C. elegans touch receptor neurons direct mechanosensory complex organization via repurposing conserved basal lamina proteins.

The sense of touch is conferred by the conjoint function of somatosensory neurons and skin cells. These cells meet across a gap filled by a basal lamina, an ancient structure found in metazoans. Using Caenorhabditis elegans, we investigate the composition and ultrastructure of the extracellular matrix at the epidermis and touch receptor neuron (TRN) interface. We show that membrane-matrix complexes containing laminin, nidogen, and the MEC-4 mechano-electrical transduction channel reside at this interface and are central to proper touch sensation. Interestingly, the dimensions and spacing of these complexes correspond with the discontinuous beam-like extracellular matrix structures observed in serial-section transmission electron micrographs. These complexes fail to coalesce in touch-insensitive extracellular matrix mutants and in dissociated neurons. Loss of nidogen reduces the density of mechanoreceptor complexes and the amplitude of the touch-evoked currents they carry. Thus, neuron-epithelium cell interfaces are instrumental in mechanosensory complex assembly and function. Unlike the basal lamina ensheathing the pharynx and body wall muscle, nidogen recruitment to the puncta along TRNs is not dependent upon laminin binding. MEC-4, but not laminin or nidogen, is destabilized by point mutations in the C-terminal Kunitz domain of the extracellular matrix component, MEC-1. These findings imply that somatosensory neurons secrete proteins that actively repurpose the basal lamina to generate special-purpose mechanosensory complexes responsible for vibrotactile sensing.

Replacement of fishmeal with a microbial single-cell protein induced enteropathy and poor growth outcomes in barramundi (Lates calcarifer) fry.

Fish meal (FM) replacement is essential for the sustainable expansion of aquaculture. This study focussed on the feasibility of replacing FM with a single-cell protein (SCP) derived from methanotrophic bacteria (Methylococcus capsulatus, Bath) in barramundi fry (Lates calcarifer). Three isonitrogenous and isoenergetic diets were formulated with 0%, 6.4% and 12.9% inclusion of the SCP, replacing FM by 0%, 25% and 50%. Barramundi fry (initial body weight 2.5 ± 0.1 g) were fed experimental diets for 21 days to assess growth performance, gut microbiome composition and gut histopathology. Our findings revealed that both levels of SCP inclusion induced detrimental effects in barramundi fry, including impaired growth and reduced survival compared with the control group (66.7% and 71.7% survival in diets replacing FM with SCP by 25% and 50%, respectively; p < .05). Both dietary treatments presented mild necrotizing enteritis with subepithelial oedema and accumulation of PAS positive, diastase resistant droplets within hepatocytes (ceroid hepatopathy) and pancreatic atrophy. Microbiome analysis revealed a marked shift in the gut microbial community with the expansion of potential opportunistic bacteria in the genus Aeromonas. Reduced overall performance in the highest inclusion level (50% SCP) was primarily associated with reduced feed intake, likely related to palatability issues, albeit pathological changes observed in gut and liver may also play a role. Our study highlights the importance of meticulous optimization of SCP inclusion levels in aquafeed formulations, and the need for species and life-stage specific assessments to ensure the health and welfare of fish in sustainable aquaculture practices.

Transcriptional profiling links unique human macrophage phenotypes to the growth of intracellular Salmonella enterica serovar Typhi.

Macrophages provide a crucial environment for Salmonella enterica serovar Typhi (S. Typhi) to multiply during typhoid fever, yet our understanding of how human macrophages and S. Typhi interact remains limited. In this study, we delve into the dynamics of S. Typhi replication within human macrophages and the resulting heterogeneous transcriptomic responses of macrophages during infection. Our study reveals key factors that influence macrophage diversity, uncovering distinct immune and metabolic pathways associated with different stages of S. Typhi intracellular replication in macrophages. Of note, we found that macrophages harboring replicating S. Typhi are skewed towards an M1 pro-inflammatory state, whereas macrophages containing non-replicating S. Typhi exhibit neither a distinct M1 pro-inflammatory nor M2 anti-inflammatory state. Additionally, macrophages with replicating S. Typhi were characterized by the increased expression of genes associated with STAT3 phosphorylation and the activation of the STAT3 transcription factor. Our results shed light on transcriptomic pathways involved in the susceptibility of human macrophages to intracellular S. Typhi replication, thereby providing crucial insight into host phenotypes that restrict and support S. Typhi infection.

Acceptability of Prenatal Screening Tests Among Expectant Mothers in India: Insights and Implications for Public Health.

INTRODUCTION: Prenatal screening tests are essential for preventing common genetic disorders, yet their acceptability among pregnant women in India remains unexplored. This study aims to investigate the acceptability of prenatal screening tests and their correlation with demographic characteristics among pregnant women in India. METHODS: A cross-sectional study was conducted at a tertiary care, public hospital, involving 200 pregnant women. Data were collected through a self-administered questionnaire assessing demographic information and the acceptability of prenatal screening tests. Statistical analysis included chi-square tests and logistic regression. RESULTS: Most participants demonstrated adequate acceptability toward prenatal screening tests, with 73% scoring above the threshold. Factors associated with higher acceptability included younger maternal age, second-trimester gestational age, higher education, salaried employment, and urban residence. However, factors such as parity, consanguinity, mode of conception, and family history of genetic disease showed no significant associations. CONCLUSION: The study highlights positive attitudes toward prenatal screening tests among pregnant women in India, particularly among younger, more educated, and urban populations. These findings emphasize the need for targeted interventions to enhance awareness and accessibility of prenatal screening, ultimately contributing to the reduction of the genetic disorder burden in India.

The Limb Girdle Muscular Dystrophy Health Index (LGMD-HI).

Limb girdle muscular dystrophy (LGMD) is a debilitating disease and the fourth most common muscular dystrophy. This study describes the development of the LGMD-Health Index (LGMD-HI). Participants were aged >18 years and recruited from three LGMD registries and GRASP-LGMD consortium. The initial instrument, comprised of 16 thematic subscales and 161 items, underwent expert review resulting in item removal as well as confirmatory factor analysis followed by inter-rater reliability and internal consistency of the subscales. Following expert review, one subscale and 59 items were eliminated. Inter-rater reliability was assessed and five items were removed due to Cohen's kappa <0.5. The final subscales had high internal consistencies with an average Cronbach alpha of 0.92. Test re-test reliability of the final instrument was high (intraclass correlation coefficient=0.97). Known groups validity testing showed a statistically significant difference in LGMD-HI scores amongst subjects based on ambulation status (28.7 vs 50.0, p < 0.0001), but not sex, employment status, or genetic subtype. The final instrument is comprised of 15 subscales and 97 items. The LGMD-HI is a disease-specific, patient-reported outcome measure designed in compliance with published FDA guidelines. This instrument is capable of measuring burden of disease with no significant variation based on LGMD subtype.

Understanding the Awareness of Prenatal Genetic Screening Tests Among Pregnant Women in India: A Cross-Sectional Study.

Introduction Genetic disorders pose a significant health challenge in India, with chromosomal abnormalities ranking second only to congenital anomalies in terms of disease burden. Prenatal testing offers a crucial strategy for identifying and managing these disorders. However, the awareness and understanding of prenatal screening tests among pregnant women in India remain understudied. This study aims to fill this gap by investigating the awareness quotient of prenatal screening tests for genetic disorders among pregnant women in India. Methods A hospital-based cross-sectional study was conducted at the Genetics Unit, Department of Anatomy, and Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, Mangalagiri. Ethical clearance was obtained, and data were collected using a self-administered questionnaire covering demographic characteristics and awareness assessment. Descriptive statistics, chi-square tests, and logistic regression analysis were employed for data analysis. Results Among the 200 pregnant women surveyed, the majority demonstrated inadequate awareness of prenatal screening tests for genetic disorders, with only 36.5% possessing adequate knowledge. Significant associations were found between awareness levels and factors such as age, trimester of pregnancy, and education level. Notably, awareness about non-invasive prenatal testing (NIPT) was notably low at 7%, indicating a need for targeted educational interventions. Comparison with international studies revealed varying levels of awareness across different populations, highlighting the influence of socio-cultural factors and healthcare systems. Conclusion This study underscores the need for improved awareness of prenatal screening tests among pregnant women in India. Addressing disparities in awareness, particularly among younger age groups and those with lower education levels, is crucial for informed decision-making in prenatal care. Targeted educational interventions can empower pregnant women to make informed choices, ultimately contributing to better maternal and child health outcomes. Further research should explore the effectiveness of such interventions in diverse settings to enhance prenatal care delivery.

A Study of Valvular Incompetencies in the Lower Limb Veins Using Doppler Ultrasound Findings.

INTRODUCTION: Varicose veins (VV) are one of the most common pathologies associated with the venous system of the lower limb. In the Indian population, its incidence is higher, and it is one of the most commonly encountered cases in the hospital. The study aimed to note the widely affected anatomical structure in male and female varicose patients using Doppler ultrasound (DU) examination findings. METHODS: A total of 200 Doppler ultrasound reports of varicose patients were retrospectively analyzed and categorized based on the affected structure. The demographic data of all cases, such as age, sex, brief history, signs, symptoms, and affected side of the lower limb, was noted. Anatomical structures causing venous refluxes in the saphenous systems, junctions, and perforating venous systems were noted. Pearson's correlation coefficient was applied to find out its association. RESULTS: Out of 200 Doppler reports studied, 133 (67%) were male and 67 (33%) were female patients. The majority, 180 (90%) cases, belonged to C1-C3 stages according to the Clinical, Etiology, Anatomy, and Pathological (CEAP) classification, while 20 (10%) were in C4-C5 stages. Male patients aged between 31 and 40 years were predominantly affected, with their left side being affected most commonly. In female patients, the older age group of 50-60 years was predominantly affected. Great saphenous reflux in the groin due to incompetent terminal valve was noted in 126 (63%) cases. In the perforator venous (PV) system, defects in the medial leg perforator (189 (95%)), posterior leg (92 (46%)), and thigh perforator (20 (10%)) were noted. CONCLUSION: In the present study, the occurrence of varicose veins is due to the involvement of superficial, deep, and perforator veins with varying percentages. Among the structures, the medial leg perforator was predominantly involved, followed by other perforators. Since most patients were in C1-C3 stages, the involvement of deep veins was noted minimally.

Facilitators and barriers to using a DeskCycle as a sedentary behavior intervention in the work environment.

BACKGROUND: Sedentary behavior is a public health threat with extensive health burden on society. High levels of sedentary behavior have been associated with cardiovascular diseases, diabetes, obesity, and cancer. Individuals working in desk-related occupations are more likely to be sedentary for most of the day. Health researchers have responded by implementing and promoting interventions and wellness programs in work environments to reduce this behavior. This study examined the feasibility and experience of using the DeskCycle to reduce sedentary behavior among female workers in an academic office environment. METHODS: This was an intervention study where participants used the DeskCycle in two consecutive eight-week phases and uploaded DeskCycle use data daily. A questionnaire was administered after week 2 and week 8 (pre-post) of DeskCycle use in each phase to assess dimensions of feasibility, including an open-ended question for user experience. RESULTS: The participants (N = 78) had an average age of 44.4 (±11.3) years and were primarily non-Hispanic White (88.5%). DeskCycle daily use varied from Phase I: 84% to 64.9% (weeks 1-7), and 49.4% in week 8, to Phase II: 73.5% to 52.2% (week 1-7), and 40.2% in week 8. In Phase I, 96.6% (week 2) and 87% (week 8) agreed that the DeskCycle decreased sedentary behavior, and in Phase II, 74.3% (week 2) and 76.9% (week 8) agreed. The analysis of open-ended responses found challenges with the desk set up, cycling interfering with typing, and thinking critically, as barriers to DeskCycle use, while enjoying cycling and cycling improving mood were reported as facilitators. CONCLUSIONS: Using a DeskCycle in an academic office environment to reduce sedentary behavior is feasible in female office workers. Consideration should be given to the type of tasks performed while cycling.

Cognition in older age bipolar disorder: An analysis of archival data across the globe.

BACKGROUND: Cognitive deficits in bipolar disorder (BD) impact functioning and are main contributors to disability in older age BD (OABD). We investigated the difference between OABD and age-comparable healthy comparison (HC) participants and, among those with BD, the associations between age, global cognitive performance, symptom severity and functioning using a large, cross-sectional, archival dataset harmonized from 7 international OABD studies. METHODS: Data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database, spanning various standardized measures of cognition, functioning and clinical characteristics, were analyzed. The sample included 662 euthymic to mildly symptomatic participants aged minimum 50years (509 BD, 153 HC), able to undergo extensive cognitive testing. Linear mixed models estimated associations between diagnosis and global cognitive performance (g-score, harmonized across studies), and within OABD between g-score and severity of mania and depressive symptoms, duration of illness and lithium use and of global functioning. RESULTS: After adjustment for study cohort, age, gender and employment status, there was no significant difference in g-score between OABD and HC, while a significant interaction emerged between employment status and diagnostic group (better global cognition associated with working) in BD. Within OABD, better g-scores were associated with fewer manic symptoms, higher education and better functioning. LIMITATIONS: Cross-sectional design and loss of granularity due to harmonization. CONCLUSION: More research is needed to understand heterogenous longitudinal patterns of cognitive change in BD and understand whether particular cognitive domains might be affected in OABD in order to develop new therapeutic efforts for cognitive dysfunction OABD.

Polar bear energetic and behavioral strategies on land with implications for surviving the ice-free period.

Declining Arctic sea ice is increasing polar bear land use. Polar bears on land are thought to minimize activity to conserve energy. Here, we measure the daily energy expenditure (DEE), diet, behavior, movement, and body composition changes of 20 different polar bears on land over 19-23 days from August to September (2019-2022) in Manitoba, Canada. Polar bears on land exhibited a 5.2-fold range in DEE and 19-fold range in activity, from hibernation-like DEEs to levels approaching active bears on the sea ice, including three individuals that made energetically demanding swims totaling 54-175 km. Bears consumed berries, vegetation, birds, bones, antlers, seal, and beluga. Beyond compensating for elevated DEE, there was little benefit from terrestrial foraging toward prolonging the predicted time to starvation, as 19 of 20 bears lost mass (0.4-1.7 kg•day-1). Although polar bears on land exhibit remarkable behavioral plasticity, our findings reinforce the risk of starvation, particularly in subadults, with forecasted increases in the onshore period.

Epigenetic Regulation of Cardiomyocyte Maturation by Arginine Methyltransferase CARM1.

BACKGROUND: During the neonatal stage, the cardiomyocyte undergoes a constellation of molecular, cytoarchitectural, and functional changes known collectively as cardiomyocyte maturation to increase myocardial contractility and cardiac output. Despite the importance of cardiomyocyte maturation, the molecular mechanisms governing this critical process remain largely unexplored. METHODS: We leveraged an in vivo mosaic knockout system to characterize the role of Carm1, the founding member of protein arginine methyltransferase, in cardiomyocyte maturation. Using a battery of assays, including immunohistochemistry, immuno-electron microscopy imaging, and action potential recording, we assessed the effect of loss of Carm1 function on cardiomyocyte cell growth, myofibril expansion, T-tubule formation, and electrophysiological maturation. Genome-wide transcriptome profiling, H3R17me2a chromatin immunoprecipitation followed by sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing were used to investigate the mechanisms by which CARM1 (coactivator-associated arginine methyltransferase 1) regulates cardiomyocyte maturation. Finally, we interrogated the human syntenic region to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks for single-nucleotide polymorphisms associated with human heart diseases. RESULTS: We report that mosaic ablation of Carm1 disrupts multiple aspects of cardiomyocyte maturation cell autonomously, leading to reduced cardiomyocyte size and sarcomere thickness, severe loss and disorganization of T tubules, and compromised electrophysiological maturation. Genomics study demonstrates that CARM1 directly activates genes that underlie cardiomyocyte cytoarchitectural and electrophysiological maturation. Moreover, our study reveals significant enrichment of human heart disease-associated single-nucleotide polymorphisms in the human genomic region syntenic to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks. CONCLUSIONS: This study establishes a critical and multifaceted role for CARM1 in regulating cardiomyocyte maturation and demonstrates that deregulation of CARM1-dependent cardiomyocyte maturation gene expression may contribute to human heart diseases.

Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Factors Associated with Provider Counseling Against Breastfeeding in the Setting of Marijuana Use: A Population-Based Survey.

INTRODUCTION: The purpose of this study was to explore patient demographic factors associated with counseling against breastfeeding and concurrent marijuana use. METHODS: A cross-sectional study derived using data from the Centers for Disease Control and Prevention administered Pregnancy Risk Assessment Monitoring System (PRAMS) in collaboration with state and local health departments. This study sample included survey participants whose responses indicate they received counseling discouraging breastfeeding with concurrent marijuana use. Bivariate and multivariate regression analyses assessed the relationship between factors associated with counseling against breastfeeding and concurrent marijuana use. RESULTS: Of the 10,911 participants in this sample, 9,695 participants who answered the question about receiving counseling discouraging breastfeeding while using marijuana were included in the analysis (89% response rate for the total sample). Twenty nine percent of participants were advised by a provider not to breastfeed while using marijuana. Participants who received this counseling were more likely to be people of color, age less than or equal to 29, with a high school education or less, unmarried, report governmental or no insurance prepregnancy, and report marijuana use postpartum. In the multivariate analysis, age less than or equal to 20 (P = .001), being unmarried (P = .023), and marijuana use postpartum (P = .034) remained associated with counseling against breastfeeding. DISCUSSION: Our results suggest that individuals are being counseled differently. Unmarried and young people (age <20 years) were more likely to report receiving counseling against breastfeeding with concurrent marijuana use. Given the growing national acceptability of marijuana use, the known benefits of breastfeeding, and the unclear risks of marijuana in human milk, there is a need to standardize counseling to avoid a missed opportunity to educate breastfeeding populations who use marijuana and to reduce the risk of counseling based on providers' personal attitudes and biases not aligned with evidence-based guidelines.

Can Pharmacological Conditioning as an Add-On Treatment Optimize Standard Pharmacological Treatment in Patients with Recent-Onset Rheumatoid Arthritis? A Proof-of-Principle Randomized Clinical Trial.

Medication regimens using conditioning via variable reinforcement have shown similar or improved therapeutic effects as full pharmacological treatment, but evidence in patient populations is scarce. This proof-of-principle double-blind randomized clinical trial examined whether treatment effects in recent-onset rheumatoid arthritis (RA) can be optimized through pharmacological conditioning. After four months of standardized treatment (n = 46), patients in clinical remission (n = 19) were randomized to the Control group (C), continuing standardized treatment (n = 8), or the Pharmacological Conditioning (PC) group, receiving variable treatment according to conditioning principles (n = 11). After eight months, treatment was tapered and discontinued linearly (C) or variably (PC). Standard treatment led to large improvements in disease activity and HRQoL in both groups. The groups did not differ in the percentage of drug-free clinical remission obtained after conditioning or continued standard treatment. The PC group did show a larger decrease in self-reported disease activity (Cohen's d = 0.9) and a smaller increase in TNF-α levels (Cohen's d = 0.7) than the C group. During all phases, more differences between groups were found for the patients who followed protocol than for the intention-to-treat sample. Although the results are not conclusive, pharmacological conditioning may have some advantages in terms of disease progression and stability, especially during the conditioning phase, compared with standard clinical treatment. The effects may be particularly beneficial for patients who show a good initial response to increased medication dosages.

Interprofessional obstetric simulation training improves postpartum haemorrhage management and decreases maternal morbidity: a before-and-after study.

OBJECTIVE: To determine the impact of the Obstetric Simulation Training and Teamwork (OB-STaT) curriculum on postpartum haemorrhage (PPH) rates and outcomes. DESIGN: Before-and-after study. SETTING: Maternity care hospitals within the USA. POPULATION: Patients who delivered between February 2018 and November 2019. METHODS: Interprofessional obstetric teamwork training (OB-STaT) conducted at each hospital. Electronic medical records for deliveries were reviewed for 6 months before and after conducting OB-STaT at participating hospitals. MAIN OUTCOME MEASURES: The PPH rate (blood loss of ≥1000 ml), uterotonic medications used, tranexamic acid use, blood product transfusion, hysterectomy, length of stay and composite maternal morbidity (postpartum haemorrhage, hysterectomy, transfusion of ≥4 units of blood products and intensive care unit admission for PPH). RESULTS: A total of 9980 deliveries were analysed: 5059 before and 4921 after OB-STaT. The PPH rates did not change significantly (5.48% before vs 5.14% after, p = 0.46). Composite maternal morbidity decreased significantly by 1.1% (6.35%-5.28%, p = 0.03), massive transfusions decreased by 57% (0.42%-0.18%, p = 0.04) and the mean postpartum length of stay decreased from 2.05 days (1.05 days SD) to 2.01 days (0.91 days SD) (p = 0.04). Following OB-STaT, haemorrhage medication use increased by 36% (14.8%-51.2%, p = 0.03), the use of tranexamic acid for PPH treatment almost doubled (2.7%-4.8%, p < 0.001) and the rate of hysterectomy significantly increased (0%-0.1%, p = 0.03). CONCLUSIONS: Although the PPH rates did not decrease, OB-STaT significantly improved maternal morbidity, decreased massive transfusions, and improved PPH management by increasing the utilization of uterotonic medications, tranexamic acid and hysterectomy.

Studying the Effects of Shoulder Dystocia and Neonate-Focused Delivery Maneuvers on Brachial Plexus Strain: A Computational Study.

The purpose of this computational study was to investigate the effects of neonate-focused clinical delivery maneuvers on brachial plexus (BP) during shoulder dystocia. During shoulder dystocia, the anterior shoulder of the neonate is obstructed behind the symphysis pubis of the maternal pelvis, postdelivery of the neonate's head. This is managed by a series of clinical delivery maneuvers. The goal of this study was to simulate these delivery maneuvers and study their effects on neonatal BP strain. Using madymo models of a maternal pelvis and a 90th-percentile neonate, various delivery maneuvers and positions were simulated including the lithotomy position alone of the maternal pelvis, delivery with the application of various suprapubic pressures (SPPs), neonate in an oblique position, and during posterior arm delivery maneuver. The resulting BP strain (%) along with the required maternal delivery force was reported in these independently simulated scenarios. The lithotomy position alone served as the baseline. Each of the successive maneuvers reported a decrease in the required delivery force and resulting neonatal BP strain. As the applied SPP force increased (three scenarios simulated), the required maternal delivery force and neonatal BP strain decreased. A further decrease in both delivery force and neonatal BP strain was observed in the oblique position, with the lowest delivery force and neonatal BP strain reported during the posterior arm delivery maneuver. Data obtained from the improved computational models in this study enhance our understanding of the effects of clinical maneuvers on neonatal BP strain during complicated birthing scenarios such as shoulder dystocia.

International Water Quality Guidelines for Polycyclic Aromatic Hydrocarbons: Advances to Improve Jurisdictional Uptake of Guidelines Derived Using The Target Lipid Model.

A large number of different of polycyclic aromatic hydrocarbons (PAHs) have been found in environmental media, yet water quality guidelines (WQGs) are only available for a small subset of PAHs, limiting our ability to adequately assess environmental risks from these compounds. The target lipid model (TLM) was published over 20 years ago and has been extensively validated in the literature, but it has still not been widely adopted by jurisdictions to derive WQGs for PAHs. The goal of our study was to better align the methods for deriving TLM-based WQGs with international derivation protocols. This included updating the TLM with rescreened data to identify datapoints by which effect concentrations were estimated rather than measured, modernizing the statistics used to generate the hazard concentration, and testing the applicability of a chronic TLM model rather than using the acute-to-chronic ratio. The results show that the acute TLM model did not deviate substantially from the previous iteration, indicating that the model has reached a point of stability after over 20 years of testing and improvements. Water quality guidelines derived directly from a chronic TLM provided a similar level of protection as previous iterations of the TLM. The major advantage of adopting TLM-derived WQGs is the expanded list of PAH WQGs, which will allow a more fulsome quantification of environmental risks and the ability to apply the model to mixtures. Environ Toxicol Chem 2024;43:686-700. © 2023 SETAC.

Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion.

Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH. We compared the temporal growth of homogeneous, genetically-similar single-cell clones that are rejected vs. those that are not-rejected after transplantation in-vivo using single-cell RNA sequencing and immunophenotyping. Non-rejected clones showed high infiltration of tumor-associated-macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate mediators, identified Mif (macrophage migration inhibitory factor) as a regulator of immune rejection. Mif knockout led to smaller tumors and reversed non-rejection-associated immune composition, particularly, leading to the reduction of immunosuppressive macrophage infiltration. Finally, we validated these results in melanoma patient data.

How Hospitals Are Addressing The Effects Of Racism: A Mixed-Methods Study Of Hospital Equity Officers.

Hospital equity officers have become critical leaders in the effort to address the determinants of health care disparities, including structural racism. In this mixed-methods study, we surveyed a national sample of equity officers and interviewed a subset of respondents to provide additional perspective. About one-half of survey respondents reported at least some obstacles to achieving their health equity objectives, including racist beliefs among people working in their hospitals and health care systems, policies that perpetuate racism, and a lack of staff diversity. To address these challenges, some hospitals are collecting information about instances of racism, reviewing clinical algorithms for evidence of bias, or forming community partnerships. However, in interviews, equity officers pointed out that racism is a public health issue that cannot be adequately addressed solely within the health care system. Given the relative newness of most hospital equity officer positions, our research may be viewed as an early glimpse into the challenges and opportunities of this evolving work.