Body mass index in pediatric kidney transplant selection criteria.

BACKGROUND: Obesity is associated with increased complications, rejection, and graft loss after kidney transplantation in adult and pediatric recipients. Elevated body mass index (BMI) is a common contraindication to transplant at adult kidney transplant programs; however, there is no data on such limitations for pediatric patients. METHODS: Between October and December 2022, we conducted a survey of Pediatric Nephrology Research Consortium centers assessing the use of BMI in pediatric kidney transplant evaluation. Centers reporting utilization of BMI cutoffs were invited to submit patient-level data on children declined for active transplant listing due to BMI. RESULTS: Thirty-nine centers responded to the survey (42% response rate); 51% include BMI in their written listing criteria, with a median BMI "cutoff" of 39 kg/m2 (range 30-50 kg/m2). Between January 1, 2016, and December 31, 2021, 30 children at 15 transplant centers were declined for listing status due to BMI. Patient-level data was provided for 19 children (63%) who were denied active listing status; median BMI was 42 kg/m2 (range 35.8-49.4 kg/m2) and 84% were on dialysis. One year after evaluation, seven patients (37%) had proceeded to active wait list status. Eight (42%) remained in inactive status and four (21%) were unlisted; ten of these 12 patients (83%) were on dialysis. CONCLUSIONS: The use of BMI in pediatric kidney transplant evaluation and listing varies among centers, but BMI limits access to transplant for some children. More information is needed on the outcomes of obese pediatric kidney candidates who are and are not transplanted, to guide development of national and international consensus.

Infant formula supplemented with milk fat globule membrane compared with standard infant formula for the cognitive development of healthy term-born formula-fed infants: protocol for a randomised controlled trial.

INTRODUCTION: Milk fat globule membrane (MFGM) is a complex lipid-protein structure in mammalian milk and human milk that is largely absent from breastmilk substitutes. The objective of this trial is to investigate whether providing infant formula enriched with MFGM versus standard infant formula improves cognitive development at 12 months of age in exclusively formula-fed full-term infants. METHODS AND ANALYSIS: This is a randomised, controlled, clinician-blinded, researcher-blinded and participant-blinded trial of two parallel formula-fed groups and a breastfed reference group that were recruited in the suburban Adelaide (Australia) community by a single study centre (a medical research institute). Healthy, exclusively formula-fed, singleton, term-born infants under 8 weeks of age were randomised to either an MFGM-supplemented formula (intervention) or standard infant formula (control) from enrolment until 12 months of age. The reference group was not provided with formula. The primary outcome is the Cognitive Scale of the Bayley Scales of Infant Development, Fourth Edition (Bayley-IV) at 12 months. Secondary outcomes are the Bayley-IV Cognitive Scale at 24 months, other Bayley-IV domains (language, motor, emotional and behavioural development) at 12 and 24 months of age, infant attention at 4 and 9 months of age, parent-rated language at 12 and 24 months of age, parent-rated development at 6 and 18 months of age as well as growth, tolerance and safety of the study formula. To ensure at least 80% power to detect a 5-point difference in the mean Bayley-IV cognitive score, >200 infants were recruited in each group. ETHICS AND DISSEMINATION: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/19/WCHN/140). Caregivers gave written informed consent prior to enrolling in the trial. Findings of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12620000552987; Australian and New Zealand Clinical Trial Registry: anzctr.org.au.

Evolution of Whirly1 in the angiosperms: sequence, splicing, and expression in a clade of early transitional mycoheterotrophic orchids.

The plastid-targeted transcription factor Whirly1 (WHY1) has been implicated in chloroplast biogenesis, plastid genome stability, and fungal defense response, which together represent characteristics of interest for the study of autotrophic losses across the angiosperms. While gene loss in the plastid and nuclear genomes has been well studied in mycoheterotrophic plants, the evolution of the molecular mechanisms impacting genome stability is completely unknown. Here, we characterize the evolution of WHY1 in four early transitional mycoheterotrophic orchid species in the genus Corallorhiza by synthesizing the results of phylogenetic, transcriptomic, and comparative genomic analyses with WHY1 genomic sequences sampled from 21 orders of angiosperms. We found an increased number of non-canonical WHY1 isoforms assembled from all but the greenest Corallorhiza species, including intron retention in some isoforms. Within Corallorhiza, phylotranscriptomic analyses revealed the presence of tissue-specific differential expression of WHY1 in only the most photosynthetically capable species and a coincident increase in the number of non-canonical WHY1 isoforms assembled from fully mycoheterotrophic species. Gene- and codon-level tests of WHY1 selective regimes did not infer significant signal of either relaxed selection or episodic diversifying selection in Corallorhiza but did so for relaxed selection in the late-stage full mycoheterotrophic orchids Epipogium aphyllum and Gastrodia elata. Additionally, nucleotide substitutions that most likely impact the function of WHY1, such as nonsense mutations, were only observed in late-stage mycoheterotrophs. We propose that our findings suggest that splicing and expression changes may precede the selective shifts we inferred for late-stage mycoheterotrophic species, which therefore does not support a primary role for WHY1 in the transition to mycoheterotrophy in the Orchidaceae. Taken together, this study provides the most comprehensive view of WHY1 evolution across the angiosperms to date.

A Prospective Observational Cohort Study for Newly Diagnosed Osteosarcoma Patients in the UK: ICONIC Study Initial Results.

There has been little change to the standard treatment for osteosarcoma (OS) over the last 25 years and there is an unmet need to identify new biomarkers and novel therapeutic approaches if outcomes are to improve. Furthermore, there is limited evidence on the impact of OS treatment on patient-reported outcomes (PROs). ICONIC (Improving Outcomes through Collaboration in Osteosarcoma; NCT04132895) is a prospective observational cohort study recruiting newly diagnosed OS patients across the United Kingdom (UK) with matched longitudinal collection of clinical, biological, and PRO data. During Stage 1, which assessed the feasibility of recruitment and data collection, 102 patients were recruited at 22 sites with representation from patient groups frequently excluded in OS studies, including patients over 50 years and those with less common primary sites. The feasibility of collecting clinical and biological samples, in addition to PRO data, has been established and there is ongoing analysis of these data as part of Stage 2. ICONIC will provide a unique, prospective cohort of newly diagnosed OS patients representative of the UK patient population, with fully annotated clinical outcomes linked to molecularly characterised biospecimens, allowing for comprehensive analyses to better understand biology and develop new biomarkers and novel therapeutic approaches.

Geographic Disparities in Availability of General and Specialized Pediatricians in the US and Prevalence of Childhood Neurodevelopmental Disorders.

General pediatricians and those specialized in developmental-behavioral and neurodevelopmental disabilities support children with neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). We identified substantial geographic disparities in pediatrician availability (eg, urban > rural areas), as well as regions with low pediatrician access but high ASD/ADHD prevalence estimates (eg, the US Southeast).

Sex differences in heat stress vulnerability among middle-aged and older adults (PSU HEAT project).

Individuals over the age of 65 are the most vulnerable population during severe environmental heat events, experiencing worse health outcomes than any other age cohort. The risk is greater in older women than in age-matched men; however, whether that reflects a greater susceptibility to heat in women or simply population sex proportionality is unclear. Seventy-two participants (29 M/43 F) aged 40-92 yrs were exposed to progressive heat stress at a metabolic rate designed to reflect activities of daily living. Experiments were conducted in both hot-dry (HD; up to 53°C; ≤25% rh) and warm-humid (WH; ~35°C; ≥50% rh) environments. After determining critical limits for each condition, forward stepwise multiple linear regression analyses were conducted with net metabolic rate (Mnet) and age entered into the model first, followed by sex, body mass (mb), V̇o2max, body surface area, and LDL cholesterol. After accounting for Mnet and age, sex further improved the regression model in the HD environment (R2adj = 0.34, p < 0.001) and WH environment (R2 adj = 0.36, P < 0.005). Sex explained approximately 15% of the variance in critical environmental limits in HD conditions and 12% in WH conditions. Heat compensability curves were shifted leftward for older women indicating age and sex-dependent heat vulnerability compared to middle-aged women and older men in WH (p=0.007, p=0.03) and HD (p=0.001, p=0.01) environments. This reflects the heterogeneity of thermal-balance thresholds associated with aging relative to those seen in young adults and suggests that older females are more vulnerable than their age-matched male counterparts.

Norovirus Management and Outcomes in a Multicenter Pediatric Kidney Transplant Population.

BACKGROUND: Norovirus is the most common cause of viral gastroenteritis. Studies in adult kidney recipients have documented significant morbidity associated with norovirus infection, but there are few studies in pediatric recipients. METHODS: Multicenter retrospective cohort study of pediatric kidney transplant recipients with norovirus, confirmed by stool PCR, between January 1, 2008, and December 31, 2018. Outcomes of interest included duration of diarrhea, incidence of chronic diarrhea, management strategies, and graft function. RESULTS: Forty pediatric kidney transplant recipients from four centers were identified for inclusion. Median age at transplant was 5.4 years (IQR 2.2-11.2 years), and median time post-transplant was 1.9 years (IQR 0.8-3.8 years). Median diarrheal duration was 16 days (IQR 6.0-41.5 days); 15 patients (43%) had acute diarrhea, 8 (23%) had persistent, and 12 (30%) had chronic diarrhea. Twenty-one (53%) patients developed acute kidney injury. Thirty-five (88%) patients required supplemental fluids, 8 (20%) patients underwent immunosuppression reduction for a median of 22 days, 5 (13%) were treated with nitazoxanide, and 5 (13%) received oral immunoglobulin. Acute rejection was diagnosed in 3 (8%) patients within 6 months of norovirus diagnosis. We observed no sustained decline in eGFR at 12 months after diarrhea resolution (median eGFR difference: 2.8 mL/min/1.73 m2 [IQR: -17.1, 7.4]). Of the patients in the cohort, two lost their graft at 6.8 and 30.0 months after the onset of diarrhea. CONCLUSION: Norovirus is associated with significant morbidity in pediatric kidney transplant recipients. Various treatment interventions are being employed for norovirus infection. Larger studies, both observational and interventional, are needed to determine the optimal treatment.

Machine learning classification of new firearm injury encounters in the St Louis region: 2010-2020.

OBJECTIVES: To improve firearm injury encounter classification (new vs follow-up) using machine learning (ML) and compare our ML model to other common approaches. MATERIALS AND METHODS: This retrospective study used data from the St Louis region-wide hospital-based violence intervention program data repository (2010-2020). We randomly selected 500 patients with a firearm injury diagnosis for inclusion, with 808 total firearm injury encounters split (70/30) for training and testing. We trained a least absolute shrinkage and selection operator (LASSO) regression model with the following predictors: admission type, time between firearm injury visits, number of prior firearm injury emergency department (ED) visits, encounter type (ED or other), and diagnostic codes. Our gold standard for new firearm injury encounter classification was manual chart review. We then used our test data to compare the performance of our ML model to other commonly used approaches (proxy measures of ED visits and time between firearm injury encounters, and diagnostic code encounter type designation [initial vs subsequent or sequela]). Performance metrics included area under the curve (AUC), sensitivity, and specificity with 95% confidence intervals (CIs). RESULTS: The ML model had excellent discrimination (0.92, 0.88-0.96) with high sensitivity (0.95, 0.90-0.98) and specificity (0.89, 0.81-0.95). AUC was significantly higher than time-based outcomes, sensitivity was slightly (but not significantly) lower than other approaches, and specificity was higher than all other methods. DISCUSSION: ML successfully delineated new firearm injury encounters, outperforming other approaches in ruling out encounters for follow-up. CONCLUSION: ML can be used to identify new firearm injury encounters and may be particularly useful in studies assessing re-injuries.

Predictors of Aneurysm Obliteration in Patients Treated with the WEB Device: Results of a Multicenter Retrospective Study.

BACKGROUND AND PURPOSE: Despite the numerous studies evaluating the occlusion rates of aneurysms following WEB embolization, there are limited studies identifying predictors of occlusion. Our purpose was to identify predictors of aneurysm occlusion and the need for retreatment. MATERIALS AND METHODS: This is a review of a prospectively maintained database across 30 academic institutions. We included patients with previously untreated cerebral aneurysms embolized using the WEB who had available intraprocedural data and long-term follow-up. RESULTS: We studied 763 patients with a mean age of 59.9 (SD, 11.7) years. Complete aneurysm occlusion was observed in 212/726 (29.2%) cases, and contrast stasis was observed in 485/537 (90.3%) of nonoccluded aneurysms. At the final follow-up, complete occlusion was achieved in 497/763 (65.1%) patients, and retreatment was required for 56/763 (7.3%) patients. On multivariable analysis, history of smoking, maximal aneurysm diameter, and the presence of an aneurysm wall branch were negative predictors of complete occlusion (OR, 0.5, 0.8, and 0.4, respectively). Maximal aneurysm diameter, the presence of an aneurysm wall branch, posterior circulation location, and male sex increase the chances of retreatment (OR, 1.2, 3.8, 3.0, and 2.3 respectively). Intraprocedural occlusion resulted in a 3-fold increase in the long-term occlusion rate and a 5-fold decrease in the retreatment rate (P < .001), offering a specificity of 87% and a positive predictive value of 85% for long-term occlusion. CONCLUSIONS: Intraprocedural occlusion can be used to predict the chance of long-term aneurysm occlusion and the need for retreatment after embolization with a WEB device. Smoking, aneurysm size, and the presence of an aneurysm wall branch are associated with decreased chances of successful treatment.

Changes in the wing shape and size in fruit flies exposed to micro and nanoplastics.

Geometric morphometrics analysis (GMA) is a well-known technique to identify minute changes in Drosophila wings. This study aimed to determine potential changes in Drosophila wings shape and size after exposure to polystyrene nanoplastics (NPs) (50 nm) and microplastics (MPs) (1 µm). Flies were exposed from eggs to pupal eclosion and analyzed using GMA. Results revealed a difference in shape and size between male and female wings, as expected, due to sexual dimorphism. Therefore, wings were analyzed by sex. Wings of MPs and NPs treated females were elongated compared to controls and had a constriction of the wing joint. Additionally, MPs treated female flies had the most dissimilar shape compared to controls. In male flies, NPs flies had smaller wings compared to MPs and control flies. Compared to control, NPs wings of males were shrunken at the joint and in the entire proximal region of the wing. However, male MPs wings had a narrower anal region and were slightly elongated. These results reveal that wing shape and size can change in a different way based on the sex of the flies and size of plastic particles that larvae interacted with. All the changes in the wings occurred only within the normally allowed wing variation and treatment with NPs/MPs did not cause development of the aberrant phenotypes. Results can pave the way for further understanding of how MPs and NPs can alter phenotypes of flies.

Qualitative analysis of preparation and planning habits of students with low-performance on high-stakes practice examinations (pre-NAPLEX®).

OBJECTIVE: The purpose of this analysis was to identify, analyze, and report patterns (or themes) of planning and preparation considerations of students that scored less than the historic average score on the Pre-NAPLEX® exam. METHODS: This qualitative study was a retrospective, inductive thematic analysis of de-identified semi-structured interview field notes collected from student interviews for those students that scored less than the historic average score on the Pre-NAPLEX® exam. RESULTS: Ninety-one students were initially contacted based on their score on the Pre-NAPLEX® exam to participate in one-on-one virtual discussions (i.e., interviews) with faculty members. Fifty-two responded and participated with their responses analyzed and included in thematic categorization. Four major themes were identified during the analysis. These include 1) Organization and Messaging of NAPLEX® Preparation Efforts, 2) Time Management during Competing Obligations, 3) Test Taking Experience, and 4) Curricular Disconnect. CONCLUSION: Student performance on the NAPLEX licensing exam is of great concern to many colleges of pharmacy. As a result, many institutions are looking at root-causes for poor performance and working to implement structural changes at their institution to address these concerns. This investigation identified four major themes surrounding the preparation and planning for the Pre-NAPLEX® for students that scored less than the historic average score on the Pre-NAPLEX®. These include 1) Organization and Messaging of NAPLEX® Preparation Efforts, 2) Time Management during Competing Obligations, 3) Test Taking Experience, and 4) Curricular Disconnect. Each of these themes provides potentially actionable items to improve how students prepare and plan for the Pre-NAPLEX®, which may be translatable to informing actions to improve results on the actual NAPLEX exam itself.

Lifestyle Behaviors and Needs After Breast Cancer Diagnosis: A Qualitative Assessment.

PURPOSE: There is a need to gain a deeper understanding of facilitators and barriers involving lifestyle behaviors among newly diagnosed breast cancer patients. Design: Research team explored influences (e.g., social, cultural, environmental) for healthy lifestyle behaviors (nutrition, physical activity (PA), and self-care). METHOD: One researcher conducted semi-structured interviews. Qualitative data were analyzed through content analysis. Demographic data were collected via survey, and descriptive statistics were generated. SETTING: Patients were recruited, and interviews conducted via Zoom or phone. PARTICIPANTS: Twenty-eight newly diagnosed, treatment naïve breast cancer patients were interviewed, a majority were non-Hispanic White women (n=23; 82%) with invasive (n=14; 50%) breast cancer. RESULTS: Themes related to nutrition, PA, and self-care emerged, including influences (e.g., environmental, cultural, social), barriers, facilitators, and lived experiences. Most patients stressed the importance of maintaining healthy eating habits (n=23), and some were interested in understanding the relationship between nutrition and cancer (n=7). Sixteen reported sustaining their PA levels, while others (n=11) explained barriers, such as time, distance, and pain. All patients reported utilizing self-care strategies, and most reported increased engagement in self-care since being diagnosed (n=14). CONCLUSION: This study sheds light on factors influencing and hindering the adoption of healthy eating, PA, and self-care strategies among newly diagnosed breast cancer patients. The findings reflect the importance of healthy lifestyle behaviors as critical areas for upstream intervention.

Tissue-specific effects of temperature and salinity on the cell cycle and apoptosis in the Nile Tilapia (Oreochromis niloticus).

The Nile Tilapia (Oreochromis niloticus) evolved in warm, freshwater rivers, but possesses a broad physiological tolerance to a range of environmental conditions. Due to this hardiness and resilience, this species has been successfully introduced to regions widely outside of its native range. Here, we examine the impact of temperature and salinity variation on this species at the sub-lethal level. Specifically, Nile Tilapia were exposed to two temperatures (21 °C or 14 °C) and three salinities (0, 16, 34 ppt) for 1-h. Given their native habitat, the 21 °C / 0 ppt exposure was considered the control condition. Both cell cycle arrest and apoptosis represent sub-lethal but deleterious responses to environmental stress. Flow cytometry was used to assess the percentage of cells in a given stage of the cell cycle as a metric of cell cycle arrest in spleen and liver. Percentage of apoptotic cells were also quantified. Spleen was more sensitive to cold stress, demonstrating an increase in cells in the G2/M phase after experimental treatment. Liver, however, was more sensitive to salinity stress, with a significant increase in cells stalled in G2/M phase at higher salinities, which is in keeping with the freshwater evolutionary history of the species. A modest apoptotic signal was observed in liver but not in spleen. Together, these findings demonstrate that even short, acute exposures to cold temperatures and elevated salinity can cause sub-lethal damage in a species that is otherwise tolerant of environmental stress at the whole organism level.

Prognostic value of myocardial deformation parameters for outcome prediction in tetralogy of Fallot.

INTRODUCTION: The prognostic value of myocardial deformation parameters in adults with repaired tetralogy of Fallot (rTOF) has not been well-elucidated. We therefore aimed to explore myocardial deformation parameters for outcome prediction in adults with rTOF using cardiovascular magnetic resonance imaging (CMR). METHODS: Adults with rTOF and at least moderate pulmonary regurgitation (PR) were identified from an institutional prospective CMR registry. Left (LV) and right ventricular (RV) global strain were recorded in longitudinal (GLS), circumferential (GCS) and radial (GRS) directions. Major adverse cardiovascular events (MACE) were defined as a composite of mortality, resuscitated sudden death, sustained ventricular tachycardia (>30seconds) or heart failure (hospital admission >24hours). In patients with pulmonary valve replacement (PVR), pre-and post-PVR CMR studies were analysed to assess for predictors of complete RV reverse remodelling, which we defined as RV end-diastolic volume indexed (RVEDVi) <110ml/m2. Logistic regression models were used to estimate the odds ratio (OR) per unit change in absolute strain value associated with clinical outcomes and receiver operator characteristic (ROC) curves were constructed with area under the curve (AUC) for select CMR variables. RESULTS: We included 307 patients (age 35±13 years, 59% male). During 6.1 years (3.3-8.8) of follow-up, pulmonary valve replacement (PVR) was performed in 142 (46%) and MACE occurred in 31 (10%). On univariate analysis, baseline biventricular ejection fraction (EF), mass and all strain parameters were associated with MACE. After adjustment for LVEF, only LVGLS remained independently predictive of MACE (OR 0.822 [0.693-0.976] p=0.025). Receiver operator curves identified an absolute LVGLS value less than 15 and LVEF <51% as thresholds for MACE prediction (AUC 0.759 [0.655-0.840] and 0.720 [0.608-0.810]). After adjusting for baseline RVEDVi, RVGCS (OR 1.323 [1.094-1.600] p=0.004), LVGCS (OR 1.276 [1.029-1.582] p=0.027) and LVGRS (OR 1.101 [1.0210-1.200], p=0.028) were independent predictors of complete remodelling post-PVR remodelling. CONCLUSIONS: Biventricular strain parameters predict clinical outcomes and post-PVR remodelling in rTOF. Further study will be necessary to establish the role of myocardial deformation parameters in clinical practice.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

IL-10 inhibition during immunization improves vaccine-induced protection against Staphylococcus aureus infection.

Staphylococcus aureus is a major human pathogen. An effective anti-S. aureus vaccine remains elusive as the correlates of protection are ill-defined. Targeting specific T cell populations is an important strategy for improving anti-S. aureus vaccine efficacy. Potential bottlenecks that remain are S. aureus-induced immunosuppression and the impact this might have on vaccine-induced immunity. S. aureus induces IL-10, which impedes effector T cell responses, facilitating persistence during both colonization and infection. Thus, it was hypothesized that transient targeting of IL-10 might represent an innovative way to improve vaccine efficacy. In this study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, and this was associated with reduced systemic S. aureus-specific Th1 responses. This suggests that systemic responses are remodeled because of commensal exposure to S. aureus, which negatively implicates vaccine function. To provide proof of concept that targeting immunosuppressive responses during immunization may be a useful approach to improve vaccine efficacy, we immunized mice with T cell-activating vaccines in combination with IL-10-neutralizing antibodies. Blocking IL-10 during vaccination enhanced effector T cell responses and improved bacterial clearance during subsequent systemic and subcutaneous infection. Taken together, these results reveal a potentially novel strategy for improving anti-S. aureus vaccine efficacy.

Variant patterns of electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging.

AIMS: Although electrical activity of the normal human heart is well characterized by the electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using non-invasive electrocardiographic imaging (ECGI) as a basis to better understand pathology. METHODS AND RESULTS: Epicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles [left ventricle (LV) and right ventricle (RV)], sexes, and age groups (<50/≥50years). Pearson's correlation coefficient (CC) was used for within-subject and between-subject comparisons. Age of normal subjects averaged 49 ± 14 years, 6/22 were male, and no structural/electrical heart disease was present. The average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males. Median CCs of between-subject comparisons of the ECG signals, activation, and recovery patterns were 0.61, 0.32, and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89, and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population. CONCLUSION: Activation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression, and treatment of electrical heart disease.

Immune gene regulation is associated with age and environmental adversity in a nonhuman primate.

Phenotypic aging is ubiquitous across mammalian species, suggesting shared underlying mechanisms of aging. Aging is linked to molecular changes to DNA methylation and gene expression, and environmental factors, such as severe external challenges or adversities, can moderate these age-related changes. Yet, it remains unclear whether environmental adversities affect gene regulation via the same molecular pathways as chronological, or 'primary', aging. Investigating molecular aging in naturalistic animal populations can fill this gap by providing insight into shared molecular mechanisms of aging and the effects of a greater diversity of environmental adversities - particularly those that can be challenging to study in humans or laboratory organisms. Here, we characterised molecular aging - specifically, CpG methylation - in a sample of free-ranging rhesus macaques living off the coast of Puerto Rico (n samples = 571, n individuals = 499), which endured a major hurricane during our study. Age was associated with methylation at 78,661 sites (31% of all sites tested). Age-associated hypermethylation occurred more frequently in areas of active gene regulation, while hypomethylation was enriched in regions that show less activity in immune cells, suggesting these regions may become de-repressed in older individuals. Age-associated hypomethylation also co-occurred with increased chromatin accessibility while hypermethylation showed the opposite trend, hinting at a coordinated, multi-level loss of epigenetic stability during aging. We detected 32,048 CpG sites significantly associated with exposure to a hurricane, and these sites overlapped age-associated sites, most strongly in regulatory regions and most weakly in quiescent regions. Together, our results suggest that environmental adversity may contribute to aging-related molecular phenotypes in regions of active gene transcription, but that primary aging has specific signatures in non-regulatory regions.

Elevated Metal Levels in U.S. Honeys: Is There a Concern for Human Health?

Honey is a bioactive food used for millennia to improve health and treat diseases. More recently, researchers employ honey as a tool to assess local environmental pollution. Honeybees effectively 'sample' their environment within a ~ 7 km radius, actively collecting nectar, pollen, and water to bring to their hive. Foraging honeybees also sample the air as dust particles accumulate on their pubescence, adding to the hive's contaminant load. Many studies from around the world report elevated metal levels in honey, with the most reports from Iran, Italy, and Turkey, but only two reports have measured metal levels in honey from the United States (U.S.). We report levels of 20 metals from 28 honeys collected from 15 U.S. states between 2022-2023. We then focus on four toxic metals recognized as hazards in foodstuffs when the concentrations are above safety recommendations - lead, cadmium, arsenic, and mercury. Two of these metals (lead and mercury) are regulated in honey by the European Union (EU), though the U.S. currently lacks defined regulations for metal levels in honey. We consider the levels of these toxic metals by state, then compare the U.S. mean honey level for these metals against the provisional tolerable weekly intake (PTWI). Our results suggest U.S. honey have levels metal that exceed the PWTI and EU regulations and may be hazardous to human health. Further research is needed to determine if the effects of these toxic metal at measured levels outweigh the health benefits from consumption of honey.

Reversal of cerebral ischaemia and hypoxia and of sickness behaviour by megadose sodium ascorbate in ovine Gram-negative sepsis.

BACKGROUND: The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis. METHODS: Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg-1 over 30 min+0.5 g kg-1 h-1 for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70-80 mm Hg. RESULTS: At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] µM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all PTreatment<0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both PGroupxTime<0.01), and increased plasma ascorbate (20 000 [300] µM; PGroup<0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate. CONCLUSIONS: Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.