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Objective: We previously reported the possible pathogenic role, among infants born ≤29 weeks, of transfusions in bronchopulmonary dysplasia. The present study examined this association in infants born >31 weeks., Study Design: Analysis of red blood cell (RBC) and platelet transfusions in five NICUs to infants born >31 weeks, and chronic neonatal lung disease (CNLD) at six-weeks of age., Results: Seven-hundred-fifty-one infants born >31 weeks were still in the NICU when six-weeks of age. CNLD was identified in 397 (53%). RBC and platelet transfusions were independently associated with CNLD after controlling for potential confounders. For every transfusion, the adjusted odds of developing CNLD increased by a factor of 1.64 (95% CI, 1.38-2.02; p < 0.001)., Conclusions: Among NICU patients born >31 weeks, transfusions received by six weeks are associated with CNLD incidence and severity. Though we controlled for known confounding variables in our regression models, severity of illness is an important confounder that limits our conclusions., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: There is growing recognition of the consequences of a person's health and illness experience for the health and wider welfare of those close to them. However, estimation of these health spillovers is challenging. This study adopts a longitudinal approach to examine maternal mental health spillovers associated with various forms of child illness and disability., Methods: Dynamic panel models are used in estimating maternal mental health spillovers related to 7 subcategories of chronic child illness and disability. In particular, we use longitudinal data from the Growing Up in Ireland study and a system generalized method of moments approach. We also consider heterogeneity in these spillovers by the severity of the child's illness/disability and by household deprivation., Results: We find that a child's experience of chronic nervous system conditions and chronic mental and behavioral disorders are associated with 10.8 and 5.1 percentage point increases in the probability of maternal depression, respectively. Similar associations were not observed for other health conditions. Spillover magnitude is also found to be strongly related to illness/disability severity. Finally, subsample analyses reveal a larger association between severe child illness and maternal depression among deprived households., Conclusions: This analysis, in observing health spillovers related to certain disease categories but not others, draws further attention to their context specificity. Our findings also further corroborate calls for inclusion of caregiver and family member outcomes in the economic evaluation of child health services and support consensus guidelines for collection of these outcomes alongside patient outcomes in clinical trials., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Pediatric patients may need both tracheostomy and gastrostomy tube (G-tube) placement to satisfy both oxygen and nutritional requirements for sustaining life. It is unclear if combining both procedures under one anesthetic is associated with reductions in total operative time or surgical risk, compared to performing the two procedures separately., Methods: Our study used the 2016-2021 National Surgical Quality Improvement Program-Pediatric Participant Use Files. Patients age 0-2 years were included if they underwent elective tracheostomy or G-tube placement and no concomitant procedures other than direct laryngoscopy or bronchoscopy. The initial cohort included 14,047 patients undergoing G-tube placement only, 571 undergoing tracheostomy only, and 236 undergoing both procedures concurrently. Multivariable analysis used propensity score matching to compare combined procedures to matched synthetic controls, created by combining data from patients undergoing each procedure independently (N = 180 matched pairs)., Results: After matching, combined procedures were associated with lower complication risk (odds ratio: 0.42; 95% confidence interval [CI]: 0.27, 0.65) and reduced anesthesia time (mean difference: 57 min; 95% CI: 47, 68) when compared to synthetic controls, but did not differ on total operative time (mean difference: -4.5 min; 95% CI: -12.6, +3.6)., Conclusion: Combined procedures are theorized to reduce risks associated with prolonged exposure to anesthesia. We found a reduction in total anesthesia time associated with combining tracheostomy and G-tube placement under one anesthetic, and lower risk of complications, but no change in total operative time relative to performing 2 separate surgeries., Level of Evidence: III., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)-the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation.

Purpose: To determine if postanesthesia forced-air warming as a nonpharmacologic intervention for emergence delirium (ED)/emergence agitation (EA) decreased the incidence and severity of ED in children aged 18 months to 6 years old., Design: Prospective nonrandomized controlled trial., Methods: Participants included children aged 18 months to 6 years old receiving general anesthesia within a radiation oncology setting. Status of ED/EA was based on the participants' Pediatric Anesthesia Emergence Delirium (PAED) scale score (two consecutive scores greater than 10 out of 20) or inconsolable agitation behaviors post computed tomography simulation (day 0). Interrater reliability was conducted among the center's perianesthesia care nurses. Participants who scored positive for ED/EA received a forced-air warming blanket for the remainder of treatment with data collection 1 to 14 days postanesthesia. Non-ED/EA participants were followed for 14 days and provided forced-air warming if ED/EA occurred. Data consisted of daily PAED scores and self- or parent-report on the anxiety scale. If the participants received forced-air warming, nurses' clinical observations and parent satisfaction surveys were collected 3 times during the 14-day study period., Findings: A total of 59 participants completed the study (mean age 3.43 years; 60% male; 63% non-Hispanic White); 16 were identified with ED or EA (mean age 3.56 years; 50% male; 69% non-Hispanic White) with an incidence rate of 28%. For the 16 participants with ED/EA, the primary diagnosis consisted of solid tumors and an American Society of Anesthesia Classification III to IV. Prior to the forced-air warming intervention, all 16 participants exhibited inconsolable ED/EA behaviors, including 8 who had PAED scores greater than 10. ED/EA behaviors expressed included inconsolability, confusion, thrashing, and combativeness. Within the 14-day period, 3 participants received forced-air warming on day 1, while the other 13 received an average of 4.23 days of treatment (range 1 to 11 days; mode 1 day; median 4 days). Comparison of PAED scores pre (mean 4.4) and post (mean 1.8) indicated that the use of forced-air warming was statistically significant (P = .001). ED/EA behaviors and PAED scores after the forced-air warming period decreased in all but one participant. Some agitation behaviors were not captured within the PAED score., Conclusions: Forced-air warming impacted PAED scores and agitation behaviors for studied participants, offering a safe, nonpharmacological nursing intervention that may be an effective tool for helping to manage this baffling condition., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2024 The American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Despite advances in the prevention of rhesus (Rh)(D) alloimmunization, alloantibodies to Rh(D) and non-Rh(D) red blood cell antigens continue to be detected in ∼4% of US pregnancies and can result in hemolytic disease of the fetus and newborn (HDFN). Recent reports on HDFN lack granularity and are unable to provide antibody-specific outcomes. The objective of this study was to calculate the frequency of alloimmunization in our large hospital system and summarize the outcomes based on antibody specificity, titer, and other clinical factors., Methods: We identified all births in a 6-year period after a positive red blood cell antibody screen result during pregnancy and summarized their characteristics and outcomes., Results: A total of 707 neonates were born after a positive maternal antibody screen result (3.0/1000 live births). In 31 (4%), the positive screen result was due to rhesus immune globulin alone. Of the 676 neonates exposed to alloantibodies, the direct antibody test (DAT) result was positive, showing antigen-positivity and evidence of HDFN in 37% of those tested. Neonatal disease was most severe with DAT-positive anti-Rh antibodies (c, C, D, e, E). All neonatal red blood cell transfusions (15) and exchange transfusions (6) were due to anti-Rh alloimmunization. No neonates born to mothers with anti-M, anti-S, anti-Duffy, anti-Kidd A, or anti-Lewis required NICU admission for hyperbilirubinemia or transfusion., Conclusions: Alloimmunization to Rh-group antibodies continues to cause a majority of the severe HDFN cases in our hospital system. In neonates born to alloimmunized mothers, a positive DAT result revealing antigen-positivity is the best predictor of anemia and hyperbilirubinemia., (Copyright © 2024 by the American Academy of Pediatrics.)

Objectives: To assess the feasibility of drawing, processing, safety-testing, and banking term umbilical cord blood to meet the packed red blood cell transfusion (RBC Tx) needs of extremely-low-gestational-age neonates (ELGANs)., Design: (1) Retrospectively analyze all ELGANs RBC Tx over the past three years, (2) Estimate local cord blood availability, (3) Assess interest in this project, and implementation barriers, through stakeholder surveys., Results: In three years we cared for 266 ELGANs; 165 (62%) received ≥1 RBC Tx. Annual RBC Tx averaged 197 (95% CI, 152-243). If 10% of our 10,353 annual term births had cord blood drawn and processed, and half of those tested were acceptable for Tx, collections would exceed the 95th % upper estimate for need by >four-fold. Interest exceeded 97%. Identified barriers included FDA approval, training to collect cord blood, and cost., Conclusion: RBC Tx needs of ELGANS could be met by local cord blood collection., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Building a fault-tolerant quantum computer will require vast numbers of physical qubits. For qubit technologies based on solid-state electronic devices 1-3 , integrating millions of qubits in a single processor will require device fabrication to reach a scale comparable to that of the modern complementary metal-oxide-semiconductor (CMOS) industry. Equally important, the scale of cryogenic device testing must keep pace to enable efficient device screening and to improve statistical metrics such as qubit yield and voltage variation. Spin qubits 1,4,5 based on electrons in Si have shown impressive control fidelities 6-9 but have historically been challenged by yield and process variation 10-12 . Here we present a testing process using a cryogenic 300-mm wafer prober 13 to collect high-volume data on the performance of hundreds of industry-manufactured spin qubit devices at 1.6 K. This testing method provides fast feedback to enable optimization of the CMOS-compatible fabrication process, leading to high yield and low process variation. Using this system, we automate measurements of the operating point of spin qubits and investigate the transitions of single electrons across full wafers. We analyse the random variation in single-electron operating voltages and find that the optimized fabrication process leads to low levels of disorder at the 300-mm scale. Together, these results demonstrate the advances that can be achieved through the application of CMOS-industry techniques to the fabrication and measurement of spin qubit devices., (© 2024. The Author(s).)

Health spillovers arise when an individual's serious illness affects those close to them emotionally, psychologically, and/or physically. As a result, healthcare interventions that improve the lives of patients may also confer wider health benefits. However, contrary to widespread calls for health spillovers to be included in health economic evaluation, others have argued this could have adverse distributional consequences and equity implications. This paper presents a novel approach to spillover inclusion in health economic evaluation using a 'prioritarian transformation' of health gains that allows these equity concerns to be addressed. Affording greater weight to the incremental change in patient outcomes when incorporating carer/family health spillovers into resource allocation decisions, the method provides a feasible means of moderating the distributional impact of spillover inclusion. It also introduces a normative, theoretical perspective to a largely empirical extant literature and, as such, its axiomatic basis is examined. Finally, an illustrative example of the approach is presented to demonstrate its application., (© 2024 The Authors. Health Economics published by John Wiley & Sons Ltd.)

The pesticide registration process in North America, including the USA and Canada, involves conducting a risk assessment based on relatively conservative modeling to predict pesticide concentrations in receiving waterbodies. The modeling framework does not consider some commonly adopted best management practices that can reduce the amount of pesticide that may reach a waterbody, such as vegetative filter strips (VFS). Currently, VFS are being used by growers as an effective way to reduce off-site movement of pesticides, and they are being required or recommended on pesticide labels as a mitigation measure. Given the regulatory need, a pair of multistakeholder workshops were held in Raleigh, North Carolina, to discuss how to incorporate VFS into pesticide risk assessment and risk management procedures within the North American regulatory framework. Because the risk assessment process depends heavily on modeling, one key question was how to quantitatively incorporate VFS into the existing modeling approach. Key outcomes from the workshops include the following: VFS have proven effective in reducing pesticide runoff to surface waterbodies when properly located, designed, implemented, and maintained; Vegetative Filter Strip Modeling System (VFSMOD), a science-based and widely validated mechanistic model, is suitable for further vetting as a quantitative simulation approach to pesticide mitigation with VFS in current regulatory settings; and VFSMOD parametrization rules need to be developed for the North American aquatic exposure assessment. Integr Environ Assess Manag 2024;20:454-464. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

Introduction: To achieve more equitable health, health care must be grounded in an understanding of social determinants of health. Clinicians need hands-on, equity-centered training in interdisciplinary settings where they can further develop leadership skills and apply learnings in real-time. The Clinical Scholars program trained five cohorts of health care professionals in 25 leadership development competencies to contribute toward advancing health equity within the organizations and communities where they work. This study describes the self-reported ratings of three dimensions of competencies within four domains., Methods: Data from 169 Fellows were collected at three time-points during the three-year training program using Qualtrics and Research Electronic Data Captrue software. Analysis was conducted in R and included descriptive statistics, fitting a linear mixed-effects model using random intercepts, and paired-sample t tests to assess significance between baseline and endpoint ratings., Results: We found improved ratings over time for each of the three competency dimensions (knowledge, self-efficacy, use) and significant differences in ratings from baseline to endpoint, by domain (personal, interpersonal, organizational, community, and systems)., Discussion: These findings support the effectiveness of an equity-centered leadership development curriculum in training health care professionals to address health challenges in their communities and organizations, thereby furthering the broader goal of achieving more equitable health for all., (Copyright © 2024 The Alliance for Continuing Education in the Health Professions, the Association for Hospital Medical Education, and the Society for Academic Continuing Medical Education.)

Background: Omission of family and caregiver health spillovers from the economic evaluation of healthcare interventions remains common practice. When reported, a high degree of methodological inconsistency in incorporating spillovers has been observed., Aim: To promote emerging good practice, this paper from the Spillovers in Health Economic Evaluation and Research (SHEER) task force aims to provide guidance on the incorporation of family and caregiver health spillovers in cost-effectiveness and cost-utility analysis. SHEER also seeks to inform the basis for a spillover research agenda and future practice., Methods: A modified nominal group technique was used to reach consensus on a set of recommendations, representative of the views of participating subject-matter experts. Through the structured discussions of the group, as well as on the basis of evidence identified during a review process, recommendations were proposed and voted upon, with voting being held over two rounds., Results: This report describes 11 consensus recommendations for emerging good practice. SHEER advocates for the incorporation of health spillovers into analyses conducted from a healthcare/health payer perspective, and more generally inclusive perspectives such as a societal perspective. Where possible, spillovers related to displaced/foregone activities should be considered, as should the distributional consequences of inclusion. Time horizons ought to be sufficient to capture all relevant impacts. Currently, the collection of primary spillover data is preferred and clear justification should be provided when using secondary data. Transparency and consistency when reporting on the incorporation of health spillovers are crucial. In addition, given that the evidence base relating to health spillovers remains limited and requires much development, 12 avenues for future research are proposed., Conclusions: Consideration of health spillovers in economic evaluations has been called for by researchers and policymakers alike. Accordingly, it is hoped that the consensus recommendations of SHEER will motivate more widespread incorporation of health spillovers into analyses. The developing nature of spillover research necessitates that this guidance be viewed as an initial roadmap, rather than a strict checklist. Moreover, there is a need for balance between consistency in approach, where valuable in a decision making context, and variation in application, to reflect differing decision maker perspectives and to support innovation., (© 2023. The Author(s).)

Evidence of stable liquid water oceans beneath the ice crust of moons within the Solar System is of great interest for astrobiology. In particular, subglacial oceans may present hydrothermal processes in their abysses, similarly to terrestrial hydrothermal vents. Therefore, terrestrial extremophilic deep life can be considered a model for putative icy moon extraterrestrial life. However, the comparison between putative extraterrestrial abysses and their terrestrial counterparts suffers from a potentially determinant difference. Indeed, some icy moons oceans may be so deep that the hydrostatic pressure would exceed the maximal pressure at which hydrothermal vent organisms have been isolated. While terrestrial microorganisms that are able to survive in such conditions are known, the effect of high pressure on fundamental biochemical processes is still unclear. In this study, the effects of high hydrostatic pressure on DNA synthesis catalyzed by DNA polymerases are investigated for the first time. The effect on both strand displacement and primer extension activities is measured, and pressure tolerance is compared between enzymes of various thermophilic organisms isolated at different depths.

Objective: To evaluate whether transfusions in infants born preterm contribute to the pathogenesis of bronchopulmonary dysplasia (BPD)., Study Design: We conducted a multihospital, retrospective study seeking associations between red blood cell or platelet transfusions and BPD. We tabulated all transfusions administered from January 2018 through December 2022 to infants born ≤29 weeks or <1000 g until 36 weeks postmenstrual age and compared those with BPD grade. We performed a sensitivity analysis to assess the possibility of a causal relationship. We then determined whether each transfusion was compliant with restrictive guidelines, and we estimated effects fewer transfusions might have on future BPD incidence., Results: Eighty-four infants did not develop BPD and 595 did; 352 developed grade 1 (mild), 193 grade 2 (moderate), and 50 grade 3 (severe). Transfusions were given at <36 weeks to 7% of those who did not develop BPD, 46% who did, and 98% who developed severe BPD. For every transfusion the odds of developing BPD increased by a factor of 2.27 (95% CI, 1.59-3.68; P < .001). Sensitivity analyses suggested that transfusions might contribute to BPD. Fifty-seven percent of red blood cell transfusions and 68% of platelet transfusions were noncompliant with new restrictive guidelines. Modeling predicted that complying with restrictive guidelines could reduce the transfusion rate by 20%-30% and the moderate to severe BPD rate by ∼4%-6%., Conclusions: Transfusions were associated with BPD incidence and severity. Lowering transfusion rates to comply with current restrictive guidelines might result in a small but meaningful reduction in BPD rates., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate the pharmacokinetics and safety profile of MT218, a peptide-targeted gadolinium-based contrast agent, in healthy males., Materials and Methods: This was a double-blind, randomized, placebo-controlled, single-ascending-dose study including 30 healthy male subjects. In each dose group (0.01, 0.02, 0.04, and 0.08 mmol/kg), 4 subjects received MT218 and 2 subjects received placebo (saline) in bolus injections. The highest dose group (0.08 mmol/kg) was assessed in 2 cohorts, 1 fasted and 1 nonfasted. Clinical laboratory tests, vital signs, and electrocardiograms were investigated. Gadolinium concentrations were measured in plasma samples collected before administration and over a 24-hour period postinjection, and in urine specimens collected until 22 days. A noncompartmental model was used for pharmacokinetic analysis. A clinical and biological safety follow-up was carried out for up to 6 months., Results: No clinically significant modifications in biochemistry, hematology, urinalysis, electrocardiogram parameters, or vital signs were reported at any time point for any treatment group. No serious adverse events were observed in any dose group. Transient dizziness, hyperhidrosis, and injection site coldness were the main adverse events reported in both the MT218 and placebo groups. The mean total apparent clearance decreased slightly with increasing dose, and the median plasma t 1/2 ranged from 1.7 hours in the 0.01 mmol/kg group to 2.7 hours in the 0.08 mmol/kg nonfasted group. MT218 was rapidly excreted via renal filtration with 42.9% to 52.8% of the injected dose measured in urine within the first hour after administration, and 92.5% to 117.3% in urine within 24 hours. No Gd was detected by inductively coupled plasma mass spectrometry in urine after 21 days., Conclusion: Single intravenous administration of MT218 was safely tolerated in the healthy males. Its pharmacokinetic parameters and safety profile are well aligned with those of other gadolinium-based contrast agents., Competing Interests: Conflicts of interest none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Nucleases are ubiquitous in the environment, present in biospecimens and widely used in many laboratory processes. However, in the wrong context, as contaminants, they have catastrophic potential because of their ability to rapidly degrade nucleic acids whilst retaining high resilience to inactivation. Although laboratories undertake rigorous precautions to prevent nuclease contamination, such measures are not infallible. In 2015, we devised and integrated a novel routine nuclease testing regimen into our Quality Management System that uses cleavable, fluorescent DNA and RNA substrates to detect, monitor and control for nuclease contamination in our laboratory processes, equipment and consumables. The testing regimen enables us to identify higher-risk activities, design our laboratory workflows such that risk is minimized and help fulfil our obligations in respect of ISO 20387:2018 General Requirements for Biobanking and ISO 17025 Testing and Calibrations Laboratory standards, both of which stipulate that environmental conditions in our laboratory must be monitored with defined quality control criteria. In seventeen rounds of testing (30 Test Items per round), 1.1 % of RNase tests and 0.2 % of DNase tests returned elevated nuclease levels (≥2.90 x 10 -9 U RNase or 1.67 x 10 -3 U DNase) and we were able to take remedial action. In no instance was an elevated nuclease level consequential in terms of an impact on sample quality. We present our protocols, results and observations., 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., (© 2024 The Authors.)

Background: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated., Objective: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent., Methods: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4 + or DN T cells., Results: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations., Conclusions: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)