Characterizing and Predicting nvPM Size Distributions for Aviation Emission Inventories and Environmental Impact.

Concerns about civil aviation's air quality and environmental impacts have led to recent regulations on nonvolatile particulate matter (nvPM) mass and number emissions. Although these regulations do not mandate measuring particle size distribution (PSD), understanding PSDs is vital for assessing the environmental impacts of aviation nvPM. This study introduces a comprehensive data set detailing PSD characteristics of 42 engines across 19 turbofan types, ranging from unregulated small business jets to regulated large commercial aircraft. Emission tests were independently performed by using the European and Swiss reference nvPM sampling and measurement systems with parallel PSD measurements. The geometric mean diameter (GMD) at the engine exit strongly correlated with the nvPM number-to-mass ratio (N/M) and thrust, varying from 7 to 52 nm. The engine-exit geometric standard deviation ranged from 1.7 to 2.5 (mean of 2.05). The study proposes empirical correlations to predict GMD from N/M data of emissions-certified engines. These predictions are expected to be effective for conventional rich-burn engines and might be extended to novel combustor technologies if additional data become available. The findings support the refinement of emission models and help in assessing the aviation non-CO2 climate and air quality impacts.

Self-Trephination in Cranial Excoriation Disorder.

BACKGROUND AND IMPORTANCE: Trephination is a procedure in which a small hole is made in the skull. Rare cases of self-trephination by individuals seeking medical benefit have been reported. Excoriation disorder is a compulsive skin-picking condition in which an individual self-inflicts cutaneous lesions. Left untreated, severe excoriation disorder can pose significant health risks. CLINICAL PRESENTATION: Here, we describe 5 patients who presented with self-trephination due to a severe form of compulsive cranial excoriation at 2 neighboring academic medical centers over a 4-year period. We review the clinical presentation of self-trephination in cranial excoriation disorder and associated risk factors, surgical and nonsurgical interventions, complications of the disease, treatments, and mortality. Defining clinical characteristics include repetitive self-induced destruction of the scalp and skull with entry into the intracranial compartment, frequent psychiatric comorbidities, infection or injury of the brain with consequent neurological morbidity or mortality, and frequent treatment failures because of poor adherence. CONCLUSION: Self-trephination in cranial excoriation disorder is a severe neuropsychological disorder and neurosurgical emergency that exposes the brain and is often life-threatening. Appropriate therapy requires antibiotics, surgical debridement and repair of the wound, and concomitant effective psychiatric management of the underlying compulsion, including the use of antidepressants and behavioral therapy.

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.

Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.

Perinatal outcomes after in-utero exposure to beta-blockers in women with heart disease: Data from the ESC EORP registry of pregnancy and cardiac disease (ROPAC).

BACKGROUND: Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied. METHODS: In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders). RESULTS: Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most. CONCLUSIONS: In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.

Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. METHODS AND RESULTS: The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). CONCLUSIONS: Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

Scalable Transdiagnostic Early Assessment of Mental Health (STREAM): a study protocol.

INTRODUCTION: Early childhood development forms the foundations for functioning later in life. Thus, accurate monitoring of developmental trajectories is critical. However, such monitoring often relies on time-intensive assessments which necessitate administration by skilled professionals. This difficulty is exacerbated in low-resource settings where such professionals are predominantly concentrated in urban and often private clinics, making them inaccessible to many. This geographic and economic inaccessibility contributes to a significant 'detection gap' where many children who might benefit from support remain undetected. The Scalable Transdiagnostic Early Assessment of Mental Health (STREAM) project aims to bridge this gap by developing an open-source, scalable, tablet-based platform administered by non-specialist workers to assess motor, social and cognitive developmental status. The goal is to deploy STREAM through public health initiatives, maximising opportunities for effective early interventions. METHODS AND ANALYSIS: The STREAM project will enrol and assess 4000 children aged 0-6 years from Malawi (n=2000) and India (n=2000). It integrates three established developmental assessment tools measuring motor, social and cognitive functioning using gamified tasks, observation checklists, parent-report and audio-video recordings. Domain scores for motor, social and cognitive functioning will be developed and assessed for their validity and reliability. These domain scores will then be used to construct age-adjusted developmental reference curves. ETHICS AND DISSEMINATION: Ethical approval has been obtained from local review boards at each site (India: Sangath Institutional Review Board; All India Institute of Medical Science (AIIMS) Ethics Committee; Indian Council of Medical Research-Health Ministry Screening Committee; Malawi: College of Medicine Research and Ethics Committee; Malawi Ministry of Health-Blantyre District Health Office). The study adheres to Good Clinical Practice standards and the ethical guidelines of the 6th (2008) Declaration of Helsinki. Findings from STREAM will be disseminated to participating families, healthcare professionals, policymakers, educators and researchers, at local, national and international levels through meetings, academic journals and conferences.

Low hunting costs in an expensive marine mammal predator.

Many large terrestrial mammalian predators use energy-intensive, high-risk, high-gain strategies to pursue large, high-quality prey. However, similar-sized marine mammal predators with even higher field metabolic rates (FMRs) consistently target prey three to six orders of magnitude smaller than themselves. Here, we address the question of how these active and expensive marine mammal predators can gain sufficient energy from consistently targeting small prey during breath-hold dives. Using harbor porpoises as model organisms, we show that hunting small aquatic prey is energetically cheap (<20% increase in FMR) for these marine predators, but it requires them to spend a large proportion (>60%) of time foraging. We conclude that this grazing foraging strategy on small prey is viable for marine mammal predators despite their high FMR because they can hunt near continuously at low marginal expense. Consequently, cessation of foraging due to human disturbance comes at a high cost, as porpoises must maintain their high thermoregulation costs with a reduced energy intake.

Trans-activating mutations of the pseudokinase ERBB3.

Genetic changes in the ERBB family of receptor tyrosine kinases serve as oncogenic driver events and predictive biomarkers for ERBB inhibitor drugs. ERBB3 is a pseudokinase member of the family that, although lacking a fully active kinase domain, is well known for its potent signaling activity as a heterodimeric complex with ERBB2. Previous studies have identified few transforming ERBB3 mutations while the great majority of the hundreds of different somatic ERBB3 variants observed in different cancer types remain of unknown significance. Here, we describe an unbiased functional genetics screen of the transforming potential of thousands of ERBB3 mutations in parallel. The screen based on a previously described iSCREAM (in vitro screen of activating mutations) platform, and addressing ERBB3 pseudokinase signaling in a context of ERBB3/ERBB2 heterodimers, identified 18 hit mutations. Validation experiments in Ba/F3, NIH 3T3, and MCF10A cell backgrounds demonstrated the presence of both previously known and unknown transforming ERBB3 missense mutations functioning either as single variants or in cis as a pairwise combination. Drug sensitivity assays with trastuzumab, pertuzumab and neratinib indicated actionability of the transforming ERBB3 variants.

Spectroscopic Evidence for Doubly Hydrogen-Bonded Cationic Dimers in the Solid, Liquid, and Gaseous Phases of Carboxyl-Functionalized Ionic Liquids.

Intermolecular interactions determine whether matter sticks together, gases condense into liquids, or liquids freeze into solids. The most prominent example is hydrogen bonding in water, responsible for the anomalous properties in the liquid phase and polymorphism in ice. The physical properties are also exceptional for ionic liquids (ILs), wherein a delicate balance of Coulomb interactions, hydrogen bonds, and dispersion interactions results in a broad liquid range and the vaporization of ILs as ion pairs. In this study, we show that strong, local, and directional hydrogen bonds govern the structures and arrangements in the solid, liquid, and gaseous phases of carboxyl-functionalized ILs. For that purpose, we explored the H-bonded motifs by X-ray diffraction and attenuated total reflection (ATR) infrared (IR) spectroscopy in the solid state, by ATR and transmission IR spectroscopy in the liquid phase, and by cryogenic ion vibrational predissociation spectroscopy (CIVPS) in the gaseous phase at low temperature. The analysis of the CO stretching bands reveals doubly hydrogen-bonded cationic dimers (c═c), resembling the archetype H-bond motif known for carboxylic acids. The like-charge doubly hydrogen-bonded ion pairs are present in the crystal structure of the IL, survive phase transition into the liquid state, and are still present in the gaseous phase even in (2,1) complexes wherein one counterion is removed and repulsive Coulomb interaction increased. The interpretation of the vibrational spectra is supported by quantum chemical methods. These observations have implications for the fundamental nature of the hydrogen bond between ions of like charge.

Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects: A Randomized Clinical Trial.

Importance: Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. Objectives: To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. Design, Setting, and Participants: This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Intervention: Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. Main Outcomes and Measures: The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. Results: The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). Conclusions and Relevance: In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. Trial Registration: ClinicalTrials.gov Identifier: NCT02133573.

Evaluation of a Military Global Health Engagement Mission for Critical Wartime Surgical Specialty Readiness.

INTRODUCTION: Surgical volume at Military Treatment Facilities (MTFs) has been gradually decreasing for roughly the past 2 decades. The Knowledge, Skills, and Abilities (KSA) Clinical Readiness Program linked surgical volume and readiness using a tool known as the KSA metric. However, the extent to which military medical missions contribute to the readiness of critical wartime specialties has not been evaluated using this metric. METHODS: In this study, a retrospective analysis was conducted using the surgical case logs from the US Naval Ship (USNS) Comfort missions in 2018 and 2019. The comprehensive case log data were categorized by year, surgeon, procedure, and location. The analysis focused on providing detailed descriptive statistics, including percentages pertaining to the types of procedures performed during these missions. The 2018 mission was 11 weeks in duration, and supported activities in Ecuador, Peru, Colombia, and Honduras. The USNS Comfort mission in 2019 lasted 6 months (June-November 2019), and visited 12 countries in Central America, South America, and the Caribbean. RESULTS: The 2019 mission case log, spanning 6 months, was evaluated using the KSA score in order to assess readiness and compare against 6 months of MTF KSA values within the same calendar year. In 2019, the orthopedic surgeon aboard the USNS Comfort had a total KSA score of 44,006, but the 6-month USNS Comfort mission only contributed 5,364 points (12% of the annual score). The general surgery practice aboard the USNS Comfort produced lower KSA scores compared to each surgeon's respective MTF practice (Table III). Analyzing the cases logged by general surgeons also highlights minimal surgical diversity during these missions, with more than 90% of cases being hernia repairs or laparoscopic cholecystectomies (Table I). In addition, 35% of total procedures performed in 2018 and 2019 were performed laparoscopically. CONCLUSIONS: The analysis of operative data from the 2019 USNS Comfort mission, in comparison with the surgeons' work at their respective MTFs, reveals limited benefit in the ability of hospital-ship missions to bolster surgical readiness as measured by the KSA score. However, this is not a reflection on the value of Global Health Engagement (GHE) itself but a review of the way in which it is leveraged to support surgical readiness. Military surgeons participate in GHE as part of a larger strategy to strengthen relationships with partner nations, improve military medical force interoperability, and bolster partner nation medical capacity and capabilities. The KSA score offers an excellent tool to compare readiness metrics across significantly different GHE missions, and facilitates the opportunity for future prospective studies to improve case volume, diversity, and ultimately readiness.

CeO2 nanoparticle dose and exposure modulate soybean development and plant-mediated responses in root-associated bacterial communities.

Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg-1. Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops.

Comparison of qPCR and metabarcoding for environmental DNA surveillance of a freshwater parasite.

Analysis of environmental DNA (eDNA) has been successfully used across freshwater ecological parasitology to inform management of ecologically and economically important species. However, most studies have used species-specific quantitative polymerase chain reaction (qPCR) assays to detect target taxa. While generally effective, this approach limits the amount of community and management-supporting data that can be obtained from eDNA samples. If eDNA metabarcoding could be conducted with the same accuracy of a single species approach, researchers could simultaneously detect a target species while obtaining vast community data from eDNA samples. We sampled 38 freshwater sites on Fort McCoy, Wisconsin and compared qPCR to metabarcoding for eDNA detection of the ectoparasitic gill louse Salmincola edwardsii, an obligate parasite of Salvelinus fishes (chars). We found no evidence to suggest S. edwardsii occupancy or detection probabilities differed between qPCR and metabarcoding. Further, we found that the number of S. edwardsii reads from metabarcoding were negatively predictive of C T values from qPCR (C T value indicates cycle a significant amount of target eDNA is detected, with lower C Ts indicative of more DNA), demonstrating that our metabarcoding reads positively predicted qPCR DNA quantities. However, the number of reads was not predictive of overall qPCR score (number of positive qPCR replicates). In addition to S. edwardsii, metabarcoding led to the detection of a vast community of over 2600 invertebrate taxa. We underscore the necessity for conducting similar analyses across environments and target species, as the ecology of eDNA will vary on a per-study basis. Our results suggest that eDNA metabarcoding provides a highly sensitive and accurate method for detecting parasitic gill lice while also illuminating the broader biological community and co-occurrence of species in the environment.

High-resolution detection of copy number alterations in single cells with HiScanner.

Improvements in single-cell whole-genome sequencing (scWGS) assays have enabled detailed characterization of somatic copy number alterations (CNAs) at the single-cell level. Yet, current computational methods are mostly designed for detecting chromosome-scale changes in cancer samples with low sequencing coverage. Here, we introduce HiScanner (High-resolution Single-Cell Allelic copy Number callER), which combines read depth, B-allele frequency, and haplotype phasing to identify CNAs with high resolution. In simulated data, HiScanner consistently outperforms state-of-the-art methods across various CNA types and sizes. When applied to high-coverage scWGS data from human brain cells, HiScanner shows a superior ability to detect smaller CNAs, uncovering distinct CNA patterns between neurons and oligodendrocytes. For 179 cells we sequenced from longitudinal meningioma samples, integration of CNAs with point mutations revealed evolutionary trajectories of tumor cells. These findings show that HiScanner enables accurate characterization of frequency, clonality, and distribution of CNAs at the single-cell level in both non-neoplastic and neoplastic cells.

Native aortic root thrombus leading to myocardial infarction in a single ventricle patient.

We report a 14-month-old male with hypoplastic left heart syndrome, mitral stenosis, and aortic stenosis with native aortic root thrombus. He developed a wide complex ventricular tachycardia and ST-segment elevation myocardial infarction with troponin I levels peaking at 388 ng/mL. He was treated safely with systemic alteplase with a resolution of his regional wall motion abnormality 18 hours later.

A Longitudinal Assessment of Resident and New Graduate Well-Being According to Length of Training: A Report From the Length of Training Pilot in Family Medicine.

Background & Objectives: No prior studies have examined how length of training may influence wellness. As part of the Length of Training Pilot (LoTP), we explored resident and new graduate well-being according to program year and length of training in 3- and 4-year family medicine residency training programs. METHODS: Two surveys captured data included in these analyses. One was a resident survey that included the Mayo Clinic physician-expanded Well-Being Index (eWBI) administered annually during the In-Training Examination (2014-2019). The second was administered to graduates 1 year after completion of training between 2016 and 2022 and included the same well-being questions. Response rates ranged between 77.7% and 96.8%. RESULTS: The eWBI summary scores for burnout were highest in postgraduate year 1 (PGY1) and did not differ statistically according to length of training (PGY1: 2.02 in 3-year [3YR] programs vs 1.93 in 4-year [4YR] programs, P=.55; postgraduate year 2 [PGY2]: 2.42 in 3YR programs vs 2.38 in 4YR programs, P=.83; postgraduate year 3 [PGY3]: 2.18 in 3YR programs vs 2.28 in 4YR programs, P=.59; and 2.34 in postgraduate year 4 [PGY4] for those in 4YR programs), though some statistical differences were noted for three items. New graduates' eWBI summary scores before the COVID-19 pandemic were 1.77 among 3YR graduates and 1.66 among 4YR graduates (P=.59). These scores were higher during COVID-19 at 1.89 for 3YR graduates and 2.02 for 4YR graduates (P=.62). Length of training was not associated with differences in well-being before or during COVID-19. CONCLUSIONS: We found no associations between length of training and physician well-being during training or among new graduates before or during COVID-19.

Perspectives on community-based system change for people living with persistent pain: insights from developing the "Rethinking Pain service".

In this perspective article we advocate community-based system change for people living with persistent pain. Our view is that greater use of the voluntary and community sector, in partnership with the clinical sector, creates the conditions for a "whole person" approach to pain management, leading to greater personalised care for adults living with long-term pain whilst having the potential to ease some of the pressures on General Practitioners and other clinical services. We advocate pain care that is socially connected, meaningful within socio-cultural contexts and aligned with the principles of salutogenesis. We provide an example of a UK National Health Service (NHS) commissioned pain service called "Rethinking Pain" that operationalises this perspective. Led by the voluntary and community sector, Rethinking Pain works in partnership with the clinical sector to provide a central holistic pathway of care for people experiencing persistent pain. This is the first time that this model of care has been commissioned for persistent pain in this area of England. The Rethinking Pain service is underpinned by core values to work with people to manage their pain holistically. The Rethinking Pain team proactively engage with people in the community, actively approaching and engaging those who experience the biggest health inequalities. In this article we provide an overview of the context of pain services in the UK, the rationale and supporting evidence for community-based system change, and the context, pathway, values, goals, and aspirations of the Rethinking Pain service.