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Background Traditionally, conventional radiography has been used to identify the structural damage associated with juvenile idiopathic arthritis (JIA). As other modalities have developed, however, the practice of assessing and monitoring JIA with radiographs has been questioned.Objective The purpose of this study was to examine the current best practices for imaging JIA and to assess various imaging modalities.Method A literature review was conducted to examine to what extent radiography, magnetic resonance (MR) imaging, ultrasonography and computed tomography (CT) aid in diagnosing and managing JIA, and the benefits and limitations of each modality.Conclusion No single modality meets every imaging need at this time, but methods for detecting JIA are dramatically improving. Diagnostic radiography, MR imaging, ultrasonography and CT all play an important role in diagnosing or monitoring JIA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: For healthcare providers, witnessed cardiopulmonary resuscitation (CPR) is controversial. However, little is known about the public's stance on this issue. This study was performed to develop insight concerning the general public's thoughts about witnessed CPR. DESIGN: A random telephone survey. SETTING: Rural southwest Pennsylvania. SUBJECTS: Four hundred and eight respondents, >/=18 yrs old, residing in Conemaugh Health System's Memorial Medical Center's service area. INTERVENTIONS:: Demographic information was gathered concerning the respondents, who rated their level of agreement with questions concerning witnessed resuscitation. MEASUREMENTS AND MAIN RESULTS: Of the respondents, 49.3% desired to be present while CPR is performed on a loved one. Respondents desiring CPR were more apt to believe that significant others have a right to be present during CPR (p = .010) and want significant others present with them while undergoing CPR than those declining CPR (p < .001). Respondents desiring CPR felt more strongly that the presence of family or friends during CPR would benefit the patient (p = .022). The desire to be present in the room with a loved one during CPR did not reach statistical significance (p = .275) between the two groups, nor did the belief that that being present would benefit family and friends (p = .093). Of the respondents, 43% believed that the physician should have the most authority in making decisions about witnessed resuscitation, 40% believed that the patient should have the most authority, and 17% believed that family and friends should have the most authority (p < .001). Those who believed that family and friends should have the most authority were more favorable toward witnessed resuscitation than were those who believed that either the patient or the physician should have the most authority. CONCLUSIONS: This study offers insights into the public's attitude concerning witnessed resuscitation. A large segment of the population desires the presence of significant others during CPR and conversely want to be with loved ones during CPR. Further studies should investigate the public's attitude in more diverse settings, and formal programs to accommodate those who wish to remain together during CPR should be developed. [ABSTRACT FROM AUTHOR]

Renal transplantation is the preferred treatment for patients with chronic renal failure. The causes of renal transplant dysfunction include perinephric fluid collections, vascular complications, hydronephrosis, and rejection. Ultrasound examination provides valuable information regarding the cause of graft dysfunction. Postoperative complications can be assessed using gray-scale and Doppler ultrasound. Sonography is also useful in renal biopsy to determine the precise cause of graft dysfunction. [ABSTRACT FROM AUTHOR]

Sonohysterography is a noninvasive procedure that uses fluid to artificially distend the uterine cavity. The fluid fills the endometrial cavity, allowing visualization of any pathology that might be present. Sonohysterography is not difficult to perform and is usually well-tolerated by the patient. It provides valuable information to the physician, and may prove other, more invasive, procedures unnecessary. [ABSTRACT FROM AUTHOR]

Abstract Background Humans and rodents with impaired phytanic acid (PA) metabolism can accumulate toxic stores of PA that have deleterious effects on multiple organ systems. Ruminants and certain fish obtain PA from the microbial degradation of dietary chlorophyll and/or through chlorophyll-derived precursors. In contrast, humans cannot derive PA from chlorophyll and instead normally obtain it only from meat, dairy, and fish products. Results Captive apes and Old world monkeys had significantly higher red blood cell (RBC) PA levels relative to humans when all subjects were fed PA-deficient diets. Given the adverse health effects resulting from PA over accumulation, we investigated the molecular evolution of thirteen PA metabolism genes in apes, Old world monkeys, and New world monkeys. All non-human primate (NHP) orthologs are predicted to encode full-length proteins with the marmoset Phyh gene containing a rare, but functional, GA splice donor dinucleotide. Acox2, Scp2, and Pecr sequences had amino acid positions with accelerated substitution rates while Amacr had significant variation in evolutionary rates in apes relative to other primates. Conclusions Unlike humans, diverse captive NHPs with PA-deficient diets rich in plant products have substantial RBC PA levels. The favored hypothesis is that NHPs can derive significant amounts of PA from the degradation of ingested chlorophyll through gut fermentation. If correct, this raises the possibility that RBC PA levels could serve as a biomarker for evaluating the digestive health of captive NHPs. Furthermore, the evolutionary rates of the several genes relevant to PA metabolism provide candidate genetic adaptations to NHP diets.

Abstract Background Dysregulation of microRNA (miRNA) expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis. Results Using Next Generation Illumina sequencing methods, we sequenced hepatic small RNA libraries from baboons differing in their LDL-C response to a high-cholesterol, high-fat (HCHF) challenge diet (low LDL-C, n = 3; high LDL-C, n = 3), resulting in 517 baboon miRNAs: 490 were identical to human miRNAs and 27 were novel. We compared miRNA expression profiles from liver biopsies collected before and after the challenge diet and observed that HCHF diet elicited expression of more miRNAs compared to baseline (chow) diet for both low and high LDL-C baboons. Eighteen miRNAs exhibited differential expression in response to HCHF diet in high LDL-C baboons compared to 10 miRNAs in low LDL-C baboons. We used TargetScan/Base tools to predict putative miRNA targets; miRNAs expressed in high LDL-C baboons had significantly more gene targets than miRNAs expressed in low LDL-C responders. Further, we identified miRNA isomers and other non-coding RNAs that were differentially expressed in response to the challenge diet in both high LDL-C and low LDL-C baboons. Conclusions We sequenced and annotated baboon liver miRNAs from low LDL-C and high LDL-C responders using high coverage Next Gen sequencing methods, determined expression changes in response to a HCHF diet challenge, and predicted target genes regulated by the differentially expressed miRNAs. The identified miRNAs will enrich the database for non-coding small RNAs including the extent of variation in these sequences. Further, we identified other small non-coding RNAs differentially expressed in response to diet. Our discovery of differentially expressed baboon miRNAs in response to a HCHF diet challenge that differ by LDL-C phenotype is a fundamental step in understating the role of non-coding RNAs in dyslipidemia.

Abstract Background MicroRNAs (miRNAs) are small noncoding RNAs (~22 nucleotides) that regulate gene expression by cleaving mRNAs or inhibiting translation. The baboon is a well-characterized cardiovascular disease model; however, no baboon miRNAs have been identified. Evidence indicates that the baboon and human genomes are highly conserved; based on this conservation, we hypothesized that comparative genomic methods could be used to identify baboon miRNAs. Methods We employed an in silico comparative genomics approach and human miRNA arrays to identify baboon expressed miRNAs in liver (n = 6) and lymphocytes (n = 6). Expression profiles for selected miRNAs in multiple tissues were validated by RT-PCR. Results We identified in silico 555 putative baboon pre-miRNAs, of which 41% exhibited 100% identity and an additional 58% shared more than 90% sequence identity with human pre-miRNAs. Some of these miRNAs are primate-specific and are clustered in the baboon genome like human miRNA clusters. We detected expression of 494 miRNAs on the microarray and validated expression of selected miRNAs in baboon liver and lymphocytes by RT-PCR. We also observed miRNA expression in additional tissues relevant to dyslipidemia and atherosclerosis. Approximately half of the miRNAs expressed on the array were not predicted in silico suggesting that we have identified novel baboon miRNAs, which could not be predicted using the current draft of the baboon genome. Conclusion We identified a subset of baboon miRNAs using a comparative genomic approach, identified additional baboon miRNAs using a human array and showed tissue-specific expression of baboon miRNAs. Our discovery of baboon miRNAs in liver and lymphocytes will provide resources for studies on the roles of miRNAs in dyslipidemia and atherosclerosis, and for translational studies.

Abstract Background Carboxylesterases (CES) perform diverse metabolic roles in mammalian organisms in the detoxification of a broad range of drugs and xenobiotics and may also serve in specific roles in lipid, cholesterol, pheromone and lung surfactant metabolism. Five CES families have been reported in mammals with human CES1 and CES2 the most extensively studied. Here we describe the genetics, expression and phylogeny of CES isozymes in the opossum and report on the sequences and locations of CES1, CES2 and CES6 'like' genes within two gene clusters on chromosome one. We also discuss the likely sequence of gene duplication events generating multiple CES genes during vertebrate evolution. Results We report a cDNA sequence for an opossum CES and present evidence for CES1 and CES2 like genes expressed in opossum liver and intestine and for distinct gene locations of five opossum CES genes,CES1, CES2.1, CES2.2, CES2.3 and CES6, on chromosome 1. Phylogenetic and sequence alignment studies compared the predicted amino acid sequences for opossum CES with those for human, mouse, chicken, frog, salmon and Drosophila CES gene products. Phylogenetic analyses produced congruent phylogenetic trees depicting a rapid early diversification into at least five distinct CES gene family clusters: CES2, CES1, CES7, CES3, and CES6. Molecular divergence estimates based on a Bayesian relaxed clock approach revealed an origin for the five mammalian CES gene families between 328–378 MYA. Conclusion The deduced amino acid sequence for an opossum cDNA was consistent with its identity as a mammalian CES2 gene product (designated CES2.1). Distinct gene locations for opossum CES1 (1: 446,222,550–446,274,850), three CES2 genes (1: 677,773,395–677,927,030) and a CES6 gene (1: 677,585,520–677,730,419) were observed on chromosome 1. Opossum CES1 and multiple CES2 genes were expressed in liver and intestine. Amino acid sequences for opossum CES1 and three CES2 gene products revealed conserved residues previously reported for human CES1 involved in catalysis, ligand binding, tertiary structure and organelle localization. Phylogenetic studies indicated the gene duplication events which generated ancestral mammalian CES genes predated the common ancestor for marsupial and eutherian mammals, and appear to coincide with the early diversification of tetrapods.

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Sex-specific Kaplan-Meier survival curves were computed in 12 translational aging models: baboon, bonnet macaque, chimpanzee, common marmoset, coppery titi monkey, cotton-top tamarin, cynomolgus macaque, Japanese macaque, pigtail macaque, rhesus macaque, squirrel monkey, and vervet/African green. After employing strict inclusion criteria, primary results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. Results show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan since research NHP are typically euthanized for humane welfare reasons before their natural end of life. This resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. These results clarify relationships among NHP ages and provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of expected survival rates, providing a metric for comparisons in future studies, and contributing to understanding of factors driving lifespan differences within and among species.

Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum . MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

This post-hoc analysis of the ALLEGRO phase 2b/3 study (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral Janus kinase 3/TEC family kinase inhibitor, in patients with alopecia totalis (AT) and alopecia universalis (AU). Patients aged ≥ 12 years with alopecia areata (AA) and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (± 4-week 200-mg loading dose) or placebo for 24 weeks. In a subsequent 24-week extension period, the ritlecitinib groups continued their doses and patients initially assigned to placebo switched to ritlecitinib (200/50 or 50 mg daily). In this analysis, clinician- and patient-reported hair regrowth outcomes were assessed at weeks 24 and 48 in four AA subgroups: AT/AU, AT, AU, and non-AT/AU. Safety was monitored throughout. Of the 718 randomized patients, 151 (21%) and 147 (20%) were defined as having AT or AU, respectively. At week 24, Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp hair loss) response rates were higher in the ritlecitinib-treated AT/AU, AT, and AU groups (7%-14%, 7%-21%, and 4%-10%, respectively) vs the placebo group (0% in the AT/AU, AT, and AU groups). The proportions of patients with a SALT score of ≤20 increased through week 48 (AT/AU, 13%-31%; AT, 11%-27%; AU, 6%-41%). Additionally, at week 24, 25%-43%, 32%-42%, and 12%-50% of patients with AT/AU, AT, and AU, respectively, who received ritlecitinib achieved a moderately or greatly improved response based on the Patient Global Impression of Change scale. Response rates generally increased through week 48 and were similar across AA subgroups. In patients with AT/AU, ritlecitinib was well tolerated with a safety profile consistent with that of the overall AA population. Ritlecitinib demonstrated clinical efficacy, patient-reported improvement, and an acceptable safety profile in patients with AT and AU through week 48. A plain language summary of this study is available at https://doi.org/10.25454/pfizer.figshare.26879161. Clinicaltrials.gov: NCT03732807., (© 2024 Pfizer Inc. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

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.

Many recent articles in public health risk assessment have stated that causal conclusions drawn from observational data must rely on inherently untestable assumptions. They claim that such assumptions ultimately can only be evaluated by informed human judgments. We call this the subjective approach to causal interpretation of observational results. Its theoretical and conceptual foundation is a potential outcomes model of causation in which counterfactual outcomes cannot be observed. It risks depriving decision-makers and the public of the key benefits of traditional objective science, which invites scrutiny and independent verification through testable causal models and interventional hypotheses. We introduce an alternative objective approach to causal analysis of exposure-response relationships in observational data. This is designed to be more objective in the specific sense that it is independently verifiable (or refutable) and data-driven, requiring no inherently untestable assumptions. This approach uses empirically testable interventional causal models, specifically causal Bayesian networks (CBNs), instead of untestable potential outcomes models. It enables empirical validation of causal claims through Invariant Causal Prediction (ICP) tests across multiple studies. We explain how to use CBNs and individual conditional expectation (ICE) plots to quantify the effects on health risks of changing exposures while taking into account realistic complexities such as imperfectly controlled confounding, missing data, and measurement error. By ensuring that all causal assumptions are explicit and empirically testable, our framework may help to improve the reliability and transparency of causal inferences in health risk assessments.

Metabolic conversion of benzene (Bz) is thought to be required for the hematotoxic effects observed following Bz exposures. Most safe exposure limits set for Bz utilize epidemiology data on the hematotoxic effects of Bz for the dose-response assessments. These hematotoxic effects occurred among workers exposed to elevated Bz levels, thus dose extrapolation is required for assessing relevant risks for populations exposed orders of magnitude lower. Thus, understanding how Bz is metabolized over a wide range of air Bz levels is an important topic for risk assessments for Bz. Here, we analyze biomonitoring data for workers exposed to Bz to make evaluations of how the metabolism of Bz varies across a wide range of exposures. Our analysis indicates that the presence of metabolites derived from exposures to sources other than Bz (nonspecific metabolites of Bz) are significant confounders among biomonitoring studies and this precludes making any assessments of how Bz metabolism differs below approximately 3 ppm air Bz exposures using such nonspecific metabolites.

Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H 2 O 2 ), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Mitochondria play a crucial role in brain aging due to their involvement in bioenergetics, neuroinflammation and brain steroid synthesis. Mitochondrial dysfunction is linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. Using a novel approach, we assessed mitochondrial bioenergetics from frozen prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when activities were normalized for citrate synthase activity, suggesting that the decline in respiration is predominantly driven by changes in the specific activity of individual complexes rather than changes in mitochondrial number. Moreover, when donor sex was used as a covariate, we found that mitochondrial respiration was preserved with age in females, whereas males showed significant loss of ETC activity with age. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity relative to females. Circulating cortisol levels correlated only with complex II-linked respiration in males. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a previously unknown link between aging and bioenergetics across multiple tissues linking frailty and bioenergetic function. This study highlights a potential molecular mechanism for sexual dimorphism in brain resilience and suggests that in males changes in PFC bioenergetics contribute to reduced motor function with age., Competing Interests: Competing Interest The authors declare no competing interest.

The use of unverified models for risk estimates and policy recommendations can be highly misleading, as their predictions may not reflect real-world health impacts. For example, a recent article states that NO 2 from gas stoves "likely causes ∼50,000 cases of current pediatric asthma from long-term NO 2 exposure alone" annually in the United States. This explicitly causal claim, which is contrary to several methodology and review articles published in this journal, among others, reflects both (a) An unverified modeling assumption that pediatric asthma burden is approximately proportional to NO 2 ; and (b) An unverified causal assumption that the assumed proportionality between exposure and response is causal. The article is devoid of any causal analysis showing that these assumptions are likely to be true. It does not show that reducing NO 2 exposure from gas stoves would reduce pediatric asthma risk. Its key references report no significant associations - let alone causation - between NO 2 and pediatric asthma. Thus, the underlying data suggests that the number of pediatric asthma cases caused by gas stoves in the United States is indistinguishable from zero. This highlights the need to rigorously validate modeling assumptions and causal claims in public health risk assessments to ensure scientifically sound foundations for policy decisions., Competing Interests: I declare no competing interests that could influence the work presented in this manuscript. Funding for this work was provided by Cox Associates, LLC. Cox Associates has reasonable expectation of receiving funds in the future from the American Gas Association (AGA) to cover part of the cost of writing up these comments and/or defraying open access charges. Cox Associates has also previously received support from the 10.13039/100000199United States Department of Agriculture (USDA) for research on statistical methods for causal analysis of observational and interventional data. The author has previously received support from the USEPA for a part of the work related to duties related to NAAQS reviews. The research questions, methods, and conclusions are solely those of the author and do not necessarily reflect the views of any funding organizations., (© 2024 The Author.)

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829., (© 2024. The Author(s).)

The marmoset is a fundamental nonhuman primate model for the study of aging, neurobiology, and many other topics. Genetic management of captive marmoset colonies is complicated by frequent chimerism in the blood and other tissues, a lack of tools to enable cost-effective, genome-wide interrogation of variation, and historic mergers and migrations of animals between colonies. We implemented genotype-by-sequencing (GBS) of hair follicle derived DNA (a minimally chimeric DNA source) of 82 marmosets housed at the Southwest National Primate Research Center (SNPRC). Our primary goals were the genetic characterization of our marmoset population for pedigree verification and colony management and to inform the scientific community of the functional genetic makeup of this valuable resource. We used the GBS data to reconstruct the genetic legacy of recent mergers between colonies, to identify genetically related animals whose relationships were previously unknown due to incomplete pedigree information, and to show that animals in the SNPRC colony appear to exhibit low levels of inbreeding. Of the >99,000 single-nucleotide variants (SNVs) that we characterized, >9800 are located within gene regions known to harbor pathogenic variants of clinical significance in humans. Overall, we show the combination of low-resolution (sparse) genotyping using hair follicle DNA is a powerful strategy for the genetic management of captive marmoset colonies and for identifying potential SNVs for the development of biomedical research models., (© 2024 Wiley Periodicals LLC.)

Debate exists on life-course adrenocortical zonal function trajectories. Rapid, phasic blood steroid concentration changes, such as circadian rhythms and acute stress responses, complicate quantification. To avoid pitfalls and account for life-stage changes in adrenocortical activity indices, we quantified zonae fasciculata (ZF) and reticularis (ZR) across the life-course, by immunohistochemistry of key regulatory and functional proteins. In 28 female baboon adrenals (7.5-22.1 years), we quantified 12 key proteins involved in cell metabolism, division, proliferation, steroidogenesis (including steroid acute regulatory protein, StAR), oxidative stress, and glucocorticoid and mitochondrial function. Life-course abundance of ten ZF proteins decreased with age. Cell cycle inhibitor and oxidative stress markers increased. Seven of the 12 proteins changed in the same direction for ZR and ZF. Importantly, ZF StAR decreased, while ZR StAR was unchanged. Findings indicate ZF function decreased, and less markedly ZR function, with age. Causes and aging consequences of these changes remain to be determined., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Introduction: Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define interventional probability of causation (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of causal assigned share (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed. Traditional approaches used to evaluate the preventable risk implications of epidemiological associations, including population attributable fraction (PAF) and the Bradford Hill considerations, cannot reveal whether removing a risk factor would reduce disease incidence. We argue that modern formal causal models coupled with causal artificial intelligence (CAI) and realistically partial and imperfect knowledge of underlying disease mechanisms, show great promise for determining and quantifying IPoC and CAS for exposures and diseases of practical interest., Methods: We briefly review key CAI concepts and terms and then apply them to define IPoC and CAS. We present steps to quantify IPoC using a fully specified causal Bayesian network (BN) model. Useful bounds for quantitative IPoC and CAS calculations are derived for a two-stage clonal expansion (TSCE) model for carcinogenesis and illustrated by applying them to benzene and formaldehyde based on available epidemiological and partial mechanistic evidence., Results: Causal BN models for benzene and risk of acute myeloid leukemia (AML) incorporating mechanistic, toxicological and epidemiological findings show that prolonged high-intensity exposure to benzene can increase risk of AML (IPoC of up to 7e-5, CAS of up to 54%). By contrast, no causal pathway leading from formaldehyde exposure to increased risk of AML was identified, consistent with much previous mechanistic, toxicological and epidemiological evidence; therefore, the IPoC and CAS for formaldehyde-induced AML are likely to be zero., Conclusion: We conclude that the IPoC approach can differentiate between likely and unlikely causal factors and can provide useful upper bounds for IPoC and CAS for some exposures and diseases of practical importance. For causal factors, IPoC can help to estimate the quantitative impacts on health risks of reducing exposures, even in situations where mechanistic evidence is realistically incomplete and individual-level exposure-response parameters are uncertain. This illustrates the strength that can be gained for causal inference by using causal models to generate testable hypotheses and then obtaining toxicological data to test the hypotheses implied by the models-and, where necessary, refine the models. This virtuous cycle provides additional insight into causal determinations that may not be available from weight-of-evidence considerations alone.

Steady-state expression quantitative trait loci (eQTLs) explain only a fraction of disease-associated loci identified through genome-wide association studies (GWASs), while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Using a baboon model, we found hundreds of eQTLs that emerge in adipose, liver, and muscle after prolonged exposure to high dietary fat and cholesterol. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using non-human primate models., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Despite strengthening HIV prevention with the introduction of pre-exposure prophylaxis (PrEP), STI services have remained relatively unchanged and the standard of care remains syndromic management. We used a discrete choice experiment to investigate service users' preferences for the diagnosis and treatment of STIs in South Africa., Methods: Between 1 March 2021 and 20 April 2021, a cross-sectional online questionnaire hosted on REDCap was administered through access links sent to WhatsApp support groups for HIV PrEP users and attendees of two primary healthcare clinics and two mobile facilities in the Eastern Cape and Gauteng provinces aged between 18 and 49 years. Participants either self-completed the questionnaire or received support from a research assistant. We used a conditional logit model for the initial analysis and latent class model (LCM) to establish class memberships, with results displayed as ORs and probabilities., Results: We enrolled 496 individuals; the majority were female (69%) and <30 years (74%). The LCM showed two distinct groups. The first group, comprising 68% of the participants, showed a strong preference for self-sampling compared with no sampling (OR 2.16, 95% CI 1.62 to 2.88). A clinic follow-up appointment for treatment was less preferable to same-day treatment (OR 0.78, 95% CI 0.63 to 0.95). Contact slip from index patient (OR 0.86, 95% CI 0.76 to 0.96) and healthcare professional (HCP)-initiated partner notification (OR 0.63, 95% CI 0.55 to 0.73) were both less preferable than expedited partner treatment (EPT). The second group included 32% of participants with a lower preference for self-sampling compared with no sampling (OR 0.65, 95% CI 0.41 to 1.04). There was no treatment option that was significantly different from the others; however, there was a strong preference for HCP-initiated partner notification to EPT (OR 1.53, 95% CI 1.10 to 2.12)., Conclusions: Our results suggest that service users preferred STI testing prior to treatment, with the majority preferring self-taken samples and receiving aetiology-based treatment on the same day., Competing Interests: Competing interests: CI has received conference support and research grants from Gilead Sciences., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Drawing sound causal inferences from observational data is often challenging for both authors and reviewers. This paper discusses the design and application of an Artificial Intelligence Causal Research Assistant (AIA) that seeks to help authors improve causal inferences and conclusions drawn from epidemiological data in health risk assessments. The AIA-assisted review process provides structured reviews and recommendations for improving the causal reasoning, analyses and interpretations made in scientific papers based on epidemiological data. Causal analysis methodologies range from earlier Bradford-Hill considerations to current causal directed acyclic graph (DAG) and related models. AIA seeks to make these methods more accessible and useful to researchers. AIA uses an external script (a "Causal AI Booster" (CAB) program based on classical AI concepts of slot-filling in frames organized into task hierarchies to complete goals) to guide Large Language Models (LLMs), such as OpenAI's ChatGPT or Google's LaMDA (Bard), to systematically review manuscripts and create both (a) recommendations for what to do to improve analyses and reporting; and (b) explanations and support for the recommendations. Review tables and summaries are completed systematically by the LLM in order. For example, recommendations for how to state and caveat causal conclusions in the Abstract and Discussion sections reflect previous analyses of the Study Design and Data Analysis sections. This work illustrates how current AI can contribute to reviewing and providing constructive feedback on research documents. We believe that such AI-assisted review shows promise for enhancing the quality of causal reasoning and exposition in epidemiological studies. It suggests the potential for effective human-AI collaboration in scientific authoring and review processes., Competing Interests: The research presented here was supported by the author's employer, Cox Associates. Cox Associates received seed funding from the American Chemistry Council in 2022 and 2023 to develop the core ideas and technology for the AI Causal Research Assistant (AIA) and its application to reviewing documents, as described in this paper. All research questions, technical approaches and innovations, example, and conclusions are solely those of the author. 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., (© 2023 Published by Elsevier Inc.)

South Africa has a high incidence of human immunodeficiency virus and sexually transmitted infections (STIs), particularly among adolescent girls and young women. National and global guidelines recommend varied strategies for integrating STI and pre-exposure prophylaxis (PrEP) services., Purpose: This paper describes the implementation of a syndromic compared to an etiological approach to STI integration within PrEP services in South Africa., Methods: We analysed program data from eight fixed and four mobile clinics to describe a cascade of STI care and integration of syndromic management among clients accessing PrEP services. Diagnostic testing was conducted in a subset of clients to determine the prevalence of STIs and estimate the burden of disease missed using a syndromic approach., Results: Between December 2018 and December 2021, 22,505 clients sought services and a high proportion (92.9%) was screened for STI symptoms. Of these, 9% of females and 3% of males had symptoms and 89.5% had recorded treatment. In a subset of PrEP clients (406 females, 70 males) screened through laboratory testing, chlamydia was identified in 25.7% of female and 20.0% of male samples, gonorrhea in 14.1% of female and 18.6% of male samples, and syphilis in 2.3% of female and 1.4% of male samples. Highest prevalence was found among females aged 18-20 years., Discussion: Syndromic STI screening and management can be integrated into routine PrEP service delivery and can identify symptomatic STIs, but misses asymptomatic infections. PrEP clients have a high prevalence of treatable STIs. Etiologic approaches can identify more infections than syndromic screening, but cheap point-of-care tests are needed., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: This study describes the patterns of pre-exposure prophylaxis (PrEP) use among adolescent girls and young women (AGYW) initiated on daily oral PrEP for the prevention of HIV, within routine sexual and reproductive health services in South Africa., Methods: We analysed clinical and survey data from a nested cohort of 967 AGYW initiated on oral PrEP between January 2019 and December 2021 in four geographical clusters in South Africa. We describe the periods of PrEP use, and the proportion who discontinued and subsequently restarted PrEP. Logistic regression analyses were conducted to determine factors associated with early PrEP discontinuation, PrEP use for ≥4 months and PrEP restart., Results: PrEP use for ≤1 month was high (68.6%), although 27% returned and restarted PrEP; and 9% restarted more than once. Initiating PrEP at a mobile clinic (AOR 2.10, 95% CI 1.51 - 2.93) and having a partner known to be HIV negative or whose HIV status was unknown (AOR 7.11, 95% CI 1.45 - 34.23; AOR 6.90, 95% CI 1.44 - 33.09) were associated with PrEP use for ≤1 month. AGYW receiving injectable contraceptives were more likely to restart PrEP (AOR 1.61, 95% CI 1.10 - 2.35). Compared to those aged 15-17 years, participants 18 - 20 and 21 - 24 years were less likely to restart PrEP (AOR 0.51, 95% CI 0.35 - 0.74; AOR 0.60, 95%, CI 0.41 - 0.87), as were those initiating PrEP at a mobile clinic compared to a fixed facility (AOR 0.66, 95% CI 0.47 - 0.92)., Discussion: Although early PrEP discontinuation was high, it appears that PrEP use is frequently cyclical in nature. Further research is needed to determine if these cycles of PrEP correlate to periods of perceived or actual vulnerability to HIV, which may also be cyclical. PrEP delivery presents a unique opportunity to address multiple unmet health needs of young people., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Poor mental health is associated with sexual and reproductive health (SRH) risks, including human immunodeficiency virus (HIV) and pre-exposure prophylaxis discontinuation. Adolescents and young people (AYP) are vulnerable to HIV and depression. This paper describes the prevalence and severity of depression and associated factors in AYP accessing SRH services in South Africa., Methods: A cross-sectional analysis of enrollment data (January 2019 to December 2021) from a cohort of individuals receiving pre-exposure prophylaxis services at eight clinics in three provinces in South Africa was conducted. Females (n = 1,074) and males (n = 231) aged 15-24 years were included. Interviewer-administered questionnaires were conducted, and the prevalence and severity of depression assessed using the Patient Health Questionnaire-9. Multivariate analysis was used to identify factors associated with depression., Results: Over 40% of participants had experienced any depression symptoms (43.7% of females, 38.5% of males). For males, experiencing intimate partner violence was the only predictor of depression symptoms (adjusted odds ratio (AOR) 8.81, 95% confidence intervals (CI) 1.03-75.44). For females, living with both parents (AOR 1.70, 95% CI 1.15-2.51), having transactional sex (AOR 1.63, 95% CI 1.00-2.65), experiencing any intimate partner violence (AOR 1.96, 95% CI 1.34-2.89), and using drugs (AOR 1.78, 95% CI 1.03-3.11) were all positively associated with depression symptoms. Resilience was a protective factor against depression symptoms for both sexes (males: AOR 0.96, 95% CI 0.93-0.98; females: AOR 0.96, 95% CI 0.95-0.97)., Discussion: There is a high burden of depression among AYP accessing SRH services in South Africa. Mental health screening should be integrated into SRH and HIV prevention programs for AYP., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: This study describes a cohort of men seeking oral pre-exposure prophylaxis (PrEP) services and explores their patterns of PrEP use within an implementation project seeking to integrate PrEP provision within sexual and reproductive health services in public health clinics in South Africa., Methods: Routine program and survey data from 364 males initiated on oral PrEP between July 2020 and May 2022 were analyzed. PrEP use was examined, including time to first discontinuation and restart patterns. Factors associated with early PrEP discontinuation and PrEP restart were analyzed., Results: Despite primarily focusing on access for adolescent girls and young women, PrEP services reached males with HIV prevention needs. PrEP use for ≤1 month (early discontinuation) was high at 58%; however, 18% restarted on PrEP, with 4% restarting repeatedly. Having depression symptoms was associated with early PrEP discontinuation (adjusted odds ratio [AOR]: 1.71, 95% CI [confidence interval]: 1.06-2.78). Those ≥25 years were less likely to discontinue early, as were those with a partner treated for a sexually transmitted infection in the preceding three months (AOR: 0.33, 95% CI: 0.13-0.84) and those who had been circumcised (AOR: 0.59, 95% CI: 0.36-0.96). Those 18-20 years old were less likely to restart PrEP than those ≥25 years (AOR: 0.43, 95% CI: 0.19-0.97), as were those whose partner's HIV status was unknown (AOR: 0.33, 95% CI: 0.12-0.88)., Discussion: This study identified interest and uptake of oral PrEP among an underrepresented population of predominantly heterosexual males seeking sexual and reproductive health services. It found high rates of early PrEP discontinuation, with a subset returning to restart PrEP. Further research is needed to determine whether these periods of PrEP use are associated with periods of HIV risk., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

The prefrontal cortex (PFC) has been implicated as a key brain region responsible for age-related cognitive decline. Little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods with integrated analyses to determine PFC molecular changes in healthy female primates. We quantified PFC changes associated with healthy aging in female baboons by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis to integrate data and treat age as a continuous variable, revealed highly interconnected known and novel pathways associated with PFC aging. We found Gamma-aminobutyric acid (GABA) tissue content associated with these signaling pathways, providing 1 potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Intra-uterine growth restriction (IUGR) is a common cause of fetal/neonatal morbidity and mortality and is associated with increased offspring predisposition for cardiovascular disease (CVD) development. Mitochondria are essential organelles in maintaining cardiac function, and thus, fetal cardiac mitochondria could be responsive to the IUGR environment. In this study, we investigated whether in utero fetal cardiac mitochondrial programming can be detectable in an early stage of IUGR pregnancy. Using a well-established nonhuman IUGR primate model, we induced IUGR by reducing by 30% the maternal diet (MNR), both in males (MNR-M) and in female (MNR-F) fetuses. Fetal cardiac left ventricle (LV) tissue and blood were collected at 90 days of gestation (0.5 gestation, 0.5 G). Blood biochemical parameters were determined and heart LV mitochondrial biology assessed. MNR fetus biochemical blood parameters confirm an early fetal response to MNR. In addition, we show that in utero cardiac mitochondrial MNR adaptations are already detectable at this early stage, in a sex-divergent way. MNR induced alterations in the cardiac gene expression of oxidative phosphorylation (OXPHOS) subunits (mostly for complex-I, III, and ATP synthase), along with increased protein content for complex-I, -III, and -IV subunits only for MNR-M in comparison with male controls, highlight the fetal cardiac sex-divergent response to MNR. At this fetal stage, no major alterations were detected in mitochondrial DNA copy number nor markers for oxidative stress. This study shows that in 90-day nonhuman primate fetuses, a 30% decrease in maternal nutrition generated early in utero adaptations in fetal blood biochemical parameters and sex-specific alterations in cardiac left ventricle gene and protein expression profiles, affecting predominantly OXPHOS subunits. Since the OXPHOS system is determinant for energy production in mitochondria, our findings suggest that these early IUGR-induced mitochondrial adaptations play a role in offspring's mitochondrial dysfunction and can increase predisposition to CVD in a sex-specific way.