Endonasal endoscopic surgery for pituitary adenomas.

Pituitary adenomas are slow-growing, benign intracranial tumors that can be characterized as functional (hormone-producing) or non-functional (non-hormone producing). Symptoms therefore arise from either endocrinologic abnormalities or mass effect on surrounding structures resulting in symptoms such as visual impairment and headache. In the last two decades, technical innovations have shifted surgical resection of such adenomas to endoscopic endonasal approaches. In this review, we describe the evolving approach to pituitary adenomas in the modern endoscopic era, including preoperative multidisciplinary review, relevant surgical anatomy, and a description of the technical nuances of standard and expanded approaches to the anterior skull base.

Intra-urban variability of long-term exposure to PM2.5 and NO2 in five cities in Colombia.

Rapidly urbanizing cities in Latin America experience high levels of air pollution which are known risk factors for population health. However, the estimates of long-term exposure to air pollution are scarce in the region. We developed intraurban land use regression (LUR) models to map long-term exposure to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) in the five largest cities in Colombia. We conducted air pollution measurement campaigns using gravimetric PM2.5 and passive NO2 sensors for 2 weeks during both the dry and rainy seasons in 2021 in the cities of Barranquilla, Bucaramanga, Bogotá, Cali, and Medellín, and combined these data with geospatial and meteorological variables. Annual models were developed using multivariable spatial regression models. The city annual PM2.5 mean concentrations measured ranged between 12.32 and 15.99 µg/m3 while NO2 concentrations ranged between 24.92 and 49.15 µg/m3. The PM2.5 annual models explained 82% of the variance (R2) in Medellín, 77% in Bucaramanga, 73% in Barranquilla, 70% in Cali, and 44% in Bogotá. The NO2 models explained 65% of the variance in Bucaramanga, 57% in Medellín, 44% in Cali, 40% in Bogotá, and 30% in Barranquilla. Most of the predictor variables included in the models were a combination of specific land use characteristics and roadway variables. Cross-validation suggests that PM2.5 outperformed NO2 models. The developed models can be used as exposure estimate in epidemiological studies, as input in hybrid models to improve personal exposure assessment, and for policy evaluation.

Impact of hydrocolloid dressings in the prevention of pressure ulcers in high-risk patients: a randomized controlled trial (PENFUP).

It is uncertain whether hydrocolloid dressings, a more costly intervention than offering standard care with petrolatum, is superior to prevent pressure ulcers among hospitalized high-risk adults. Randomized, parallel-group, open-label, superiority trial with an active control group, blinded for investigators, event validators, and analysts (December 1, 2015 to December 12, 2017). Eligible patients were ≥ 18 years of age with intact skin judged as high-risk for skin ulcers (Braden scale), admitted to surgical or medical wards of two tertiary-level hospitals. Participants were randomized (1:1) to protection with hydrocolloid dressings or petrolatum. The primary outcome was the first occurrence of pressure ulcers (with post-injury photographs adjudicated by three judges) under intention-to-treat analysis. Based on prior cost analysis, and the available resources (assumed incidence of 6 ulcers/1000 patient-days in controls), inclusion of up to 1500 participants allowed to surpass a one-sided superiority threshold > 5% based on a target efficacy > 40% for dressings. We planned an economic analysis using a decision tree model based on the effectiveness of the study results from a perspective of the third payer of health care. After inclusion of 689 patients (69 events), the trial was stopped for futility after a planned interim analysis (conditional power < 0.1 for all scenarios if the trial was completed). Pressure ulcers had occurred in 34 (10.2%) patients in the intervention group [9.6 per 1000 patient-days] and 35 (9.9%) participants in the control group [7.9 per 1000 patient-days], HR = 1.07 [95% CI 0.67 to 1.71]. The estimated incremental cost for dressings (a dominated strategy) was USD 52.11 per patient. Using hydrocolloid dressings was found similar to petrolatum for preventing pressure ulcers among hospitalized high-risk patients. As it conveys additional costs, and in this study was unlikely to demonstrate enough superiority, this strategy did not overcome conventional skin care.Trial registration: ClinicalTrials.gov identifier (NCT number): NCT02565745 registered on December 1, 2015.

Transcriptome-wide association study identifies novel candidate susceptibility genes for migraine.

Genome-wide association studies (GWASs) have identified more than 130 genetic susceptibility loci for migraine; however, how most of these loci impact migraine development is unknown. To identify novel genes associated with migraine and interpret the transcriptional products of those genes, we conducted a transcriptome-wide association study (TWAS). We performed tissue-specific and multi-tissue TWAS analyses to assess associations between imputed gene expression from 53 tissues and migraine susceptibility using FUSION software. Meta-analyzed GWAS summary statistics from 26,052 migraine cases and 487,214 controls, all of European ancestry and from two cohorts (the Kaiser Permanente GERA and the UK Biobank), were used. We evaluated the associations for genes after conditioning on variant-level effects from GWAS, and we tested for colocalization of GWAS migraine-associated loci and expression quantitative trait loci (eQTLs). Across tissue-specific and multi-tissue analyses, we identified 53 genes for which genetically predicted gene expression was associated with migraine after correcting for multiple testing. Of these 53 genes, 10 (ATF5, CNTNAP1, KTN1-AS1, NEIL1, NEK4, NNT, PNKP, RUFY2, TUBG2, and VAT1) did not overlap known migraine-associated loci identified from GWAS. Tissue-specific analysis identified 45 gene-tissue pairs and cardiovascular tissues represented the highest proportion of the Bonferroni-significant gene-tissue pairs (n = 22 [49%]), followed by brain tissues (n = 6 [13%]), and gastrointestinal tissues (n = 4 [9%]). Colocalization analyses provided evidence of shared genetic variants underlying eQTL and GWAS signals in 18 of the gene-tissue pairs (40%). Our TWAS reports novel genes for migraine and highlights the important contribution of brain, cardiovascular, and gastrointestinal tissues in migraine susceptibility.

SARS-CoV-2 seroprevalence on the north coast of Peru: A cross-sectional study after the first wave.

BACKGROUND: Peru had the second-highest number of COVID-19 cases in Latin America. After the first wave, Peru registered more than 900,000 cases of COVID-19 and more than 36,000 confirmed deaths from the disease. Tumbes, a border area with poor sanitation and not enough water, had the fifth highest death rate. The cross-sectional analytic study aimed: a) to assess seroprevalence of COVID-19 after the first wave; b) to assess sociodemographic determinants and symptoms associated with a positive COVID-19 antibody lateral flow test. METHODOLOGY/PRINCIPAL FINDINGS: We performed this study between November 11th and November 30th, 2020, in an informal settlement in Tumbes. Individuals older than two years were invited to participate in a systematic random sample from one in every four households. Finger-prick blood samples were collected, and a census and symptom survey were applied. Within the chosen house, one adult over 18 years of age was chosen for a PCR-RT molecular test. Overall seroprevalence was 25.59%, adjusted seroprevalence was 24.82% (95%CI 22.49-27.25). Women had higher adjusted seroprevalence (28.03% vs 21.11%; 95% CI 24.83-31.41, p = 0.002). Symptoms as fever (PR 1.89: 95% CI 1.44-2.48, p<0.001), general discomfort (PR 1.67; 95% CI 1.23-2.26, p = 0.001), cough (PR 2.0; 95% CI 1.60-2.50, p<0.001), nasal congestion (PR 1.46; 95% CI 1.03-2.09, p = 0.036), respiratory distress (PR 1.64; 95% CI 1.04-2.56, p = 0.031), headache (PR 1.54; 95% CI 1.09-2.17, p = 0.014), anosmia (PR 1.78; 95% CI 1.01-3.14, p = 0.046) and ageusia (PR 2.31; 95% CI 1.48-3.61, p<0.001) were associated with a positive covid-19 antibody lateral flow test. CONCLUSIONS/SIGNIFICANCE: The COVID-19 transmission and distribution were highlighted by this cross-sectional study. The data will help the Ministry of Health improve its monitoring, surveillance, and monitoring of respiratory community sequelae in the future.

Dietary Patterns and Anti-Flavivirus IgG Seroconversion in Colombian Children.

The burden of flaviviral infections, especially dengue and Zika, is high in the Americas. Malnutrition affects the risk and response to infections, but the role of diet on flaviviral infection risk is uncertain. The objective of this study was to investigate the relations between dietary patterns adherence and anti-flavivirus IgG seroconversion in children during a Zika epidemic in a dengue-endemic area of Colombia. In 2015-2016, we followed 424 anti-flavivirus IgG seronegative children aged 2 to 12 years for 1 year. Baseline data included children's sociodemographic, anthropometric, and dietary information collected through a 38-item food frequency questionnaire (FFQ). IgG testing was repeated at the end of follow-up. The primary exposure was adherence to each of four dietary patterns (animal foods, traditional, ultraprocessed foods, and prudent) that were identified from the FFQ through principal component analysis. Secondary exposures were intake frequencies of foods contributing to relevant patterns. We estimated risk of seroconversion by quartiles of adherence scores and compared them using relative risks (RR) and 95% CI from Poisson regression adjusted for sex, age, and socioeconomic status indicators. Seroconversion risk was 32.1%. Adherence to the traditional pattern was positively related to seroconversion. RR comparing fourth versus first quartiles of adherence was 1.52 (95% CI: 1.04-2.21; P trend = 0.02). Of the most representative foods in this pattern, potato and sugarcane water intake frequencies were related to increased seroconversion risk. In conclusion, adherence to a traditional foods pattern, including potatoes and sugarcane water, was positively associated with anti-flavivirus IgG seroconversion.

Microsurgical and illustrative anatomy of the cavernous sinus, middle fossa, and paraclival triangles: a straightforward, comprehensive review.

The middle fossa, cavernous sinus, and paraclival triangles consist of ten triangles. Their use in a surgical approach is vast; most are used as landmarks to access and identify other structures of surgical interest. Multiple labels, borders, and contents mentioned by different authors make understanding and reproduction challenging and confusing. This study aims to organize and clarify recent or most relevant publications and disclose our portrayal of the ten triangles using cadaveric dissection and simple and practical figures. Four middle fossa triangles, four cavernous sinus triangles, and two paraclival triangles were dissected and delineated in a cadaveric specimen. Drawings were simplified to eliminate confusion and evaluate the triangles effortlessly. Similarities and differences in triangle names, border limits, and contents are described in a precise form. The recognition of triangle landmarks allows for treating pathologies in a frequently distorted anatomy or challenging to access structure. That is why an accurate knowledge of the surgical anatomy should be mastered, and a safe approach should be accomplished.

Intraurban Geographic and Socioeconomic Inequalities of Mortality in Four Cities in Colombia.

Mortality inequalities have been described across Latin American countries, but less is known about inequalities within cities, where most populations live. We aimed to identify geographic and socioeconomic inequalities in mortality within the urban areas of four main cities in Colombia. We analyzed mortality due to non-violent causes of diseases in adults between 2015 and 2019 using census sectors as unit of analysis in Barranquilla, Bogotá, Cali, and Medellín. We calculated smoothed Bayesian mortality rates as main health outcomes and used concentration indexes (CInd) for assessing inequalities using the multidimensional poverty index (MPI) as the socioeconomic measure. Moran eigenvector spatial filters were calculated to capture the spatial patterns of mortality and then used in multivariable models of the association between mortality rates and quintiles of MPI. Social inequalities were evident but not consistent across cities. The most disadvantaged groups showed the highest mortality rates in Cali. Geographic inequalities in mortality rates, regardless of the adults and poverty distribution, were identified in each city, suggesting that other social, environmental, or individual conditions are impacting the spatial distribution of mortality rates within the four cities.

Avoidable mortality due to long-term exposure to PM2.5 in Colombia 2014-2019.

OBJECTIVE: To compare estimates of spatiotemporal variations of surface PM2.5 concentrations in Colombia from 2014 to 2019 derived from two global air quality models, as well as to quantify the avoidable deaths attributable to the long-term exposure to concentrations above the current and projected Colombian standard for PM2.5 annual mean at municipality level. METHODS: We retrieved PM2.5 concentrations at the surface level from the ACAG and CAMSRA global air quality models for all 1,122 municipalities, and compare 28 of them with available concentrations from monitor stations. Annual mortality data 2014-2019 by municipality of residence and pooled effect measures for total, natural and specific causes of mortality were used to calculate the number of annual avoidable deaths and years of potential life lost (YPLL) related to the excess of PM2.5 concentration over the current mean annual national standard of 25 µg/m3 and projected standard of 15 µg/m3. RESULTS: Compared to surface data from 28 municipalities with monitoring stations in 2019, ACAG and CAMSRA models under or overestimated annual mean PM2.5 concentrations. Estimations from ACAG model had a mean bias 1,7 µg/m3 compared to a mean bias of 4,7 µg/m3 from CAMSRA model. Using ACAG model, estimations of total nationally attributable deaths to PM2.5 exposure over 25 and 15 µg/m3 were 142 and 34,341, respectively. Cardiopulmonary diseases accounted for most of the attributable deaths due to PM2.5 excess of exposure (38%). Estimates of YPLL due to all-cause mortality for exceeding the national standard of 25 µg/m3 were 2,381 years. CONCLUSION: Comparison of two global air quality models for estimating surface PM2.5 concentrations during 2014-2019 at municipality scale in Colombia showed important differences. Avoidable deaths estimations represent the total number of deaths that could be avoided if the current and projected national standard for PM2.5 annual mean have been met, and show the health-benefit of the implementation of more restrictive air quality standards.

Extended resection for seizure control of pure motor strip focal cortical dysplasia during awake craniotomy: illustrative case.

BACKGROUND: Focal cortical dysplasias (FCD) represent highly intrinsically epileptogenic lesions that require complete resection for seizure control. Resection of pure motor strip FCD can be challenging. Effective control of postoperative seizures is crucial and extending the boundaries of resection in an eloquent zone remains controversial. OBSERVATIONS: The authors report a 52-year-old right-handed male with refractory epilepsy. The seizure phenotype was a focal crisis with preserved awareness and a clonic motor onset of right-hemibody. Epilepsy surgery protocol demonstrated a left pure motor strip FCD and a full-awake resective procedure with motor brain mapping was performed. Further resection of surgical boundaries monitoring function along intraoperative motor tasks with no direct electrical stimulation corroborated by intraoperative-neuromonitorization was completed as the final part of the surgery. In the follow-up period of 3-years, the patient has an Engel-IB seizure-control with mild distal lower limb palsy and no gate compromise. LESSONS: This report represents one of the few cases with pure motor strip FCD resection. In a scenario similar to this case, the authors consider that this variation can be useful to improve seizure control and the quality of life of these patients by extending the resection of a more extensive epileptogenic zone minimizing functional damage.

Financiamiento en investigación en salud: obteniendo financiamiento. Consejos útiles para aumentar las chances de éxito. Parte 2 / Health research funding: obtaining grants. Tips to improve the success rate. Part 2

Esta es la segunda parte de un artículo sobre la búsqueda de financiamiento para un proyecto de investigación. Todo proyecto de investigación requiere una fuente de financiamiento para poder ser llevado adelante. La búsqueda de fondos es una tarea que lleva tiempo y esfuerzo con una baja tasa de éxito. Compartimos algunos consejos que podrían ayudar a aumentar esa tasa de éxito en relación con: 1) cómo reconocer la necesidad de búsqueda de una fuente de financiamiento externo, 2) de dónde provienen los fondos, 3) qué gastos se pueden financiar habitualmente con los fondos y 4) cómo mejorar la escritura y la presentación a una convocatoria. (AU)

This is the second part of our series on searching funds for a research plan. Every research proposal requires a source of funding to be carried out. Looking for funds is a time and effort consuming task with a low success rate. We share some tips that may help to improve that success rate related to (1) how to recognize the need of an external funding source, (2) where the funds are coming from, (3) what costs can be funded and (4) how to improve a proposal writing and submission. (AU)

Surgical treatment of a ruptured internal carotid artery pseudoaneurysm following transsphenoidal surgery.

Development of Internal Carotid Artery pseudoaneurysms (ICAp) after transsphenoidal surgery is extremely rare, occurring only in 0.4% of cases. Surgical treatment of ICAp poses a real challenge to the neurosurgeon as treatment may require parent vessel sacrifice or artery reconstruction with bypass grafting. Furthermore, surgical resolution of these lesions is rarely reported in the literature. The internal carotid artery is prone to iatrogenic injury in transsphenoidal surgery due to its frequent involvement in pituitary adenomas. Intracranial pseudoaneurysms may be at high risk for rupture and increased morbidity and mortality. Here we present a case of a patient with an ICAp rupture two months after transsphenoidal surgery for a pituitary adenoma.

Using Data-Driven Machine Learning to Predict Unplanned ICU Transfers with Critical Deterioration from Electronic Health Records.

OBJECTIVE: We aimed to develop a data-driven machine learning model for predicting critical deterioration events from routinely collected EHR data in hospitalized children. MATERIALS: This retrospective cohort study included all pediatric inpatients hospitalized on a medical or surgical ward between 2014-2018 at a quaternary children's hospital. METHODS: We developed a large data-driven approach and evaluated three machine learning models to predict pediatric critical deterioration events. We evaluated the models using a nested, stratified 10-fold cross-validation. The evaluation metrics included C-statistic, sensitivity, and positive predictive value. We also compared the machine learning models with patients identified as high-risk Watchers by bedside clinicians. RESULTS: The study included 57,233 inpatient admissions from 34,976 unique patients. 3,943 variables were identified from the EHR data. The XGBoost model performed best (C-statistic=0.951, CI: 0.946 ∼ 0.956). CONCLUSIONS: Our data-driven machine learning models accurately predicted patient deterioration. Future sociotechnical analysis will inform deployment within the clinical setting.

Automatic Integration of Clinical and Genetic Data Using cBioPortal.

Precision medicine seeks to improve the prevention, diagnosis and treatment of patients based on genetic characteristics unique to each person. In oncology, therapeutic decisions have been established based on the genomic characteristics of each patient's tumor. Data integration is key for the successful implementation of precision medicine since it is necessary for both studying a large volume of data from different sources and working with an interdisciplinary and translational vision. In this work, a bioinformatic process was successfully implemented that allows the integration of patients' genomic data, from two molecular biology laboratories, with their clinical data provided by their electronic medical records. For this, the REDCap data capture software, the cBioPortal visualization and analysis software, and a computer tool developed to automate the processing and annotation of the information in REDCap were used to be included in cBioPortal, for the "Map of Tumor Genomic Actionability of Argentina" project.

Financiamiento en investigación: ¿qué necesito antes de comenzar a buscar una fuente de financiamiento?: parte 1 / Research funding: what do I need before I start looking for a funding source?: part 1

Esta es la primera parte de un artículo sobre la búsqueda de financiamiento para un proyecto de investigación. Esta entrega resume los principales ítems para tener en consideración a la hora de postularse a una convocatoria. Requerimientos del proceso: 1. Tiempo protegido. 2. Propuesta de investigación sólida. 3. Equipo calificado y con experiencia. 4. Definición y organización de actividades. 5. Cronograma de actividades. 6. Estimación de costos. (AU)

This is the first part of an article about finding funding for a research project. This delivery summarizes the main ítems to take into consideration when applying for a call. Process requirements: 1. Protected time. 2. Strong research proposal. 3. Qualified and experienced team. 4. Definition and organization of activities. 5. Schedule of activities. 6. Cost estimate. (AU)

Social determinants of violence against women in Panama: results from population-based cross-sectional studies and a femicide registry.

BACKGROUND: We aimed to investigate the prevalence of violence against women (VAW) in Panama and its association with social determinants of health (SDH) and to estimate the femicide rates from 2014 to 2017. METHODS: Data were derived from three cross-sectional population-based studies. Logistic regression models were used to estimate the association between SDH and VAW, expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Age-standardized femicide rates were estimated using data from the Public Ministry. RESULTS: Compared to the reference categories, women in the lowest quintile (Q) of income distribution (Q1: OR 4.0 [95% CI 1.4-11.7], Q2: OR 3.0 [95% CI 1.1-7.9]), divorced/separated women (OR 1.5 [95% CI 1.0-2.1]) and those in the age categories 25-33 y and 34-49 y (OR 1.9 [95% CI 1.2-3.1]) were more likely to have experienced violence in the past year. Indigenous ethnicity (OR 2.3 [95% CI 1.3-4.1]), age 15-19 y (OR 1.8 [95% CI 1.1-2.9]) and lowest education levels (very low: OR 4.7 [95% CI 1.4-15.5]; low: OR 4.5 [95% CI 1.4-14.6]) were associated with permissive attitudes towards violence. Indigenous (OR 2.7 [95% CI 1.3-6.1]), Afro-Panamanians (OR 3.1 [95% CI 1.3-7.6]) and education level (low: OR 2.5 [95% CI 1.2-4.9]; medium: OR 3.0 [95% CI 1.4-6.6]) were associated with physical/sexual intimate partner violence. Standardized adjusted femicide rates (×100 000) from 2015 to 2017 were 1.5, 0.9 and 0.8, respectively. CONCLUSIONS: Our findings highlight the importance of prevention programmes.

Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury.

It has been established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocyte pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists in the current pandemic. ACE2 serves as a regulatory enzyme in maintaining homeostasis between proinflammatory angiotensin II and anti-inflammatory angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome. Augmentation of the ACE2/Ang 1,7 axis represents a critical target in the supportive management of coronavirus disease 2019-associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists, requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.

Non-Invasive Monitoring of Ethanol and Methanol Levels in Grape-Derived Pisco Distillate by Vibrational Spectroscopy.

Handheld Raman and portable FT-IR spectroscopy devices were evaluated for fast and non-invasive determination of methanol and ethanol levels in Peruvian Pisco. Commercial Peruvian Pisco (n = 171) samples were kindly provided by the UNALM Alliance for Research in Alcohol and its Derivatives (Lima, Peru) and supplemented by purchases at grocery and online stores. Pisco spectra were collected on handheld Raman spectrometers equipped with either a 1064 nm or a 785 nm excitation laser and a portable infrared unit operating in transmission mode. The alcohol levels were determined by GC-MS. Calibration models used partial least-squares regression (PLSR) to develop prediction algorithms. GC-MS data revealed that 10% of Pisco samples had ethanol levels lower than 38%, indicating possible water dilution. Methanol levels ranged from 10 to 130 mg/100 mL, well below the maximum levels allowed for fruit brandies. Handheld Raman equipped with a 1064 nm excitation laser gave the best results for determining ethanol (SEP = 1.2%; RPre = 0.95) and methanol (SEP = 1.8 mg/100 mL; RPre = 0.93). Randomly selected Pisco samples were spiked with methanol (75 to 2800 mg/100 mL), and their Raman spectra were collected through their genuine commercial bottles. The prediction models gave an excellent performance (SEP = 98 mg/100 mL; RPre = 0.97), allowing for the non-destructive and non-contact determination of methanol and ethanol concentrations without opening the bottles.

ICU outcomes and survival in patients with severe COVID-19 in the largest health care system in central Florida.

BACKGROUND: Observational studies have consistently described poor clinical outcomes and increased ICU mortality in patients with severe coronavirus disease 2019 (COVID-19) who require mechanical ventilation (MV). Our study describes the clinical characteristics and outcomes of patients with severe COVID-19 admitted to ICU in the largest health care system in the state of Florida, United States. METHODS: Retrospective cohort study of patients admitted to ICU due to severe COVID-19 in AdventHealth health system in Orlando, Florida from March 11th until May 18th, 2020. Patients were characterized based on demographics, baseline comorbidities, severity of illness, medical management including experimental therapies, laboratory markers and ventilator parameters. Major clinical outcomes analyzed at the end of the study period were: hospital and ICU length of stay, MV-related mortality and overall hospital mortality of ICU patients. RESULTS: Out of total of 1283 patients with COVID-19, 131 (10.2%) met criteria for ICU admission (median age: 61 years [interquartile range (IQR), 49.5-71.5]; 35.1% female). Common comorbidities were hypertension (84; 64.1%), and diabetes (54; 41.2%). Of the 131 ICU patients, 109 (83.2%) required MV and 9 (6.9%) received ECMO. Lower positive end expiratory pressure (PEEP) were observed in survivors [9.2 (7.7-10.4)] vs non-survivors [10 (9.1-12.9] p = 0.004]. Compared to non-survivors, survivors had a longer MV length of stay (LOS) [14 (IQR 8-22) vs 8.5 (IQR 5-10.8) p< 0.001], Hospital LOS [21 (IQR 13-31) vs 10 (7-1) p< 0.001] and ICU LOS [14 (IQR 7-24) vs 9.5 (IQR 6-11), p < 0.001]. The overall hospital mortality and MV-related mortality were 19.8% and 23.8% respectively. After exclusion of hospitalized patients, the hospital and MV-related mortality rates were 21.6% and 26.5% respectively. CONCLUSIONS: Our study demonstrates an important improvement in mortality of patients with severe COVID-19 who required ICU admission and MV in comparison to previous observational reports and emphasizes the importance of standard of care measures in the management of COVID-19.

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling.

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.