Search

Objectives: The aim of the study was to investigate the prevalence of renal function and liver enzyme abnormalities among HIV‐infected children, changes in prevalence with time on combination antiretroviral therapy (cART), and the factors associated with these abnormalities. Methods: A prospective cohort study was conducted among HIV‐infected children < 18 years old (n = 705) who were on first‐line cART. Liver enzymes, renal function, haematology, immunology and virological response were assessed at enrolment and followed bi‐annually for 18 months. Liver fibrosis and cirrhosis were assessed using noninvasive markers including the aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis score (FIB‐4). Results: The median age was 12 [interquartile range (IQR) 8–14] years; 53.3% of patients were male. At enrolment, the median cART duration was 3.3 (IQR 1.1–6.1) years; 177 (25.1%) and 83 (11.8%) patients had elevated AST and alanine aminotransferase (ALT), respectively. A tenth of the children had an APRI score > 0.5, suggesting liver fibrosis. Being on a zidovudine (ZDV)‐ or nevirapine (NVP)‐based regimen and having a viral load > 1000 HIV‐1 RNA copies/mL were significantly associated with elevated ALT. Twenty‐four (3.4%) and 84 (12.1%) patients had elevated creatinine and blood urea nitrogen (BUN), respectively. As cART duration increased by 6 months, median BUN increased by 1.6 [95% confidence interval (CI) 0.4–2.7] mg/dL (P = 0.01); the glomerular filtration rate (GFR) decreased by 35.6 (95% CI 17.7–53.4) mL/min/1.73 m2 (P < 0.0001); and AST and ALT decreased by 1.4 (95% CI 0.4–2.5) IU/L (P = 0.01) and 1.4 (95% CI 0.2–2.6) IU/L (P = 0.01), respectively. Conclusions: A high prevalence of liver enzyme and renal function abnormalities was observed at enrolment. Decreasing liver enzyme levels during follow‐up are possibly reassuring, while the progressive reduction in GFR and the increase in BUN are worrisome and require further study. [ABSTRACT FROM AUTHOR]

Background: Small and medium enterprises (SMEs) in South Africa and globally struggle to gain access to external funding. The current lending instruments used by the banks are more suitable for large enterprises than for SMEs. Financially constrained SMEs are less likely to contribute to economic growth and job creation. Small and medium enterprises in South Africa are expected to create 90% of the 11 million jobs as per the National Development Plan. Aim: The objective of this study was to deliver innovatively designed funding mechanisms through which improved access to external funding can be achieved. Setting: Participating stakeholders in this research were entrepreneurs and suppliers of funding, policymakers and experts. Methods: The purposive sampling method was used in this study where 24 in-depth interviews were conducted, and 160 survey questionnaires were recorded. Mixed-methods approach was used to incorporate both qualitative and quantitative techniques. A literature review related to entrepreneurship and capital structure theories was conducted. Thematic and statistical graphical data analyses were applied in both the qualitative and quantitative data, respectively. Results: The critical findings of this study are the blended SME funding model and the SME risk reduction model. Designing the lending instruments in a way that blends both private and public financial resources increases the risk appetite on the side of the private lending institutions. Conclusion: The proposed model requires more improved public–private partnerships. Furthermore, the findings include the need for supportive regulatory framework and embracing alternative emerging technology-enabled funding options.

Abstract Background Anti-IgE therapy inhibits mast cell and basophil activation, blocks IgE binding to both FcεRI and CD23 and down regulates FcεRI expression by antigen (Ag) presenting cells (APCs). In addition to its classical role in immediate hypersensitivity, IgE has been shown in vitro to facilitate Ag presentation of allergens, whereby APC bound IgE preferentially takes up allergens for subsequent processing and presentation. The purpose of this study was to determine whether anti-IgE therapy, by blocking facilitated Ag presentation in vivo, attenuates allergen specific Th2 cell responses. Methods To test this hypothesis, food allergen specific T cell responses were examined during a 16-week clinical trial of omalizumab in nine subjects with eosinophilic gastroenteritis and food sensitization. Allergen specific T cell responses were measured using carboxyfluorescein succinimidyl ester dye dilution coupled with intracellular cytokine staining and polychromatic flow cytometry. Four independent indices of allergen specific T cell response (proliferation, Ag dose response, precursor frequency, and the ratio of Th2:Th1 cytokine expression) were determined. Results Eight of the 9 subjects had measurable food allergen specific responses, with a median proliferation index of 112-fold. Allergen specific T cell proliferation was limited to CD4 T cells, whereas CD8 T cell did not proliferate. Food allergen specific responses were Th2 skewed relative to tetanus specific responses in the same subjects. In contradistinction to the original hypothesis, anti-IgE treatment did not diminish any of the four measured indices of allergen specific T cell response. Conclusions In sum, using multiple indices of T cell function, this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses in vivo. Trial registration ClinicalTrials.gov identifier NCT00084097

Abstract Background We have shown previously that acute infection with the respiratory pathogen, pneumonia virus of mice (PVM), results in local production of the proinflammatory chemokine, CCL3, and that neutrophil recruitment in response to PVM infection is reduced dramatically in CCL3 -/- mice. Results In this work, we demonstrate that CCL3-mediated neutrophil recruitment is coordinated by interferon-gamma (IFNγ). Neutrophil recruitment in response to PVM infection was diminished five-fold in IFNγ receptor gene-deleted mice, although neutrophils from IFNγR -/- mice expressed transcripts for the CCL3 receptor, CCR1 and responded functionally to CCL3 ex vivo. Similarly, in the absence of PVM infection, CCL3 overexpression alone could not elicit neutrophil recruitment in the absence of IFNγ. Interestingly, although supplemental IFNγ restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFNγ -/- mice, CCL3-mediated neutrophil recruitment alone did not result in the pulmonary edema or respiratory failure characteristic of severe viral infection, suggesting that CCL3 and IFN-γ together are sufficient to promote neutrophil recruitment but not pathologic activation. Conclusion Our findings reveal a heretofore unrecognized hierarchical interaction between the IFNγ and CCL3, which demonstrate that IFNγ is crucial for CCL3-mediated neutrophil recruitment in vivo.

Objective: Understanding of twin growth in the United States (US) is based on outdated or predominantly non-Hispanic White samples, and the age at which twins catch up to singletons is unclear. In this study, we characterized normative weight trajectories of twins and singletons in a contemporary, diverse cohort., Methods: Data were from the PROMISE study, an electronic health record-based cohort of pregnant people and their children in the US (2005-2021). The Jenss model was used to characterize weight trajectories from 0 to 24 months of age. Twins ( n  = 716) were compared to the full cohort of singletons ( n  = 40,075) and a matched sample with similar gestational age at birth (GA) ( n  = 7160)., Results: Male and female twins had lower birth weight compared to singletons and experienced a high rate of weight gain throughout infancy. Among males, twins caught up in weight to the full singleton cohort and to GA-matched singletons at approximately 12 and 6 months, respectively. Among females, twins caught up to GA-matched singletons at approximately 15 months but did not fully overcome their birth weight disadvantage to the full singleton sample by 24 months., Conclusions: These findings highlight that the use of singleton growth charts or preterm singleton growth charts among twins may be inappropriate and suggest the need for a twin-specific growth chart. Future research is needed to understand factors that drive differences in weight trajectories between twins and singletons and to guide twin-specific guidelines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025 The Authors.)

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.

Bladder cancer is one of the most common malignant tumors of the urinary system globally. It is also one of the most expensive cancers to manage, due to the need for extensive treatment and follow-ups that often involve invasive and costly procedures. Although there have been some improvements in treatment options, the quality of life they offer has not improved at the same rate as other cancers. Therefore, there is an urgent need to find new alternatives to ease the burden of bladder cancer on patients. Recent discoveries have opened new avenues for the diagnosis and management of bladder cancer even though the clinical approach has largely remained the same for years. The decline in bladder cancer-specific mortality in regions that promote social awareness of risk factors and reduction of carcinogenic exposure demonstrates the effectiveness of such measures. New agents have been approved for patients who have undergone radical cystectomy after Bacillus Calmette-Guérin failure. Current best practices for diagnosing and treating bladder cancer are presented in this review. The review discusses radiation therapy, photodynamic therapy, gene therapy, chemotherapy, and nanomedicine in relation to non muscle-invasive cancers and muscle-invasive bladder cancers, as well as systemic treatments., Competing Interests: The authors declare no competing financial interest., (© 2025 American Chemical Society.)

Background: Childhood obesity is a risk factor for poor cardiovascular, metabolic, and respiratory health. The studies examining influences of socio-ecologic factors on weight trajectories using longitudinal data are limited, often examine single measures (e.g., proximity to parks), and have not examined the specific trajectories of children with obesity. Methods: We examined influences on weight among 1518 children, 6-12 years of age, who had obesity using body mass index (BMI) criteria. BMI slope trajectories were categorized as decreasing, flat, or increasing, with a median of 2.1 years of follow-up. We examined socio-ecologic exposures, stratified by rural and urban settings, using census tracts to map indices, including food access, proximity to parks, normalized difference vegetation index, and area deprivation index (ADI). We used ordinal logistic regression to examine the associations between the socio-ecologic factors and BMI trajectories. Results: Among the 1518 children, 360 (24%) had a decreasing BMI trajectory with the remainder having flat (23%) or increasing (53%) trajectories. Children in rural areas were more likely to live in high disadvantage areas, 85%, compared with urban children, 46%. In the multivariable ordinal model, living in a lower ADI census tract had a 0.78 (95% CI 0.61-0.99) lower odds of being in an increasing BMI slope group, and no other socio-ecologic factor was associated. Conclusions: The area deprivation index captures a range of resources and social context compared with the built environment indicators, which had no association with BMI trajectory. Further work examining how to develop effective interventions in high deprivation areas is warranted.

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Protoporphyrin IX (PpIX)-based photodynamic therapy (PDT) has shown limited efficacy in nonmuscle-invasive bladder cancer (NMIBC). To improve PDT efficacy, we developed singlet oxygen-cleavable prodrugs. These prodrugs, when combined with PpIX-PDT, induce cancer cell death through both PDT and drug release mechanisms. Inhibition of PpIX efflux was reported to be an effective strategy to improve PpIX-PDT in certain cancer cells. Our main goal was to investigate whether adding an efflux inhibitor to the combination of PpIX and prodrugs can improve the PpIX levels in bladder cancer cells and the release of active drugs, thus improving the overall efficacy of the treatment. We treated bladder cancer cell lines with lapatinib and evaluated intracellular PpIX fluorescence, finding significantly increased accumulation. Combining lapatinib with prodrugs led to significantly reduced cell viability compared to prodrugs or PpIX-PDT alone. The effect of lapatinib depended on the expression level of the efflux pump in bladder cancer cells. Interestingly, lapatinib increased paclitaxel (PTX) prodrug uptake by threefold compared to prodrug alone. Adding an efflux inhibitor (e.g., lapatinib) into bladder instillation solutions could be a straightforward and effective strategy for NMIBC treatment, particularly in tumors expressing efflux pumps, with the potential for clinical translation., (© 2024 American Society for Photobiology.)

Photodynamic therapy (PDT) initially employed red light, which caused some patients to experience permanent bladder contractions. PDT using the FDA-approved drug hexaminolevulinate (HAL), which produces protoporphyrin IX (PpIX) in the tumor, showed some promise but has low efficacy in treating non-muscle-invasive bladder cancer (NMIBC). We developed singlet oxygen-activatable prodrugs of two anticancer drugs, paclitaxel and mitomycin C, to enhance the antitumor effect of PpIX-PDT without producing systemic side effects, by promoting only local release of the active chemotherapeutic agent. Orthotopic NMIBC model was used to compare the efficacy of prodrugs only, PpIX-PDT, and prodrugs + PpIX-PDT. 532 nm laser with a total power of 50 mW for 20 min (60 J, single treatment) was used with HAL and prodrugs. Histology and microscopic methods with image analysis were used to evaluate the tumor staging, antitumor efficacy, and local toxicity. Prodrug + PpIX-PDT produced superior antitumor efficacy than PpIX-PDT alone with statistical significance. Both PpIX-PDT alone and combination therapy resulted in mild damage to the bladder epithelium in the normal bladder area with no apparent damage to the muscle layer. Overall, SO-cleavable prodrugs improved the antitumor efficacy of PpIX-PDT without causing severe and permanent damage to the bladder muscle layer., (© 2023 American Society for Photobiology.)

It has been 30 years since Photofrin-PDT was approved for the treatment of bladder cancer in Canada. However, Photofrin-PDT failed to gain popularity due to bladder complications. The PDT with red light and IV-administered Photofrin could permanently damage the bladder muscle. We have been developing a new combination strategy of PpIX-PDT with singlet oxygen-cleavable prodrugs for NMIBC with minimal side effects, avoiding damage to the bladder muscle layer. PpIX can be excited by either green (532 nm) or red (635 nm) light. Red light could be more efficacious in vivo due to its deeper tissue penetration than green light. Since HAL preferentially produces PpIX in tumors, we hypothesized that illuminating PpIX with red light might spare the muscle layer. PpIX-PDT was used to compare green and red laser efficacy in vitro and in vivo. The IC 50 of in vitro PpIX-PDT was 18 mW/cm 2 with the red laser and 22 mW/cm 2 with the green laser. The in vivo efficacy of the red laser with 50, 75, and 100 mW total dose was similar to the same dose of green laser in reducing tumor volume. Combining PpIX-PDT with prodrugs methyl-linked mitomycin C (Mt-L-MMC) and rhodamine-linked SN-38 (Rh-L-SN-38) significantly improved efficacy (tumor volume comparison). PpIX-PDT or PpIX-PDT + prodrug combination did not cause muscle damage in histological analysis. Overall, a combination of PpIX-PDT and prodrug with 635 nm laser is promising for non-muscle invasive bladder cancer treatment., (© 2024 American Society for Photobiology.)

Mitochondria play an essential role in cancer treatment by providing apoptotic signals. Hexyl aminolevulinate, an FDA-approved diagnosis for non-muscle invasive bladder cancer, induces the production of protoporphyrin IX (PpIX) preferentially by mitochondria in cancer cells. Photosensitizer PpIX upon illumination can release active chemotherapy drugs from singlet oxygen-activatable prodrugs. Prodrugs placed close enough to PpIX formed in mitochondria can improve the antitumor efficiency of PpIX-PDT. The preferred uptake of prodrugs by cancer cells and tumors can further enhance the selective damage of cancer cells over non-cancer cells and surrounding normal tissues. Mitochondriotropic prodrugs of anticancer drugs, such as paclitaxel and SN-38, were synthesized using rhodamine, a mitochondrial-targeting moiety. In vitro, the mitochondrial targeting helped achieve preferential cellular uptake in cancer cells. In RT112 cells (human bladder cancer cells), intracellular prodrug concentrations were 2-3 times higher than the intracellular prodrug concentrations in BdEC cells (human bladder epithelial cells), after 2 h incubation. In an orthotopic rat bladder tumor model, mitochondria-targeted prodrugs achieved as much as 34 times higher prodrug diffusion in the tumor area compared to the nontumor bladder area. Overall, mitochondria targeting made prodrugs more effective in targeting cancer cells and tumors over non-tumor areas, thereby reducing nonspecific toxicity., (© 2024 American Society for Photobiology.)

Background: Gestational weight gain (GWG) is a routinely monitored aspect of pregnancy health, yet critical gaps remain about optimal GWG in pregnant people from socially marginalized groups, or with pre-pregnancy body mass index (BMI) in the lower or upper extremes. The PROMISE study aims to determine overall and trimester-specific GWG associated with the lowest risk of adverse birth outcomes and detrimental infant and child growth in these underrepresented subgroups. This paper presents methods used to construct the PROMISE cohort using electronic health record data from a network of community-based healthcare organizations and characterize the cohort with respect to baseline characteristics, longitudinal data availability, and GWG., Methods: We developed an algorithm to identify and date pregnancies based on outpatient clinical data for patients 15 years or older. The cohort included pregnancies delivered in 2005-2020 with gestational age between 20 weeks, 0 days and 42 weeks, 6 days; and with known height and adequate weight measures needed to examine GWG patterns. We linked offspring data from birth records and clinical records. We defined study variables with attention to timing relative to pregnancy and clinical data collection processes. Descriptive analyses characterize the sociodemographic, baseline, and longitudinal data characteristics of the cohort, overall and within BMI categories., Results: The cohort includes 77,599 pregnancies: 53% had incomes below the federal poverty level, 82% had public insurance, and the largest race and ethnicity groups were Hispanic (56%), non-Hispanic White (23%) and non-Hispanic Black (12%). Pre-pregnancy BMI groups included 2% underweight, 34% normal weight, 31% overweight, and 19%, 8%, and 5% Class I, II, and III obesity. Longitudinal data enable the calculation of trimester-specific GWG; e.g., a median of 2, 4, and 6 valid weight measures were available in the first, second, and third trimesters, respectively. Weekly rate of GWG was 0.00, 0.46, and 0.51 kg per week in the first, second, and third trimesters; differences in GWG between BMI groups were greatest in the second trimester., Conclusions: The PROMISE cohort enables characterization of GWG patterns and estimation of effects on child growth in underrepresented subgroups, ultimately improving the representativeness of GWG evidence and corresponding guidelines., (© 2024. The Author(s).)

The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53 Mut ) cancer are largely ineffective. Here, we report a therapeutic strategy for p53 Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53 Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53 Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53 Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53 Mut cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We examined the impact of hospitalization for bronchiolitis on patient-centered outcomes across patients with varying levels of support., Methods: The participants included primary caregivers of children aged 0 to 24 months hospitalized for bronchiolitis at an 150-bed tertiary care children's hospital. Data were collected using a 30-item questionnaire examining quality of life impact, adapted from the previously validated survey, the Impact of Bronchiolitis Hospitalization Questionnaire.1 The survey contained questions asking to what extent the hospitalization interfered with different aspects of care. After all surveys were collected, the patients were split into groups categorized by level of support and defined as no support, low support (low-flow nasal cannula only or nasogastric [NG] only), moderate support (high-flow nasal cannula without NG), high support (high-flow nasal cannula with NG support), and positive pressure (with or without NG support). Descriptive statistics were used to examine the distribution of mean impact scores across these groups., Results: A total of 92 caregivers and their children were included. The mean impact score for variables of difficult to hold, difficult to bond, and breastfeeding disruption increased with greater levels of support with P values of P = .003, P = .04, and P < .001, respectively., Conclusions: We found that the impact on patient-reported outcomes varied by level of support, as defined here, among children hospitalized with bronchiolitis, with significant impacts being in areas of caregiver bonding, caregiver holding, and breastfeeding., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Many studies examining weight trajectories have used adiposity measures shown to be problematic for trajectory analysis in children with obesity, and remission of obesity remains poorly understood., Objectives: To describe weight trajectories for school-aged children, the rate of obesity remission and factors associated., Methods: Children between 6 and 11 years of age with ≥3 valid height and weight measurements from an Oregon hospital-system over a minimum six-month period were included. Percent distance from the median body mass index (BMI) was used for modeling. Latent class analysis and linear mixed models were used to classify children based on their weight trajectory., Results: We included 11,247 subjects with a median of 2.1 years of follow-up, with 1,614 (14.4%) classified as overweight and 1,794 (16.0%) classified as obese. Of subjects with obesity, 1% experienced remission during follow-up, whereas 23% of those with overweight moved to within a healthy weight range. Latent class analysis identified three classes within each weight-based stratum over time. The majority of children with overweight or obesity had a flat trajectory over time. Lower socioeconomic status was associated with a worsening trajectory. Latent class models using alternate measures (BMI, BMI z-scores, tri-ponderal mass index (TMI)) differed substantially from each other., Conclusions: Obesity remission was uncommon using the adiposity metric of distance from the median though transition from overweight to healthy weight was more common. Children with low socioeconomic status have worse trajectories overall. The choice of adiposity metric may have a substantial effect on the outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Foster et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Hair cortisol concentrations may serve as a measure of biologically embedded stress. While the cross-sectional association between hair cortisol and obesity in children has been examined, the data examining this relationship over time are limited. Methods: We examined hair cortisol and anthropometrics in 40 children with obesity from Latino families enrolled in a Head Start program serving farmworkers. All participants were enrolled in a clinical trial using parent mentors to encourage healthy lifestyles. We analyzed the proximal 3 cm of hair at the beginning and the end of the trial, a period of about 8 months. Linear mixed models were used to examine if changes in hair cortisol were associated with changes in adiposity. Results: Children had a median BMI percentile of 98% and parents with lower education with 25 of 40 having less than high school diploma and high food insecurity (17 of 40, 43%). Among the 40 children with valid data for both time points, the median hair cortisol concentration at baseline was 4.09 pg/mg (interquartile range [IQR] 2.65-8.68) and 6.05 pg/mg (IQR 3.95-9.33) at the end point. Increases in cortisol from baseline to follow-up had a small but significant association with decreased obesity over time. Hair cortisol did not moderate an association between food security and weight. Conclusion: In children with chronic stressors and obesity, we found that increases in cortisol over time were associated with decreases in adiposity. Further studies following hair cortisol concentrations over time are needed to understand how this biomarker relates to weight status and stressors. Clinicaltrials.gov ID: NCT03330743.

Background and Objectives: Current viral bronchiolitis guidelines exclude infants with congenital heart disease (CHD). Variations in the use of common therapeutics in this population and their associations with clinical outcomes are unknown. Our objective was to evaluate variations in (1) the use of β-2-agonists and hypertonic saline across hospitals among infants with CHD hospitalized with bronchiolitis, and (2) hospital-level associations between medication use and outcomes., Methods: We performed a multicenter retrospective cohort study using administrative data from 52 hospitals in the Pediatric Health Information System. We included infants ≤12 months old hospitalized from January 1, 2015 to June 30, 2019 for bronchiolitis with a secondary diagnosis of CHD. Primary exposures were the hospital-level proportion of days that patients received β-2-agonists or hypertonic saline. Linear regression models assessed the association between the primary exposure and length of stay, 7-day readmission, mechanical ventilation use, and ICU utilization, adjusting for patient covariates and accounting for clustering by center., Results: We identified 6846 index hospitalizations for bronchiolitis in infants with CHD. Overall, 43% received a β-2-agonist, and 23% received hypertonic saline. The proportion of days with the use of β-2-agonists (3.6% to 57.4%) and hypertonic saline (0.0% to 65.8%) varied widely across hospitals in our adjusted model. For both exposures, adjusted models revealed no association between days of use and patient outcomes., Conclusions: For children with CHD hospitalized with bronchiolitis, hospital-level use of β-2-agonists and hypertonic saline varied widely, and their use was not associated with clinical outcomes., (Copyright © 2023 by the American Academy of Pediatrics.)

More than 80,000 new cases of bladder cancer are estimated to be diagnosed in 2023. However, the 5-year survival rate for bladder cancer has not changed in decades, highlighting the need for prevention. Numerous cancer-causing mutations are present in the urothelium long before signs of cancer arise. Mutation hotspots in cancer-driving genes were identified in non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) tumor samples. Mutation burden within the hotspot regions was measured in normal urothelium with a low and high risk of cancer. A significant correlation was found between the mutation burden in normal urothelium and bladder cancer tissue within the hotspot regions. A combination of measured hotspot burden and personal risk factors was used to fit machine learning classification models. The efficacy of each model to differentiate between adjacent benign urothelium from bladder cancer patients and normal urothelium from healthy donors was measured. A random forest model using a combination of personal risk factors and mutations within MIBC hotspots yielded the highest AUC of 0.9286 for the prediction of high- vs. low-risk normal urothelium. Currently, there are no effective biomarkers to assess subclinical field disease and early carcinogenic progression in the bladder. Our findings demonstrate novel differences in mutation hotspots in NMIBC and MIBC and provide the first evidence for mutation hotspots to aid in the assessment of cancer risk in the normal urothelium. Early risk assessment and identification of patients at high risk of bladder cancer before the clinical presentation of the disease can pave the way for targeted personalized preventative therapy.

Regular consumption of cruciferous vegetables has numerous health benefits, including reduced cancer risk and improved patient outcomes. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables with a chemoprotective role against epithelial cancers, particularly of the bladder. Epithelial cells have several functions, including secretion, absorption, filtration, and protection from environmental insults. The specialized stratified epithelium of the bladder has direct and frequent contact with carcinogenic agents, increasing the likelihood of cancer initiation at this site. Carcinogen exposure, particularly from cigarette smoke or occupational exposure to aromatic amines, are the most significant risk factors for bladder cancer due to their ability to activate inflammatory pathways, induce free radicals, and damage DNA. SFN acts as an antioxidant by activating phase II enzymes involved in carcinogen detoxification to prevent DNA damage and inhibit tumor initiation, modulates multiple signaling pathways to inhibit tumor growth and progression, and has anti-inflammatory and immune-modulating properties to help protect against cancer. Due to these chemoprotective mechanisms, SFN has been studied as both mono- and adjuvant therapy in several bladder cancer models. Here we present a review of the effects of SFN on carcinogen-induced bladder cancer to support the inclusion of cruciferous vegetables as a chemoprotective strategy., Competing Interests: None., (AJCEU Copyright © 2023.)

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.

Bladder cancer is the first cancer for which PDT was clinically approved in 1993. Unfortunately, it was unsuccessful due to side effects like bladder contraction. Here, we summarized the recent progress of PDT for bladder cancers, focusing on photosensitizers and formulations. General strategies to minimize side effects are intravesical administration of photosensitizers, use of targeting strategies for photosensitizers and better control of light. Non-muscle invasive bladder cancers are more suitable for PDT than muscle invasive and metastatic bladder cancers. In 2010, the FDA approved blue light cystoscopy, using PpIX fluorescence, for photodynamic diagnosis of non-muscle invasive bladder cancer. PpIX produced from HAL was also used in PDT but was not successful due to low therapeutic efficacy. To enhance the efficacy of PpIX-PDT, we have been working on combining it with singlet oxygen-activatable prodrugs. The use of these prodrugs increases the therapeutic efficacy of the PpIX-PDT. It also improves tumor selectivity of the prodrugs due to the preferential formation of PpIX in cancer cells resulting in decreased off-target toxicity. Future challenges include improving prodrugs and light delivery across the bladder barrier to deeper tumor tissue and generating an effective therapeutic response in an In vivo setting without causing collateral damage to bladder function., (© 2022 American Society for Photobiology.)

Introduction: Bladder cancer is a heterogenous disease and the emerging knowledge on molecular classification of bladder tumors may impact treatment decisions based on molecular subtype. Pre-clinical models representing each subtype are needed to test novel therapies. Carcinogen-induced bladder cancer models represent heterogeneous, immune-competent, pre-clinical testing options with many features found in the human disease., Methods: Invasive bladder tumors were induced in C57BL/6 mice when continuously exposed to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in the drinking water. Tumors were excised and serially passed by subcutaneous implantation into sex-matched syngeneic C57BL/6 hosts. Eight lines were named BBN-induced Urothelium Roswell Park (BURP) tumor lines. BURP lines were characterized by applying consensus molecular classification to RNA expression, histopathology, and immune profiles by CIBERSORT. Two lines were further characterized for cisplatin response., Results: Eight BURP tumor lines were established with 3 male and 3 female BURP tumor lines, having the basal/squamous (BaSq) molecular phenotype and morphology. BURP-16SR was established from a male mouse and has a stromal-rich (SR) molecular phenotype and a sarcomatoid carcinoma morphology. BURP-19NE was established from a male mouse and has a neuroendocrine (NE)-like molecular phenotype and poorly differentiated morphology. The established BURP tumor lines have unique immune profiles with fewer immune infiltrates compared to their originating BBN-induced tumors. The immune profiles of the BURP tumor lines capture some of the features observed in the molecular classifications of human bladder cancer. BURP-16SR growth was inhibited by cisplatin treatment, while BURP-24BaSq did not respond to cisplatin., Discussion: The BURP lines represent several molecular classifications, including basal/squamous, stroma-rich, and NE-like. The stroma-rich (BURP-16SR) and NE-like (BURP-19NE) represent unique immunocompetent models that can be used to test novel treatments in these less common bladder cancer subtypes. Six basal/squamous tumor lines were established from both male and female mice. Overall, the BURP tumor lines have less heterogeneity than the carcinogen-induced tumors and can be used to evaluate treatment response without the confounding mixed response often observed in heterogeneous tumors. Additionally, basal/squamous tumor lines were established and maintained in both male and female mice, thereby allowing these tumor lines to be used to compare differential treatment responses between sexes., Competing Interests: SS is currently an employee of GSK and holds stock/ownership interests, However, all work and analysis presented in the paper was done during her time at Roswell Park. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shah, Gillard, Wrobel, Karasik, Moser, Mastri, Long, Sule, Brackett, Huss and Foster.)

Background: Tolerance of uncertainty may influence how physicians and other providers practice and make clinical decisions. We hypothesized that increased tolerance of uncertainty would be associated with an increased uptake of a quality improvement (QI) intervention., Methods: We examined tolerance of uncertainty using the Physicians' Reactions to Uncertainty Scale in the context of a national QI project in the Value in Inpatient Pediatrics network. The QI project aimed to increase exclusive isotonic fluid use and decrease laboratory draws. Exposure to the intervention was measured by using the stepped wedge design with sequential implementation across a diverse group of US hospitals. Multivariable analysis was conducted by using exposure to the intervention and tolerance of uncertainty as independent variables and exclusive isotonic fluid use or laboratory testing as the dependent variable., Results: Of 106 participating hospitals, 97 contributed valid responses, with an overall mean reported tolerance of uncertainty of 3.39 (95% confidence interval: 3.27-3.50), with lower numbers on the 6-point scale indicating greater tolerance of uncertainty. Exposure to the QI intervention was significantly associated with exclusive isotonic fluid use (P <.001). Lower tolerance of uncertainty at baseline was associated with lower baseline isotonic fluid use and greater uptake of the use of isotonic fluids but not reduction in laboratory testing., Conclusions: Contrary to our hypothesis, lower tolerance of uncertainty was associated with greater uptake of the QI intervention for the outcome of isotonic fluids. This initial association warrants further study to evaluate how tolerance of uncertainty plays a role in quality improvement science., (Copyright © 2023 by the American Academy of Pediatrics.)

Objective: To examine the association between food security and feeding practices in Latinx parents of pre-school-aged children and examine possible effect modification by parental self-efficacy., Design: Cross-sectional assessment using the US Department of Agriculture screener for food insecurity as the exposure and sub-scales of the Comprehensive Feeding Practices Questionnaire as the outcome with the General Self-Efficacy Scale as an effect modifier. Non-parametric descriptive statistics were used to compare groups based on food security status., Setting: Two Latinx communities with low-socioeconomic status in Texas in 2017 and in Oregon in 2018-2019., Participants: Latinx parents of preschool aged children, English and Spanish speaking. Dyads were excluded if they had moderate-severe developmental disabilities, a seizure disorder with a restrictive diet or taking medications known to influence typical growth., Results: Of the 168 families in Oregon, 65 (38 %) reported food insecurity, and 10 (21 %) of the 48 families in Texas reported food insecurity. Food security was associated with greater parental monitoring practices in both the Texas and Oregon samples. We observed no differences in creating a healthy home food environment by food security status in either sample. Parental general self-efficacy showed evidence of effect modification in Oregon - only parents with lower self-efficacy showed a significant association between food security and feeding practices., Conclusions: Latinx parents of preschool children experience high levels of food insecurity, which are associated with maladaptive parental feeding practices. Greater parental general self-efficacy moderates this association and could buffer the effects of food insecurity on children's health.

Benign prostate hyperplasia (BPH) is a progressive disease with a direct correlation between incidence and age. Since the treatment and management of BPH involve harmful side effects and decreased quality of life for the patient, the primary focus of research should be to find better and longer-lasting therapeutic options. The mechanisms regulating prostate stem cells in development can be exploited to decrease prostate growth. BPH is defined as the overgrowth of the prostate, and BPH is often diagnosed when lower urinary tract symptoms (LUTS) of urine storage or voiding symptoms cause patients to seek treatment. While multiple factors are involved in the hyperplastic growth of the stromal and epithelial compartments of the prostate, the clonal proliferation of stem cells is considered one of the main reasons for BPH initiation and regrowth of the prostate after therapies for BPH fail. Several theories explain possible reasons for the involvement of stem cells in the development, progression, and pathogenesis of BPH. The aim of the current review is to discuss current literature on the fundamentals of prostate development and the role of stem cells in BPH. This review examines the rationale for the hypothesis that unregulated stem cell properties can lead to BPH and therapeutic targeting of stem cells may reduce treatment-related side effects and prevent the regrowth of the prostate., Competing Interests: None., (AJCEU Copyright © 2022.)

Background: Positive deviance as a methodology is increasing in application yet there is high variability in how this approach is applied in health services research., Methods: We conducted a scoping review of the literature for positive deviance applied to health outcomes informed by PRISMA-ScR. We searched the literature from 1945 to 2020, including articles on positive deviance or positive outliers, and restricted to examining individual rather than organizational outcomes. We analyzed the methodology applied including the process of identifying deviants, the use of control groups, and the degree of community engagement., Results: Our initial search identified 1140 manuscripts; we included 104 papers describing 98 studies, 11 topical and one miscellaneous category. Most studies used objective measures of health or survey-based responses to identify deviants from a sub-set of the population at risk. The use of controls was less common in some topics (hospital infections), whereas controls were universally applied in other topics (malnutrition). The degree of community engagement varied widely., Conclusions: Positive deviance would benefit from improvements in reporting and standardized approaches to defining deviance. Studies could be improved through clarified definitions of deviance/risk, explicit descriptions of community engagement, and more consistent use of controls., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Parent mentors are a potential community-based mechanism for delivering behavioral interventions. For communities at a higher risk of obesity and challenges with access to care, such as migrant and seasonal farm workers, this may be an effective intervention for obesity. This study examined the effect of parent mentors on weight outcomes. Methods: This randomized clinical trial assigned parents of 2- to 5 year-old children enrolled in Head Start 1:1:1 to control, a parent mentor teaching We Can!, or a parent mentor teaching an intervention derived from positive deviance methods. The parent mentor arms were designed to have weekly interactions and monthly community meetings over 6 months. The primary outcome was change in adiposity, as measured by body mass indices. Results: We randomized 188 parents, and 155 completed the 6-month visit. Most parents, 107 (58%), had less than a high school education, and 170 (90%) reported Latino ethnicity. In the intention-to-treat analysis, no difference between the groups was observed for change in percent distance from the median or BMI z -score. The median number of interactions was 14 (IQR 10-20) over 6 months for those who did engage, though 24 of 118 (20%) had no interaction. Those with no interactions in We Can! had a mean increase in change from median of 6.7 [standard deviation (SD) = 8.2]; those with higher participation experienced a 0.4 (SD = 9.2) change, p  = 0.04. Conclusions: Parent mentors were not effective in changing the adiposity indices in this study overall, with some evidence of efficacy after accounting for participation. Clinicaltrials.gov registration number: NCT03330743.

The evolving paradigm of the molecular classification of bladder cancer requires models that represent the classifications with less heterogeneity. Robust transcriptome based molecular classifications are essential to address tumor heterogeneity. Patient derived models (PDMs) are a powerful preclinical tool to study specific tumor compartments. We tested if the consensus molecular subtype analysis was applicable to PDMs and evaluated the tumor compartment each model represents. PDMs derived from surgical specimens were established as xenografts (PDX), organoids (PDO), and spheroids (PDS). The surgical specimens and PDMs were molecularly characterized by RNA sequencing. PDMs that were established in immune deficient mice or in vitro significantly downregulated transcripts related to the immune and stromal compartments compared to the surgical specimens. However, PDMs upregulate a patient-specific bladder cancer cell signal which allowed for analysis of cancer cell pathways independent of the tumor microenvironment. Based on transcriptomic signatures, PDMs are more similar to their surgical specimen than the model type; indicating that the PDMs retained unique features of the tumor from which the PDM was derived. When comparing models, PDX models were the most similar to the surgical specimen, while PDO and PDS models were most similar to each other. When the consensus molecular subtype classification system was applied to both the surgical samples and the three PDMs, good concordance was found between all samples indicating that this system of classification can be applied to PDO and PDS models. PDMs reduce tumor heterogeneity and allow analysis of tumor cells while maintaining the gene expression profile representative of the original tumor., Competing Interests: None., (AJCEU Copyright © 2021.)

Objective: Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies., Methods: This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes., Results: Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough <10 µg/mL, and 63% had a ratio of AUC to MIC <400 μg-hr/mL. Three percent had a supratherapeutic initial trough >20 µg/mL or ratio of AUC to MIC >600 μg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity., Conclusions: Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Heat stress affects oocyte developmental competence and is a major cause of reduced fertility in heat stressed cattle. Negative effects of heat stress on the oocyte have been observed at morphological, biochemical and developmental levels. However, the mechanisms by which heat stress affects the oocyte at the transcriptional and epigenetic levels remain to be further elucidated. Here we aimed to investigate the effect of heat stress on oocyte quality, transcriptomic profiles and DNA methylation of oocytes collected through the transition from spring to summer under Louisiana conditions. Summer season resulted in a lower number of high quality oocytes obtained compared to the spring season. There was no difference in in vitro maturation rates of oocytes collected during spring as compared to summer. RNA sequencing analysis showed that a total of 211 and 92 genes were differentially expressed as a result of heat stress in GV and MII oocytes, respectively. Five common genes ( E2F8, GATAD2B, BHLHE41, FBXO44 , and RAB39B ) were significantly affected by heat in both GV and MII oocytes. A number of pathways were also influenced by heat stress including glucocorticoid biosynthesis, apoptosis signaling, and HIPPO signaling in GV oocytes, and Oct4 pluripotency, Wnt/beta-catenin signaling, and melatonin degradation I in MII oocytes. In addition, fluorescent immunocytochemistry analysis showed no difference in global levels of DNA methylation and DNA hydroxymethylation at either the GV or MII stage between spring and summer oocytes. The results of this study contribute to a better understanding of the effect of heat stress on the molecular mechanisms altered in bovine oocytes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with one of the authors ZJ., (Copyright © 2021 Diaz, Gutierrez-Castillo, Foster, Hardin, Bondioli and Jiang.)

Background: High-flow nasal cannula therapy (HFNC) may increase aerosol generation, putting healthcare workers at risk, including from SARS-CoV-2., Aim: To examine whether use of HFNC increases near-field aerosols and whether there is an association with flow rate., Methods: Subjects aged four weeks to 24 months were recruited. Each child received HFNC therapy at different flow rates. Three stations with particle counters were deployed to measure particle concentrations and dispersion in the room: station 1 within 0.5 m, station 2 at 2 m, and station 3 on the other side of the room. Carbon dioxide (CO 2 ) and relative humidity were measured. Far-field measurements were used to adjust the near-field measurements., Findings: Ten children were enrolled, aged from 6 to 24 months (median: 9). Elevated CO 2 indicated that the near-field measurements were in the breathing plane. Near-field breathing plane concentrations of aerosols with diameter 0.3-10 μm were elevated by the presence of the patient with no HFNC flow, relative to the room far-field, by 0.45 particles/cm 3 . Whereas variability between subjects in their emission and dispersion of particles was observed, no association was found between HFNC use, at any flow rate, and near-field particle counts., Conclusion: This method of particle sampling is feasible in hospital settings; correcting the near-patient aerosol and CO 2 levels for the room far-field may provide proxies of exposure risk to pathogens generated. In this pilot, near-patient levels of particles with a diameter between 0.3 and 10 μm and CO 2 were not affected by the use of HFNC., (Copyright © 2021 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Background: The TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model remains one of the most widely used transgenic mouse models of prostate cancer. This is due to its ability to recapitulate with ~100% penetrance multiple aspects of the human disease such as prostatic intraepithelial neoplasia lesions, invasive carcinoma, progression to castration-resistant prostate cancer including aggressive neuroendocrine prostate cancer and metastasis. Despite its popularity, the use of TRAMP mice is limited/slowed by the inability to distinguish the zygosity of the TRAMP transgene. This is especially true for breeding strategies implementing multiple crosses and alleles and when the rapid generation of large animal cohorts with the desired genotype is needed., Methods: We developed a quantitative PCR (qPCR) approach to determine the relative TRAMP transgene copy number of mice., Results: This method was validated by three independent laboratories across two institutions, which successfully identified the genotype of the mice 98.2% of the time (165/168) in the first attempt. The genotypes of the uncertain mice were correctly identified in the repeated experiments., Conclusions: We develop the first straightforward, qPCR approach to reliably determine the TRAMP transgene zygosity. The development of this qPCR-based genotyping method enables researchers to streamline breeding strategies when creating complex genetic mouse models involving TRAMP mice; thus, ultimately reducing the required animal numbers, cost, and investigator time.

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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Children with developmental disabilities experience disparately high rates of obesity yet there are few reports detailing clinical outcomes for this population., Aim: To describe outcomes of obesity treatment for children with developmental disabilities and a comparison group of children without developmental disabilities., Methods and Procedures: We examined weight outcomes of children with and without developmental disabilities seen in a family-centered, multidisciplinary treatment center over a ten-year period. We stratified by age and developmental disability diagnosis. We assessed whether intake demographic or health behavior data was associated with successful reduction of adiposity over six and twelve month follow-up periods, using a ≥5% absolute reduction in percent over the 95th percentile body mass index (BMIp95) as the primary outcome., Outcomes and Results: Over a ten-year period, 148 of 556 children in the obesity clinic (27 %) had a developmental disability. In children <12 years of age, 36 % of children with developmental disabilities reduced their adiposity compared with 18 % of children without developmental disabilities at six months, p = .01. This pattern continued at twelve months. Active transport to school was associated with reduced adiposity for those without a disability. Older children with disabilities rarely had a significant reduction (2 of 26 children), and they took more medications with weight-related side effects., Conclusions and Implications: Younger children with developmental disabilities experienced relative success in reducing their adiposity. Challenges to addressing obesity in this population include structural barriers to physical activity and medications for behavioral management with weight-related side effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Optimal care for children with HIV infection includes timely assessment of treatment failure. Using HIV viral load to define treatment failure remains a challenge in resource-limited settings., Methods: Children with HIV infection who were already on or starting first-line antiretroviral therapy were enrolled and followed over time. We examined clinical and immunologic predictors of virologic failure (VF), defined as consecutive viral load measurements > 1000 copies/mL (VF). Children were followed every 6 months with clinical assessments, immunologic assays and viral load testing until treatment failure or up to 18 months., Results: Of the 484 children with complete data, we observed a prevalence of 15% who had VF at enrollment, and 18 who developed VF over 10.5 person-years of follow-up for an incidence of 4.97 [95% CI: 3.04-7.70) per 100 person-years. Lower adherence, lower CD4 T-cell count, lower white blood cells count, lower platelets and a lower glomerular filtration rate were all associated with increased VF. However, in a multivariable analysis, renal function (estimated glomerular filtration rate < 90 mL/min), odds ratio: 11.5 (95% CI: 1.5-63.7), and lower adherence, odds ratio: 3.9 (95% CI: 1.1-13.4), were the only factors associated with development of VF., Conclusions: We identified a significant risk of VF in children with HIV infection in a prospective cohort study in southern Ethiopia and limited predictive value of clinical variables for VF. This provides further evidence that rapid and reliable viral load testing is needed to adequately address the HIV epidemic, along with implementation of adherence interventions in sub-Saharan Africa.

Children with cerebral palsy (CP) and other medical complexity comprise an outsized proportion of health care use. In this review, we describe the current science of assessment of nutritional status for children with CP, outline a systematic approach to assessing their nutritional status, delineate ramifications of malnutrition on hospitalization-associated outcomes, and identify knowledge gaps and means of addressing those gaps using quality improvement and clinical research tools. Methods to accurately assess body composition and adiposity in this population by using skinfolds, age, sex, and activity level are available but are not widely used. There are limitations in our current method of estimating energy needs in children with CP, who are at higher risk of both obesity and micronutrient deficiencies. There is some evidence of an association between malnutrition, defined as either underweight or obesity, and hospitalization-associated outcomes in children generally, although we lack specific data for CP. The gaps in our current understanding of optimal nutritional status and between current science and practice need to be addressed to improve health outcomes for this vulnerable patient population., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Objectives: Excess adiposity upregulates proinflammatory adipokines in infancy that have also been implicated in the pathogenesis of bronchiolitis. The association between excess adiposity and severity of disease in bronchiolitis is unclear. We sought to examine the association between adiposity and length of hospitalization and risk of PICU transfer in children with bronchiolitis., Methods: We conducted a retrospective cohort study examining infants 24 months and younger hospitalized at an academic children's hospital with bronchiolitis, grouped by weight status (BMI z score and ponderal index). Data were extracted from the medical record, including the following relevant covariates: age, sex, race and/or ethnicity, and International Classification of Diseases, 10th Revision codes. Outcomes included length of stay (LOS) and PICU transfer. We used multiple regression to examine the association between each anthropometric measure and LOS and likelihood of PICU transfer., Results: There were 765 children in the final sample, 599 without a significant comorbidity (eg, prematurity, congenital heart disease). The median LOS was 2.8 days (interquartile range 1.7-4.9 days). LOS increased with increasing ponderal index quartile ( P = .001). After accounting for age and significant comorbidities, we used multivariable regression to identify a significant association between increasing ponderal index and LOS ( P = .04) and no association between BMI and LOS. Logistic regression did not reveal an association between either anthropometric measure and PICU transfer., Conclusions: In this study, we identified an association between a measure of excess adiposity in infants and length of hospitalization for bronchiolitis. Further work is needed to confirm this association, examine potential mechanisms, and account for other potential confounders., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epithelium-specific Pten -knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug's tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention., Competing Interests: CONFLICTS OF INTEREST M.P.A. and A.V.G. served as consultants for Everon Biosciences, Inc.; O.V.C. and A.V.G. are co-founders and shareholders of Everon Biosciences, Inc.

Context: Vancomycin is a medication with potential for significant harm with both overdosing and underdosing. Obesity may affect vancomycin pharmacokinetics and is increasingly common among children., Objective: We aimed to determine if children with overweight or obesity have increased vancomycin trough concentrations with total body weight (TBW) dosing compared with children with normal weight., Data Sources: We conducted a search of Medline and Medline In-Process & Other Non-Indexed Citations from 1952 (the year vancomycin was discovered) to November 2017., Study Selection: Search terms included vancomycin, body weight, and body composition terms and were limited to children. Studies were reviewed and screened by ≥2 reviewers., Data Extraction: The primary outcome was vancomycin level. Data were extracted by 2 reviewers. We performed quality assessment using the Newcastle-Ottawa quality assessment scale., Results: We identified 271 records. After abstract and full-text screening, we identified 7 studies for full review. Six of the 7 studies used a matched case-control design, although there was significant variation in study methodology. Four of the 7 studies were included in a meta-analysis, which revealed a small but significant difference in vancomycin trough levels between children with normal weight and children with overweight or obesity when dosed by using TBW ( N = 521; mean difference 2.2 U [95% confidence interval: 1.0-3.4])., Conclusions: High-quality data to guide vancomycin dosing in children with obesity are lacking. More studies evaluating dosing strategies in children with obesity are warranted because using TBW to dose vancomycin may lead to higher vancomycin concentrations and potential toxicity., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)