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The photochemistry of heterocyclic molecules plays a decisive role for processes and applications like DNA photo-protection from UV damage and organic photocatalysis. The photochemical reactivity of heterocycles is determined by the redistribution of photoenergy into electronic and nuclear degrees of freedom, initially involving ultrafast internal conversion. Most heterocycles are planar in their ground state and internal conversion requires symmetry breaking. To lower the symmetry, the molecule must undergo an out-of-plane motion, which has not yet been observed directly. Here we show using the example of 2-thiouracil, how Coulomb explosion imaging can be utilized to extract comprehensive information on this molecular deformation, linking the extracted deplanarization of the molecular geometry to the previously studied temporal evolution of its electronic properties. Particularly, the protons of the exploded molecule are well-suited messengers carrying rich information on its geometry at distinct times after electronic excitation. We expect that our new analysis approach centered on these peripheral protons can be adapted as a general concept for future time-resolved studies of complex molecules in the gas phase., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The authors offer reflections and lessons learned in a single pediatric tertiary center's experience during a pediatric mass casualty incident (MCI). The MCI occurred at a holiday parade and the patients were brought to multiple community emergency departments for initial resuscitation prior to transfer to the Pediatric level 1 trauma center. In total, 18 children presented with severe blunt force trauma after a motor vehicle entered the parade route. Following initial triage in emergency departments, 10 of 18 children injured during the incident were admitted to the Pediatric Intensive Care Unit, collectively representing a system-wide stressor of emergency medicine, critical care, and surgical services. Institutional characteristics, activation of personnel and supplies, and psychosocial support for families during an MCI are important to consider in children's hospitals' disaster preparedness planning.

Temperate forests cover 25% of the world's forest area and most of them are managed for timber production. To increase yields, native deciduous trees have been commonly replaced by fast-growing conifers, especially in Western and Central Europe. Despite the importance of forest soils for a variety of ecosystem functions, the effects of forest management intensity on soil biological processes have not yet been sufficiently understood. Using a standardized sampling protocol that covers 200 plots across four regions with different abiotic site conditions, our study aims at disentangling the effects of individual components of forest management intensity such as (i) share of native deciduous trees, (ii) timber harvesting volume, and (iii) natural deadwood volume on soil biological processes. Our findings indicate that the effects of management practices on soil biological processes are as important as abiotic factors, such as subsoil pH value and soil texture. Piecewise structural equation modeling revealed that forest management has both direct and indirect effects on soil biological processes via humus form and topsoil pH. Generally, the ratio of deciduous and coniferous trees had the most significant effect on nutrient cycling and soil properties, followed by nutrient extraction through timber harvesting and natural deadwood volume. The strength of the observed effects was modified by regional variations in climate, topography, and bedrock. Our findings underline the high diagnostic value of humus form as an indicator of biological processes in mineral topsoil (particularly pH, C/N, and microbial characteristics can be predicted) that can guide forest managers in evaluating soil quality and identifying management impacts., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

The circular dichroism (CD) of photoelectrons generated by near-infrared (NIR) laser pulses using multiphoton ionization of excited He + ions in the 3p(m= +1) state is investigated. The ions were prepared by circularly polarized extreme ultraviolet (XUV) pulses. For circularly polarized NIR pulses co- and counter-rotating relative to the polarization of the XUV pulse, a complex variation of the CD is observed as a result of intensity- and polarization-dependent Freeman resonances, with and without additional dichroic AC-Stark shifts. The experimental results are compared with numerical solutions of the time-dependent Schrödinger equation to identify and interpret the pronounced variation of the experimentally observed CD., (© 2024. The Author(s).)

A permanently available molecular-beam injection setup for controlled molecules (COMO) was installed and commissioned at the small quantum systems (SQS) instrument at the European x-ray free-electron laser (EuXFEL). A b-type electrostatic deflector allows for pure state-, size-, and isomer-selected samples of polar molecules and clusters. The source provides a rotationally cold (T ≈ 1 K) and dense (ρ ≈ 108 cm-3) molecular beam with pulse durations up to 100 µs generated by a new version of the Even-Lavie valve. Here, a performance overview of the COMO setup is presented along with characterization experiments performed both with an optical laser at the Center for Free-Electron-Laser Science and with x rays at EuXFEL under burst-mode operation. COMO was designed to be attached to different instruments at the EuXFEL, in particular, the SQS and single particles, clusters, and biomolecules (SPB) instruments. This advanced controlled-molecules injection setup enables x-ray free-electron laser studies using highly defined samples with soft and hard x-ray FEL radiation for applications ranging from atomic, molecular, and cluster physics to elementary processes in chemistry and biology., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND) license (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Climate change is reducing winter ice cover on lakes; yet, the full societal and environmental consequences of this ice loss are poorly understood. The socioeconomic implications of declining ice include diminished access to ice-based cultural activities, safety concerns in traversing ice, changes in fisheries, increases in shoreline erosion, and declines in water storage. Longer ice-free seasons allow more time and capacity for water to warm, threatening water quality and biodiversity. Food webs likely will reorganize, with constrained availability of ice-associated and cold-water niches, and ice loss will affect the nature, magnitude, and timing of greenhouse gas emissions. Examining these rapidly emerging changes will generate more-complete models of lake dynamics, and transdisciplinary collaborations will facilitate translation to effective management and sustainability.

Imaging ultrafast atomic and molecular hydrogen motion with femtosecond time resolution is a challenge for ultrafast spectroscopy due to the low mass and small scattering cross section of the moving neutral hydrogen atoms and molecules. Here, we propose time- and momentum-resolved photoelectron diffraction (TMR-PED) as a way to overcome limitations of existing methodologies and illustrate its performance using a prototype molecular dissociation process involving the sequential ejection of a neutral hydrogen molecule and a proton from the methanol dication. By combining state-of-the-art molecular dynamics and electron-scattering methods, we show that TMR-PED allows for direct imaging of hydrogen atoms in action. More specifically, the fingerprint of hydrogen dynamics reflects the time evolution of polarization-averaged molecular-frame photoelectron angular distributions (PA-MFPADs) as would be recorded in X-ray pump/X-ray probe experiments with few-femtosecond resolution. We present the results of two precursor experiments that support the feasibility of this approach.

Importance: There is a recognized unmet need for clinical trials to provide evidence-informed care for infants, children and adolescents. This Special Communication outlines the capacity of 3 distinct trial design strategies, sequential, parallel, and a unified adult-pediatric bayesian adaptive design, to incorporate children into clinical trials and transform this current state of evidence inequity. A unified adult-pediatric whole-of-life clinical trial is demonstrated through the Staphylococcus aureus Network Adaptive Platform (SNAP) trial., Observations: Bayesian methods provide a framework for synthesizing data in the form of a probability model that can be used in the design and analysis of a clinical trial. Three trial design strategies are compared: (1) a sequential adult-pediatric bayesian approach that involves a separate, deferred pediatric trial that incorporates existing adult trial data into the analysis model to potentially reduce the pediatric trial sample size; (2) a parallel adult-pediatric bayesian trial whereby separate pediatric enrollment occurs in a parallel trial, running alongside an adult randomized clinical trial; and (3) a unified adult-pediatric bayesian adaptive design that supports the enrollment of both children and adults simultaneously in a whole-of-life bayesian adaptive randomized clinical trial. The SNAP trial whole-of-life design uses a bayesian hierarchical model that allows information sharing (also known as borrowing) between trial age groups by linking intervention effects of children and adults, thereby improving inference in both groups., Conclusion and Relevance: Bayesian hierarchical models may provide more precision for estimates of safety and efficacy of treatments in trials with heterogenous populations compared to traditional methods of analysis. They facilitate the inclusion of children in clinical trials and a shift from children deemed therapeutic orphans to the vision of no child left behind in clinical trials to ensure evidence for clinical practice exists across the life course. The SNAP trial provides an example of a bayesian adaptive whole-of-life inclusion design that enhances trial population inclusivity and diversity overall, as well as generalizability and translation of findings into clinical practice.

Background and Study Aim: Regular physical activity is highly recommended for patients with Fontan hemodynamics. Our aim was to investigate the effects of a long-term individualized home-based endurance training (IHET) on a bicycle ergometer in combination with inspiratory muscle training (IMT) in pediatric and adult patients after Fontan palliation. Additionally, factors influencing the trainability of Fontan palliated patients were analyzed., Methods: From 2018 to 2021 a single-center prospective study was performed initially including 25 Fontan palliated patients. During study period nine patients were excluded due to incompliance. A Magbike® bicycle ergometer (DKN Technology, France) was used for IHET and a POWERbreathe® Medic plus device (HaB GmbH, Germany) was utilized for the IMT. Over the study period, bike training was increased from 90 min of basic endurance training per week to additional 25 min of interval training per week. IMT consisted of 30 breaths per day for 6-7 days per week with pressure adaption over time. Patients underwent cardiopulmonary exercise testing (CPET) and body plethysmography including measurement of respiratory muscle strength at baseline and at follow-up examinations at 4, 10 and 22 months., Results: Follow-up examinations were completed by 18/25 patients (72.0%) at 4 and 10 months and 16/25 patients (64.0%) at 22 months. Median exercise capacity slightly increased by 0.13 W/kg from baseline to last follow-up ( p  = 0.055, 95%CI: 0.0-0.36). However, a significant increase of oxygen pulse of 0.7 ml/beat ( p  = 0.006, 95%CI: 0.38-2.22) was detectable. IMT significantly improved respiratory function with an increase of inspiratory vital capacity (VCin/reference) by 4.0% ( p  = 0.016, 95%CI: 0.8-8). Median maximal inspiratory pressure increased by 1.2 kPa ( p  = 0.003, 95%CI: 0.64-3.19) and expiratory pressure by 1.5 kPa ( p  = 0.036, 95%CI: 0.08-2.29). No adverse events or unplanned interventions occurred during the study. Patients' subjective quality of life did not significantly change over the study period., Conclusion: In Fontan palliated patients, IHET in combination with IMT leads to a significant increase in oxygen pulse, inspiratory vital capacity as well as median maximal inspiratory and expiratory pressure but not to significant improvement of quality of life. Fontan patients should be encouraged to perform regular home-based exercise training., 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 reviewer MK declared a shared affiliation with the author HS to the handling editor at the time of review., (© 2024 Walzer, Sallmon, Kelm, Dirks, Meyer, Kramer, Wolfarth, Thouet, Ovroutski, Berger and Schleiger.)

Xray free-electron lasers (XFELs) enable experiments that would have been impractical or impossible at conventional X-ray laser facilities. Indeed, more XFEL facilities are being built and planned, with their aim to deliver larger pulse energies and higher peak brilliance. While seeking to increase the pulse power, it is quintessential to consider the maximum pulse fluence that a grazing-incidence FEL mirror can withstand. To address this issue, several studies were conducted on grazing-incidence damage by soft X-ray FEL pulses at the European XFEL facility. Boron carbide (B 4 C) coatings on polished silicon substrate were investigated using 1 keV photon energy, similar to the X-ray mirrors currently installed at the soft X-ray beamlines (SASE3). The purpose of this study is to compare the damage threshold of B 4 C and Si to determine the advantages, tolerance and limits of using B 4 C coatings., (open access.)

A 1D imaging soft X-ray spectrometer installed on the small quantum systems (SQS) scientific instrument of the European XFEL is described. It uses movable cylindrical constant-line-spacing gratings in the Rowland configuration for energy dispersion in the vertical plane, and Wolter optics for simultaneous 1D imaging of the source in the horizontal plane. The soft X-ray fluorescence spectro-imaging capability will be exploited in pump-probe measurements and in investigations of propagation effects and other nonlinear phenomena., (open access.)

Methods: Sugammadex vials were fractionated into 25, 50, or 100 mg aliquots, which would be distributed to anesthesia staff by pharmacy staff in approximate 2 mg/kg of actual body weight doses (±10%). We analyzed changes in sugammadex waste and dosing practices 1/1/2019 to 3/15/2023 pre/postintervention (4/1/2021). We gauged dose appropriateness using last train of four (TOF) prior to sugammadex administration., Results: 7,889 patients 2-17 years (4,771 with documented TOF), ASA 1-4 receiving general anesthesia with a steroidal NMB medication and sugammadex reversal. Pre- and postintervention mean doses were 2.5 mg/kg (SD: 1.2) and 2.4 mg/kg (SD: 0.96), respectively. A smaller proportion of cases received standard 2 or 4 mg/kg doses (pre: 77.6 vs. post: 66.7%). Mean waste per case declined from 4.2 mg/kg (SD: 4.1) to 0.22 mg/kg (SD: 0.38). Among cases with 0 or 1 measured twitches on TOF that should receive at least 4 mg/kg, fewer received at least 3.6 mg/kg (post: 56.7% vs. pre: 66.8%), and a greater proportion received less than 2.2 mg/kg (post: 27.4% vs. pre: 20.7%). Among cases that should have received at least 2 mg/kg by TOF, the proportion of patients receiving more than 3.6 mg/kg declined from 9.5% to 5.2%. Discussion . Fractionating sugammadex vials was associated with decreases in waste, but not dose, and significant underdosing was more likely to occur. While vial fractionation could enable increased access to sugammadex and other costly medications, it may introduce unintended consequences., Competing Interests: Drs. Brown and Colquhoun declare research support unrelated to current project from Merck Sharp and Dohme Corp., a subsidiary of Merck and Co., Inc. (Rahway, New Jersey), and Chiesi USA, Inc. (Cary, NC), paid to the University of Michigan. Dr. Colquhoun reports honorarium from Medscape, Inc. neither Merck and Co., Inc., nor Medscape, Inc. had an impact on the results or outcomes of the study., (Copyright © 2024 Sydney E. S. Brown et al.)

Importance: Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment., Objective: To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia., Design, Setting, and Participants: This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours)., Interventions: Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol., Main Outcome and Measures: The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks., Results: Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo., Conclusions and Relevance: In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo., Trial Registration: ANZCTR.org.au Identifier: ACTRN12620000129987.

Background: Most moderate-to-late-preterm infants need nutritional support until they are feeding exclusively on their mother's breast milk. Evidence to guide nutrition strategies for these infants is lacking., Methods: We conducted a multicenter, factorial, randomized trial involving infants born at 32 weeks 0 days' to 35 weeks 6 days' gestation who had intravenous access and whose mothers intended to breast-feed. Each infant was assigned to three interventions or their comparators: intravenous amino acid solution (parenteral nutrition) or dextrose solution until full feeding with milk was established; milk supplement given when maternal milk was insufficient or mother's breast milk exclusively with no supplementation; and taste and smell exposure before gastric-tube feeding or no taste and smell exposure. The primary outcome for the parenteral nutrition and the milk supplement interventions was the body-fat percentage at 4 months of corrected gestational age, and the primary outcome for the taste and smell intervention was the time to full enteral feeding (150 ml per kilogram of body weight per day or exclusive breast-feeding)., Results: A total of 532 infants (291 boys [55%]) were included in the trial. The mean (±SD) body-fat percentage at 4 months was similar among the infants who received parenteral nutrition and those who received dextrose solution (26.0±5.4% vs. 26.2±5.2%; adjusted mean difference, -0.20; 95% confidence interval [CI], -1.32 to 0.92; P = 0.72) and among the infants who received milk supplement and those who received mother's breast milk exclusively (26.3±5.3% vs. 25.8±5.4%; adjusted mean difference, 0.65; 95% CI, -0.45 to 1.74; P = 0.25). The time to full enteral feeding was similar among the infants who were exposed to taste and smell and those who were not (5.8±1.5 vs. 5.7±1.9 days; P = 0.59). Secondary outcomes were similar across interventions. Serious adverse events occurred in one infant., Conclusions: This trial of routine nutrition interventions to support moderate-to-late-preterm infants until full nutrition with mother's breast milk was possible did not show any effects on the time to full enteral feeding or on body composition at 4 months of corrected gestational age. (Funded by the Health Research Council of New Zealand and others; DIAMOND Australian New Zealand Clinical Trials Registry number, ACTRN12616001199404.)., (Copyright © 2024 Massachusetts Medical Society.)

Polymyalgia rheumatica (PMR) is an inflammatory disorder of unknown etiology, sharing symptoms with giant cell arthritis (GCA) and rheumatoid arthritis (RA). The pathogenic inflammatory roots are still not well understood, and there is a lack of extensive biomarker studies to explain the disease debut and post-acute phase. This study aimed to deeply analyze the serum proteome and inflammatory response of PMR patients before and after glucocorticoid treatment. We included treatment-naïve PMR patients, collecting samples before and after 3 months of treatment. For comparison, disease-modifying antirheumatic drug (DMARD)-naïve RA patients were included and matched to healthy controls (CTL). The serum proteome was examined using label-free quantitative mass spectrometry, while inflammation levels were assessed using multiplex inflammatory cytokine and cell-free DNA assays. The serum proteomes of the four groups comprised acute phase reactants, coagulation factors, complement proteins, immunoglobulins, and apolipoproteins. Serum amyloid A (SAA1) was significantly reduced by active PMR treatment. Cell-free DNA levels in PMR and RA groups were significantly higher than in healthy controls due to acute inflammation. Complement factors had minimal changes post-treatment. The individual serum proteome in PMR patients showed over 100 abundantly variable proteins, emphasizing the systemic impact of PMR disease debut and the effect of treatment. Interleukin (IL)-6 and interferon-gamma (IFN-γ) were significantly impacted by glucocorticoid treatment. Our study defines the PMR serum proteome during glucocorticoid treatment and highlights the role of SAA1, IL-6, and IFN-γ in treatment responses. An involvement of PGLYRP2 in acute PMR could indicate a response to bacterial infection, highlighting its role in the acute phase of the immune response. The results suggest that PMR may be an aberrant response to a bacterial infection with an exacerbated IL-6 and acute phase inflammatory response and molecular attempts to limit the inflammation.

Competing Interests: Declaration of competing interest 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.

Quantum entanglement between the degrees of freedom encountered in the classical world is challenging to observe due to the surrounding environment. To elucidate this issue, we investigate the entanglement generated over ultrafast timescales in a bipartite quantum system comprising two massive particles: a free-moving photoelectron, which expands to a mesoscopic length scale, and a light-dressed atomic ion, which represents a hybrid state of light and matter. Although the photoelectron spectra are measured classically, the entanglement allows us to reveal information about the dressed-state dynamics of the ion and the femtosecond extreme ultraviolet pulses delivered by a seeded free-electron laser. The observed generation of entanglement is interpreted using the time-dependent von Neumann entropy. Our results unveil the potential for using short-wavelength coherent light pulses from free-electron lasers to generate entangled photoelectron and ion systems for studying spooky action at a distance.

Deferred cord clamping (DCC) has been associated with reduced mortality in preterm infants, and a period of at least 30 s has been recommended before clamping. However, preterm infants assessed as being in need of resuscitation have often had earlier cord clamping. In this study, we aimed to compare neonatal outcomes for preterm infants undergoing DCC who established early breathing movements compared to those who were not breathing. After a 5 yr recruitment period, we recently completed the ABC study, in which preterm infants <31 weeks undergoing 50 s of DCC who were not breathing by 15 s of age were randomised into two groups: one received intermittent positive pressure ventilation (IPPV) and the other was a standard group, which received no breathing support. The outcomes in the two groups were similar, and for the present analysis, the groups were combined. Infants in the ABC study were compared with the cohort excluded from the original ABC study because they were breathing by 15 s (called the Breathing Before Clamping or BBC group). There were significant differences in demographics between the ABC and BBC groups. Spontaneous preterm labour was more common in the BBC group, and these infants were more likely to be delivered vaginally. Gestational age and birth weight were significantly higher in the BBC group ( p < 0.01). Soon after birth, Apgar scores were significantly higher in the BBC group, with a lower base deficit on first obtained blood gas, and a smaller proportion were intubated in the delivery room. Fewer BBC infants were hypothermic (<36.5 °C) on admission. Multivariate regression analysis indicated whether infants were breathing or not at 15 s of age was linked predominantly to gestation. Important neonatal outcomes and a composite of these outcomes (mortality, severe intraventricular haemorrhage, bronchopulmonary dysplasia) were not significantly different between the ABC and BBC groups (odds ratio for the composite outcome was 1.77 CI 0.84-3.76 corrected for gestation). For very preterm infants undergoing DCC, important neonatal outcomes were related to gestational age and not independently associated with early breathing. There was a small group (7% of total) who were deemed compromised at birth and did not undergo DCC. These infants had significantly worse neonatal outcomes.

Introduction: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine., Methods: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months., Results: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups., Conclusions: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies., Trial Registration: ClinTrials.gov-NCT05127486 (I5Q-MC-CGBD)., (© 2023. The Author(s).)

Lake trophic state is a key ecosystem property that integrates a lake's physical, chemical, and biological processes. Despite the importance of trophic state as a gauge of lake water quality, standardized and machine-readable observations are uncommon. Remote sensing presents an opportunity to detect and analyze lake trophic state with reproducible, robust methods across time and space. We used Landsat surface reflectance data to create the first compendium of annual lake trophic state for 55,662 lakes of at least 10 ha in area throughout the contiguous United States from 1984 through 2020. The dataset was constructed with FAIR data principles (Findable, Accessible, Interoperable, and Reproducible) in mind, where data are publicly available, relational keys from parent datasets are retained, and all data wrangling and modeling routines are scripted for future reuse. Together, this resource offers critical data to address basic and applied research questions about lake water quality at a suite of spatial and temporal scales., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aims: High-sensitive troponin T (hs-TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) are established prognostic biomarkers for cardiovascular (CV) morbidity and mortality and frequently used in symptomatic and/or hospitalized adults with congenital heart disease (ACHD). Their prognostic value in clinically stable ACHD has not yet been well established. This study investigates the predictive value of hs-TnT, NT-proBNP, and CRP for survival and CV events in stable ACHD., Methods and Results: In this prospective cohort study, 495 outpatient ACHD (43.9 ± 10.0 years, 49.1% female) underwent venous blood sampling including hs-TnT, NT-proBNP, and CRP. Patients were followed up for survival status and the occurrence of CV events. Survival analyses were performed with Cox proportional hazards regression analysis and Kaplan-Meier curves. During a mean follow-up of 2.8 ± 1.0 years, 53 patients (10.7%) died or reached a cardiac-related endpoint including sustained ventricular tachycardia, hospitalization with cardiac decompensation, ablation, interventional catheterization, pacer implantation, or cardiac surgery. Multivariable Cox regression revealed hs-TnT (P = 0.005) and NT-proBNP (P = 0.018) as independent predictors of death or cardiac-related events in stable ACHD, whilst the prognostic value of CRP vanished after multivariable adjustment (P = 0.057). Receiver-operator characteristic curve analysis identified cut-off values for event-free survival of hs-TnT ≤9 ng/L and NT-proBNP ≤200 ng/L. Patients with both increased biomarkers had a 7.7-fold (confidence interval 3.57-16.40, P < 0.001) higher risk for death and cardiac-related events compared with patients without elevated blood values., Conclusion: Subclinical values of hs-TnT and NT-proBNP are a useful, simple, and independent prognostic tool for adverse cardiac events and survival in stable outpatient ACHD., Registration: German Clinical Trial Registry DRKS00015248., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The idea of using ultrashort X-ray pulses to obtain images of single proteins frozen in time has fascinated and inspired many. It was one of the arguments for building X-ray free-electron lasers. According to theory, the extremely intense pulses provide sufficient signal to dispense with using crystals as an amplifier, and the ultrashort pulse duration permits capturing the diffraction data before the sample inevitably explodes. This was first demonstrated on biological samples a decade ago on the giant mimivirus. Since then, a large collaboration has been pushing the limit of the smallest sample that can be imaged. The ability to capture snapshots on the timescale of atomic vibrations, while keeping the sample at room temperature, may allow probing the entire conformational phase space of macromolecules. Here we show the first observation of an X-ray diffraction pattern from a single protein, that of Escherichia coli GroEL which at 14 nm in diameter is the smallest biological sample ever imaged by X-rays, and demonstrate that the concept of diffraction before destruction extends to single proteins. From the pattern, it is possible to determine the approximate orientation of the protein. Our experiment demonstrates the feasibility of ultrafast imaging of single proteins, opening the way to single-molecule time-resolved studies on the femtosecond timescale., (© 2024. The Author(s).)

Objective: Gestational diabetes mellitus (GDM) is associated with offspring metabolic disease, including childhood obesity, but causal mediators remain to be established. We assessed the impact of lower versus higher thresholds for detection and treatment of GDM on infant risk factors for obesity, including body composition, growth, nutrition, and appetite., Research Design and Methods: In this prospective cohort study within the Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS), pregnant women were randomly allocated to detection of GDM using the lower criteria of the International Association of Diabetes and Pregnancy Study Groups or higher New Zealand criteria (ACTRN12615000290594). Randomly selected control infants of women without GDM were compared with infants exposed to A) GDM by lower but not higher criteria, with usual treatment for diabetes in pregnancy; B) GDM by lower but not higher criteria, untreated; or C) GDM by higher criteria, treated. The primary outcome was whole-body fat mass at 5-6 months., Results: There were 760 infants enrolled, and 432 were assessed for the primary outcome. Fat mass was not significantly different between control infants (2.05 kg) and exposure groups: A) GDM by lower but not higher criteria, treated (1.96 kg), adjusted mean difference (aMD) -0.09 (95% CI -0.29, 0.10); B) GDM by lower but not higher criteria, untreated (1.94 kg), aMD -0.15 (95% CI -0.35, 0.06); and C) GDM detected and treated using higher thresholds (1.87 kg), aMD -0.17 (95% CI -0.37, 0.03)., Conclusions: GDM detected using lower but not higher criteria, was not associated with increased infant fat mass at 5-6 months, regardless of maternal treatment. GDM detected and treated using higher thresholds was also not associated with increased fat mass at 5-6 months., (© 2023 by the American Diabetes Association.)

Aims: Central SBP (cSBP) was shown to be increased already in children with congenital heart disease (CHD). However, its development over time has not yet been investigated. The aim of this study was to evaluate the natural course of cSBP over time from longitudinal assessment in children with CHD., Methods: In this longitudinal study, 306 children and adolescents (11.3 ± 2.9 years, 34% girls) with various CHD were prospectively examined from July 2014 to May 2022. Over a mean follow-up length of 30.1 ± 18.9 months, 467 follow-up assessments have been conducted. cSBP was noninvasively assessed by oscillometric measurement via Mobil-O-Graph. A linear mixed effect model was performed to examine the course of cSBP., Results: cSBP increased significantly over time by 1.22 mmHg per year of age (P < 0.001). The longitudinal increase in cSBP over time remained significant when including sex (b = 0.68, P < 0.001), BMI (b = 1.12, P < 0.001), hypertensive medication (b = 1.13, P < 0.001), disease severity (b = 1.04, P < 0.001), and CHD type (b = 3.74, P = 0.03) in the model. Patients with transposition of the great arteries (TGA) after arterial switch had a significantly higher cSBP increase over time (b = 1.78, P < 0.001). The longitudinal cSBP increase was significantly higher in obese CHD children (b = 2.52, P = 0.005) and in boys (b = 0.85, P < 0.001)., Conclusion: This study shows a longitudinal increase in cSBP in children with CHD. Whether observed trajectories of cSBP are normal or abnormal needs to be investigated in further studies. Monitoring of the vascular function with a special focus on patients with TGA and obese CHD children seems indicated., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

We investigate how nonprofit organizations (NPOs) construct imaginaries of their premises, their local environment, and beyond. Based on a qualitative analysis of the websites of 209 randomly sampled NPOs in a metropolitan region in Central Europe, we find four distinct spatial imaginaries: (1) The world polity imaginary constructs NPOs as a part of a spatial environment that is neatly divided into nation states, supranational structures, and subnational units. (2) In the world society imaginary, NPOs are active in blurred, fluid, and overlapping spaces such as networks, commercialized spaces, or natural habitats. (3) In a religious imaginary, the material world is complemented by a transcendental realm and categorized into spaces of the sacred and the evil. (4) Finally, in a lococentric imaginary, NPOs construct a dichotomy between "home" and the alien rest of the world. Each of these spatial imaginaries conveys distinctive ways of situating the organization in their spatial environment and implies specific organizational practices and emotional enchantments of space., Supplementary Information: The online version contains supplementary material available at 10.1007/s11266-023-00603-w., Competing Interests: Conflict of interestWe have no actual or potential conflicts of interest to disclose., (© The Author(s) 2023.)

Excited double-core-hole states of isolated water molecules resulting from the sequential absorption of two x-ray photons have been investigated. These states are formed through an alternative pathway, where the initial step of core ionization is accompanied by the shake-up of a valence electron, leading to the same final states as in the core-ionization followed by core-excitation pathway. The capability of the x-ray free-electron laser to deliver very intense, very short, and tunable light pulses is fully exploited to identify the two different pathways.

Background: Endovascular treatment of aortic coarctation (CoA) in children and adults frequently requires stent implantation. The aim of this study was to analyze long-term results after CoA treatment with bare and covered Cheatham-Platinum TM (CP) stents in our institution and to derive recommendations for the differential use of these stent types., Methods: In this retrospective single institution study, 212 patients received endovascular CoA treatment with bare (n = 71) and covered (n = 141) CP stents between September 1999 and July 2021, respectively. The indications for treatment were native CoA in 110/212 patients (51.9%) and re-coarctation after primary surgical or interventional treatment in 102/212 patients (48.1%). Median patient age at endovascular CoA treatment was 18.8 years [IQR 11.9; 35.8]. Long-term follow-up was available in 158/212 patients (74.5%) with a median follow-up of 7.3 years [IQR 4.3; 12.6]., Results: Procedural success was achieved in 187/212 (88.2%) patients. Survival rate was 98.1% after 5, and 95.6% after 10 and 15 years, respectively. The probability of freedom from re-intervention was 93.0% after 5, 82.3% after 10 and 77.8% after 15 years, respectively. Freedom from re-interventions (44/158, 27.8%) did not differ between patients who received bare or covered CP stents (p = 0.715). Multivariable risk factor analysis identified previous CoA surgery (HR: 2.0, 95% confidence interval (CI): 1.1-3,9, p = 0.029), postdilatation (HR: 2,9, 95% CI: 1.1-6.3, p = 0.028) and age at intervention (HR: 0.96, 95% CI: 0.94-0.99, p = 0.002) as independent risk factors for re-intervention. Peri-procedural complications occurred in 15/212 (7.1%) patients (dissection/thrombosis of vascular access vessel: n = 9; bleeding: n = 1; stent dislocation: n = 2; aortic dissection/aortic wall rupture: n = 3). Long-term complications were observed in 36 patients and included stent fracture (n = 19), aneurysm formation (n = 14), endoleak (n = 1) and subclavian artery stenosis (n = 2). Peri-procedural and long-term complications did not differ between patients who received CoA treatment with bare or covered CP stents (all p > 0.05)., Conclusion: Endovascular treatment of CoA using bare or covered CP stents can be performed safely and effectively with excellent long-term results. Survival, re-intervention and complication rate did not significantly differ between both stent types. However, individual stent selection is advisable with regard to CoA morphology and severity as well as patient age., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Understanding the interaction of intense, femtosecond X-ray pulses with heavy atoms is crucial for gaining insights into the structure and dynamics of matter. One key aspect of nonlinear light-matter interaction was, so far, not studied systematically at free-electron lasers-its dependence on the photon energy. Here, we use resonant ion spectroscopy to map out the transient electronic structures occurring during the complex charge-up pathways of xenon. Massively hollow atoms featuring up to six simultaneous core holes determine the spectra at specific photon energies and charge states. We also illustrate how different X-ray pulse parameters, which are usually intertwined, can be partially disentangled. The extraction of resonance spectra is facilitated by the possibility of working with a constant number of photons per X-ray pulse at all photon energies and the fact that the ion yields become independent of the peak fluence beyond a saturation point. Our study lays the groundwork for spectroscopic investigations of transient atomic species in exotic, multiple-core-hole states that have not been explored previously., (© 2023. Springer Nature Limited.)

The development of SAR around substituted N-piperidinyl indole-based nociceptin opioid receptor (NOP) ligands led to the discovery of a novel series of 2-substituted N-piperidinyl indoles that provide both selective NOP full agonists and bifunctional NOP full agonists-μ opioid (MOP) receptor partial agonists. 2-substituted N-piperidinyl indoles have improved potency at the NOP receptor and are NOP full agonists, compared to our previously reported 3-substituted N-piperidinyl indoles that are selective NOP partial agonists. SAR in this series of 2-substituted N-piperidinyl indoles shows that 2-substitution versus 3-substitution on the indole moiety affects their intrinsic activity and opioid receptor selectivity. Molecular docking of these 2-substituted N-piperidinyl indoles in an active-state NOP homology model and MOP receptor structures provides a rationale for the differences observed in the binding, functional profiles and selectivity of 2-substituted versus 3-substituted N-piperidinyl indoles., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Clear outcome reporting in clinical trials facilitates accurate interpretation and application of findings and improves evidence-informed decision-making. Standardized core outcomes for reporting neonatal trials have been developed, but little is known about how primary outcomes are reported in neonatal trials. Our aim was to identify strengths and weaknesses of primary outcome reporting in recent neonatal trials., Methods: Neonatal trials including ≥100 participants/arm published between 2015 and 2020 with at least 1 primary outcome from a neonatal core outcome set were eligible. Raters recruited from Cochrane Neonatal were trained to evaluate the trials' primary outcome reporting completeness using relevant items from Consolidated Standards of Reporting Trials 2010 and Consolidated Standards of Reporting Trials-Outcomes 2022 pertaining to the reporting of the definition, selection, measurement, analysis, and interpretation of primary trial outcomes. All trial reports were assessed by 3 raters. Assessments and discrepancies between raters were analyzed., Results: Outcome-reporting evaluations were completed for 36 included neonatal trials by 39 raters. Levels of outcome reporting completeness were highly variable. All trials fully reported the primary outcome measurement domain, statistical methods used to compare treatment groups, and participant flow. Yet, only 28% of trials fully reported on minimal important difference, 24% on outcome data missingness, 66% on blinding of the outcome assessor, and 42% on handling of outcome multiplicity., Conclusions: Primary outcome reporting in neonatal trials often lacks key information needed for interpretability of results, knowledge synthesis, and evidence-informed decision-making in neonatology. Use of existing outcome-reporting guidelines by trialists, journals, and peer reviewers will enhance transparent reporting of neonatal trials., (Copyright © 2023 by the American Academy of Pediatrics.)

Superfluid helium nanodroplets are an ideal environment for the formation of metastable, self-organized dopant nanostructures. However, the presence of vortices often hinders their formation. Here, we demonstrate the generation of vortex-free helium nanodroplets and explore the size range in which they can be produced. From x-ray diffraction images of xenon-doped droplets, we identify that single compact structures, assigned to vortex-free aggregation, prevail up to 10^{8} atoms per droplet. This finding builds the basis for exploring the assembly of far-from-equilibrium nanostructures at low temperatures.

Background: Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease., Methods: VWDMin, a phase 3, open-label, randomised crossover trial, was done in 13 haemophilia treatment centres in the USA. Female patients aged 13-45 years with mild or moderate von Willebrand disease, defined as VWF ristocetin cofactor less than 0·50 IU/mL, and heavy menstrual bleeding, defined as a pictorial blood assessment chart (PBAC) score more than 100 in one of the past two cycles were eligible for enrolment. Participants were randomly assigned (1:1) to two consecutive cycles each of intravenous recombinant VWF, 40 IU/kg over 5-10 min on day 1, and oral tranexamic acid 1300 mg three times daily on days 1-5, the order determined by randomisation. The primary outcome was a 40-point reduction in PBAC score by day 5 after two cycles of treatment. Efficacy and safety were analysed in all patients with any post-baseline PBAC scores. The trial was stopped early due to slow recruitment on Feb 15, 2022, by a data safety monitoring board request, and was registered at ClinicalTrials.gov, NCT02606045., Findings: Between Feb 12, 2019, and Nov 16, 2021, 39 patients were enrolled, 36 of whom completed the trial (17 received recombinant VWF then tranexamic acid and 19 received tranexamic acid then recombinant VWF). At the time of this unplanned interim analysis (data cutoff Jan 27, 2022), median follow-up was 23·97 weeks (IQR 21·81-28·14). The primary endpoint was not met, neither treatment corrected PBAC score to the normal range. Median PBAC score was significantly lower after two cycles with tranexamic acid than with recombinant VWF (146 [95% CI 117-199] vs 213 [152-298]; adjusted mean treatment difference 46 [95% CI 2-90]; p=0·039). There were no serious adverse events or treatment-related deaths and no grade 3-4 adverse events. The most common grade 1-2 adverse events were mucosal bleeding (four [6%] patients during tranexamic acid treatment vs zero during recombinant VWF treatment) and other bleeding (four [6%] vs two [3%])., Interpretation: These interim data suggest that recombinant VWF is not superior to tranexamic acid in reducing heavy menstrual bleeding in patients with mild or moderate von Willebrand disease. These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience., Funding: National Heart Lung Blood Institute (National Institutes of Health)., Competing Interests: Declaration of interests MVR reports research funding to her institution from BioMarin, Sanofi, SPARK, and Takeda Pharmaceuticals; and service on advisory boards of BeBio, BioMarin, Hemab Therapeutics, Sanofi, SPARK, and Takeda Pharmaceuticals. DN reports research funding from Bayer; service on advisory boards for Alnylam, Aptevo, Bioverativ, Genentech, Octapharma; and service on speaker's bureaus for Octopharma, American Porphyria Foundation, BPL/Soleo Health, and Alnylam. ADL reports research funding from BioMarin and Pfizer; and service on advisory boards for BioMarin, CSL, Dova, and Pfizer. RSJ reports research funding from Takeda and Octapharma; and consulting with Sanofi/Sobi, Takeda, Octapharma, NovoNordisk, Bayer, Pfizer, Hema Biologics, Guardian Therapeutics, and Hemab Therapeutics. CP serves on advisory boards for Takeda, Hema Biologics, and Coagulant Therapeutics. RP receives honoraria from CSL Behring, Genentech, Bayer Healthcare, Hema Biologics, Instrumentation Laboratory, and Merck. APW serves on advisory boards of NovoNordisk, Hema Biologics, Takeda, Sanofi, Genentech, Octapharma, Pfizer, Bioverativ, Bayer, and Spark. RK serves on advisory boards of CSL Behring, Sanofi, NovoNordisk, and Pfizer. CS serves as a consultant to Genentech, Hema Biologics, Novo Nordisk, and Takeda. KJS reports research funding from Sanofi Pasteur. TCN reports research funding from Pfizer and Spark. ADA is currently an employee of Medtronic. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Transmission measurements of the soft X-ray beamline to the Small Quantum Systems (SQS) scientific instrument at the SASE3 undulator of European XFEL are presented. Measurements are reported for a wide range of photon energies (650 eV to 2400 eV), using X-ray gas monitors as well as a bolometric radiometer. The results are in good agreement with simulations for the beam transport and show a transmission of up to 80% over the whole photon energy range. The contribution of second- and third-harmonic radiation of the soft X-ray undulator is determined at selected photon energies by performing transmission measurements using a gas absorber to provide variable attenuation of the incoming photon flux. A comparison of the results with semi-analytic calculations for the generation of free-electron laser pulses in the SASE3 undulator reveals an influence of apertures along the beam transport on the exact harmonic content to be accounted for at the experiment. The second-harmonic content is measured to be in the range of 0.1% to 0.3%, while the third-harmonic contributed a few percent to the SASE3 emission. For experiments at the SQS instrument, these numbers can be reduced through specific selections of the mirror reflection angles., (open access.)

Importance: Morbidity and mortality after pediatric cardiac arrest are chiefly due to hypoxic-ischemic brain injury. Brain features seen on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after arrest may identify injury and aid in outcome assessments., Objective: To analyze the association of brain lesions seen on T2-weighted MRI and diffusion-weighted imaging and N-acetylaspartate (NAA) and lactate concentrations seen on MRS with 1-year outcomes after pediatric cardiac arrest., Design, Setting, and Participants: This multicenter cohort study took place in pediatric intensive care units at 14 US hospitals between May 16, 2017, and August 19, 2020. Children aged 48 hours to 17 years who were resuscitated from in-hospital or out-of-hospital cardiac arrest and who had a clinical brain MRI or MRS performed within 14 days postarrest were included in the study. Data were analyzed from January 2022 to February 2023., Exposure: Brain MRI or MRS., Main Outcomes and Measures: The primary outcome was an unfavorable outcome (either death or survival with a Vineland Adaptive Behavior Scales, Third Edition, score of <70) at 1 year after cardiac arrest. MRI brain lesions were scored according to region and severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) by 2 blinded pediatric neuroradiologists. MRI Injury Score was a sum of T2-weighted and diffusion-weighted imaging lesions in gray and white matter (maximum score, 34). MRS lactate and NAA concentrations in the basal ganglia, thalamus, and occipital-parietal white and gray matter were quantified. Logistic regression was performed to determine the association of MRI and MRS features with patient outcomes., Results: A total of 98 children, including 66 children who underwent brain MRI (median [IQR] age, 1.0 [0.0-3.0] years; 28 girls [42.4%]; 46 White children [69.7%]) and 32 children who underwent brain MRS (median [IQR] age, 1.0 [0.0-9.5] years; 13 girls [40.6%]; 21 White children [65.6%]) were included in the study. In the MRI group, 23 children (34.8%) had an unfavorable outcome, and in the MRS group, 12 children (37.5%) had an unfavorable outcome. MRI Injury Scores were higher among children with an unfavorable outcome (median [IQR] score, 22 [7-32]) than children with a favorable outcome (median [IQR] score, 1 [0-8]). Increased lactate and decreased NAA in all 4 regions of interest were associated with an unfavorable outcome. In a multivariable logistic regression adjusted for clinical characteristics, increased MRI Injury Score (odds ratio, 1.12; 95% CI, 1.04-1.20) was associated with an unfavorable outcome., Conclusions and Relevance: In this cohort study of children with cardiac arrest, brain features seen on MRI and MRS performed within 2 weeks after arrest were associated with 1-year outcomes, suggesting the utility of these imaging modalities to identify injury and assess outcomes.

Nonprofit organizations (NPOs) contribute to vital neighborhoods by building communities of citizens and acting as intermediaries between citizens and organizations. We investigate how NPOs' engagement in social and systemic integration is shaped by neighborhood characteristics, and how it relates to the organizational practices of managerialism and organizational democracy. We combine survey data with administrative data from a representative sample of NPOs in a major European city. To measure the effect of neighborhood on organizational integration, we separated the city into 7,840 grid cells characterized by population, per capita income, share of immigrant population, and density of organizations. Findings indicate that managerialism positively relates with systemic integration, as organizational democracy relates with social integration. Neighborhood characteristics, however, are not related with NPOs' engagement in integration. Our findings contribute to research on urban social cohesion by illuminating the interplay between NPOs' organizing practices, local neighborhoods, and contributions to both forms of integration., Supplementary Information: The online version contains supplementary material available at 10.1007/s11266-023-00571-1., Competing Interests: Ethical ApprovalThe material is the authors’ own original work, which has not been previously published elsewhere. The study is based on statistical- and survey data. All procedures involving human participants were in accordance with national and institutional ethical standards. We have not received any third-party funding and have no actual or potential conflicts of interest to disclose., (© The Author(s) 2023.)

Background: Handgrip strength (HGS) indicates current and future health. Although preterm infants have an increased risk of poor grip strength in later life, its determinants and relationship with neurodevelopment are not well understood., Aims: To determine HGS in children born preterm and explore the relationship of HGS with demography, anthropometry, nutritional factors, and neurodevelopmental outcomes., Study Design: A prospective cohort study of moderate-late preterm babies enrolled in a randomised trial of nutritional support strategies, the DIAMOND trial., Subjects: A total of 116 children born between 32 and 35 weeks' gestation, whose HGS was measured at 2 years' corrected age., Outcome Measures: HGS was measured using a dynamometer, and neurodevelopment was assessed using the Bayley Scales of Infant Development-III. Anthropometry and body composition were assessed at birth, discharge, and at 4 months' and 2 years' corrected age. Information on demographics and breastfeeding practices, including type of milk at discharge and duration of exclusive breastfeeding, was collected using questionnaires., Results: The mean (standard deviation) HGS was 2.26 (1.07) kg. The Bayley scores were < 85 (-1 standard deviation) in 6 %, 20 %, and 1 % for the cognitive, language, and motor scales, respectively. Multiple regression analysis revealed that HGS was positively associated with language and motor scores (p < .05) after adjusting for confounding factors. HGS was not associated with sex, anthropometry, body composition, or breastfeeding practices. Maternal education was independently associated with HGS (p < .01)., Conclusions: HGS at age 2 years in children born moderate-late preterm is associated with language and motor development and maternal education level., Competing Interests: Declaration of competing interest No conflicts to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In the United States and globally, contaminant exposure in unregulated private-well point-of-use tapwater (TW) is a recognized public-health data gap and an obstacle to both risk-management and homeowner decision making. To help address the lack of data on broad contaminant exposures in private-well TW from hydrologically-vulnerable (alluvial, karst) aquifers in agriculturally-intensive landscapes, samples were collected in 2018-2019 from 47 northeast Iowa farms and analyzed for 35 inorganics, 437 unique organics, 5 in vitro bioassays, and 11 microbial assays. Twenty-six inorganics and 51 organics, dominated by pesticides and related transformation products (35 herbicide-, 5 insecticide-, and 2 fungicide-related), were observed in TW. Heterotrophic bacteria detections were near ubiquitous (94 % of the samples), with detection of total coliform bacteria in 28 % of the samples and growth on at least one putative-pathogen selective media across all TW samples. Health-based hazard index screening levels were exceeded frequently in private-well TW and attributed primarily to inorganics (nitrate, uranium). Results support incorporation of residential treatment systems to protect against contaminant exposure and the need for increased monitoring of rural private-well homes. Continued assessment of unmonitored and unregulated private-supply TW is needed to model contaminant exposures and human-health risks., Competing Interests: Declaration of competing interest 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., (Published by Elsevier B.V.)

Successful anterior cruciate ligament (ACL) reconstructions strive for a firm bone-ligament integration. With the aim to establish an enthesis-like construct, embroidered functionalized scaffolds were colonized with spheroids of osteogenically differentiated human mesenchymal stem cells (hMSCs) and lapine (l) ACL fibroblasts in this study. These triphasic poly(L-lactide-co-ε-caprolactone) and polylactic acid (P(LA-CL)/PLA) scaffolds with a bone-, a fibrocartilage transition- and a ligament zone were colonized with spheroids directly after assembly (DC) or with 14-day pre-cultured lACL fibroblast and 14-day osteogenically differentiated hMSCs spheroids (=longer pre-cultivation, LC). The scaffolds with co-cultures were cultured for 14 days. Cell vitality, DNA and sulfated glycosaminoglycan (sGAG) contents were determined. The relative gene expressions of collagen types I and X , Mohawk , Tenascin C and runt-related protein (RUNX) 2 were analyzed. Compared to the lACL spheroids, those with hMSCs adhered more rapidly. Vimentin and collagen type I immunoreactivity were mainly detected in the hMSCs colonizing the bone zone. The DNA content was higher in the DC than in LC whereas the sGAG content was higher in LC. The gene expression of ECM components and transcription factors depended on cell type and pre-culturing condition. Zonal colonization of triphasic scaffolds using spheroids is possible, offering a novel approach for enthesis tissue engineering.

Although autografts represent the gold standard for anterior cruciate ligament (ACL) reconstruction, tissue-engineered ACLs provide a prospect to minimize donor site morbidity and limited graft availability. This study characterizes the ligamentogenesis in embroidered poly(L-lactide-co-ε-caprolactone) (P(LA-CL)) / polylactic acid (PLA) constructs using a dynamic nude mice xenograft model. (P(LA-CL))/PLA scaffolds remained either untreated (co) or were functionalized by gas fluorination (F), collagen foam cross-linked with hexamethylene diisocyanate (HMDI) (coll), or F combined with the foam (F + coll). Cell-free constructs or those seeded for 1 week with lapine ACL ligamentocytes were implanted into nude mice for 12 weeks. Following explantation, cell vitality and content, histo(patho)logy of scaffolds (including organs: liver, kidney, spleen), sulphated glycosaminoglycan (sGAG) contents and biomechanical properties were assessed.Scaffolds did not affect mice weight development and organs, indicating no organ toxicity. Moreover, scaffolds maintained their size and shape and reflected a high cell viability prior to and following implantation. Coll or F + coll scaffolds seeded with cells yielded superior macroscopic properties compared to the controls. Mild signs of inflammation (foreign-body giant cells and hyperemia) were limited to scaffolds without collagen. Microscopical score values and sGAG content did not differ significantly. Although remaining stable after explantation, elastic modulus, maximum force, tensile strength and strain at F max were significantly lower in explanted scaffolds compared to those before implantation, with no significant differences between scaffold subtypes, except for a higher maximum force in F + coll compared with F samples (in vivo). Scaffold functionalization with fluorinated collagen foam provides a promising approach for ACL tissue engineering. a Lapine anterior cruciate ligament (LACL): red arrow, posterior cruciate ligament: yellow arrow. Medial anterior meniscotibial ligament: black arrow. b Explant culture to isolate LACL fibroblasts. c Scaffold variants: co: controls; F: functionalization by gas-phase fluorination; coll: collagen foam cross-linked with hexamethylene diisocyanate (HMDI). c1-2 Embroidery pattern of the scaffolds. d Scaffolds were seeded with LACL fibroblasts using a dynamical culturing approach as depicted. e Scaffolds were implanted subnuchally into nude mice, fixed at the nuchal ligament and sacrospinal muscle tendons. f Two weeks after implantation. g Summary of analyses performed. Scale bars 1 cm (b, d), 0.5 cm (c). (sketches drawn by G.S.-T. using Krita 4.1.7 [Krita foundation, The Netherlands])., (© 2022. The Author(s).)

The Small Quantum Systems instrument is one of the six operating instruments of the European XFEL, dedicated to the atomic, molecular and cluster physics communities. The instrument started its user operation at the end of 2018 after a commissioning phase. The design and characterization of the beam transport system are described here. The X-ray optical components of the beamline are detailed, and the beamline performances, transmission and focusing capabilities are reported. It is shown that the X-ray beam can be effectively focused as predicted by ray-tracing simulations. The impact of non-ideal X-ray source conditions on the focusing performances is discussed., (open access.)

Why did some individuals react to the Covid-19 crisis in a prosocial manner, whereas others withdrew from society? To shed light onto this question, we investigate changing patterns of charitable giving during the pandemic. The study analyzes survey data of 2000 individuals, representative of the populations of Germany and Austria. Logistic regressions reveal that personal affectedness by Covid-19 seems to play a crucial role: those who were personally affected either mentally, financially, or health-wise during the first 12 months of Covid-19 were most likely to have changed their giving behavior. The observed patterns fit psychological explanations of how human beings process existential threats. Our findings indicate that a profound societal crisis in itself mainly leads to changes in charitable giving if individuals are severely affected on a personal level. Thereby, we contribute to a better understanding of the mechanisms underlying individuals' charitable giving behavior in times of crisis., Supplementary Information: The online version contains supplementary material available at 10.1007/s11266-023-00558-y., (© The Author(s) 2023.)

Watersheds of the Great Lakes Basin (USA/Canada) are highly modified and impacted by human activities including pesticide use. Despite labeling restrictions intended to minimize risks to nontarget organisms, concerns remain that environmental exposures to pesticides may be occurring at levels negatively impacting nontarget organisms. We used a combination of organismal-level toxicity estimates (in vivo aquatic life benchmarks) and data from high-throughput screening (HTS) assays (in vitro benchmarks) to prioritize pesticides and sites of concern in streams at 16 tributaries to the Great Lakes Basin. In vivo or in vitro benchmark values were exceeded at 15 sites, 10 of which had exceedances throughout the year. Pesticides had the greatest potential biological impact at the site with the greatest proportion of agricultural land use in its basin (the Maumee River, Toledo, OH, USA), with 72 parent compounds or transformation products being detected, 47 of which exceeded at least one benchmark value. Our risk-based screening approach identified multiple pesticide parent compounds of concern in tributaries of the Great Lakes; these compounds included: eight herbicides (metolachlor, acetochlor, 2,4-dichlorophenoxyacetic acid, diuron, atrazine, alachlor, triclopyr, and simazine), three fungicides (chlorothalonil, propiconazole, and carbendazim), and four insecticides (diazinon, fipronil, imidacloprid, and clothianidin). We present methods for reducing the volume and complexity of potential biological effects data that result from combining contaminant surveillance with HTS (in vitro) and traditional (in vivo) toxicity estimates. Environ Toxicol Chem 2023;42:367-384. Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Background: Hematopoietic stem cell (HSC) harvest apheresis and leukapheresis are performed in the pediatric intensive care unit (PICU) for high-risk pediatric patients who require procedural sedation. Patients need central access either with their own central lines, ports or require apheresis catheter (CVL) placement. Previously, patients were either awake or emerging from sedation on PICU admission. Uncertainty regarding procedural sedation plans caused delays initiating sedation and apheresis. A guideline was developed to standardize Dexmedetomidine (DEX) for procedural sedation. We investigated if guideline implementation would improve efficiency during PICU admission as demonstrated by shorter time intervals for initiation of sedation, apheresis, PICU length of stay and less alternative sedating medication., Methods: Data was collected retrospectively from electronic health records of preguideline and post-guideline patients who were admitted to the PICU for sedated apheresis. We compared demographic and clinical characteristics, time intervals for sedation, apheresis, PICU length of stay, and sedation agents between the two groups using Fisher Exact tests and Mann-Whitney tests, as appropriate., Results: The groups did not differ in age or weight at the time of apheresis. All intervals of time compared were shorter post-guideline. Time intervals from admission to start of sedation, admission to start of apheresis, and admission to end of apheresis were statistically significantly different. The type and number of alternative sedating medications administered did not differ between the two groups., Conclusion: This guideline implementation improved efficiency during PICU admission. This study might have been too small to demonstrate statistically significant differences in other time intervals studied., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To determine if providing respiratory support to very preterm infants who fail to breathe regularly during deferred cord clamping (DCC) decreased red cell transfusion., Study Design: Infants less than 31 weeks of gestation undergoing DCC who were apneic or not breathing regularly at 15 seconds underwent stratified randomization. Pale, limp, and nonresponsive infants were excluded. The standard group received gentle stimulation in a neutral position for 50 seconds; the intervention group received intermittent positive pressure ventilation via face mask and T piece from 20 to 50 seconds of age with a fractional inspired oxygen of 0.3. The primary outcome was the proportion transfused, with a secondary composite outcome of death, severe intraventricular hemorrhage, or chronic lung disease., Results: Of 311 assessed infants, 113 met the inclusion criteria and were studied; 57 received the intervention and 56 standard treatment. Patient characteristics were similar. Overall, 105 infants (93%) received the intended 50 seconds DCC (54 in the intervention group and 51 in the standard group). Rates of transfusion were similar (28% vs 30% in the intervention vs control groups), as were rates of the composite outcome (46% vs 38% in the intervention vs the control arms; P = .45)., Conclusions: Providing breathing support during 50 seconds of DCC in this single-center cohort seemed to be safe and feasible, but did not decrease the transfusion rates or improve outcomes., Trial Registration: http://www.anzctr.org.au/ACTRN12615001026516.aspx., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to prospectively investigate the role of near-infrared spectroscopy (NIRS) in identifying pediatric trauma patients who required lifesaving interventions (LSIs)., Methods: Prospective cohort study of children age 0 to 18 years who activated the trauma team response between August 15, 2017, and February 12, 2019, at a large, urban pediatric emergency department (ED).The relationship between the lowest somatic NIRS saturation and the need for LSIs (based on published consensus definition) was investigated. Categorical variables were analyzed by χ 2 test, and continuous variables were analyzed by Student t test., Results: A total of 148 pediatric trauma patients had somatic NIRS monitoring and met the inclusion criteria. Overall, 65.5% were male with a mean ± SD age of 10.9 ± 6.0 years. Injuries included 67.6% blunt trauma and 28.4% penetrating trauma with mortality of 3.4% (n = 5). Overall, the median lowest somatic NIRS value was 72% (interquartile range, 58%-88%; range, 15%-95%), and 43.9% of patients had a somatic NIRS value <70%. The median somatic NIRS duration recorded was 11 minutes (interquartile range, 7-17 minutes; range, 1-105 minutes). Overall, 36.5% of patients required a LSI including 53 who required a lifesaving procedure, 17 required blood products, and 17 required vasopressors. Among procedures, requiring a thoracostomy was significant.Pediatric trauma patients with a somatic NIRS value <70% had a significantly increased odds of requiring a LSI (odds ratio, 2.11; 95% confidence interval, 1.07-4.20). Somatic NIRS values <70% had a sensitivity and specificity of 56% and 63%, respectively., Conclusions: Pediatric trauma patients with somatic NIRS values <70% within 30 minutes of ED arrival have an increased odds of requiring LSIs. Among LSIs, pediatric trauma patients requiring thoracostomy was significant. The role of NIRS in incrementally improving the identification of critically injured children in the ED and prehospital setting should be evaluated in larger prospective multicenter studies., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Socio-economic status (SES) and ethnicity have been associated with worse maternal and fetal outcomes. Counties Manukau is a region of New Zealand which has a high portion of the population living in areas of low SES and has a higher population of ethnic minorities (Pacific Islander, Asian and Maaori). To determine whether SES and ethnicity are associated with worse mortality and morbidity in preterm infants in Counties Manukau Hospital, New Zealand., Methods: This retrospective cohort study compared the infants of mothers who live in the most deprived neighbourhoods to the infants of mothers who live in the least deprived neighbourhoods. Infants born between 2000 and 2019 were included if <30 weeks gestation or <1500 g and born in hospital. Primary outcome was combined mortality/morbidity., Results: Univariate analysis showed demographic differences between the SES and ethnic groups, for example maternal age and maternal smoking. Using logistic regression, SES was not associated with worse neonatal outcomes for the most deprived SES (n = 624) compared to least deprived SES (n = 164). Ethnicity (n = 1326) was not associated with worse neonatal outcomes. Gestational age and maternal smoking were associated with neonatal mortality/morbidity; gestational age and antenatal steroids were associated with neonatal mortality. It was notable that the proportion of the study population in the less deprived groups used for the comparisons was relatively low., Conclusions: For preterm, in-hospital births in Counties Manukau over a 20-year period, neonatal outcomes were the same regardless of SES or ethnicity., (© 2022 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Studies of the proteome would benefit greatly from methods to directly sequence and digitally quantify proteins and detect posttranslational modifications with single-molecule sensitivity. Here, we demonstrate single-molecule protein sequencing using a dynamic approach in which single peptides are probed in real time by a mixture of dye-labeled N-terminal amino acid recognizers and simultaneously cleaved by aminopeptidases. We annotate amino acids and identify the peptide sequence by measuring fluorescence intensity, lifetime, and binding kinetics on an integrated semiconductor chip. Our results demonstrate the kinetic principles that allow recognizers to identify multiple amino acids in an information-rich manner that enables discrimination of single amino acid substitutions and posttranslational modifications. With further development, we anticipate that this approach will offer a sensitive, scalable, and accessible platform for single-molecule proteomic studies and applications.

Fiber-shaped materials have great potential for tissue engineering applications as they provide structural support and spatial patterns within a three-dimensional construct. Here we demonstrate the fabrication of mechanically stable, meter-long collagen hollow filaments by a direct extrusion printing process. The fibres are permeable for oxygen and proteins and allow cultivation of primary human endothelial cells (ECs) at the inner surface under perfused conditions. The cells show typical characteristics of a well-organized EC lining including VE-cadherin expression, cellular response to flow and ECM production. The results demonstrate that the collagen tubes are capable of creating robust soft tissue filaments. The mechanical properties and the biofunctionality of these collagen hollow filaments facilitate the engineering of prevascularised tissue engineering constructs., 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., (© 2022 The Authors. Published by Elsevier Ltd.)

Objectives: To assess recent advances in interfacility critical care transport., Data Sources: PubMed English language publications plus chapters and professional organization publications., Study Selection: Manuscripts including practice manuals and standard (1990-2021) focused on interfacility transport of critically ill patients., Data Extraction: Review of society guidelines, legislative requirements, objective measures of outcomes, and transport practice standards occurred in work groups assessing definitions and foundations of interfacility transport, transport team composition, and transport specific considerations. Qualitative analysis was performed to characterize current science regarding interfacility transport., Data Synthesis: The Task Force conducted an integrative review of 496 manuscripts combined with 120 from the authors' collections including nonpeer reviewed publications. After title and abstract screening, 40 underwent full-text review, of which 21 remained for qualitative synthesis., Conclusions: Since 2004, there have been numerous advances in critical care interfacility transport. Clinical deterioration may be mitigated by appropriate patient selection, pretransport optimization, and transport by a well-resourced team and vehicle. There remains a dearth of high-quality controlled studies, but notable advances in monitoring, en route management, transport modality (air vs ground), as well as team composition and training serve as foundations for future inquiry. Guidance from professional organizations remains uncoupled from enforceable regulations, impeding standardization of transport program quality assessment and verification., Competing Interests: Drs. Wilcox, Cohen, and Frakes receive partial salary support from Boston MedFlight. Dr. Cohen disclosed that he serves as Chief Medical Officer for Boston MedFlight. Dr. Wax receives partial salary support from Ornge. Dr. Guyette receives partial salary support from STAT MedEvac. Dr. Kaplan received funding from the Society of Critical Care Medicine as President from February 2020 to February 2021. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

There are two recently completed large randomized clinical trials of blood transfusions in the preterm infants most at risk of requiring them. Liberal and restrictive strategies were compared with composite primary outcome measures of death and neurodevelopmental impairment. Infants managed under restrictive guidelines fared no worse in regard to mortality and neurodevelopment in early life. The studies had remarkably similar demographics and used similar transfusion guidelines. In both, there were fewer transfusions in the restrictive arm. Nevertheless, there were large differences between the studies in regard to transfusion exposure with almost 3 times the number of transfusions per participant in the transfusion of prematures (TOP) study. Associated with this, there were differences between the studies in various outcomes. For example, the combined primary outcome of death or neurodevelopmental impairment was more likely to occur in the TOP study and the mortality rate itself was considerably higher. Whilst the reasons for these differences are likely multifactorial, it does raise the question as to whether they could be related to the transfusions themselves? Clearly, every effort should be made to reduce exposure to transfusions and this was more successful in the Effects of Transfusion Thresholds on Neurocognitive Outcomes (ETTNO) study. In this review, we look at factors which may explain these transfusion differences and the differences in outcomes, in particular neurodevelopment at age 2 years. In choosing which guidelines to follow, centers using liberal guidelines should be encouraged to adopt more restrictive ones. However, should centers with more restrictive guidelines change to ones similar to those in the studies? The evidence for this is less compelling, particularly given the wide range of transfusion exposure between studies. Individual centers already using restrictive guidelines should assess the validity of the findings in light of their own transfusion experience. In addition, it should be remembered that the study guidelines were pragmatic and acceptable to a large number of centers. The major focus in these guidelines was on hemoglobin levels which do not necessarily reflect tissue oxygenation. Other factors such as the level of erythropoiesis should also be taken into account before deciding whether to transfuse., 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., (Copyright © 2022 Meyer, O'Connor and Meyer.)