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Objectives: Rapid initiation of antiretroviral therapy (ART) is important for individuals with high baseline viral loads, such as in primary HIV‐1 infection (PHI). Four‐drug regimens are sometimes considered; however, data are lacking on tolerability. We aimed to evaluate the tolerability of four‐drug regimens used in the Research in Viral Eradication of HIV‐1 Reservoirs (RIVER) study. Methods: At enrolment, ART‐naïve adult participants or those newly commenced on ART were initiated or intensified to four‐drug regimens within 4 weeks of PHI. Rapid start was defined as pre‐confirmation or ≤ 7 days of confirmed diagnosis. Primary and secondary outcomes were patient‐reported adherence measured by 7‐day recall and regimen switches between enrolment and randomization, respectively. Results: Overall, 54 men were included: 72.2% were of white ethnicity, with a median age of 32 years old, 42.6% had a viral load of ≥ 100 000 HIV‐1 RNA copies/mL, and in 92.6% sex with men was the mode of acquisition of HIV‐1. Twenty (37%) started a four‐drug regimen and 34 (63%) were intensified. Rapid ART initiation occurred in 28%, 100% started in ≤ 4 weeks. By weeks 4, 12, and 24, 37.0%, 69.0%, and 94.0% were undetectable (viral load < 50 copies/mL), respectively. Adherence rates of 100% at weeks 4, 12, 22 and 24 were reported in 88.9%, 87.0%, 82.4% and 94.1% of participants, respectively. Five individuals switched to three drugs, four changed their regimen constituents, and two switched post‐randomization. Conclusions: Overall, four‐drug regimens were well tolerated and had high levels of adherence. Whilst their benefit over three‐drug regimens is lacking, our findings should provide reassurance if a temporarily intensified regimen is clinically indicated to help facilitate treatment. [ABSTRACT FROM AUTHOR]

BackgroundChronic obstructive pulmonary disease (COPD) is highly prevalent and significantly affects the daily functioning of patients. Self-management strategies, including increasing physical activity, can help people with COPD have better health and a better quality of life. Digital mobile health (mHealth) techniques have the potential to aid the delivery of self-management interventions for COPD. We developed an mHealth intervention (Self-Management supported by Assistive, Rehabilitative, and Telehealth technologies-COPD [SMART-COPD]), delivered via a smartphone app and an activity tracker, to help people with COPD maintain (or increase) physical activity after undertaking pulmonary rehabilitation (PR). ObjectiveThis study aimed to determine the feasibility and acceptability of using the SMART-COPD intervention for the self-management of physical activity and to explore the feasibility of conducting a future randomized controlled trial (RCT) to investigate its effectiveness. MethodsWe conducted a randomized feasibility study. A total of 30 participants with COPD were randomly allocated to receive the SMART-COPD intervention (n=19) or control (n=11). Participants used SMART-COPD throughout PR and for 8 weeks afterward (ie, maintenance) to set physical activity goals and monitor their progress. Questionnaire-based and physical activity–based outcome measures were taken at baseline, the end of PR, and the end of maintenance. Participants, and health care professionals involved in PR delivery, were interviewed about their experiences with the technology. ResultsOverall, 47% (14/30) of participants withdrew from the study. Difficulty in using the technology was a common reason for withdrawal. Participants who completed the study had better baseline health and more prior experience with digital technology, compared with participants who withdrew. Participants who completed the study were generally positive about the technology and found it easy to use. Some participants felt their health had benefitted from using the technology and that it assisted them in achieving physical activity goals. Activity tracking and self-reporting were both found to be problematic as outcome measures of physical activity for this study. There was dissatisfaction among some control group members regarding their allocation. ConclusionsmHealth shows promise in helping people with COPD self-manage their physical activity levels. mHealth interventions for COPD self-management may be more acceptable to people with prior experience of using digital technology and may be more beneficial if used at an earlier stage of COPD. Simplicity and usability were more important for engagement with the SMART-COPD intervention than personalization; therefore, the intervention should be simplified for future use. Future evaluation will require consideration of individual factors and their effect on mHealth efficacy and use; within-subject comparison of step count values; and an opportunity for control group participants to use the intervention if an RCT were to be carried out. Sample size calculations for a future evaluation would need to consider the high dropout rates.

Background: Allograft survival among black recipients is poorer than among whites. Delayed allograft function is associated with a significant reduction in renal allograft survival. The relationship between delayed allograft function and black race is incompletely specified and was the focus of this investigation. [ABSTRACT FROM PUBLISHER]

Little is known about infectious complications of lumbar puncture (LP) in children. We reviewed records of children with bacterial meningitis, intraspinal abscess, and vertebral osteomyelitis over a 3-year period to identify infections following LP. Four children with bacterial meningitis and 1 child with vertebral osteomyelitis were identified and their clinical presentations were described. These cases were scored by infectious disease experts, using a Likert scale, for the possibility of iatrogenic causation; these scores were variable, reflecting uncertainty. The bacterial meningitis cases had repeat LPs, and the latter cerebrospinal fluid analyses were diagnostic of bacterial meningitis; the interval between the initial "index" LP (I-LP) and symptom onset was 8 to 10 hours in most cases. Pediatricians should be aware of this possibility, and have a low threshold to repeat LP if there is a clinical change after the I-LP that could be consistent with meningitis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Metabolic dysfunction associated fatty liver disease (MAFLD) is over-represented in people with HIV (PWH). Maraviroc (MVC) and/or metformin (MET) may reduce MAFLD by influencing inflammatory pathways and fatty acid metabolism., Design: Open-label, 48-week randomized trial with a 2 x 2 factorial design., Setting: Multicenter HIV clinics., Participants: Nondiabetic, virologically suppressed PLWH, aged at least 35 years, with confirmed/suspected MAFLD (≥1 biochemical/anthropometric/radiological/histological features)., Intervention: Adjunctive MVC; MET; MVC+MET vs. antiretroviral therapy (ART) alone., Primary Outcome: Change in liver fat fraction (LFF) between baseline and week-48 using magnetic resonance proton density fat fraction (MR PDFF)., Results: Six sites enrolled 90 participants (93% male; 81% white; median age 52 [interquartile range, IQR 47-57] years) between March 19, 2018, and November 11, 2019. Seventy percent had imaging/biopsy and at least one 1 MAFLD criteria. The analysis included 82/90 with week-0 and week-48 scans. Median baseline MR PDFF was 8.9 (4.6-17.1); 40, 38, 8, and 14% had grade zero, one, two, and three steatosis, respectively. Mean LFF increased slightly between baseline and follow-up scans: 2.22% MVC, 1.26% MET, 0.81% MVC+MET, and 1.39% ART alone. Prolonged intervention exposure (delayed week-48 scans) exhibited greater increases in MR PDFF (estimated difference 4.23% [95% confidence interval, 95% CI 2.97-5.48], P  < 0.001). There were no differences in predicted change for any intervention compared to ART alone: MVC (-0.42% [95% CI -1.53 to 0.68, P  = 0.45]), MET (-0.62 [-1.81 to 0.56, P  = 0.30]), and MVC+MET (-1.04 [-2.74 to 0.65, P  = 0.23]). Steatosis grade remained unchanged in 55% and increased in 24%., Conclusion: Baseline levels of liver fat were lower than predicted. Contrary to our hypothesis, neither MVC, MET, or the combination significantly reduced liver fat as measured by MRPDFF compared to ART alone., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Congenital enterovirus infection can be associated with a pro-inflammatory state triggering haemophagocytic lymphohistiocytosis (HLH). Enteroviruses are also known to cause transient neutropenia in healthy children. Two infants presented with temperature instability, lethargy, thrombocytopaenia, hepatosplenomegaly and evidence of hyperinflammation in the setting of perinatal maternal rash and household contacts with gastrointestinal symptoms. Whilst HLH was successfully treated in both, protracted neutropenia persisted. Immune dysregulation with enterovirus in the neonatal period can provoke the generation of autoantibodies to hematologic cells giving rise to conditions such as autoimmune neutropenia. Sustained neutropaenia, after resolution of secondary infectious forms of HLH, requires investigation for underlying aetiologies., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: Repurposed medications for acute coronavirus disease 2019 (COVID-19) continued to be prescribed after results from rigorous studies and national guidelines discouraged use. We aimed to describe prescribing rates of nonrecommended medications for acute COVID-19 in children, associations with demographic factors, and provider type and specialty., Methods: In this retrospective cohort of children <18 years in a large United States all-payer claims database, we identified prescriptions within 2 weeks of an acute COVID-19 diagnosis. We calculated prescription rate, performed multivariable logistic regression to identify risk factors, and described prescriber type and specialty during nonrecommended periods defined by national guidelines., Results: We identified 3 082 626 COVID-19 diagnoses in 2 949 118 children between March 7, 2020 and December 31, 2022. Hydroxychloroquine (HCQ) and ivermectin were prescribed in 0.03% and 0.14% of COVID-19 cases, respectively, during nonrecommended periods (after September 12, 2020 for HCQ and February 5, 2021 for ivermectin) with considerable variation by state. Prescription rates were 4 times the national average in Arkansas (HCQ) and Oklahoma (ivermectin). Older age, nonpublic insurance, and emergency department or urgent care visit were associated with increased risk of either prescription. Additionally, residence in nonurban and low-income areas was associated with ivermectin prescription. General practitioners had the highest rates of prescribing., Conclusions: Although nonrecommended medication prescription rates were low, the overall COVID-19 burden translated into high numbers of ineffective and potentially harmful prescriptions. Understanding overuse patterns can help mitigate downstream consequences of misinformation. Reaching providers and parents with clear evidence-based recommendations is crucial to children's health., (Copyright © 2024 by the American Academy of Pediatrics.)

Objective: Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate., Design: Open-label, randomized controlled trial., Setting: Single-site, outpatient, secondary care., Participants: Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks., Intervention: Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization)., Main Outcome Measures: :[ 18 F]NaF-PET/CT for bone turnover (standardized uptake values, SUV mean ) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD., Results: Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23-103 (median 55) weeks. LS-SUV mean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P  = 0.57). TH-SUV mean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P  = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P  = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX ( P  = 0.02, P1NP, P  = 0.17)., Conclusion: Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUV mean ) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUV mean may be due to inadequate power., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Alterations of fibroblast growth factor receptors (FGFRs) are common in bladder and other cancers and result in disrupted signalling via several pathways. Therapeutics that target FGFRs have now entered the clinic, but, in common with many cancer therapies, resistance develops in most cases. To model this, we derived resistant sublines of two FGFR-driven bladder cancer cell lines by long-term culture with the FGFR inhibitor PD173074 and explored mechanisms using expression profiling and whole-exome sequencing. We identified several resistance-associated molecular profiles. These included HRAS mutation in one case and reversible mechanisms resembling a drug-tolerant persister phenotype in others. Upregulated IGF1R expression in one resistant derivative was associated with sensitivity to linsitinib and a profile with upregulation of a YAP/TAZ signature to sensitivity to the YAP inhibitor CA3 in another. However, upregulation of other potential therapeutic targets was not indicative of sensitivity. Overall, the heterogeneity in resistance mechanisms and commonality of the persister state present a considerable challenge for personalised therapy. Nevertheless, the reversibility of resistance may indicate a benefit from treatment interruptions or retreatment following disease relapse in some patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Objectives: Coronavirus disease 2019 (COVID-19) treatment guidelines rapidly evolved during the pandemic. The December 2020 Infectious Diseases Society of America (IDSA) guideline, endorsed by the Pediatric Infectious Diseases Society, recommended steroids for critical disease, and suggested steroids and remdesivir for severe disease. We evaluated how medications for children hospitalized with COVID-19 changed after guideline publication., Methods: We performed a multicenter, retrospective cohort study of children aged 30 days to <18 years hospitalized with acute COVID-19 at 42 tertiary care US children's hospitals April 2020 to December 2021. We compared medication use before and after the December 2020 IDSA guideline (pre- and postguideline) stratified by COVID-19 disease severity (mild-moderate, severe, critical) with interrupted time series., Results: Among 18 364 patients who met selection criteria, 80.3% were discharged in the postguideline period. Remdesivir and steroid use increased postguideline relative to the preguideline period, although the trend slowed. Postguideline, among patients with severe disease, 75.4% received steroids and 55.2% remdesivir, and in those with critical disease, 82.4% received steroids and 41.4% remdesivir. Compared with preguideline, enoxaparin use increased overall but decreased among patients with critical disease. Postguideline, tocilizumab use increased and hydroxychloroquine, azithromycin, anakinra, and antibiotic use decreased. Antibiotic use remained high in severe (51.7%) and critical disease (81%)., Conclusions: Although utilization of COVID-19 medications changed after December 2020 IDSA guidelines, there was a decline in uptake and incomplete adherence for children with severe and critical disease. Efforts should enhance reliable delivery of guideline-directed therapies to children hospitalized with COVID-19 and assess their effectiveness., (Copyright © 2022 by the American Academy of Pediatrics.)

Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2-5% of cases. It often presents late and is unresponsive to cisplatin-based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole-exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle-invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non-SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD-L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel-associated (KRAB) domain-containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited., (© 2022 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

Objectives: Integrase strand transfer inhibitors (INSTIs) are commonplace in modern antiretroviral therapy (ART). Increased weight gain with their use is increasingly scrutinized. We evaluated weight changes in treatment-naïve adults with HIV-1 attending a UK centre who started regimens including raltegravir or dolutegravir., Methods: A retrospective cohort study of adults prescribed an INSTI between January 2015 and March 2020 were categorized as having started an ART regimen containing raltegravir, dolutegravir, a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Individuals with one or more weight measurement ≤ 5 years both pre- and post-ART initiation, who started a three-drug regimen with ≥ 6 months duration and achieved virological suppression (< 50 copies/mL) within 6 months were included. A random effects model with linear slope pre- and post-ART was used, adjusting for age, gender, ethnicity, ART regimen, backbone and year of initiation., Results: The cohort included 390 adults; 88.7% were male, 66.4% were of white ethnicity, their median age was 40 years, there was a median of six weight measurements, 2.2 years from diagnosis to ART initiation, 2.9 years from ART to the last weight measurement, and weight and body mass index at initiation were 75 kg and 24.1 kg/m 2 respectively. Of these, 254 (65%) started an INSTI. The average pre-ART rate of weight gain was 0.44 kg/year [95% confidence interval (CI): 0.19-0.70], increasing to 0.88 kg/year (0.63-1.10, p = 0.04) after ART initiation. Our adjusted model found no evidence of an association between ART regimen and rate of weight gain., Conclusions: Weight increased in the cohort both pre- and post-ART. We found no evidence of a higher rate of weight gain following ART initiation with an INSTI compared with other regimens., (© 2021 British HIV Association.)

Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.

Introduction: Variants of the APOL1 gene are associated with chronic kidney disease (CKD) in people of African ancestry, although evidence for their impact in people with HIV are sparse., Methods: We conducted a cross-sectional study investigating the association between APOL1 renal risk alleles and kidney disease in people of African ancestry with HIV in the UK. The primary outcome was end-stage kidney disease (ESKD; estimated glomerular filtration rate [eGFR] of <15 ml/min per 1.73 m 2 , chronic dialysis, or having received a kidney transplant). The secondary outcomes included renal impairment (eGFR <60 ml/min per 1.73 m 2 ), albuminuria (albumin-to-creatinine ratio [ACR] >30 mg/mmol), and biopsy-proven HIV-associated nephropathy (HIVAN). Multivariable logistic regression was used to estimate the associations between APOL1 high-risk genotypes (G1/G1, G1/G2, G2/G2) and kidney disease outcomes., Results: A total of 2864 participants (mean age 48.1 [SD 10.3], 57.3% female) were genotyped, of whom, 354 (12.4%) had APOL1 high-risk genotypes, and 99 (3.5%) had ESKD. After adjusting for demographic, HIV, and renal risk factors, individuals with APOL1 high-risk genotypes were at increased odds of ESKD (odds ratio [OR] 10.58, 95% CI 6.22-17.99), renal impairment (OR 5.50, 95% CI 3.81-7.95), albuminuria (OR 3.34, 95% CI 2.00-5.56), and HIVAN (OR 30.16, 95% CI 12.48-72.88). An estimated 49% of ESKD was attributable to APOL1 high-risk genotypes., Conclusion: APOL1 high-risk genotypes were strongly associated with kidney disease in people of African ancestry with HIV and accounted for approximately half of ESKD cases in this cohort., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Understanding the molecular determinants that underpin the clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk of progression and requires improved understanding. We present a detailed multi-omics study containing gene expression, copy number, and mutational profiles that show relationships to immune infiltration, disease recurrence, and progression to muscle invasion. We compare expression and genomic subtypes derived from all NMIBCs with those derived from the individual disease stages Ta and T1. We show that sufficient molecular heterogeneity exists within the separate stages to allow subclassification and that this is more clinically meaningful for stage T1 disease than that derived from all NMIBCs. This provides improved biological understanding and identifies subtypes of T1 tumors that may benefit from chemo- or immunotherapy., Competing Interests: M.A.K. has an advisory/consulting role at Janssen, LOXO Oncology, QED, and Rainier Therapeutics. L.D. has sponsored research agreements with C2i-genomics, Natera, AstraZeneca, and Ferring and an advisory/consulting role at Ferring. L.D. has received a speaker honorarium from Roche., (© 2021 The Authors.)

Introduction: Sickle cell trait (SCT) has been associated with chronic kidney disease (CKD) in African Americans, although evidence for its impact in Africans and people with HIV is currently lacking. We conducted a cross-sectional study investigating the association between SCT and kidney disease in people of African ancestry with HIV in the UK., Methods: The primary outcome was estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 . Secondary outcomes were eGFR <90 ml/min per 1.73 m 2 , end-stage kidney disease (ESKD; eGFR <15 ml/min per 1.73 m 2 , chronic dialysis, or having received a kidney transplant), proteinuria (protein-to-creatinine ratio >50 mg/mmol), and albuminuria (albumin-to-creatinine ratio >3 mg/mmol). Multivariable logistic regression was used to estimate the associations between SCT and kidney disease outcomes., Results: A total of 2895 participants (mean age 48.1 [SD 10.3], 57.2% female) were included, of whom 335 (11.6%) had SCT and 352 (12.2%) had eGFR <60 ml/min per 1.73 m 2 . After adjusting for demographic, HIV, and kidney risk factors including APOL1 high-risk genotype status, individuals with SCT were more likely to have eGFR <60 ml/min per 1.73 m 2 (odds ratio 1.62 [95% CI 1.14-2.32]), eGFR <90 ml/min per 1.73 m 2 (1.50 [1.14-1.97]), and albuminuria (1.50 [1.09-2.05]). Stratified by APOL1 status, significant associations between SCT and GFR <60 ml/min per 1.73 m 2 , eGFR <90 ml/min per 1.73 m 2 , proteinuria, and albuminuria were observed for those with APOL1 low-risk genotypes., Conclusion: Our results extend previously reported associations between SCT and kidney disease to people with HIV. In people of African ancestry with HIV, these associations were largely restricted to those with APOL1 low-risk genotypes., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: Little is known about the clinical factors associated with COVID-19 disease severity in children and adolescents., Methods: We conducted a retrospective cohort study across 45 US children's hospitals between April 2020 to September 2020 of pediatric patients discharged with a primary diagnosis of COVID-19. We assessed factors associated with hospitalization and factors associated with clinical severity (eg, admission to inpatient floor, admission to intensive care unit [ICU], admission to ICU with mechanical ventilation, shock, death) among those hospitalized., Results: Among 19,976 COVID-19 encounters, 15,913 (79.7%) patients were discharged from the emergency department (ED) and 4063 (20.3%) were hospitalized. The clinical severity distribution among those hospitalized was moderate (3222, 79.3%), severe (431, 11.3%), and very severe (380, 9.4%). Factors associated with hospitalization vs discharge from the ED included private payor insurance (adjusted odds ratio [aOR],1.16; 95% CI, 1.1-1.3), obesity/type 2 diabetes mellitus (type 2 DM) (aOR, 10.4; 95% CI, 8.9-13.3), asthma (aOR, 1.4; 95% CI, 1.3-1.6), cardiovascular disease, (aOR, 5.0; 95% CI, 4.3- 5.8), immunocompromised condition (aOR, 5.9; 95% CI, 5.0-6.7), pulmonary disease (aOR, 5.3; 95% CI, 3.4-8.2), and neurologic disease (aOR, 3.2; 95% CI, 2.7-5.8). Among children and adolescents hospitalized with COVID-19, greater disease severity was associated with Black or other non-White race; age greater than 4 years; and obesity/type 2 DM, cardiovascular, neuromuscular, and pulmonary conditions., Conclusions: Among children and adolescents presenting to US children's hospital EDs with COVID-19, 20% were hospitalized; of these, 21% received care in the ICU. Older children and adolescents had a lower risk for hospitalization but more severe illness when hospitalized. There were differences in disease severity by race and ethnicity and the presence of selected comorbidities. These factors should be taken into consideration when prioritizing mitigation and vaccination strategies.

Bladder cancer is the 10th most common cancer worldwide. For muscle-invasive bladder cancer (MIBC), treatment includes radical cystectomy, radiotherapy, and chemotherapy; however, the outcome is generally poor. For non-muscle-invasive bladder cancer (NMIBC), tumor recurrence is common. There is an urgent need for more effective and less harmful therapeutic approaches. Here, bladder cancer cell metabolic reprogramming to rely on aerobic glycolysis (the Warburg effect) and expression of associated molecular therapeutic targets by bladder cancer cells of different stages and grades, and in freshly resected clinical tissue, is investigated. Importantly, analyses indicate that the Warburg effect is a feature of both NMIBCs and MIBCs. In two in vitro inducible epithelial-mesenchymal transition (EMT) bladder cancer models, EMT stimulation correlated with increased lactate production, the end product of aerobic glycolysis. Protein levels of lactate dehydrogenase A (LDH-A), which promotes pyruvate enzymatic reduction to lactate, were higher in most bladder cancer cell lines (compared with LDH-B, which catalyzes the reverse reaction), but the levels did not closely correlate with aerobic glycolysis rates. Although LDH-A is expressed in normal urothelial cells, LDH-A knockdown by RNAi selectively induced urothelial cancer cell apoptotic death, whereas normal cells were unaffected-identifying LDH-A as a cancer-selective therapeutic target for bladder cancers. LDH-A and other potential therapeutic targets (MCT4 and GLUT1) were expressed in patient clinical specimens; however, positive staining varied in different areas of sections and with distance from a blood vessel. This intratumoral heterogeneity has important therapeutic implications and indicates the possibility of tumor cell metabolic coupling., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. The risk of CKD is increased in people of African ancestry and with Human Immunodeficiency Virus (HIV) infection., Methods: We conducted a cross-sectional study investigating the relationship between region of ancestry (East, Central, South or West Africa) and kidney disease in people of sub-Saharan African ancestry with HIV in the UK between May 2018 and February 2020. The primary outcome was renal impairment (estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m 2 ). Secondary outcomes were stage 5 CKD (eGFR <15 ml/min/1.73 m 2 , on dialysis for over 3 months or who had received a kidney transplant), proteinuria (urine protein/creatinine ratio >50 mg/mmol), and biopsy-confirmed HIV-associated nephropathy (HIVAN), focal segmental glomerulosclerosis (FSGS) or arterionephrosclerosis. Multivariable robust Poisson regression estimated the effect of region of African ancestry on kidney disease outcomes., Findings: Of the 2468 participants (mean age 48.1 [SD 9.8] years, 62% female), 193 had renal impairment, 87 stage 5 CKD, 126 proteinuria, and 43 HIVAN/FSGS or arterionephrosclerosis. After adjusting for demographic characteristics, HIV and several CKD risk factors and with East African ancestry as referent, West African ancestry was associated with renal impairment (prevalence ratio [PR] 2.06 [95% CI 1.40-3.04]) and stage 5 CKD (PR 2.23 [1.23-4.04]), but not with proteinuria (PR 1.27 [0.78-2.05]). West African ancestry (as compared to East/South African ancestry) was also strongly associated with a diagnosis of HIVAN/FSGS or arterionephrosclerosis on kidney biopsy (PR 6.44 [2.42-17.14])., Interpretation: Our results indicate that people of West African ancestry with HIV are at increased risk of kidney disease. Although we cannot rule out the possibility of residual confounding, geographical region of origin appears to be a strong independent risk factor for CKD as the association did not appear to be explained by several demographic, HIV or renal risk factors., Competing Interests: Dr Hung has nothing to disclose. Dr Santana-Suarez has nothing to disclose. Dr Binns-Roemer has nothing to disclose. Dr Campbell has nothing to disclose. Dr Bramham has nothing to disclose. Dr Hamzah has nothing to disclose. Dr Fox has nothing to disclose. Dr Burns has nothing to disclose. Dr Clarke reports personal fees from Advisory boards & conference travel from Gilead Sciences, personal fees from Advisory boards from ViiV Healthcare, outside the submitted work. Dr Vincent has nothing to disclose. Dr Jones has nothing to disclose. Dr Price has nothing to disclose. Dr Onyago has nothing to disclose. Dr Harber has nothing to disclose. Dr Hilton has nothing to disclose. Dr Booth has nothing to disclose. Dr Sabin has nothing to disclose. Dr Winkler has nothing to disclose. Dr Post reports grants from Medical Research Council UK, grants, personal fees and non-financial support from Gilead, grants personal fees and non-financial support from ViiV, grants and personal fees from MSD, grants and personal fees from Janssen, during the conduct of the study., (© 2021 The Authors.)

Background: The epidemiology of congenital infections is ever changing, with a recent resurgence in syphilis infection rates seen in the UK. Identification of congenital infection is often delayed; early recognition and management of congenital infections is important. Testing modalities and investigations are often limited, leading to missed diagnostic opportunities., Methods: The SCORTCH (syphilis, cytomegalovirus (CMV), 'other', rubella, toxoplasmosis, chickenpox, herpes simplex virus (HSV) and blood-borne viruses) acronym increases the awareness of clinicians to the increased risk of congenital syphilis, while considering other infectious aetiologies including: zika, malaria, chagas disease, parvovirus, enterovirus, HIV, hepatitis B and C, and human T-lymphotropic virus 1, in addition to the classic congenital infections recognised in the 'TORCH screen' (toxoplasmosis, 'other', rubella, CMV, HSV). The SCORTCH diagnostic approach describes common signs present in infants with congenital infection, details serological testing for mother and infant and important direct diagnostics of the infant. Direct diagnostic investigations include: radiology, ophthalmology, audiology, microbiological and PCR testing for both the infant and placental tissue, the latter also warrants histopathology., Conclusion: The traditional 'TORCH screen' focuses on serology-specific investigations, often omits important direct diagnostic testing of the infant, and fails to consider emerging and re-emerging congenital infections. In recognition of syphilis as a re-emerging pathogen and the overlapping clinical presentations of various infectious aetiologies, we advocate for a broader outlook using the SCORTCH diagnostic approach., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Survival rates for pediatric acute leukemia vary dramatically worldwide. Infections are a leading cause of morbidity and mortality, and the impact is amplified in low and middle-income countries. Defining the epidemiology of infection in a specific health care setting is paramount to developing effective interventions. This study aimed to define the epidemiology of and outcomes from infection in children with acute leukemia treated in a large public pediatric hospital in the Dominican Republic. A retrospective cohort was assembled of children newly diagnosed with acute leukemia between July 1, 2015 to June 30, 2017 at Hospital Infantil Dr. Robert Reid Cabral in Santo Domingo. Patients were identified from the Pediatric Oncology Network Database (PONDTM) and hospital admissions from the Oncology admissions logbook. Medical records and microbiology results were reviewed to identify all inpatient invasive infections. Distance from a child's home to the hospital was determined using ArcGIS by Esri. Infection rates were described in discrete time periods after diagnosis and risk factors for invasive infection were explored using negative binomial regression. Overall, invasive infections were common and a prominent source of death in this cohort. Rates were highest in the first 60 days after diagnosis. Gastroenteritis/colitis, cellulitis, and pneumonia were most frequent, with bacteremia common early on. Multidrug resistant bacteria were prevalent among a small number of positive cultures. In a multivariate negative binomial regression model, age ≥ 10 years and distance from the hospital > 100 km were each protective against invasive infection in the first 180 days after diagnosis, findings that were unexpected and warrant further investigation. Over one-third of patient deaths were related to infection. Interventions aimed at reducing infection should target the first 60 days after diagnosis, improved supportive care inside and outside the hospital, and increased antimicrobial stewardship and infection prevention and control measures., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BTF: His institution receives funding from Merck and Pfizer for research studies. He also serves on a Data Safety Monitoring Committee for Astellas. These studies are not related to this project. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Understanding the role that children play in the clinical burden and propagation of severe acute respiratory syndrome coronavirus 2, responsible for coronavirus disease 2019 (COVID-19) infections, is emerging. While the severe manifestations and acute clinical burden of COVID-19 have largely spared children compared with adults, understanding the epidemiology, clinical presentation, diagnostics, management, and prevention opportunities and the social and behavioral impacts on child health is vital. Foremost is clarifying the contribution of asymptomatic and mild infections to transmission within the household and community and the clinical and epidemiologic significance of uncommon severe post-infectious complications. Here, we summarize the current knowledge, identify resources, and outline research opportunities. Pediatric infectious diseases clinicians have a unique opportunity to advocate for the inclusion of children in epidemiological, clinical, treatment, and prevention studies to optimize their care as well as to represent children in the development of guidance and policy during pandemic response., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Congenital cytomegalovirus (CCMV) accounts for high rates of infant morbidity and mortality. Neutropenia is a common finding in CCMV infection, of which the age of presentation overlaps with autoimmune neutropenia (AIN). AIN represents one of the most common forms of chronic neutropenia in childhood., Methods: A literature search exploring biologic associations between CCMV and AIN was conducted: PubMed (MEDLINE), Ovid and Web of Science. We further describe 2 cases of concurrent CCMV and AIN. Both cases were confirmed with the indirect granulocyte immunofluorescence test and alternative etiologies for neutropenia excluded., Results: Our 2 patients represent confirmed cases of AIN in infants with CCMV. One patient demonstrated neutropenia while undergoing treatment with Valganciclovir, while the other was never treated. With interruption of Valganciclovir in infant A, neutrophil counts (ANC) did not improve and upon resumption of treatment ANC remained static., Conclusions: Further studies examining a possible biologic link between CCMV and AIN are advocated for. We encourage clinicians to actively consider AIN in the differential diagnosis of all infants with CCMV presenting with neutropenia.

Rationale and Objectives: To assess whether a fully-automated deep learning system can accurately detect and analyze truncal musculature at multiple lumbar vertebral levels and muscle groupings on abdominal CT for potential use in the detection of central sarcopenia., Materials and Methods: A computer system for automated segmentation of truncal musculature groups was designed and created. Abdominal CT scans of 102 sequential patients (mean age 68 years, range 59-81 years; 53 women, 49 men) conducted between January 2015 and February 2015 were assembled as a data set. Truncal musculature was manually segmented on axial CT images at multiple lumbar vertebral levels as reference standard data, divided into training and testing subsets, and analyzed by the system. Dice similarity coefficients were calculated to evaluate system performance. IRB approval was obtained, with waiver of informed consent in this retrospective study., Results: System performance as gauged by the Dice coefficients, for detecting the total abdominal muscle cross-section at the level of the third and fourth lumbar vertebrae, were, respectively, 0.953 ± 0.015 and 0.953 ± 0.011 for the training set, and 0.938 ± 0.028 and 0.940 ± 0.026 for the testing set. Dice coefficients for detecting total psoas muscle cross-section at the level of the third and fourth lumbar vertebrae, were, respectively, 0.942 ± 0.040 and 0.951 ± 0.037 for the training set, and 0.939 ± 0.028 and 0.946 ± 0.032 for the testing set., Conclusion: This system fully-automatically and accurately segments multiple muscle groups at all lumbar spine levels on abdominal CT for detection of sarcopenia., (Copyright © 2019. Published by Elsevier Inc.)

Objective: Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically suppressed adults with HIV who switched from non-INSTI regimens to raltegravir (RAL)-containing or dolutegravir (DTG)-containing antiretroviral therapy., Design: Retrospective single-centre cohort., Methods: Adults who switched to RAL or DTG before or between January 2015 and October 2017 were identified. Virologically suppressed, treatment-experienced (≥2 years) individuals, at least 6 months on INSTI, with weight measurements 2 years or less pre and postswitch were included. Our analysis used a random effects model with linear slope pre and post-INSTI with adjustment for age, sex, ethnicity, preswitch-regimen (protease inhibitor vs. nonprotease inhibitor), and RAL vs. DTG use., Results: A total of 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and BMI at switch of 76.6 kg and 25.3 kg/m, respectively, were included. Weight increased by an average of 0.63 kg/year (95% confidence interval 0.17-1.09) preswitch with no overall change in rate of weight gain postswitch [+0.05 kg/year (-0.61-0.71, P = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain postswitch was isolated to older individuals though this lacked statistical significance [e.g., +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by sex, ethnicity, preswitch regimen, or RAL vs. DTG. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone., Conclusion: We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically suppressed individuals.

Artificial intelligence is upending many of our assumptions about the ability of computers to detect and diagnose diseases on medical images. Deep learning, a recent innovation in artificial intelligence, has shown the ability to interpret medical images with sensitivities and specificities at or near that of skilled clinicians for some applications. In this review, we summarize the history of artificial intelligence, present some recent research advances, and speculate about the potential revolutionary clinical impact of the latest computer techniques for bone and muscle imaging. © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To investigate a fully automated abdominal CT-based muscle tool in a large adult screening population., Methods: A fully automated validated muscle segmentation algorithm was applied to 9310 non-contrast CT scans, including a primary screening cohort of 8037 consecutive asymptomatic adults (mean age, 57.1±7.8 years; 3555M/4482F). Sequential follow-up scans were available in a subset of 1171 individuals (mean interval, 5.1 years). Muscle tissue cross-sectional area and attenuation (Hounsfield unit, HU) at the L3 level were assessed, including change over time., Results: Mean values were significantly higher in males for both muscle area (190.6±33.6 vs 133.3±24.1 cm 2 , p <0.001) and density (34.3±11.1 HU vs 27.3±11.7 HU, p <0.001). Age-related losses were observed, with mean muscle area reduction of -1.5 cm 2 /year and attenuation reduction of -1.5 HU/year. Overall age-related muscle density (attenuation) loss was steeper than for muscle area for both sexes up to the age of 70 years. Between ages 50 and 70, relative muscle attenuation decreased significantly more in females (-30.6% vs -18.0%, p <0.001), whereas relative rates of muscle area loss were similar (-8%). Between ages 70 and 90, males lost more density (-22.4% vs -7.5%) and area (-13.4% vs -6.9%, p <0.001). Of the 1171 patients with longitudinal follow-up, 1013 (86.5%) showed a decrease in muscle attenuation, 739 (63.1%) showed a decrease in area, and 1119 (95.6%) showed a decrease in at least one of these measures., Conclusion: This fully automated CT muscle tool allows for both individualized and population-based assessment. Such data could be automatically derived at abdominal CT regardless of study indication, allowing for opportunistic sarcopenia detection., Advances in Knowledge: This fully automated tool can be applied to routine abdominal CT scans for prospective or retrospective opportunistic sarcopenia assessment, regardless of the original clinical indication. Mean values were significantly higher in males for both muscle area and muscle density. Overall age-related muscle density (attenuation) loss was steeper than for muscle area for both sexes, and therefore may be a more valuable predictor of adverse outcomes.

Objective: HIV-positive children, adolescents, and young adults are at increased risk poor musculoskeletal outcomes. Increased incidence of vitamin D deficiency in youth living with HIV may further adversely affect musculoskeletal health. We investigated the impact of vitamin D supplementation on a range of musculoskeletal outcomes among individuals aged 0-25 years living with HIV., Methods: A systematic review was conducted using databases: PubMed/Medline, CINAHL, Web of Knowledge, and EMBASE. Interventional randomised control trials, quasi-experimental trials, and previous systematic reviews/meta-analyses were included. Outcomes included: BMD, BMC, fracture incidence, muscle strength, linear growth (height-for-age Z-score [HAZ]), and biochemical/endocrine biomarkers including bone turnover markers., Results: Of 497 records, 20 studies met inclusion criteria. Thirteen studies were conducted in North America, one in Asia, two in Europe, and four in Sub-Saharan Africa. High-dose vitamin D supplementation regimens (1,000-7,000 IU/day) were successful in achieving serum 25-hydroxyvitamin-D (25OHD) concentrations above study-defined thresholds. No improvements were observed in BMD, BMC, or in muscle power, force and strength; however, improvements in neuromuscular motor skills were demonstrated. HAZ was unaffected by low-dose (200-400 IU/day) supplementation. A single study found positive effects on HAZ with high-dose supplementation (7,000 vs 4,000IU/day)., Conclusions: Measured bone outcomes were unaffected by high-dose vitamin D supplementation, even when target 25OHD measurements were achieved. This may be due to: insufficient sample size, follow-up, intermittent dosing, non-standardised definitions of vitamin D deficiency, or heterogeneity of enrolment criteria pertaining to baseline vitamin D concentration. High-dose vitamin D may improve HAZ and neuromuscular motor skills. Adequately powered trials are needed in settings where HIV burden is greatest. PROSPERO Number: CRD42016042938., Competing Interests: The authors have declared that no competing interests exist.

The deer mouse (Peromyscus maniculatus) is the primary reservoir for Sin Nombre virus (SNV) in the western United States. Rodent surveillance for hantavirus in Death Valley National Park, California, USA, revealed cactus mice (P. eremicus) as a possible focal reservoir for SNV in this location. We identified SNV antibodies in 40% of cactus mice sampled.