BACKGROUND:Meconium aspiration syndrome (MAS) is an acute neonatal respiratory disorder resulting from aspiration of meconium-stained amniotic fluid, leading to airway obstruction, inflammation, and hypoxemia. Although its perinatal presentation is well described, its long-term association with asthma remains unknown. RESEARCH QUESTION:Is MAS associated with subsequent development of preschool asthma? STUDY DESIGN AND METHODS:A retrospective cohort study was conducted using a national database, which included infants born between 2010 and 2024 with continuous follow-up until 6 years of age. Each child with MAS was matched 1:4 with control participants without MAS using Mahalanobis distance matching. The primary outcome was asthma, defined by the Asthma Integrated Diagnosis Index, a specific composite measure. Secondary outcomes included individual asthma-related diagnoses and medication use. Kaplan-Meier analysis was performed to evaluate time to outcome, accounting for the age at which events occurred. RESULTS:Among 326,940 eligible children, 730 children (0.2%) had a diagnosis of MAS. After matching, MAS was associated with 64% higher proportion of asthma up to 6 years of age (95% CI, 1.29-2.06; P < .001). Other long-term respiratory morbidities, such as bronchiolitis and OSA, also were more frequent among survivors of MAS. Atopic conditions, including dermatitis, rhinitis, and food allergies, did not differ significantly between groups. Sensitivity analysis using inverse probability of treatment weighting supported these findings. INTERPRETATION:Our results show that MAS is associated with increased risks of asthma and bronchiolitis in early childhood. These findings suggest that neonatal lung injury resulting from MAS may impair airway development, contributing to asthma inception.

Background Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in infants. Although influenza, parainfluenza, and human metapneumovirus also contribute to LRTI-related hospitalizations, their comparative population-level healthcare burden is not well defined. This study compared population-level healthcare utilization (HCU) associated with RSV-LRTI and LRTI caused by other respiratory viruses (ORspV-LRTI). Methods This nationwide retrospective cohort study used electronic health records from Clalit Health Services (CHS), covering more than 5 million individuals in Israel. Infants born in 2015-2023 and hospitalized before 12 months of age with PCR-confirmed viral LRTI during the RSV season were included. Acute healthcare utilization (HCU) was assessed within 30 days following hospital discharge, and long-term respiratory HCU was evaluated through 6 years of age. HCU was expressed as population-level event rates per 100 000 live births during the study period, and incidence rate ratios (IRRs) were estimated using quasi-Poisson regression. Results The cohort included 5822 infants (4951 RSV-LRTI; 871 ORspV-LRTI). RSV-LRTI infants were younger at hospitalization (median 2.7 vs 4.4 months; P < .001); Acute HCU was markedly higher in the RSV-LRTI group, including hospitalization duration (IRR = 6.90; 95% CI 4.07-12.6), and anti-asthma medications use (IRR = 4.77-8.04, P < .001 for all). Elevated HCU persisted long-term, with higher rates of respiratory medication use, pediatric pulmonologist visits (94.3 vs 16.3 per 100 000; IRR 6.44), and respiratory-related hospitalizations (IRR = 5.39) through 6 years of age. These findings remained consistent in subgroups of younger children and those who experienced more severe disease during the index bronchiolitis hospitalization. Conclusions RSV-associated LRTI in infancy is associated with substantially greater population-level HCU than LRTI caused by other respiratory viruses, both acutely and throughout early childhood, supporting prioritization of early-life RSV prevention strategies.

BACKGROUND:Advances in cystic fibrosis (CF) management, quality of life, and fertility treatments have encouraged more men with CF (mwCF) to pursue parenthood. However, data on the impact of fatherhood on CF disease course, particularly in the era of CFTR modulators (CFTRm), remain limited. METHODS:We conducted a multicenter retrospective cohort study in six CF centers (2007-2023). Demographic and clinical parameters, including forced expiratory volume in 1 s (FEV1), body mass index (BMI), bacterial colonization, and pulmonary exacerbation (PEx) rates were compared for the year before and the year after fatherhood. Data were stratified by CFTRm therapy and analyzed per child for the effect of having multiple children, as well as grouped data. RESULTS:Among 170 mwCF (18-50 years), 32 fathered 52 children (17 had multiple children). Mean paternal age at childbirth was 30.5 ± 5.5, mean FEV1 declined from 74.6 ± 18.9% to 73.4 ± 19.6% (p = 0.03), while BMI remained stable (23.3 ± 3.2 to 23.4 ± 3.3; p = 1). Mild PEx increased from 0.4 ± 0.6 to 1.0 ± 1 (p = 0.001), and severe PEx (requiring intravenous antibiotic treatment), from 0.4 ± 0.9 to 0.7 ± 1.2 (p = 0.02). In mwCF on CFTRm, no significant changes were observed in FEV1, or PEx. Outcomes were not affected by the number of prior children, their order, or having had twins. CONCLUSION:Fatherhood may be associated with an increase in PEx, particularly among mwCF not treated with CFTRm. CFTRm therapy, therefore, appears to mitigate this risk, supporting its protective effect. These findings underscore the importance of routine and structured follow-up and counseling for mwCF during fatherhood.

INTRODUCTION:Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LRTIs) in young children. Additionally, RSV is associated with long-term respiratory morbidities. This study evaluates acute and long-term healthcare utilization (HCU) in infants hospitalized with RSV-associated LRTI (RSV-LRTI) compared to non-RSV LRTI (Non-RSV-LRTI) in a nationwide cohort. METHODS:A retrospective case-control study used data from Clalit Healthcare Services (CHS), Israel's largest healthcare provider. Infants born between 2015 and 2023, admitted before 12 months of age with LRTI during the RSV season, were included. PCR confirmed RSV-LRTI cases, while controls had negative RSV PCR and positive PCR for other respiratory viruses. Acute HCU was assessed within 30 days post-discharge. Long-term respiratory-related HCU was evaluated up to 6 years of age. Statistical analyses included Poisson regression, adjusting for demographic and clinical potential confounders. RESULTS:A total of 8626 infants were included, with 4,951 in the RSV-LRTI group and 3675 in the Non-RSV-LRTI group. The adjusted acute HCUs were higher in RSV-LRTI cases with increased systemic steroid use (IRR = 2.25, 95%CI: 1.94-2.62, p < 0.001) and short-acting beta-agonist use (IRR = 3.80, 95%CI: 3.36-4.30, p < 0.001). The adjusted long-term HCU trends persisted, with significantly higher use of respiratory-related medications and pediatric pulmonologist visits (IRR = 1.21, 95%CI: 1.06-1.40, p = 0.006) in the RSV-LRTI group. CONCLUSION:This nationwide study highlights the substantial acute and long-term HCU burden associated with RSV-LRTI compared to Non-RSV-LRTI, underscoring the need for effective preventive strategies for all infants, especially in the first months of life.

OBJECTIVE:To classify Still's disease (known as "systemic JIA") course into monophasic, polyphasic and chronic-persistent disease, using data collected before and after the introduction of biologic IL-1/6 inhibitors, and identify predictors for a non-monophasic disease. METHODS:A multi-center, retrospective chart review from 3 hospitals in Israel and 2 in the US, involving patients diagnosed with Still's disease between 1998-2021, with a minimum follow-up of 1 year. RESULTS:Eighty-two patients met the inclusion criteria, with a median follow up time of 2.8 years (1.1-17). Fifty-two (63.4%) were females; mean age at diagnosis was 6.4 ± 4.4 years. Fifty-nine (72%) were diagnosed in 2012 or later, when IL-1 and IL-6 inhibitors became widely used. The rates of monophasic, polyphasic and persistent disease were 34.1%, 46.3% and 19.5%, respectively, with a higher-than-expected rate of polyphasic disease. The proportion of a non-monophasic (polyphasic or persistent) disease decreased from 78.2% in cases diagnosed before 2012 to 61% in cases diagnosed after 2012 albeit not statistically significant (p = 0.22). In a multivariate logistic regression model, an active disease 3 months from diagnosis was an independent risk factor for a non-monophasic disease course (OR 4.16 [1.33-15.2], p = 0.02). CONCLUSIONS:Drug-free remissions in chronic, non-monophasic Still's disease may be more common than previously demonstrated. In the age of IL-1 and IL-6 inhibitors, a monophasic disease course may be more prevalent. This finding provides further evidence that cytokine blockers may potentially alter the natural history of this disease, and that early aggressive treatment may be warranted.

Background The use of biological response modifying drugs (BRMDs) in women of reproductive age is increasing, with reassuring safety data during pregnancy. However, their long-term impact on infant immunity remains unclear, and recommendations regarding live-attenuated vaccines in exposed infants are inconsistent. We aimed to evaluate the association between antenatal BRMD exposure and infant infection risk during the first year of life, and to compare vaccination rates between exposed and unexposed infants. Methods This nationwide cohort study included all live births in Israel between January 2012 and October 2023. Infants exposed to BRMDs during the second or third trimester were compared with unexposed infants. Propensity score analysis was adjusted for maternal comorbidities and pregnancy and delivery characteristics. Cox regression modelling evaluated the dynamics post-delivery. Infection risk was evaluated using International Classification of Diseases-10 (ICD-10) codes and vaccination rates within the national childhood immunisation programme were assessed. Results Among 297 479 live births, 395 infants were exposed to BRMDs. No differences were observed in infection risk between exposed and unexposed infants (adjusted OR: 1.11; 95% CI 0.73 to 1.74; p=0.6), supported by Cox analysis (HR: 1.00; 95% CI 0.87 to 1.15; p>0.9). Rates of antibiotic use and hospitalisation were similar. However, the rotavirus vaccination rate was significantly lower in the exposed group (p<0.001), while vaccination rates for pneumococcal/hepatitis B/DTaP-IPV-Hib (diphtheria, tetanus, acellular pertussis-inactivated polio vaccine- haemophilus influenza B) vaccines were comparable between groups. Conclusion Antenatal exposure to BRMDs was not associated with increased infection risk in the first year of life but was linked to reduced uptake of the live-attenuated rotavirus vaccine.

OBJECTIVE:Growth hormone deficiency (GHD) diagnosis typically requires the performance of two sequential stimulation tests. Glucagon stimulation test (GST) and arginine stimulation test (AST) are widely used. This study aimed to determine the most suitable order of tests. DESIGN:A retrospective study comparing GST-first group and AST-first group. PATIENTS:Children aged 1 to 17 years with suspected GHD who underwent testing between 2017 and 2022 using either GST or the AST initially. Exclusion criteria included patients with genetic syndromes or obesity and those who performed the tests more than 6 months apart. MEASUREMENTS:In order to determine the optimal order of tests, the study calculated the error rate of the first test in light of the final diagnosis after the second test using a peak GH cut-off 7.5 ng/mL. Variables such as sex, age, BMI, and socioeconomic status were analysed for their influence on outcomes. RESULTS:A total of 881 children were included. Based on the initial GHST performed, the study population was divided into two subgroups: GST-first group (712 subjects) and AST-first group (171 subjects). The proportion of discordant results was significantly lower in the GST-first group - 37.4% compared to 50.7% in the AST -first group (p = 0.048). In stepwise logistic regression none of the examined characteristics such as gender, age, BMI, priming of sex hormones prior to the tests or socioeconomic status demonstrated a statistically significant effect on the probability of discordant results in our study. CONCLUSIONS:This study demonstrated that GST is associated with a lower rate of discordant results compared to AST and potentially reduces the need for a second test, minimising patient inconvenience, lowering healthcare expenses, and decreasing time-consuming hospital visits for families.

Bronchiolitis (BRO) and Alveolar Pneumonia (PNE) are common lower respiratory infections (LRI) leading to hospitalization in children. BRO is generally caused by viruses while PNE is caused by viruses and bacteria. We analyzed transcriptomic profiles in children with LRI to investigate the differences on the immunopathogenesis of BRO vs PNETable 1.Demographic Characteristics of Study PopulationFigure 1.Transcriptomic profiling of LRI samplesDEGs were identified by comparing BRO (left) and PNE (right) patient samples vs HC (padj < 0.05 and fold change > 1.25). Heatmaps showed gene expression levels after normalization with median of HC. Red: over-expression, blue: under-expression Children < 2yr hospitalized with LRI and healthy controls (HC) were prospectively enrolled during two respiratory seasons (2018-2020) in Beer-Sheva, Israel. Diagnosis of BRO vs PNE was made according to strict predefined criteria. Nasopharyngeal (NP) swabs were analyzed for viruses (Filmarray) and bacteria (qPCR). Blood samples were collected for transcriptome analysis through RNA sequencing and data analysis performed with RFigure 2.Unsupervised clustering of LRI patient samples Machine learning approach (K-means clustering) was applied and grouped all LRI samples into 4 clusters (left). The 4 LRI clusters show the individual cases of BRO (light blue) and PNE (dark blue). Bacterial loads (PCR copy number) for Sp (purple) and Hi (orange) and ages (months) are shown on top of the heatmaps. The functional annotation of immune genes of each cluster was illustrated with a modular map, showing the percentage of significant genes in each gene module-set compared with HC (right panel). Red dot: over-expression, blue dot: under-expressionFigure 3.Molecular scores, Neutrophil percentage, CRP values and Total days of fever in all 4 clusters Transcriptomic scores, along with clinical findings were plotted for the 4 clusters identified by unsupervised analysis. P-values were shown for pairwise comparisons We enrolled 71 children diagnosed with BRO=35 and PNE=36, and 17 HC. RSV was detected in 23 BRO and 23 PNE patients. Comparison of RSVBRO and RSVPNE vs HC identified 1,001 and 3,290 differentially expressed genes (DEGs), respectively (Fig 1). Direct comparison between RSVBRO vs RSVPNE identified only 38 DEGs. Using an unsupervised machine learning approach on a combined gene list from both conditions (n=3,559), we identified four distinct clusters of LRI patients with 7, 7, 20, and 12 patients in each cluster (Fig2). Cases of RSVBRO and RSVPNE were distributed across all four clusters (C), indicating a continuum rather than distinct profiles between the two conditions. There were no significant differences in NP bacterial detection particularly for S. pneumoniae (Sp) and H. influenzae (Hi), among all 4 clusters. Functional analysis revealed increased interferon responses in all 4 clusters, but stronger in C1 and C2. C1 exhibited higher inflammation profiles and greater suppression of adaptive immune responses, alongside with higher molecular scores, % of blood neutrophils, CRP levels, and total days of fever (Fig 3) Transcriptomic analysis comparing children with RSV-associated LRI vs HC identified more DEGs in PNE than in BRO. However, when directly compared, the differences were minimal. Unsupervised clustering demonstrated overlapping gene expression patterns among the LRIs, suggesting a lack of clear distinction in the immunopathogenesis of RSVBRO vs RSVPNE Amy Leber, PhD, bioMerieux: Grant/Research Support|Biorad: Advisor/Consultant|Qiagen: Advisor/Consultant|Qiagen: Grant/Research Support Guy Hazan, Dr. MD, Sanofi: Grant/Research Support Asuncion Mejias, MD, PhD, MsCS, Enanta: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant|Sanofi-Pasteur: Advisor/Consultant Ron Dagan, Professor MD, GSK: Advisor/Consultant|GSK: Honoraria|Medimmune/AstraZeneca: Grant/Research Support|Medimmune/AstraZeneca: Honoraria|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi pasteur: Honoraria Octavio Ramilo, MD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Sanofi: Advisor/Consultant

Primary ciliary dyskinesia (PCD) is a rare inherited disorder of motile ciliary dysfunction characterized by impaired mucociliary clearance, chronic sino-pulmonary disease, and progressive bronchiectasis. Pulmonary exacerbations (PEx) are a major contributor to morbidity, lung function decline, and healthcare utilization in PCD, yet historically have been poorly defined and understudied. This review summarizes current evidence regarding the definition, epidemiology, pathophysiology, clinical impact, and management of PEx in PCD, with emphasis on recent advances that are beginning to establish a disease-specific evidence base. Recent international consensus efforts have proposed standardized definitions for PEx, although significant heterogeneity remains across clinical studies. Prospective cohort data demonstrate that PEx occur frequently across all age groups, including infancy, and are associated with impaired lung function recovery, structural lung damage, and increased disease severity, particularly in patients with chronic Pseudomonas aeruginosa infection. Emerging biomarkers such as lung clearance index and exhaled breath analysis using volatile organic compounds may improve prediction and monitoring of exacerbations. Management strategies currently rely largely on extrapolation from cystic fibrosis and non-cystic fibrosis bronchiectasis and include prompt antibiotic therapy, intensified airway clearance, and supportive care. However, recent randomized controlled trials, including BESTCILIA and CLEAN-PCD, have provided the first high-quality evidence supporting maintenance azithromycin therapy and airway hydration strategies in PCD. Despite these advances, important gaps remain regarding optimal exacerbation definitions, treatment duration, predictors of incomplete recovery, and the role of anti-inflammatory and targeted therapies. Conclusion: Continued international collaboration, validated outcome measures, and development of mechanism-based therapies will be essential to improve long-term outcomes for patients with PCD.

Children with Down syndrome (DS) often experience recurrent and prolonged hospitalizations from respiratory infections. While Azithromycin has been increasingly used for lower-respiratory tract infections (LRTIs) in children, its potential benefits for DS patients are unexplored. This study evaluates the effect of chronic azithromycin treatment on respiratory morbidity in children with DS. In this retrospective cohort study, we analyzed data from children with DS aged 0–6 years treated with Azithromycin for at least 6 weeks (10 mg/kg, thrice weekly). Respiratory morbidity indicators, such as primary care visits, medication consumption, emergency department visits, hospitalizations, and hospital length of stay (LOS), were assessed and compared six months before and after the Azithromycin treatment. Twenty-three episodes of Azithromycin treatment (≥ 6 weeks) in eighteen children with DS (mean age of 2.3 years, 78

BACKGROUND:Detection of Shigella in stool by polymerase chain reaction (PCR) is rapid and highly sensitive but presents challenges in distinguishing between disease-associated and asymptomatic Shigella carriage. This study compared children with gastroenteritis who had Shigella identified in their stool by PCR-testing and a positive stool culture to those with Shigella identified by PCR-testing but a negative culture. METHODS:All stool samples of outpatients and inpatients (<18 years) tested by multiplex-PCR at the Soroka University Medical Center laboratory between January 2020 and July 2024 were analyzed. Shigella PCR-positive samples underwent culture for species identification and antimicrobial susceptibility testing. The Vesikari scale was used to determine disease severity. Logistic regression assessed associations between culture-positivity and clinical findings, while receiver operating characteristic analysis evaluated the relationship between cycle threshold (Ct) values, culture-positivity and disease severity. RESULTS:Among 39,777 stools tested by multiplex PCR, 2041 (5.1%) were Shigella -positive, of which 897 (43.9%) were also culture-positive. Among culture-positive cases, 77% grew S. sonnei and 18% S. flexneri . Antibiotic susceptibility testing showed 36% sensitivity to ceftriaxone and 77% to azithromycin. Culture-positive cases had lower Ct values than culture-negative cases [23 (95% confidence interval [CI]: 20-26) vs. 30 (95% CI: 25-36), P < 0.001]. Among 395 hospitalized children with Shigella PCR-positive samples, 167 (42%) had positive stool cultures. Severe disease was more common in culture-positive cases (71% vs. 54%, P < 0.001). A Ct value of 28 predicted culture-positivity (adjusted odds ratios = 6.97, 95% CI: 5.62-8.68; P < 0.001) and 27 predicted severe disease (adjusted odds ratios = 1.93, 95% CI: 1.20-3.12; P = 0.007). CONCLUSIONS:Among children with Shigella -positive PCR results, those with culture-positive samples exhibited greater disease severity and lower Ct values.

Background:Chimeric antigen receptor (CAR) T cells are a leading immunotherapy for refractory B-cell malignancies, but their impact is constrained by toxicity and incomplete long-term efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success. Studies suggest that time of day influences immune-based therapies, including vaccines, hematopoietic stem cell transplantation, and checkpoint inhibitors for cancer. However, the clinical relevance of biological rhythms to CAR-T cell therapy remains unknown. Methods:We retrospectively analyzed CAR-T cell survival and complications based on infusion time at two geographically distinct hospitals in St. Louis, Missouri (n=363), and Portland, Oregon (n=307) between 2018 and 2024. The primary outcome was 90-day overall survival (OS). Secondary outcomes included event-free survival (EFS), cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), ICU admission, shock, respiratory failure, and infection. We quantified the independent relationship between infusion time and outcomes using multivariable mixed effects logistic regression, adjusting for patient, oncological, and treatment characteristics. Findings:Morning CAR-T cell infusions were associated with higher overall survival and lower rates of neurotoxicity before and after adjusting for confounders. Each hour earlier in the day that CAR-T cell treatment was given corresponded to a 22% increase in the odds of 90-day OS (adjusted odds ratio [aOR] 0·78, 95% CI 0·66-0·92, p=0·004). Simultaneously, for every hour CAR-T cell infusion was delayed, the adjusted odds of severe ICANS rose by 17% (aOR 1·17, 95% CI 1·01-1·34, p=0·031), and anakinra prescription rose by 26% (aOR 1·26, 95% CI 1·07-1·49, p=0·006). In contrast, we did not find an association between infusion time and severe CRS (aOR 0·96, 95% CI 0·74-1·23, p=0·73). Temporal patterns were most pronounced in women and patients receiving CD19-targeting CAR-T cell products for leukemia or lymphoma. Interpretation:Time of day is a potent and easily modifiable factor that could optimize CAR-T cell clinical performance. Funding:National Institutes of Health. Research in context:Evidence before this study: A review of PUBMED-cited articles shows that fundamental immune processes exhibit daily (circadian) rhythms in activity, leading immune-based therapies to vary in clinical efficacy based on the time of day. For example, the effectiveness of vaccines, checkpoint inhibitor therapy for cancer, and hematopoietic stem cell transplantation varies with the time of day they are administered to patients. One immunotherapy where dosing time remains unexplored in clinical data is CAR-T cells, a cell-based treatment for refractory B-cell cancers. Currently, the timing of CAR-T therapy is largely determined by staff availability. We hypothesized that CAR-T cell clinical safety and efficacy vary with administration time. If this hypothesis is correct, scheduling CAR-T cell infusions for specific times of day might improve the performance of this key treatment at minimal cost.Added value of this study: This study reveals that the clinical performance of CAR-T cells varies substantially with administration time. It informs practice by showing that morning CAR-T cell infusions correlate with optimal therapeutic index based on better survival and less neurotoxicity. The study also identifies women and patients receiving anti-CD19 CAR-T cells as subgroups that may benefit the most from timed CAR-T cell infusions.Implications of all the available evidence: This study on CAR-T cells should be understood in the context of growing evidence that circadian rhythms in immunity are broadly clinically translatable. The findings should prompt prospective trials that test time-of-day prioritization and, if validated, changes to CAR-T cell practice patterns. The findings also have implications for clinical trials applying CAR-T cells to new indications. Without controlling for time-of-treatment, diurnal rhythms in CAR-T cell effectiveness could be a significant confounder that could lead to false-negative or false-positive conclusions.

The purpose of the study is to evaluate the prevalence of epilepsy in children with surgically treated obstructive sleep apnea (OSA) and examine the associated healthcare utilization. This cross-sectional study included children aged 1–18 years diagnosed with moderate to severe OSA who were treated with adenoidectomy or adenotonsillectomy. A matched control group (1:3 ratio) without OSA was used for comparison. Data were obtained from Clalit Health Services, Israel’s largest healthcare provider. The study analyzed the prevalence of epilepsy, hospital admissions for seizures, use of anti-seizure medications (ASMs), and outpatient visits to pediatric neurologists. Among 55,164 children (13,791 in the OSA group and 41,373 in the control group), the prevalence of epilepsy was higher in the OSA group (0.9

BACKGROUND. Chimeric antigen receptor (CAR) T cells are a leading immunotherapy for refractory B cell malignancies; however, their effect is limited by toxicity and incomplete efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success; however, their clinical relevance to CART cell therapy remains unknown. METHODS. We retrospectively analyzed CART cell survival and complications based on infusion time at 2 geographically distinct hospitals: Washington University School of Medicine in St. Louis, Missouri, USA (n = 384) and Oregon Health & Science University in Portland, Oregon, USA (n = 331) between January 2018 and March 2025. The primary outcome was 90-day overall survival (OS). Secondary outcomes included event-free survival (EFS), cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), ICU admission, shock, respiratory failure, and infection. We quantified the independent relationship between infusion time and outcomes using multivariable mixed-effects logistic regression and time-to-event models, adjusting for patient, oncologic, and treatment characteristics. RESULTS. The therapeutic index of CAR-T cells inversely correlated with the timing of administration, with later infusions associated with lower effectiveness and more adverse outcomes. For each hour that CART cell treatment was delayed, the adjusted odds ratio (aOR) of 90-day mortality increased by 24% (aOR 0.76; 95% CI 0.64-0.88, P = 0.001), severe neurotoxicity by 17% (P = 0.023), and mechanical ventilation by 27% (P = 0.026). These temporal patterns were most pronounced in patients receiving CD19-targeting CART cell products. In contrast, we did not find an association between infusion time and severe CRS (aOR 0.99; 95% CI, 0.75-1.27; P = 0.92). CONCLUSION. Time of day is a potent and easily modifiable factor that could optimize CART cell clinical performance.

Background:Current evidence suggests that in young children with community-acquired alveolar pneumonia (CAAP), bacterial-viral coinfections (mostly respiratory syncytial virus [RSV]-pneumococcus coinfections) are more prevalent among hospitalized children than among outpatients and that RSV-pneumococcal coinfections are more frequently associated with non-PCV13 serotypes. Based on this background, we speculated that following pneumococcal conjugate vaccine [PCV] implementation, the decline of hospitalized CAAP episodes would be lower than that of outpatient episodes. Methods:This analysis was a part of an ongoing (since 2004) population-based, active surveillance in children < 5 years, including all CAAP visits to the pediatric emergency room in southern Israel. Community-acquired alveolar pneumonia was radiologically confirmed by consensus reading. Episodes were divided into hospitalized and those discharged without hospitalization (outpatients). We used a negative binomial regression model to evaluate PCV7/PCV13 impact by age and ethnic group using monthly and yearly incidence rates. Analyzed periods were pre-PCV (2004-2009), PCV7/PCV13 transition (2009-2011), early-PCV13 (2011-2015), and late-PCV13 (2015-2019). Results:Of 11 130 episodes, 3677 and 7633 were outpatients and hospitalized, respectively. Post-PCV incidence dynamics significantly diverged between the 2 study groups. (1) During the PCV7/PCV13 transition, outpatient rates significantly declined, but not those of hospitalizations. 2) During late-PCV13 period, a significantly greater decline was reached among outpatients (67%; 95% confidence interval [CI] 62%-71%) versus hospitalized (47%; 95% CI 41%-54%). This difference remained for all age and ethnic groups. Conclusions:The marked divergence in PCV impact between hospitalized and outpatient episodes is intriguing, but consistent with previous studies suggesting that hospitalized CAAP was associated with a lower proportion of PCV13 serotypes, in conjunction with viral-bacterial (mostly RSV-pneumococcus) coinfections.

Food allergies (FAs) in children have become increasingly prevalent. While early life factors such as gut microbiome disruptions have been implicated, the association between neonatal antibiotic exposure and subsequent FAs remains a topic of ongoing debate. This nationwide cohort study aimed to investigate the impact of neonatal antibiotic exposure on the development of childhood FA. This population-based retrospective cohort study analyzed data from Clalit-Healthcare-Services, Israel’s largest state-mandated healthcare provider. The cohort included neonates (aged 0–60 days) admitted with fever between 2011 and 2018. Patients with confirmed infectious etiologies were excluded. The cohort was divided into two groups: those who received systemic antibiotics (Antibiotic ( +)) and those who did not (Antibiotic ( −)). FA cases were identified using ICD-9 codes up to age 6. Multivariate logistic regression and survival analysis models were utilized and adjusted for inflammatory markers, maternal atopy, and socioeconomic status. Among 2780 neonates, 1220 received antibiotics, while 1560 did not. The incidence of FAs was significantly higher in the Antibiotic ( +) group compared to the Antibiotic ( −) group (2.5% vs. 1.3%, P = 0.02). Adjusted analysis revealed that systemic antibiotic exposure during the neonatal period was associated with a threefold increased risk of FA up to age 6 (OR = 2.89, 95% CI = 1.34–6.92, P = 0.01). Conclusions : This study provides strong evidence linking neonatal antibiotic exposure to an increased risk of childhood FAs, particularly in the first 2 years of life. The findings highlight the importance of judicious antibiotic use in young infants. What is Known: • Early-life gut microbiome disruption is linked to an increased risk of food allergies (FA). • Antibiotic use in infancy may contribute to FA, but the impact of neonatal antibiotics remains unclear. What is New: • In this large nationwide cohort, neonatal antibiotic exposure was associated with a nearly threefold increased risk of FA by age six, highlighting the need for careful antibiotic use in young infants.

Interleukin-6 receptor (IL-6R) deficiency is a rare immunodeficiency marked by impaired IL-6 signaling, affecting the inflammatory response and respiratory health. In this report, pediatric patients with IL-6R deficiency presented with a spectrum of respiratory symptoms, from mild to severe infections, but did not commonly develop early bronchiectasis. Due to the absence of typical inflammatory markers in lung infections, routine imaging is advised to monitor for potential complications, even in the absence of overt clinical signs.

BACKGROUND:Type 1 diabetes mellitus (T1DM) is an autoimmune disease with a multifactorial pathogenesis. Viral infections have been proposed as contributing triggers, supported by the disease's seasonal pattern, which typically shows higher incidence in autumn and winter. The coronavirus disease 2019 (COVID-19) pandemic and associated lockdowns created a unique context to examine the incidence and seasonality of T1DM during a period characterized by reduced circulation of common viral infections. AIM:To investigate the incidence and seasonality of T1DM before and during COVID-19 pandemic in relation to global viral infection rates. METHODS:This population-based retrospective study utilized a nationwide computerized database. Extracted data included the number of new T1DM cases over the 8 years preceding and during the COVID-19 pandemic, demographic characteristics of affected individuals, and nationwide respiratory virus polymerase chain reaction data from weekly nasal wash sample collections. RESULTS:A total of 2176 patients were diagnosed with new-onset T1DM during the pre-pandemic period, compared to 348 cases during the pandemic. In the same periods, 33727 respiratory virus-positive polymerase chain reaction results from nasal wash samples were recorded pre-pandemic, compared to 2603 during the pandemic. Additionally, 363399 positive COVID-19 cases were reported during the pandemic period. Seasonality analysis revealed a higher rate of new-onset T1DM cases and a weaker seasonal pattern during the pandemic. Trend analysis showed a consistent increase in T1DM incidence prior to COVID-19, with a more variable trend observed during the pandemic. Correlation analysis between T1DM incidence and respiratory viruses demonstrated a weak correlation between T1DM incidence and a few respiratory viruses. CONCLUSION:The observed increase in new-onset T1DM cases and the disruption of its typical seasonal pattern during the COVID-19 pandemic suggest a potential association between respiratory virus exposure and the development of T1DM.