SNCA and TPPP transcripts increase in oligodendroglial cytoplasmic inclusions in multiple system atrophy.

Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.

Impact of Respiratory Viruses and SARS-CoV-2 on Febrile Seizures in Saudi Children: Insights into Etiologies, Gender, and Familial Associations.

BACKGROUND Childhood febrile seizures occur between 5 months and 6 years of age in children without a previous history of seizure and are associated with high temperature in the absence of intracranial infection. This retrospective study identified 71 children aged 6 months to 5 years with febrile seizures between 2017 and 2021 at a single center in Saudi Arabia and aimed to identify an association between common respiratory virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MATERIAL AND METHODS Pediatric nasopharyngeal specimens were tested using a multiplex PCR respiratory panel detecting human coronaviruses (NL63, 229E, OC43, HKU1), influenza A/B, human adenovirus, parainfluenza viruses 1-4, respiratory syncytial virus, human metapneumovirus, rhinovirus/enterovirus, Middle East respiratory syndrome coronavirus, and, as of September 2021, SARS-CoV-2, confirmed using the Cepheid Xpert Xpress SARS-CoV2 RT-PCR kit. RESULTS In a cohort of 71 pediatric patients (median age, 19 months; 54.9% female), dominant pathogens included human rhinovirus/enterovirus (23.9%), influenza A/B (26.8%), and SARS-CoV-2 (14.1%). Concurrent infections were noted in 28.2%. Simple seizures occurred in 69%, and complex seizures in 31%. Females exhibited an 8.18-fold increased risk for complex seizures. Each additional fever day reduced complex seizure risk by 36%. Familial seizure history increased risk 8.76-fold. Human rhinovirus/enterovirus or parainfluenza infections inversely affected complex seizure likelihood compared with adenovirus. CONCLUSIONS In Saudi children with febrile seizures, distinct viral etiologies, sex, and familial links play pivotal roles. Given regional viral variations, region-tailored diagnostic and therapeutic strategies are paramount. A multicenter prospective cohort study is essential for comprehensive understanding.

Single-cell reconstruction and mutation enrichment analysis identifies dysregulated cardiomyocyte and endothelial cells in congenital heart disease.

Congenital heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. To catalog the putative candidate CHD risk genes, we collected 16,349 variants [single-nucleotide variants (SNVs) and Indels] impacting 8,308 genes in 3,166 CHD cases for a comprehensive meta-analysis. Using American College of Medical Genetics (ACMG) guidelines, we excluded the 0.1% of benign/likely benign variants and the resulting dataset consisted of 83% predicted loss of function variants and 17% missense variants. Seventeen percent were de novo variants. A stepwise analysis identified 90 variant-enriched CHD genes, of which six (GPATCH1, NYNRIN, TCLD2, CEP95, MAP3K19, and TTC36) were novel candidate CHD genes. Single-cell transcriptome cluster reconstruction analysis on six CHD tissues and four controls revealed upregulation of the top 10 frequently mutated genes primarily in cardiomyocytes. NOTCH1 (highest number of variants) and MYH6 (highest number of recurrent variants) expression was elevated in endocardial cells and cardiomyocytes, respectively, and 60% of these gene variants were associated with tetralogy of Fallot and coarctation of the aorta, respectively. Pseudobulk analysis using the single-cell transcriptome revealed significant (P < 0.05) upregulation of both NOTCH1 (endocardial cells) and MYH6 (cardiomyocytes) in the control heart data. We observed nine different subpopulations of CHD heart cardiomyocytes of which only four were observed in the control heart. This is the first comprehensive meta-analysis combining genomics and CHD single-cell transcriptomics, identifying the most frequently mutated CHD genes, and demonstrating CHD gene heterogeneity, suggesting that multiple genes contribute to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.NEW & NOTEWORTHY Congential heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. We present a comprehensive analysis combining genomics and CHD single-cell transcriptome. Our study identifies 90 potential candidate CHD risk genes of which 6 are novel. The risk genes have heterogenous expression suggestive of multiple genes contributing to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.

Overlapping pathogenic de novo CNVs in neurodevelopmental disorders and congenital anomalies impacting constraint genes regulating early development.

Neurodevelopmental disorders (NDDs) and congenital anomalies (CAs) are rare disorders with complex etiology. In this study, we investigated the less understood genomic overlap of copy number variants (CNVs) in two large cohorts of NDD and CA patients to identify de novo CNVs and candidate genes associated with both phenotypes. We analyzed clinical microarray CNV data from 10,620 NDD and 3176 CA cases annotated using Horizon platform of GenomeArc Analytics and applied rigorous downstream analysis to evaluate overlapping genes from NDD and CA CNVs. Out of 13,796 patients, only 195 cases contained 218 validated de novo CNVs. Eighteen percent (31/170) de novo CNVs in NDD cases and 40% (19/48) de novo CNVs in CA cases contained genomic overlaps impacting developmentally constraint genes. Seventy-nine constraint genes (10.1% non-OMIM entries) were found to have significantly enriched genomic overlap within rare de novo pathogenic deletions (P value = 0.01, OR = 1.58) and 45 constraint genes (13.3% non-OMIM entries) within rare de novo pathogenic duplications (P value = 0.01, OR = 1.97). Analysis of spatiotemporal transcriptome demonstrated both pathogenic deletion and duplication genes to be highly expressed during the prenatal stage in human developmental brain (P value = 4.95 X 10-6). From the list of overlapping genes, EHMT1, an interesting known NDD gene encompassed pathogenic deletion CNVs from both NDD and CA patients, whereas FAM189A1, and FSTL5 are new candidate genes from non-OMIM entries. In summary, we have identified constraint overlapping genes from CNVs (including de novo) in NDD and CA patients that have the potential to play a vital role in common disease etiology.

oFlowSeq: a quantitative approach to identify protein coding mutations affecting cell type enrichment using mosaic CRISPR-Cas9 edited cerebral organoids.

Cerebral organoids are comprised of diverse cell types found in the developing human brain, and can be leveraged in the identification of critical cell types perturbed by genetic risk variants in common, neuropsychiatric disorders. There is great interest in developing high-throughput technologies to associate genetic variants with cell types. Here, we describe a high-throughput, quantitative approach (oFlowSeq) by utilizing CRISPR-Cas9, FACS sorting, and next-generation sequencing. Using oFlowSeq, we found that deleterious mutations in autism-associated gene KCTD13 resulted in increased proportions of Nestin+ cells and decreased proportions of TRA-1-60+ cells within mosaic cerebral organoids. We further identified that a locus-wide CRISPR-Cas9 survey of another 18 genes in the 16p11.2 locus resulted in most genes with > 2% maximum editing efficiencies for short and long indels, suggesting a high feasibility for an unbiased, locus-wide experiment using oFlowSeq. Our approach presents a novel method to identify genotype-to-cell type imbalances in an unbiased, high-throughput, quantitative manner.

Separation of CTCs from WBCs using DEP-assisted inertial manipulation: A numerical study.

Isolation and detection of circulating tumor cells (CTCs) hold significant importance for the early diagnosis of cancer and the assessment of therapeutic strategies. However, the scarcity of CTCs among peripheral blood cells presents a major challenge to their detection. Additionally, a similar size range between CTCs and white blood cells (WBCs) makes conventional microfluidic platforms inadequate for the isolation of CTCs. To overcome these challenges, in this study, a novel inertial-dielectrophoretic microfluidic channel for size-independent, single-stage separation of CTCs from WBCs has been presented. The proposed device utilizes a spiral microchannel embedded with interdigitated electrodes. A numerical model is developed and validated to investigate the influence of various parameters related to the channel design, fluid flow, and electrode configuration. It was found that optimal separation of CTCs could be obtained at a relatively low voltage, termed the critical voltage. Furthermore, at the critical voltage of 7.5 V, the hybrid microchannel is demonstrated to be capable of separating CTCs from different WBC subtypes including granulocytes, monocytes, T-, and B-lymphocytes. The unique capabilities of the hybrid spiral microchannel allow for this size-independent isolation of CTCs from a mixture of WBCs. Overall, the proposed technique can be readily utilized for continuous and high-throughput separation of cancer cells.

Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy.

Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducing MAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial cells do not express enough MAPT. Although studies have evaluated MAPT expression in human brain tissue homogenates, it is not clear whether MAPT expression is compromised in cells accumulating pathological tau. To address these perplexing aspects of disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), and single-nuclear(sn) RNAseq to systematically map and quantify MAPT expression dynamics across different cell types and brain regions in controls (n = 3) and evaluated whether tau cytopathology affects MAPT expression in PSP (n = 3). MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP. These results propose a complex scenario in all cell types, where, in addition to the ingested misfolded tau, the preserved cellular MAPT expression provides a pool for local protein production that can (1) be phosphorylated and aggregated, or (2) feed the seeding of ingested misfolded tau by providing physiological tau, both accentuating the pathological process. Since tau cytopathology does not compromise MAPT gene expression in PSP, a complete loss of tau protein expression as an early pathogenic component is less likely. These observations provide rationale for a dual approach to therapy by decreasing cellular MAPT expression and targeting removal of misfolded tau.

Left atrial appendage closure device outcomes among cirrhosis patients with atrial fibrillation: a United States National Cohort Study.

AIMS: Literature regarding outcomes associated with atrial fibrillation among cirrhosis patients who had left atrial appendage occlusion (LAAO) device procedure is limited. We aim to evaluate the in-hospital clinical outcomes and 30-day readmissions among LAAO with and without cirrhosis. METHODS AND RESULTS: We performed a retrospective study of all hospitalizations associated with the LAAO procedure, using the Nationwide Readmissions Database for the years 2016-19. Primary outcomes were in-hospital clinical outcomes and 30-day readmissions. A total of 54 897 index hospitalizations for LAAO (female 41.8%) were reported. Of these, 905(1.65%) had cirrhosis. Gastrointestinal (GI) bleeding was reported in 44 (4.9%) vs. 1606 (2.97%) and coagulopathy in 21 (2.3%) vs. 521 (0.96%) in cirrhosis and without-cirrhosis groups, respectively. A total of 872 (1.59%) patients needed blood transfusion, 24 (2.7%) vs. 848(1.57%) in cirrhosis vs. without-cirrhosis groups (P = 0.047). Fresh frozen plasma (FFP) transfusion was reported among 888 (1.62%), with cirrhosis 26 (3%) vs. without cirrhosis 862 (1.6%) (P = 0.05). On adjusted multivariate logistic regression analysis, acute kidney injury, coagulopathy, FFP transfusion, and blood transfusion were strongly associated with cirrhosis, and GI bleeding, ischaemic stroke, and intracranial haemorrhage were not associated with cirrhosis. Readmissions in 30 days were 5028 (9.18%), 167 (18.5%) in the cirrhosis group and 4861 (9%) without-cirrhosis group (P = 0.01). On multivariate Cox regression, CHA2DS2-Vasc score of six was significantly associated with 30-day readmission compared with other scores [hazard ratio 2.24; 95% confidence interval (1.58-3.16); P < 0.001]. CONCLUSION: Left atrial appendage occlusion procedure in patients with cirrhosis had relatively similar GI bleeding and stroke rates, however, had higher rates of 30-day readmission. A higher CHA2DS2-Vasc score was more likely to be associated with 30-day readmissions and hence would help in discharge planning. The long-term safety and efficacy of LAAO in the cirrhosis population need to be demonstrated.

Characterization and whole-genome sequencing of an extreme arsenic-tolerant Citrobacter freundii SRS1 strain isolated from Savar area in Bangladesh.

Citrobacter freundii SRS1, gram-negative bacteria, were isolated from Savar, Bangladesh. The strain could tolerate up to 80 mmol L-1 sodium arsenite, 400 mmol L-1 sodium arsenate, 5 mmol L-1 manganese sulfate, 3 mmol L-1 lead nitrate, 2.5 mmol L-1 cobalt chloride, 2.5 mmol L-1 cadmium acetate, and 2.5 mmol L-1 chromium chloride. The whole-genome sequencing revealed that the genome size of C. freundii SRS1 is estimated to be 5.4 Mb long, and the G + C content is 51.7%. The genome of C. freundii SRS1 contains arsA, arsB, arsC, arsD, arsH, arsR, and acr3 genes for arsenic resistance; czcA, czcD, cbiN, and cbiM genes for cobalt resistance; chrA and chrB genes for chromium resistance; mntH, sitA, sitB, sitC, and sitD genes for manganese resistance; and zntA gene for lead and cadmium resistance. This novel acr3 gene has never previously been reported in any C. freundii strain except SRS1. A set of 130 completely sequenced strains of C. freundii was selected for phylogenomic analysis. The phylogenetic tree showed that the SRS1 strain is closely related to the C. freundii 62 strain. Further analyses of the genes involved in metal and metalloid resistance might facilitate identifying the mechanisms and pathways involved in high metal resistance in the C. freundii SRS1 strain.

Clinical Outcomes of Aortic Stenosis in Amyloidosis: A United States National Cohort Study.

BACKGROUND: Literature regarding outcomes associated with surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) among amyloidosis (AM) with aortic stenosis (AS) is limited. OBJECTIVES: We aim to study the mortality and in-hospital clinical outcomes among AM with AS associated with SAVR or TAVR. METHODS: We performed a retrospective study of all hospitalisation encounters associated with a diagnosis of AM with AS, using the Nationwide Readmissions Database for the years 2012-2019. Primary outcomes were in-hospital mortality, and 30-day readmissions. RESULTS: A total of 4,820 index hospitalisations of AS (mean age 78.35±10.11; female 37.76%) among AM were reported. Total 464 patients had mechanical intervention, 251 patients (54.1%) TAVR and 213 patients (45.9%) SAVR. A total of 317 patients (6.77%) with AS died; TAVR 4.4%, SAVR 11.9% (p=0.01) and 6.66% died among the subgroup who did not have any mechanical intervention. Higher complication rates were observed among patients who had SAVR than those who had TAVR including acute kidney injury (39.8% vs 22.4%; p=0.01), septic shock (12.1% vs 4.4%; p=0.05) and cardiogenic shock (22% vs 4.4%; p<0.001). Acute heart failure was higher among patients who had TAVR (40.2% vs 27.5%; p=0.04) than those who had SAVR. All conduction block and ischaemic stroke were similar between the two groups (p=0.09 and p=0.1). The overall 30-day readmission rate among AM with AS encounters was 16.82%, higher among TAVR compared to SAVR subgroups (21.25% vs 11.17%; p=0.001). CONCLUSIONS: Among AM with AS hospitalisations, TAVR had mortality benefits compared to SAVR and non-mechanical intervention subgroups. Moreover, higher 30-day mortality rate were observed among SAVR subgroup, which may suggest that TAVR should be strongly considered in AM patients complicated by AS.

Detection of copy number variants and genes by chromosomal microarray in an Emirati neurodevelopmental disorders cohort.

Copy number variations (CNVs) are highly implicated in the etiology of neurodevelopmental disorders (NDDs), and chromosomal microarray analysis (CMA) has been recommended as a first-tier test for many NDDs. We undertook a study to identify clinically relevant CNVs and genes in an ethnically homogenous population of the United Arab Emirates. We genotyped 98 patients with NDDs using genome-wide chromosomal microarray analysis, and observed 47.1% deletion and 52.9% duplication CNVs, of which 11.8% are pathogenic, 23.5% are likely pathogenic, and 64.7% VOUS. The average size of copy number losses (3.9 Mb) was generally higher than of gains (738.4 kb). Analysis of VOUS CNVs for constrained genes (enrichment for brain critical exons and high pLI genes) yielded 7 unique genes. Among these 7 constrained genes, we propose FNTA and PXK as potential candidate genes for neurodevelopmental disorders, which warrants further investigation. Thirty-two overlapping CNVs (Decipher and ClinVar) containing the FNTA gene were previously identified in NDD patients and 6 overlapping CNVs (Decipher and ClinVar) containing the PXK gene were previously identified in NDD patients. Our study supports the utility of CMA for CNV profiling which aids in precise genetic diagnosis and its integration into therapeutics and management of NDD patients.

ST-elevation myocardial infarction among cardiac amyloidosis patients; a national readmission database study.

Literature regarding recent trends, mortality outcomes of ST-elevation myocardial infarction (STEMI) in cardiac amyloidosis (CA) patients is limited.To study coronary interventions, and trends in prevalence and mortality outcomes among CA patients with STEMI.Data from the national readmissions database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the USA, representing more than 95% of the national population, were analyzed for hospitalizations associated with CA with STEMI. A linear p-trend was used to assess the trends.Out of the total 4252 adult patients (mean age 73.3 ± 11.7 years, 40.2% females) with diagnosis of CA, 439 (10.3%) had STEMI while 3813 (89.7%) had no STEMI. STEMI-CA patients had higher rates of multi-organ manifestations including VT/VF (12% vs 8.5%; p-value < 0.001), cardiogenic shock (12.7% vs 7.3%; p < 0.001), AKI requiring dialysis (5.3% vs 4%; p < 0.001), and ICU admissions (25.2% vs 15.3%; p < 0.001) compared to CA without STEMI. CA-STEMI had increased mortality rates (23.7% vs 16.1%, p < 0.001) compared to CA without STEMI. On multivariate logistic regression analysis, coronary interventions including PCI (OR 0.6, CI 0.4-1.1; p = 0.3) and CABG (OR 0.7, CI 0.3-1.8; p = 0.2) had no association with mortality among CA patients. The absolute yearly trends for prevalence and mortality associated with STEMI in CA patients remained steady over the study years (linear p-trends 0.2 and 0.6, respectively).CA-STEMI is associated with significant complications and mortality. Coronary interventions may not have significant mortality benefits. Thus, more research will be needed to improve mortality rates among these patients.

Trends and complications associated with acute new-onset heart failure: a National Readmissions Database-based cohort study.

Literature regarding recent trends and outcomes of acute new-onset heart failure (AHF) with preserved ejection fraction (AHFpEF) and reduced ejection fraction (AHFrEF) is limited. The objective of this study is to study the outcomes of AHFpEF and AHFrEF in the USA. Data from the National Readmissions Database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the USA, representing more than 95% of the national population, were analyzed for hospitalization visits for acute heart failure. ICD-9 and ICD-10 codes were used to identify AHF. A total of 2,559,102 adult index AHF patients (mean age 70.79 ± 14.58 years, 49.4% females), 1,028,970 (40.2%) AHFpEF and 1,330,999 (52%) AHFrEF, were recorded in the National Readmissions Database for the years 2016-2018. A total of 152,465 (5.96%) acute heart failure, 47,271 (4.6%) AHFpEF and 91,973 (6.91%) AHFrEF, died during hospitalization, and 45,810 (1.9%) were readmitted in 30 days among alive discharges. Higher complication rates which included ventricular arrhythmias, acute coronary, and cerebrovascular events were observed among AHFrEF than AHFpEF. Higher proportion of patients with AHFrEF needed intensive care unit and ventilatory support during the hospitalization. The trend of incidence of AHFrEF, mortality among AHFrEF, and overall mortality worsened while AHFpEF improved over the study years 2012-2018 (p-trend < 0.05). Coronary procedures improved mortality rates among AHFpEF and AHFrEF. AHF is very common and is associated with significant mortality. The incidence of AHFrEF and mortality among AHFrEF had worsened, which calls for urgent intervention. Improved recognition of AHF is needed, and guideline-directed treatment of underlying risk factors including coronary artery disease can improve mortality. Graphic abstract of the analysis presented (created with BioRender.com).

Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells.

BACKGROUND: In recent years, several hundred autism spectrum disorder (ASD) implicated genes have been discovered impacting a wide range of molecular pathways. However, the molecular underpinning of ASD, particularly from the point of view of 'brain to behaviour' pathogenic mechanisms, remains largely unknown. METHODS: We undertook a study to investigate patterns of spatiotemporal and cell type expression of ASD-implicated genes by integrating large-scale brain single-cell transcriptomes (> million cells) and de novo loss-of-function (LOF) ASD variants (impacting 852 genes from 40,122 cases). RESULTS: We identified multiple single-cell clusters from three distinct developmental human brain regions (anterior cingulate cortex, middle temporal gyrus and primary visual cortex) that evidenced high evolutionary constraint through enrichment for brain critical exons and high pLI genes. These clusters also showed significant enrichment with ASD loss-of-function variant genes (p < 5.23 × 10-11) that are transcriptionally highly active in prenatal brain regions (visual cortex and dorsolateral prefrontal cortex). Mapping ASD de novo LOF variant genes into large-scale human and mouse brain single-cell transcriptome analysis demonstrate enrichment of such genes into neuronal subtypes and are also enriched for subtype of non-neuronal glial cell types (astrocyte, p < 6.40 × 10-11, oligodendrocyte, p < 1.31 × 10-09). CONCLUSION: Among the ASD genes enriched with pathogenic de novo LOF variants (i.e. KANK1, PLXNB1), a subgroup has restricted transcriptional regulation in non-neuronal cell types that are evolutionarily conserved. This association strongly suggests the involvement of subtype of non-neuronal glial cells in the pathogenesis of ASD and the need to explore other biological pathways for this disorder.

Can inverse probability treatment weighting (IPTW) be used to assess differences of CRBSI rates between non-tunneled femoral and jugular CVCs in PICU patients?

BACKGROUND: In children in the ICU, catheter-related bloodstream infections (CRBSI) have also been linked to mortality, morbidity, and healthcare costs. Although CRBSI poses many potential risks, including the need to avoid femoral access, there is debate regarding whether jugular access is preferable to femoral access in adults. Study reports support both perspectives. There is no consensus in meta-analyses. Children have yet to be examined in depth. Based on compliance with the central line bundle check lists, we aim to determine CRBSI risk in pediatric intensive care units for patients with non-tunneled femoral and internal jugular venous access. METHODS: A retrospective cohort study was conducted on patients with central venous catheters in the pediatric ICU of King Abdulaziz University Hospital between January 1st, 2017 and January 30th, 2018. For the post-match balance, we use a standardized mean difference of less than 0.1 after inverse probability treatment weighting for all baseline covariates, and then we draw causal conclusions. As a final step, the Rosenbaum sensitivity test was applied to see if any bias influenced the results. RESULTS: We recorded 145 central lines and 1463 central line days with 49 femoral accesses (33.79%) and 96 internal jugular accesses (66.21%). CRBSI per 1000 central line days are 4.10, along with standardized infections of 3.16. CRBSI risk differed between non-tunneled femoral vein access and internal jugular vein access by 0.074 (- 0.021, 0.167), P-value 0.06, and relative risk was 4.67 (0.87-25.05). Using our model, the actual probability was 4.14% (0.01-0.074) and the counterfactual probability was 2.79% (- 0.006, 0.062). An unobserved confounding factor was not identified in the sensitivity analysis. CONCLUSIONS: So long as the central line bundle is maintained, a femoral line does not increase the risk of CRBSI. Causation can be determined through propensity score weighting, as this is a trustworthy method of estimating causality. There is no better way to gain further insight in this regard than through the use of randomized, double-blinded, multicenter studies.

ST-Elevation Myocardial Infarction Among Septic Shock and Coronary Interventions: A National Emergency Database Study.

OBJECTIVE: To study coronary interventions and mortality among patients with ST-elevated myocardial infarction (STEMI) who were admitted with septic shock. METHODS: Data from the national emergency department sample (NEDS) that constitutes 20% sample of hospital-owned emergency departments in the United States was analyzed for the septic shock related visits from 2016 to 2018. Septic shock was defined by the ICD codes. RESULTS: Out of 1 375 507 adult septic shock patients, 521 300 had a primary diagnosis of septic shock (mean age 67.41±15.67 years, 51.1% females) in the national emergency database for the years 2016 to 2018. Of these patients, 2768 (0.53%) had STEMI recorded during the hospitalization. Mortality rates for STEMI patients were higher than patients without STEMI (52.3% vs 23.5%). Mortality rates improved with PCI among STEMI patients (43.8% vs 56.2%). Coronary angiography was performed among 16% of patients of which percutaneous coronary intervention (PCI) rates were 7.7% among patients with STEMI septic shock. PCI numerically improved mortality, however, had no significant difference than patients without PCI on multivariate logistic regression and univariate logistic regression post coarsened exact matching of baseline characteristics among STEMI patients. Among the predictors, STEMI was a significant predictor of mortality in septic shock patients (OR 2.87, 95% CI 2.37-3.49; P<.001). Age, peripheral vascular disease, were predominant predictors of mortality in STEMI with septic shock subgroup (P <.001). Pneumonia was the predominant underlying infection among STEMI (36.4%) and without STEMI group (29.5%). CONCLUSION: STEMI complicating septic shock worsens mortality. PCI and coronary angiography numerically improved mortality, however, had no significant difference from patients without PCI. More research will be needed to improve mortality in such a critically ill subgroup of patients.

Thrombotic superior vena cava syndrome: a national emergency department database study.

Literature regarding etiology and trends of incidence of major thoracic vein thrombosis in the United States is limited. To study the causes, complications, in-hospital mortality rate, and trend in the incidence of major thoracic vein thrombosis which could have led to superior vena cava syndrome (SVCS) between 2010 and 2018. Data from the nationwide emergency department sample (NEDS) that constitutes 20% sample of hospital-owned emergency departments (ED) and in-patient sample in the United States were analyzed using diagnostic codes. A linear p-trend was used to assess the trends. Of the total 1082 million ED visits, 37,807 (3.5/100,000) (mean age 53.81 ± 18.07 years, 55% females) patients were recorded with major thoracic vein thrombosis in the ED encounters. Among these patients, 4070 (10.6%) patients had one or more cancers associated with thrombosis. Pacemaker/defibrillator-related thrombosis was recorded in 2820 (7.5%) patients, while intravascular catheter-induced thrombosis was recorded in 1755 (4.55%) patients. Half of the patients had associated complication of pulmonary embolism. A total of 59 (0.15%) patients died during these hospital encounters. The yearly trend for the thrombosis for every 100,000 ED encounters in the United States increased from 2.17/100,000 in 2010 to 5.98/100,000 in 2018 (liner p-trend < 0.001). Yearly trend for catheter/lead associated thrombosis was also up-trending (p-trend 0.015). SVCS is an uncommon medical emergency related to malignancy and indwelling venous devices. The increasing trend in SVCS incidence, predominantly catheter/lead induced, and the high rate of associated pulmonary embolism should prompt physicians to remain vigilant for appropriate evaluation.

Scleroderma hypertensive renal crisis among systemic sclerosis patients: A national emergency department database study.

BACKGROUND: Literature regarding trends for incidence and mortality of scleroderma renal crisis (SRC) in systemic sclerosis (SSc) within the United States (US) emergency departments (EDs) is limited. OBJECTIVE: To study the mortality of SRC among SSc patient encounters within the US EDs. METHODS: Data from the National Emergency Department Sample (NEDS) constitutes 20% sample of hospital-owned EDs and inpatient sample in the US were analyzed for SSc with and without SRC using ICD-9 codes. A linear p-trend was used to assess the trends. RESULTS: Of the total 180,435 encounters with the diagnosis of SSc in NEDS for the years 2009 2014, 771 or 4.27/1000 patients (mean age 59.6 ± 15.5 years, 75.4% females) were recorded with SRC. The numerical differences in mortality among SRC (32 or 4.1%) and non-SRC subgroups (5487 or 3.1%) did not reach statistical significance (p = 0.3). Major complications among SRC in comparison to non-SRC subgroup include ischemic stroke (5.6% vs 0.98%, p = 0.001), new-onset AF (8% vs 6.9%, p = 0.001), new-onset congestive heart failure (24.1% vs 8.8%, p = 0.001), pulmonary arterial hypertension (15.8% vs 10.9%, p = 0.001), respiratory failure (27.5% vs 10.5%, p = 0.001), and deep vein thrombosis (4.7% vs 4.6%, p = 0.001). Congestive heart failure (CHF) was strongly associated with SRC among SSc (OR 4.3 95%CI 2.7-6.7; p < 0.001). The absolute yearly rate of SRC had increased over the study years from 2.11/1000 to 5.79/1000 (linear p-trend 0.002) while the mortality trend remained steady. CONCLUSION: SRC is a relatively rare medical emergency. Although there has been a significant rise in the rate of SRC among SSc patients over the study years, mortality rates had remained steady. SSc patients with CHF should be considered to have low threshold for admission to inpatient services from EDs.

Factors influencing the performance of rapid SARS-CoV-2 antigen tests under field condition.

BACKGROUND: Globally, real-time reverse transcription-polymerase chain reaction (rRT-PCR) is the reference detection technique for SARS-CoV-2, which is expensive, time consuming, and requires trained laboratory personnel. Thus, a cost-effective, rapid antigen test is urgently needed. This study evaluated the performance of the rapid antigen tests (RATs) for SARS-CoV-2 compared with rRT-PCR, considering different influencing factors. METHODS: We enrolled a total of 214 symptomatic individuals with known COVID-19 status using rRT-PCR. We collected and tested paired nasopharyngeal (NP) and nasal swab (NS) specimens (collected from same individual) using rRT-PCR and RATs (InTec and SD Biosensor). We assessed the performance of RATs considering specimen types, viral load, the onset of symptoms, and presenting symptoms. RESULTS: We included 214 paired specimens (112 NP and 100 NS SARS-CoV-2 rRT-PCR positive) to the analysis. For NP specimens, the average sensitivity, specificity, and accuracy of the RATs were 87.5%, 98.6%, and 92.8%, respectively, when compared with rRT-PCR. While for NS, the overall kit performance was slightly lower than that of NP (sensitivity 79.0%, specificity 96.1%, and accuracy 88.3%). We observed a progressive decline in the performance of RATs with increased Ct values (decreased viral load). Moreover, the RAT sensitivity using NP specimens decreased over the time of the onset of symptoms. CONCLUSION: The RATs showed strong performance under field conditions and fulfilled the minimum performance limit for rapid antigen detection kits recommended by World Health Organization. The best performance of the RATs can be achieved within the first week of the onset of symptoms with high viral load.

Mixed metals exposure and cognitive function in Bangladeshi adolescents.

BACKGROUND: Over 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. They also face environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb), all of which have been previously observed in environmental and biological samples for this population. These metals have been linked to adverse neurocognitive outcomes in adults and children, though their effects on adolescents are not yet fully characterized. Additionally, previous studies have linked selenium (Se) to protective effects against the toxicity of these other metals. OBJECTIVES: To examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. METHODS: The Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years, whose parents were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Biosamples were collected from these adolescents for measurement of whole blood metalloid/metal levels of As, Cd, Mn, Pb, and Se. Participants also completed an abbreviated version of The Cambridge Neuropsychological Test Automated Battery (CANTAB), a cognitive function test designed to measure performance across several aspects of executive function. Linear regression was used to examine associations for each metal while controlling for the other metals. Bayesian Kernel Machine Regression (BKMR) assessed the overall mixture effect in addition to confirming the effects of individual metal components observed via linear regression. RESULTS: Linear regression revealed negative associations for Spatial Working Memory and both As and Mn (As B=-2.40, Mn B=-5.31, p < 0.05). We also observed negative associations between Cd and Spatial Recognition Memory (B=-2.77, p < 0.05), and Pb and Delayed Match to Sample, a measure of visual recognition and memory (B=-3.67, p < 0.05). Finally, we saw a positive association for Se and Spatial Span Length (B=0.92, p < 0.05). BKMR results were largely consistent with the regression analysis, showing meaningful associations for individual metals and CANTAB subtests, but no overall mixture effect. Via BKMR, we observed negative associations between Pb and Delayed Match to Sample, and Cd and Spatial Recognition Memory; this analysis also showed positive associations for Se and the Planning, Reaction Time, and Spatial Span subtests. BKMR posterior inclusion probability consistently reported that Se, the only component of the mixture to show a positive association with cognition, was the most important member of the mixture. CONCLUSIONS: Overall, we found Se to be positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. Our observations are consistent with previous reports on the effects of these metal exposures in adults and children. Our findings also suggest agreement between linear regression and BKMR methods for analyzing metal mixture exposures. Additional studies are needed to evaluate the impact of mixed metals exposure on adverse health and poorer cognition later in life for those exposed during adolescence. Findings also suggest that metal exposure mitigation efforts aimed at adolescents might influence lifelong cognitive outcomes in regions where environmental exposure to metals is endemic.