Health Services Use for SARS-CoV-2-Infected Children With Croup or Bronchiolitis.

BACKGROUND AND OBJECTIVES: Croup and bronchiolitis are common reasons for hospitalization in children, and the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on utilization outcomes for these conditions is not well understood. To compare health care utilization including the rates of hospitalization, readmission, length of stay, and ICU admission for croup and bronchiolitis in children with and without evidence of concurrent SARS-CoV-2 infection over the pandemic period. METHODS: This retrospective cohort study used inpatient and outpatient electronic health record data from PEDSnet institutions to examine health services use for children aged 30 days to 14 years with SARS-CoV-2 infection and diagnosed with croup or bronchiolitis. The time frame (March 2020-May 2022) was divided into predelta, delta, and omicron variant periods. Multivariable mixed effects logistic and log gamma regression models were used to calculate adjusted odds ratios for factors linked to utilization outcomes for children with versus without SARS-CoV-2 infections. Disease burden was described by variant time period. RESULTS: Across all time periods, among subjects with croup and bronchiolitis, 9.65% of croup patients and 3.92% of bronchiolitis patients were SARS-CoV-2-positive. The omicron variant period had the highest number of SARS-CoV-2 cases for both croup and bronchiolitis. After controlling for patient-level variables and hospital variability, we found no statistically significant differences in utilization outcomes comparing children with and without SARS-CoV-2. CONCLUSIONS: Pediatric patients with croup and bronchiolitis and positive SARS-CoV-2 polymerase chain reaction testing did not exhibit a significant increase in hospital and ICU admissions, which may have implications for future staffing models and public health recommendations.

Shared Decision-Making and Collaborative Care Models for Pain Management: A Scoping Review of Existing Evidence.

This article aims to summarize the existing evidence on shared decision-making and collaborative care models for acute and chronic pain management. We searched the PubMed database for articles published between 1980 and 2023 and scanned included articles' references to identify additional sources. Two reviewers independently screened titles and abstracts. Studies met inclusion criteria if they implemented or evaluated shared decision-making or collaborative care interventions in patients with acute or chronic pain. A total of 690 articles were reviewed, with 32 full text articles meeting inclusion criteria. Most studies assessed changes in prescription opioid quantities and patient-reported pain levels. Secondary measures generally included patient satisfaction, 30-day refill rate, and use of non-opioid analgesics. Shared decision-making and collaborative care models are promising interventions to improve pain management. These interventions are effective at reducing opioid consumption among acute and chronic pain patients without compromising patient-reported pain levels. There is further research needed to evaluate how shared decision-making and collaborative care interventions impact patient-centered outcomes such as patient satisfaction, quality of life, and patient-provider communication.

Characterizing Long COVID in Children and Adolescents.

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains. Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Designing and optimizing clinical trials for long COVID.

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence. We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued. Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes. Third, studies should have multiple illness comparator cohorts for IACCIs such as myalgic encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses. Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity. Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.

Dual targeting of KDM1A and antioxidants is an effective anticancer strategy.

Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF-1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.

Association between acquiring SARS-CoV-2 during pregnancy and post-acute sequelae of SARS-CoV-2 infection: RECOVER electronic health record cohort analysis.

Background: Little is known about post-acute sequelae of SARS-CoV-2 infection (PASC) after acquiring SARS-CoV-2 infection during pregnancy. We aimed to evaluate the association between acquiring SARS-CoV-2 during pregnancy compared with acquiring SARS-CoV-2 outside of pregnancy and the development of PASC. Methods: This retrospective cohort study from the Researching COVID to Enhance Recovery (RECOVER) Initiative Patient-Centred Clinical Research Network (PCORnet) used electronic health record (EHR) data from 19 U.S. health systems. Females aged 18-49 years with lab-confirmed SARS-CoV-2 infection from March 2020 through June 2022 were included. Validated algorithms were used to identify pregnancies with a delivery at >20 weeks' gestation. The primary outcome was PASC, as previously defined by computable phenotype in the adult non-pregnant PCORnet EHR dataset, identified 30-180 days post-SARS-CoV-2 infection. Secondary outcomes were the 24 component diagnoses contributing to the PASC phenotype definition. Univariable comparisons were made for baseline characteristics between individuals with SARS-CoV-2 infection acquired during pregnancy compared with outside of pregnancy. Using inverse probability of treatment weighting to adjust for baseline differences, the association between SARS-CoV-2 infection acquired during pregnancy and the selected outcomes was modelled. The incident risk is reported as the adjusted hazard ratio (aHR) with 95% confidence intervals. Findings: In total, 83,915 females with SARS-CoV-2 infection acquired outside of pregnancy and 5397 females with SARS-CoV-2 infection acquired during pregnancy were included in analysis. Non-pregnant females with SARS-CoV-2 infection were more likely to be older and have comorbid health conditions. SARS-CoV-2 infection acquired in pregnancy as compared with acquired outside of pregnancy was associated with a lower incidence of PASC (25.5% vs 33.9%; aHR 0.85, 95% CI 0.80-0.91). SARS-CoV-2 infection acquired in pregnant females was associated with increased risk for some PASC component diagnoses including abnormal heartbeat (aHR 1.67, 95% CI 1.43-1.94), abdominal pain (aHR 1.34, 95% CI 1.16-1.55), and thromboembolism (aHR 1.88, 95% CI 1.17-3.04), but decreased risk for other diagnoses including malaise (aHR 0.35, 95% CI 0.27-0.47), pharyngitis (aHR 0.36, 95% CI 0.26-0.48) and cognitive problems (aHR 0.39, 95% CI 0.27-0.56). Interpretation: SARS-CoV-2 infection acquired during pregnancy was associated with lower risk of development of PASC at 30-180 days after incident SARS-CoV-2 infection in this nationally representative sample. These findings may be used to counsel pregnant and pregnant capable individuals, and direct future prospective study. Funding: National Institutes of Health (NIH) Other Transaction Agreement (OTA) OT2HL16184.

Effect of Paxlovid Treatment During Acute COVID-19 on Long COVID Onset: An EHR-Based Target Trial Emulation from the N3C and RECOVER Consortia.

Preventing and treating post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, has become a public health priority. In this study, we examined whether treatment with Paxlovid in the acute phase of COVID-19 helps prevent the onset of PASC. We used electronic health records from the National Covid Cohort Collaborative (N3C) to define a cohort of 426,352 patients who had COVID-19 since April 1, 2022, and were eligible for Paxlovid treatment due to risk for progression to severe COVID-19. We used the target trial emulation (TTE) framework to estimate the effect of Paxlovid treatment on PASC incidence. We estimated overall PASC incidence using a computable phenotype. We also measured the onset of novel cognitive, fatigue, and respiratory symptoms in the post-acute period. Paxlovid treatment did not have a significant effect on overall PASC incidence (relative risk [RR] = 0.98, 95% confidence interval [CI] 0.95-1.01). However, it had a protective effect on cognitive (RR = 0.90, 95% CI 0.84-0.96) and fatigue (RR = 0.95, 95% CI 0.91-0.98) symptom clusters, which suggests that the etiology of these symptoms may be more closely related to viral load than that of respiratory symptoms.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

Real-World Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents.

BACKGROUND: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. OBJECTIVE: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. DESIGN: Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. SETTING: A national collaboration of pediatric health systems (PEDSnet). PARTICIPANTS: 77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase. INTERVENTION: First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine. MEASUREMENTS: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification. RESULTS: During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period. LIMITATION: Observational study design and potentially undocumented infection. CONCLUSION: This study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. PRIMARY FUNDING SOURCE: National Institutes of Health.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

IMPORTANCE: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. METHODS: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DISCUSSION: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Real-world Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents.

Background: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant's emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. Objective: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. Design: Comparative effectiveness research accounting for underreported vaccination in three study cohorts: adolescents (12 to 20 years) during the Delta phase, children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. Setting: A national collaboration of pediatric health systems (PEDSnet). Participants: 77,392 adolescents (45,007 vaccinated) in the Delta phase, 111,539 children (50,398 vaccinated) and 56,080 adolescents (21,180 vaccinated) in the Omicron period. Exposures: First dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine. Measurements: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100% with confounders balanced via propensity score stratification. Results: During the Delta period, the estimated effectiveness of BNT162b2 vaccine was 98.4% (95% CI, 98.1 to 98.7) against documented infection among adolescents, with no significant waning after receipt of the first dose. An analysis of cardiac complications did not find an increased risk after vaccination. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (95% CI, 72.2 to 76.2). Higher levels of effectiveness were observed against moderate or severe COVID-19 (75.5%, 95% CI, 69.0 to 81.0) and ICU admission with COVID-19 (84.9%, 95% CI, 64.8 to 93.5). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (95% CI, 83.8 to 87.1), with 84.8% (95% CI, 77.3 to 89.9) against moderate or severe COVID-19, and 91.5% (95% CI, 69.5 to 97.6)) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined after 4 months following the first dose and then stabilized. The analysis revealed a lower risk of cardiac complications in the vaccinated group during the Omicron variant period. Limitations: Observational study design and potentially undocumented infection. Conclusions: Our study suggests that BNT162b2 was effective for various COVID-19-related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. Primary Funding Source: National Institutes of Health.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

Importance: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER- Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. Registration: NCT05172024.

Effect of Nirmatrelvir/Ritonavir (Paxlovid) on Hospitalization among Adults with COVID-19: an EHR-based Target Trial Emulation from N3C.

This study leverages electronic health record data in the National COVID Cohort Collaborative's (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing COVID-19 hospitalization rates. From an eligible population of 632,822 COVID-19 patients seen at 33 clinical sites across the United States between December 23, 2021 and December 31, 2022, patients were matched across observed treatment groups, yielding an analytical sample of 410,642 patients. We estimate a 65% reduced odds of hospitalization among Paxlovid-treated patients within a 28-day follow-up period, and this effect did not vary by patient vaccination status. Notably, we observe disparities in Paxlovid treatment, with lower rates among Black and Hispanic or Latino patients, and within socially vulnerable communities. Ours is the largest study of Paxlovid's real-world effectiveness to date, and our primary findings are consistent with previous randomized control trials and real-world studies.

HotSPOT: A Computational Tool to Design Targeted Sequencing Panels to Assess Early Photocarcinogenesis.

Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give rise to skin cancer. Early mutation accumulation is a crucial first step in photocarcinogenesis. Therefore, a sufficient understanding of the process may help predict disease onset and identify avenues for skin cancer prevention. Early epidermal mutation profiles are typically established using high-depth targeted next-generation sequencing. However, there is currently a lack of tools for designing custom panels to capture mutation-enriched genomic regions efficiently. To address this issue, we created a computational algorithm that implements a pseudo-exhaustive approach to identify the best genomic areas to target. We benchmarked the current algorithm in three independent mutation datasets of human epidermal samples. Compared to the sequencing panel designs originally used in these publications, the mutation capture efficacy (number of mutations/base pairs sequenced) of our designed panel improved 9.6-12.1-fold. Mutation burden in the chronically sun-exposed and intermittently sun-exposed normal epidermis was measured within genomic regions identified by hotSPOT based on cutaneous squamous cell carcinoma (cSCC) mutation patterns. We found a significant increase in mutation capture efficacy and mutation burden in cSCC hotspots in chronically sun-exposed vs. intermittently sun-exposed epidermis (p < 0.0001). Our results show that our hotSPOT web application provides a publicly available resource for researchers to design custom panels, enabling efficient detection of somatic mutations in clinically normal tissues and other similar targeted sequencing studies. Moreover, hotSPOT also enables the comparison of mutation burden between normal tissues and cancer.

KDM1A inhibition increases UVA toxicity and enhances photodynamic therapy efficacy.

BACKGROUND: Lysine-specific histone demethylase 1 (KDM1A/LSD1) regulates multiple cellular functions, including cellular proliferation, differentiation, and DNA repair. KDM1A is overexpressed in squamous cell carcinoma of the skin and inhibition of KDM1A can suppress cutaneous carcinogenesis. Despite the role of KDM1A in skin and DNA repair, the effect of KDM1A inhibition on cellular ultraviolet (UV) response has not been studied. METHODS: The ability of KDM1A inhibitor bizine to modify cell death after UVA and UVB exposure was tested in normal human keratinocytes and melanocytes, HaCaT, and FaDu cell lines. KDM1A was also downregulated using shRNA and inhibited by phenelzine in HaCaT and FaDu cells to confirm the role of KDM1A in UVA response. In addition, cellular reactive oxygen species (ROS) changes were assessed by a lipid-soluble fluorescent indicator of lipid oxidation, and ROS-related gene regulation using qPCR. During photodynamic therapy (PDT) studies HaCaT and FaDu cells were treated with aminolaevulinic acid (5-ALA) or HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a) sodium and irradiated with 0-8 J/cm2 red LED light. RESULTS: KDM1A inhibition sensitized cells to UVA radiation-induced cell death but not to UVB. KDM1A inhibition increased ROS generation as detected by increased lipid peroxidation and the upregulation of ROS-responsive genes. The effectiveness of both ALA and HPPH PDT significantly improved in vitro in HaCaT and FaDu cells after KDM1A inhibition. CONCLUSION: KDM1A is a regulator of cellular UV response and KDM1A inhibition can improve PDT efficacy.

Ultradeep sequencing differentiates patterns of skin clonal mutations associated with sun-exposure status and skin cancer burden.

In ultraviolet (UV) radiation-exposed skin, mutations fuel clonal cell growth. The relationship between UV exposure and the accumulation of clonal mutations (CMs) and the correlation between CMs and skin cancer risk are largely unexplored. We characterized 450 individual-matched sun-exposed (SE) and non-SE (NE) normal human skin samples. The number and relative contribution of CMs were significantly different between SE and NE areas. Furthermore, we identified hotspots in TP53, NOTCH1, and GRM3 where mutations were significantly associated with UV exposure. In the normal skin from patients with cutaneous squamous cell carcinoma, we found that the cancer burden was associated with the UV-induced mutations, with the difference mostly conferred by the low-frequency CMs. These findings provide previously unknown information on UV's carcinogenic effect and pave the road for future development of quantitative assessment of subclinical UV damage and skin cancer risk.

Generation of cerebral cortical GABAergic interneurons from pluripotent stem cells.

The cerebral cortex functions by the complex interactions of intrinsic and extrinsic neuronal activities, glial actions, and the effects of humoral factors. The intrinsic neuronal influences are mediated by two major subclasses: excitatory glutamatergic neurons that generally have axonal projections extending beyond the neuron's locality and inhibitory GABAergic neurons that generally project locally. These interneurons can be grouped based on morphological, neurochemical, electrophysiological, axonal targeting, and circuit influence characteristics. Cortical interneurons (CIns) can also be grouped based on their origins within the subcortical telencephalon. Interneuron subtypes, of which a dozen or more are thought to exist, are characterized by combinations of these subgrouping features. Due to their well-documented relevance to the causes of and treatments for neuropsychiatric disorders, and to their remarkable capacity to migrate extensively following transplantation, there has been tremendous interest in generating cortical GABAergic interneurons from human pluripotent stem cells. In this concise review, we discuss recent progress in understanding how interneuron subtypes are generated in vivo, and how that progress is being applied to the generation of rodent and human CIns in vitro. In addition, we will discuss approaches for the rigorous designation of interneuron subgroups or subtypes in transplantation studies, and challenges to this field, including the protracted maturation of human interneurons.

Ultraviolet imaging in dermatology.

Visual examination plays a central role in the diagnosis of skin diseases. Many dermatologists use magnification, or dermoscopy, to improve diagnostic certainty when assessing the skin under visible light. In addition to magnification, other technological advances have been made over the last century to improve our visual assessment of the skin. Examination of skin under ultraviolet (UV) radiation, with Wood's light, gained traction for its utility in assessing superficial cutaneous infections and pigmentary changes. During Wood's light examination, UV light is directed at the skin and fluorescence is detected by our eyes. The variable fluorescent characteristics of endogenous and exogenous cutaneous chromophores help us better diagnose skin disease. UV fluorescent photography is based on the same concept as the Wood's light, but also allows image analysis and documentation of the captured image. In addition to UV-induced fluorescence, the differential reflection and absorption of UV light captured in the UV spectral range can also provide a new contrast for diagnosing skin diseases during UV reflectance photography. This review discusses the most widely used UV imaging techniques and provides an overview of the role of UV imaging in dermatology.