Importance After the COVID-19 pandemic, there was a surge of pediatric respiratory syncytial virus (RSV) infections, but national data on hospitalization and intensive care unit use and advanced ...respiratory support modalities have not been reported. Objective To analyze demographics, respiratory support modes, and clinical outcomes of children with RSV infections at tertiary pediatric hospitals from 2017 to 2023. Design, Setting, and Participants This cross-sectional study evaluated children from 48 freestanding US children’s hospitals registered in the Pediatric Health Information System (PHIS) database. Patients 5 years or younger with RSV from July 1, 2017, to June 30, 2023, were included. Each season was defined from July 1 to June 30. Prepandemic RSV seasons included 2017 to 2018, 2018 to 2019, and 2019 to 2020. The postpandemic season was delineated as 2022 to 2023. Exposure Hospital presentation with RSV infection. Main Outcomes and Measures Data on emergency department presentations, hospital or intensive care unit admission and length of stay, demographics, respiratory support use, mortality, and cardiopulmonary resuscitation were analyzed. Postpandemic season data were compared with prepandemic seasonal averages. Results A total of 288 816 children aged 5 years or younger (median IQR age, 8.9 3.3-21.5 months; 159 348 55.2% male) presented to 48 US children’s hospitals with RSV from July 1, 2017, to June 30, 2023. Respiratory syncytial virus hospital presentations increased from 39 698 before the COVID-19 pandemic to 94 347 after the pandemic ( P < .001), with 86.7% more hospitalizations than before the pandemic (50 619 vs 27 114; P < .001). In 2022 to 2023, children were older (median IQR age, 11.3 4.1-26.6 months vs 6.8 2.6-16.8 months; P < .001) and had fewer comorbidities (17.6% vs 21.8% of hospitalized patients; P < .001) than during prepandemic seasons. Advanced respiratory support use increased 70.1% in 2022 to 2023 (9094 vs 5340; P < .001), and children requiring high-flow nasal cannula (HFNC) or noninvasive ventilation (NIV) were older than during prepandemic seasons (median IQR age for HFNC, 6.9 2.7-16.0 months vs 4.6 2.0-11.7 months; for NIV, 6.0 2.1-16.5 months vs 4.3 1.9-11.9 months). Comorbid conditions were less frequent after the pandemic across all respiratory support modalities (HFNC, 14.9% vs 19.1%, NIV, 22.0% vs 28.5%, invasive mechanical ventilation, 30.5% vs 38.0%; P < .001). Conclusions and Relevance This cross-sectional study identified a postpandemic pediatric RSV surge that resulted in markedly increased hospital volumes and advanced respiratory support needs in older children with fewer comorbidities than prepandemic seasons. These clinical trends may inform novel vaccine allocation to reduce the overall burden during future RSV seasons.
In existing wireless networks, the control programs have been designed manually and for certain predefined scenarios. This process is complicated and error-prone, and the resulting control programs ...are not resilient to disruptive changes. Data-driven control based on Artificial Intelligence and Machine Learning (AI/ML) has been envisioned as a key technique to automate the modeling, optimization and control of complex wireless systems. However, existing AI/ML techniques rely on sufficient well-labeled data and may suffer from slow convergence and poor generalizability. In this article, focusing on digital twin-assisted wireless unmanned aerial vehicle (UAV) systems, we provide a survey of emerging techniques that can enable fast-converging data-driven control of wireless systems with enhanced generalization capability to new environments. These include simultaneous localization and sensing (SLAM)-based sensing and network softwarization for digital twin construction, robust reinforcement learning and system identification for domain adaptation, and testing facility sharing and federation. The corresponding research opportunities are also discussed.
Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant ...threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75 mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold,
p
< 0.01) and lowered ATP levels (− 1.9-fold,
p
< 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (− 41%,
p
< 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FA induced the accumulation of β-hydroxybutyrate (+ 1.4-fold,
p
< 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOS
CI
) (− 20%,
p
< 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.
Although population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic ...variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole-genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor approximately 261 ka, and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage approximately 68 ka. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of 1.4-fold around 970 ka and a recent 5.6-fold contraction in population size 23 ka. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection.
Neurofibromatosis type 1 is a genetic syndrome characterized by a wide variety of tumor and non-tumor manifestations. Bone-related issues, such as scoliosis, tibial dysplasia, and low bone mineral ...density, are a significant source of morbidity for this population with limited treatment options. Some of the challenges to developing such treatments include the lack of consensus regarding the optimal methods to assess bone health in neurofibromatosis type 1 and limited data regarding the natural history of these manifestations. In this review, the Functional Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration: (1) presents the available techniques for measuring overall bone health and metabolism in persons with neurofibromatosis type 1, (2) reviews data for use of each of these measures in the neurofibromatosis type 1 population, and (3) describes the strengths and limitations for each method as they might be used in clinical trials targeting neurofibromatosis type 1 bone manifestations. The Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration supports the development of a prospective, longitudinal natural history study focusing on the bone-related manifestations and relevant biomarkers of neurofibromatosis type 1. In addition, we suggest that the neurofibromatosis type 1 research community consider adding the less burdensome measurements of bone health as exploratory endpoints in ongoing or planned clinical trials for other neurofibromatosis type 1 manifestations to expand knowledge in the field.
Introduction: The aim of this study was to report the oncological outcomes and toxicity of stereotactic body radiotherapy (SBRT) to treat primary renal cell carcinoma (RCC) in frail patients unfit ...for surgery or standard alternative ablative therapies. Methods: We retrospectively enrolled 23 patients who had SBRT for primary, biopsy-proven RCC at our tertiary center between October 2016 and March 2020. Treatment-related toxicities were defined using CTCAE, version 4.0. The primary outcome was local control which was defined using the Response Evaluation Criteria in Solid Tumors. Results: The median age, Charlson score and tumor size were 81 (IQR 79–85) years, 7 (IQR 5–8) and 40 (IQR 28–48) mm, respectively. The most used dose fractionation schedule was 35 Gy (78.3%) in five or seven fractions. The median duration of follow-up for all living patients was 22 (IQR 10–39) months. Local recurrence-free survival, event-free survival, cancer-specific survival and overall survival were 96 (22/23), 74 (18/23), 96 (22/23) and 83% (19/23), respectively. There were no grade 3–4 side effects. No patients required dialysis during the study period. No treatment-related deaths or late complications were reported. Conclusion: SBRT appears to be a promising alternative to surgery or ablative therapy to treat primary RCC in frail patients.
Abstract
Disparities in metastatic renal cell carcinoma (mRCC) outcomes persist in the era of oral anticancer agents (OAAs) and immunotherapies (IOs). We examined variation in the utilization of mRCC ...systemic therapies among US Medicare beneficiaries from 2015 to 2019. Logistic regression models evaluated the association between therapy receipt and demographic covariates including patient race, ethnicity, and sex. In total, 15 407 patients met study criteria. After multivariable adjustment, non-Hispanic Black race and ethnicity was associated with reduced IO (adjusted relative risk ratio aRRR = 0.76, 95% confidence interval CI = 0.61 to 0.95; P = .015) and OAA receipt (aRRR = 0.76, 95% CI = 0.64 to 0.90; P = .002) compared with non-Hispanic White race and ethnicity. Female sex was associated with reduced IO (aRRR = 0.73, 95% CI = 0.66 to 0.81; P < .001) and OAA receipt (aRRR = 0.74, 95% CI = 0.68 to 0.81; P < .001) compared with male sex. Thus, disparities by race, ethnicity, and sex were observed in mRCC systemic therapy utilization for Medicare beneficiaries from 2015 to 2019.
The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an ...effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, are formulated singly for intra-venous (IV) infusion. However, due to the high degree of genetic variability in the case of HIV-1, a single broad neutralizing antibody will likely not be sufficient to protect against the broad range of viral isolates. To that end, delivery of two or more co-formulated bnAbs against HIV-1 in a single subcutaneous (SC) injection is highly desired. We, therefore, co-formulated two anti-HIV bnAbs, 3BNC117-LS and 10-1074-LS, to a total concentration of 150 mg/mL for SC administration and analyzed them using a panel of analytical techniques. Chromatographic based methods, such as RP-HPLC, CEX-HPLC, SEC-HPLC, were developed to ensure separation and detection of each antibody in the co-formulated sample. In addition, we used a panel of diverse pseudoviruses to detect the functionality of individual antibodies in the co-formulation. We also used these methods to test the stability of the co-formulated antibodies and believe that such an approach can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for SC delivery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
There are few standardized neonatal neurobehavioral instruments available for longitudinal child development research. We adapted an established clinical tool, the Newborn Behavioral Observations ...(NBO) system, for research by standardizing the administration protocol and expanding the 3-point coding scale to 5 points.
We administered the 5-point NBO to 144 racially/ethnically diverse late preterm or term infants born to low-income women (average age 5 weeks). Cronbach's alphas were calculated to determine internal consistency reliability of Autonomic, Motor, Organization of State, and Responsivity subscales. We examined concurrent validity using subscale associations with infant salivary cortisol reactivity to the NBO and maternally reported infant temperament.
Two of the 4 NBO subscales, Organization of State and Responsivity, had excellent (0.91) and good (0.76) reliability, respectively, and were retained for further analyses. Infants with higher Organization of State scores (more optimal regulation) demonstrated lower cortisol reactivity (r = -0.30, p < 0.01) and temperamental negativity (r = -0.16, p < 0.05). Responsivity was unrelated to cortisol reactivity or temperament.
State regulation, as measured by the 5-point NBO, was associated with a biologic marker of infant stress response to the NBO administration and reported temperament. Poor reliability of the NBO's 3-item Autonomic and 7-item Motor subscales suggests that further psychometric research in other samples and likely refinement are needed. Given the paucity of neurobehavioral assessment tools for infants, these findings justify such research as next steps in the incremental progression toward the development of a practical, reliable, and predictive measure of early neurobehavioral development.
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