Tumefactive Primary Central Nervous System Vasculitis: Dynamic Susceptibility Contrast Perfusion-Weighted Magnetic Resonance Imaging Findings With Histological Correlation.

Purpose: Primary central nervous system vasculitis (PCNSV) is a rare inflammatory disease affecting the central nervous system. In some cases, it presents with large, solitary lesion with extensive mass effect that mimic intracranial neoplasms. This condition results in a diagnostic confusion for neuroradiologists because the differentiation is almost impossible on conventional MRI sequences. The aim of this study is to reveal the significance of dynamic susceptibility contrast (DSC) perfusion-weighted imaging in differentiating of tumefactive PCNSV (t-PCNSV) lesions from intracranial neoplasms such as glio-blastomas and metastasis. Methods: In this retrospective study, DSC of 8 patients with biopsy-proven t-PCNSV has been compared with DSC obtained in 10 patients with glioblastoma, 10 patients with metastasis, who underwent surgery and histopathological confirmation. The ratio of relative cerebral blood volume (rrCBV) was calculated by rCBV (lesion) / rCBV (controlateral normal-appearing white matter) in the gadolinium-enhancing solid areas. Results: The mean rrCBV was 0.86±0.7 (range: 0.76-0.98) in the patients with t-PCNSV, 5,16±0.79 in patients with glioblastoma (range: 3.9-6.3), and 4.27±0.73 (range: 2.8-5.3) in patients with metastases. Conclusion: DSC-PWI seems to be useful in the diagnostic work-up of t-PCSNVs. A low rrCBV, i.e. a rCBV similar or lower to that of the contralateral normal white matter, seems to be consistent with the possibility of t-PCSNV.

Eficacia del ejercicio de alta intensidad en personas con dolor lumbar crónico: una revisión sistemática / Efficacy of high-intensity exercise in people with chronic low back pain: A systematic review

El dolor lumbar crónico causa discapacidad e impacto socioeconómico. El ejercicio de alta intensidad muestra resultados positivos en otras enfermedades, pero no existe evidencia sobre esta patología. Se pretende determinar su eficacia en la calidad de vida relacionada con la salud, la discapacidad, la intensidad del dolor y la adherencia al tratamiento en personas con dolor lumbar crónico. Se realiza una revisión bibliográfica en Pubmed, PEDro y Scopus, incluyendo ensayos clínicos aleatorizados, guías de práctica clínica y revisiones sistemáticas en español, inglés o portugués (2012-2022). Además, se hace una búsqueda en bola de nieve. Se incorporan ocho ensayos clínicos aleatorizados (n=379). Se analizan diferentes modalidades de ejercicio de alta intensidad, que parecen mejorar la calidad de vida relacionada con la salud y reducir la discapacidad y la intensidad del dolor. Estos datos se deben tomar con cautela dada la poca cantidad de estudios y el riesgo de sesgo que presentan.(AU)

Chronic low back pain causes disability and socioeconomic impact. High-intensity exercise shows positive results in other diseases, but there is no evidence on this pathology. The aim is to determine its efficacy on health-related quality of life, disability, pain intensity and adherence to treatment in people with chronic low back pain. A literature review is conducted in Pubmed, PEDro and Scopus, including randomized clinical trials, clinical practice guidelines and systematic reviews in Spanish, English or Portuguese (2012-2022). In addition, a snowball search is performed. Eight randomized clinical trials (n=379) are incorporated. Different high-intensity exercise modalities are analyzed, which seem to improve health-related quality of life and reduce disability and pain intensity. These data should be taken with caution given the small number of studies and the risk of bias presented.(AU)

Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease.

Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.

The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young.

BACKGROUND: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. METHODS: The SDY Case Registry is a National Institutes of Health/Centers for Disease Control and Prevention surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases < 20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015 to 2019. The cohort included 211 children (median age 0.33 year; range 0-20 years), determined to have died suddenly and unexpectedly and from whom DNA biospecimens for DNA extractions and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex- and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy, and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, pathogenic and likely pathogenic genetic variation was identified using a Bayesian-based artificial intelligence (AI) tool. RESULTS: The SDY cohort was 43% European, 29% African, 3% Asian, 16% Hispanic, and 9% with mixed ancestries and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy, or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, potentially damaging variants in epilepsy, cardiomyopathy, and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death. CONCLUSIONS: While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

Nozaki-Bekki solitons in semiconductor lasers.

Optical frequency-comb sources, which emit perfectly periodic and coherent waveforms of light1, have recently rapidly progressed towards chip-scale integrated solutions. Among them, two classes are particularly significant-semiconductor Fabry-Perót lasers2-6 and passive ring Kerr microresonators7-9. Here we merge the two technologies in a ring semiconductor laser10,11 and demonstrate a paradigm for the formation of free-running solitons, called Nozaki-Bekki solitons. These dissipative waveforms emerge in a family of travelling localized dark pulses, known within the complex Ginzburg-Landau equation12-14. We show that Nozaki-Bekki solitons are structurally stable in a ring laser and form spontaneously with tuning of the laser bias, eliminating the need for an external optical pump. By combining conclusive experimental findings and a complementary elaborate theoretical model, we reveal the salient characteristics of these solitons and provide guidelines for their generation. Beyond the fundamental soliton circulating inside the ring laser, we demonstrate multisoliton states as well, verifying their localized nature and offering an insight into formation of soliton crystals15. Our results consolidate a monolithic electrically driven platform for direct soliton generation and open the door for a research field at the junction of laser multimode dynamics and Kerr parametric processes.

[Efficacy of high-intensity exercise in people with chronic low back pain: A systematic review]. / Eficacia del ejercicio de alta intensidad en personas con dolor lumbar crónico: una revisión sistemática.

Chronic low back pain causes disability and socioeconomic impact. High-intensity exercise shows positive results in other diseases, but there is no evidence on this pathology. The aim is to determine its efficacy on health-related quality of life, disability, pain intensity and adherence to treatment in people with chronic low back pain. A literature review is conducted in Pubmed, PEDro and Scopus, including randomized clinical trials, clinical practice guidelines and systematic reviews in Spanish, English or Portuguese (2012-2022). In addition, a snowball search is performed. Eight randomized clinical trials (n=379) are incorporated. Different high-intensity exercise modalities are analyzed, which seem to improve health-related quality of life and reduce disability and pain intensity. These data should be taken with caution given the small number of studies and the risk of bias presented.

Denosumab in elderly osteoporotic patients. A narrative review.

Objective: Denosumab, an antiresorptive agent, has shown results in improving bone mineral density and reducing fractures in postmenopausal women. While bisphosphonates are commonly used as initial therapy for osteoporosis, some studies suggest that denosumab could be an alternative initial treatment for high-risk patients, particularly the elderly population. This narrative literature review aimed to assess the use of denosumab in elderly individuals with osteoporosis, excluding its oncology applications. Method: Multiple online databases including Scopus, PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and PEDro were searched for relevant English-language trials. Results: Between about hundred identified, the review selected 21 articles full-meeting the inclusion criteria. These papers all reporting that Denosumab demonstrated significant efficacy in reducing vertebral and nonvertebral fractures in postmenopausal and senile osteoporosis. Conclusion: Even if limited evidence exists regarding its long-term effectiveness in elderly patients, nevertheless denosumab may be considered a first-line treatment for high-risk elderly patients with senile osteoporosis, particularly for those unable to take bisphosphonates. It has shown superior outcomes in improving bone density and reducing fracture risk, even in frail elderly individuals. Long-term use of denosumab has been reported as safe and effective, enhancing treatment compliance and outcomes.

Developing an improved optical biosensing system based on gold nanoparticles acting as interferometric enhancers in Lactoferrin detection.

We report for the first time the whole development of a biosensing system based on the Interferometric Optical Detection Method (IODM) enriched with gold nanoparticles (AuNPs), acting as interferometric enhancers for improving the performance of immunoassays. For this purpose, the Lactoferrin sandwich immunoassay model was employed. We describe in detail the entire value chain from the AuNPs production, its functionalization, and characterization with anti-Lactoferrin (anti-LF), the biosensing response of these conjugates as well as their corresponding calculation of the kinetic constants, performance comparison of the readout interferometric signals versus Scanning Electron Microscopy (SEM) and the percentage of the sensing surface covered. Finally, a Lactoferrin sandwich immunoassay was carried out and correlated with Enzyme-Linked ImmunoSorbent Assay (ELISA), and the Limit of Detection and sensitivity figures were obtained. As a result, we demonstrate how the AuNPs act as interferometric amplifiers of the IODM for improving the biosensing response, opening the possibility of being applied in multiple biological detection applications.

Delivery of mutant huntingtin-lowering antisense oligonucleotides to the brain by intranasally administered apolipoprotein A-I nanodisks.

Lowering mutant huntingtin (mHTT) in the central nervous system (CNS) using antisense oligonucleotides (ASOs) is a promising approach currently being evaluated in clinical trials for Huntington disease (HD). However, the therapeutic potential of ASOs in HD patients is limited by their inability to cross the blood-brain barrier (BBB). In non-human primates, intrathecal infusion of ASOs results in limited brain distribution, with higher ASO concentrations in superficial regions and lower concentrations in deeper regions, such as the basal ganglia. To address the need for improved delivery of ASOs to the brain, we are evaluating the therapeutic potential of apolipoprotein A-I nanodisks (apoA-I NDs) as novel delivery vehicles for mHTT-lowering ASOs to the CNS after intranasal administration. Here, we have demonstrated the ability of apoA-I nanodisks to bypass the BBB after intranasal delivery in the BACHD model of HD. Following intranasal administration of apoA-I NDs, apoA-I protein levels were elevated along the rostral-caudal brain axis, with highest levels in the most rostral brain regions including the olfactory bulb and frontal cortex. Double-label immunohistochemistry indicates that both the apoA-I and ASO deposit in neurons. Most importantly, a single intranasal dose of apoA-I ASO-NDs significantly reduces mHTT levels in the brain regions most affected in HD, namely the cortex and striatum. This approach represents a novel non-invasive means for improving delivery and brain distribution of oligonucleotide therapies and enhancing likelihood of efficacy. Improved ASO delivery to the brain has widespread application for treatment of many other CNS disorders.

Selection, optimization, and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse populations.

Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.

The impact of damaging epilepsy and cardiac genetic variant burden in sudden death in the young.

Background: Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing. Methods: The SDY Case Registry is a National Institutes of Health/Centers for Disease Control surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases <20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015-2019. The cohort included 211 children (mean age 1 year; range 0-20 years), determined to have died suddenly and unexpectedly and in whom DNA biospecimens and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex-and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, genetic variation predicted to be damaging was identified using a Bayesian-based artificial intelligence (AI) tool. Results: The SDY cohort was 42% European, 30% African, 17% Hispanic, and 11% with mixed ancestries, and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, damaging variants in epilepsy, cardiomyopathy and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death. Conclusions: While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort, and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.

What factors matter in the amount of alcohol consumed? An analysis among Brazilian adolescents.

Alcohol consumption in the under-18 age group has been growing in recent years, leading to various health risks. Considering the problems this habit brings, the present study contributes to the literature dedicated to categorizing different types of drinkers. The study objective is to verify the factors associated with the intensity of alcohol use among elementary school students in the year 2015. The dataset came from the National Adolescent School-based Health Survey (PeNSE). The applied methodology was a logit model of sequential response (continuation ratio). The main results are as follows. It was found that being female is associated with a lesser chance of having consumed alcohol in the reference period, however, with a greater chance of consuming five or more doses. Economic condition and formal paid employment are positively associated with alcohol consumption, which increases with the progression of the student's age. The number of friends who drink alcohol and consumption of products originating from tobacco and illicit drugs, are good predictors of alcohol use by students. The time spent practicing physical activities increased the chance of male students consuming alcohol. The results showed that, in general, the characteristics associated with different alcohol consumption profiles remain similar but differ between genders. Intervention strategies aimed at preventing alcohol consumption by minors are suggested in order to reduce the negative effects of substance use and abuse.

Opposing effects of genetic variation in MTCH2 for obesity versus heart failure.

Genetic variation in genes regulating metabolism may be advantageous in some settings but not others. The non-failing adult heart relies heavily on fatty acids as a fuel substrate and source of ATP. In contrast, the failing heart favors glucose as a fuel source. A bootstrap analysis for genes with deviant allele frequencies in cardiomyopathy cases versus controls identified the MTCH2 gene as having unusual variation. MTCH2 encodes an outer mitochondrial membrane protein, and prior genome-wide studies associated MTCH2 variants with body mass index, consistent with its role in metabolism. We identified the referent allele of rs1064608 (p.Pro290) as being overrepresented in cardiomyopathy cases compared to controls, and linkage disequilibrium analysis associated this variant with the MTCH2 cis eQTL rs10838738 and lower MTCH2 expression. To evaluate MTCH2, we knocked down Mtch in Drosophila heart tubes which produced a dilated and poorly functioning heart tube, reduced adiposity and shortened life span. Cardiac Mtch mutants generated more lactate at baseline, and they displayed impaired oxygen consumption in the presence of glucose but not palmitate. Treatment of cardiac Mtch mutants with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, reduced lactate and rescued lifespan. Deletion of MTCH2 in human cells similarly impaired oxygen consumption in the presence of glucose but not fatty acids. These data support a model in which MTCH2 reduction may be favorable when fatty acids are the major fuel source, favoring lean body mass. However, in settings like heart failure, where the heart shifts toward using more glucose, reduction of MTCH2 is maladaptive.

Variant rs4149584 (R92Q) of the TNFRSF1A gene in patients with familial multiple sclerosis.

INTRODUCTION: Genomic studies have identified numerous genetic variants associated with susceptibility to multiple sclerosis (MS); however, each one explains only a small percentage of the risk of developing the disease. These variants are located in genes involved in specific pathways, which supports the hypothesis that the risk of developing MS may be linked to alterations in these pathways, rather than in specific genes. We analyzed the role of the TNFRSF1A gene, which encodes one of the TNF-α receptors involved in a signaling pathway previously linked to autoimmune disease. METHODS: We included 138 individuals from 23 families including at least 2 members with MS, and analyzed the presence of exonic variants of TNFRSF1A through whole-exome sequencing. We also conducted a functional study to analyze the pathogenic mechanism of variant rs4149584 (-g.6442643C > G, NM_001065.4:c.362 G > A, R92Q) by plasmid transfection into human oligodendroglioma (HOG) cells, which behave like oligodendrocyte lineage cells; protein labeling was used to locate the protein within cells. We also analyzed the ability of transfected HOG cells to proliferate and differentiate into oligodendrocytes. RESULTS: Variant rs4149584 was found in 2 patients with MS (3.85%), one patient with another autoimmune disease (7.6%), and in 5 unaffected individuals (7.46%). The 2 patients with MS and variant rs4149584 were homozygous carriers and belonged to the same family, whereas the remaining individuals presented the variant in heterozygosis. The study of HOG cells transfected with the mutation showed that the protein does not reach the cell membrane, but rather accumulates in the cytoplasm, particularly in the endoplasmic reticulum and near the nucleus; this suggests that, in the cells presenting the mutation, TNFRSF1 does not act as a transmembrane protein, which may alter its signaling pathway. The study of cell proliferation and differentiation found that transfected cells continue to be able to differentiate into oligodendrocytes and are probably still capable of producing myelin, although they present a lower rate of proliferation than wild-type cells. CONCLUSIONS: Variant rs4149584 is associated with risk of developing MS. We analyzed its functional role in oligodendrocyte lineage cells and found an association with MS in homozygous carriers. However, the associated molecular alterations do not influence the differentiation into oligodendrocytes; we were therefore unable to confirm whether this variant alone is pathogenic in MS, at least in heterozygosis.

Comparison of conventional ligatures and a vessel sealing device for haemostasis during open ovariohysterectomy in rabbits.

AIMS: To compare surgical times and rates of intra-operative and post-operative complications for open ovariohysterectomy (OVH) in female rabbits using conventional ligatures or a vessel sealing device (VSD) for haemostasis. METHODS: Female pet rabbits (n = 23) presented for OVH for either desexing or treatment of reproductive disorders were randomly assigned to a conventional ligatures (CL) group (n = 12) or a LigaSure 5-mm (LS5) group (n = 11). In the CL group, the ovarian pedicles were ligated with a single surgeon's knot. After transection of the ovarian pedicles, the broad ligament was manually broken down along the uterine horns to their respective cervices. In the LS5 group, both ovarian pedicles and the broad ligaments were sealed with a LigaSure Dolphin Tip VSD with 5-mm forceps. All the rabbits were hospitalised for 24 hours after surgery. Two weeks after discharge, a clinical recheck examination was performed. Incision length, overall surgical time (from initial incision to completion of intradermal suturing), OVH time (from identification of the first ovary to transection of the vaginal vault), and intra- and post-operative complications were recorded and compared between groups, using the Student's t-test for normally distributed continuous data, the Wilcoxon-Mann-Whitney test for non-normally distributed continuous data and Pearson's χ2 test for categorical data. RESULTS: The mean overall surgical time was 14.1 (SD 4.4) minutes. The surgery took 15.0 (SD 4.9) minutes in the CL group and 13.1 (SD 3.8) minutes in the LS5 group (p=0.10). The OVH time was shorter in the LS5 group (mean 4.2 (SD 0.9) minutes) than in the CL group (mean 6.3 (SD 1.7) minutes; p = 0.005). No intra-operative complications were encountered in the LS5 group. Haemorrhage occurred in three rabbits in the CL group. One rabbit in the LS5 group developed steatonecrosis post-operatively. There was no evidence of a difference in the proportion of rabbits that experienced intra- and post-operative complications (p = 0.25 and p = 0.94 respectively) between groups. CONCLUSIONS: The use of a LigaSure 5-mm VSD and conventional ligatures during open OVH were both associated with similar overall surgical times and complication rates. The OVH times were shorter in the LS5 group compared to the CL group. CLINICAL RELEVANCE: Use of the LigaSure 5-mm VSD allows efficient haemostasis while performing open OVH in female pet rabbits.

Bacterial Superinfection Pneumonia in Patients Mechanically Ventilated for COVID-19 Pneumonia.

Rationale: Current guidelines recommend patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia receive empirical antibiotics for suspected bacterial superinfection on the basis of weak evidence. Rates of ventilator-associated pneumonia (VAP) in clinical trials of patients with SARS-CoV-2 pneumonia are unexpectedly low. Objectives: We conducted an observational single-center study to determine the prevalence and etiology of bacterial superinfection at the time of initial intubation and the incidence and etiology of subsequent bacterial VAP in patients with severe SARS-CoV-2 pneumonia. Methods: Bronchoscopic BAL fluid samples from all patients with SARS-CoV-2 pneumonia requiring mechanical ventilation were analyzed using quantitative cultures and a multiplex PCR panel. Actual antibiotic use was compared with guideline-recommended therapy. Measurements and Main Results: We analyzed 386 BAL samples from 179 patients with SARS-CoV-2 pneumonia requiring mechanical ventilation. Bacterial superinfection within 48 hours of intubation was detected in 21% of patients. Seventy-two patients (44.4%) developed at least one VAP episode (VAP incidence rate = 45.2/1,000 ventilator days); 15 (20.8%) initial VAPs were caused by difficult-to-treat pathogens. The clinical criteria did not distinguish between patients with or without bacterial superinfection. BAL-based management was associated with significantly reduced antibiotic use compared with guideline recommendations. Conclusions: In patients with SARS-CoV-2 pneumonia requiring mechanical ventilation, bacterial superinfection at the time of intubation occurs in <25% of patients. Guideline-based empirical antibiotic management at the time of intubation results in antibiotic overuse. Bacterial VAP developed in 44% of patients and could not be accurately identified in the absence of microbiologic analysis of BAL fluid.

Genomic Autopsy of Sudden Deaths in Young Individuals.

Importance: Postmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information. Objective: To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families. Design, Setting, and Participants: Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020. Exposures: Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation. Results: A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex- and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, -1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant. Conclusions and Relevance: Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.

Photoelectrochemical cross-dehydrogenative coupling of benzothiazoles with strong aliphatic C-H bonds.

A photoelectrochemical strategy for the cross-dehydrogenative coupling of unactivated aliphatic hydrogen donors (e.g. alkanes) with benzothiazoles is reported. We used tetrabutylammonium decatungstate as the photocatalyst to activate strong C(sp3)-H bonds in the chosen substrates, while electrochemistry scavenged the extra electrons.