statement

COVID-19 will continue to threaten non-immune persons in the presence of ongoing disease transmission. We can estimate when sustained disease transmission will end by calculating the population-specific basic reproduction number ℛ0, which relates to a herd immunity threshold (HIT), given by 1 − 1/ℛ0. When the immune fraction of a population exceeds this threshold, sustained disease transmission becomes exponentially unlikely. Here, we report state-level ℛ0 estimates indicating that disease transmission varies considerably across states. Our ℛ0 estimates can also be used to determine HITs for the Delta variant of COVID-19. On the basis of Delta-adjusted HITs, vaccination data, and serological survey results, we find that no state has yet achieved herd immunity.
Prime-seq, efficient and powerful bulk RNA-sequencing
Authors: Janjic Aleksandar , Wange Lucas E. , Bagnoli Johannes W. , Geuder Johanna , Nguyen Phong , Richter Daniel , Vieth Beate , Vick Binje , Jeremias Irmela , Ziegenhain Christoph , Hellmann Ines , Enard Wolfgang
Published: September 2021

With the advent of Next Generation Sequencing, RNA-sequencing (RNA-seq) has become the major method for quantitative gene expression analysis. Reducing library costs by early barcoding has propelled single-cell RNA-seq, but has not yet caught on for bulk RNA-seq. Here, we optimized and validated a bulk RNA-seq method we call prime-seq. We show that with respect to library complexity, measurement accuracy, and statistical power it performs equivalent to TruSeq, a standard bulk RNA-seq method, but is four-fold more cost-efficient due to almost 50-fold cheaper library costs. We also validate a direct RNA isolation step that further improves cost and time-efficiency, show that intronic reads are derived from RNA, validate that prime-seq performs optimal with only 1,000 cells as input, and calculate that prime-seq is the most cost-efficient bulk RNA-seq method currently available. We discuss why many labs would profit from a cost-efficient early barcoding RNA-seq protocol and argue that prime-seq is well suited for setting up such a protocol as it is well validated, well documented, and requires no specialized equipment.
Admixture of evolutionary rates across a hybrid zone
Authors: Xiong Tianzhu , Li Xueyan , Yago Masaya , Mallet James
Published: September 2021

Hybridization is a major evolutionary force that can erode genetic differentiation between species, whereas reproductive isolation maintains such differentiation. In studying a hybrid zone between the swallowtail butterflies Papilio syfanius and Papilio maackii, we made the unexpected discovery that genomic substitution rates are unequal between the parental species. This phenomenon creates a novel process in hybridization, where genomic regions most affected by gene flow evolve at similar rates, while genomic regions with greater reproductive isolation evolve at divergent rates. Thus, hybridization mixes evolutionary rates in a way similar to its effect on ancestry. Using coalescent theory, we show that the rate-mixing process provides distinct information about levels of gene flow across different parts of genomes, and that maintenance of divergent substitution rates can be predicted quantitatively from relative sequence divergence (FST) between the hybridizing species at equilibrium. A corollary is that divergent rates will be maintained in regions linked to barrier loci. Overall, we demonstrate that reproductive isolation maintains not only the final outcome of genomic differentiation, but also the rate at which differentiation accumulates. This new information also suggests that the separation of evolutionary rates co-localizes with the separation of gene pools between genomes of incipient species.