Who's in control? Situating expertise, (mis)trust, and power among the Latine/Hispanic community in COVID-19's liminal moments.

BACKGROUND: Research has established the disproportionate impact of COVID-19 on Black, Indigenous, and People of color (BIPOC) communities, and the barriers to vaccine trust and access among these populations. Focusing on perceptions of safety, access, and trustworthiness, studies often attach barriers to community-members, and discuss vaccines as if developed from an objective perspective, or "view from nowhere" (Haraway). OBJECTIVE: We sought to follow Haraway's concept of "situated knowledges," whereby no one truth exists, and information is understood within its context, to understand the exertions of expertise surrounding vaccines. We focused on perceptions of power among a BIPOC community during a relatively unexamined moment, wherein the status of the pandemic and steps to prevent it were particularly uncertain. METHODS: We report the findings of ten focus groups conducted among members of Rhode Island's Latine/Hispanic communities between December 2021 and May 2022. We called this time COVID-19's liminal moment because vaccines were distributed, mandates were lifted, vaccine efficacy was doubted, and new strains spread. We translated, transcribed, and analyzed focus groups using thematic analysis. RESULTS: Community-member (n = 65) perceptions of control aligned with three key themes: (1) no power is capable of controlling COVID-19, (2) we are the objects of scientific and political powers, and (3) we, as individuals and communities, can control COVID-19 through our decisions and actions. CONCLUSIONS: By centering the perspectives of a minoritized community, we situated the scientific knowledge produced about COVID-19 within the realities of imperfect interventions, uncontrollable situations, and medical power-exertions. We argue that medical knowledge should not be assumed implicitly trustworthy, or even capable, but instead seen as one of many products of human labor within human systems. Trust and trustworthiness must be mutually negotiated between experts, contexts, and communities through communication, empowerment, and justice.

Strategies for DPYD testing prior to fluoropyrimidine chemotherapy in the US.

PURPOSE: Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at high risk for severe and fatal toxicity from fluoropyrimidine (FP) chemotherapy. Pre-treatment DPYD testing is standard of care in many countries, but not the United States (US). This survey assessed pre-treatment DPYD testing approaches in the US to identify best practices for broader adoption. METHODS: From August to October 2023, a 22-item QualtricsXM survey was sent to institutions and clinicians known to conduct pre-treatment DPYD testing and broadly distributed through relevant organizations and social networks. Responses were analyzed using descriptive analysis. RESULTS: Responses from 24 unique US sites that have implemented pre-treatment DPYD testing or have a detailed implementation plan in place were analyzed. Only 33% of sites ordered DPYD testing for all FP-treated patients; at the remaining sites, patients were tested depending on disease characteristics or clinician preference. Almost 50% of sites depend on individual clinicians to remember to order testing without the assistance of electronic alerts or workflow reminders. DPYD testing was most often conducted by commercial laboratories that tested for at least the four or five DPYD variants considered clinically actionable. Approximately 90% of sites reported receiving results within 10 days of ordering. CONCLUSION: Implementing DPYD testing into routine clinical practice is feasible and requires a coordinated effort among the healthcare team. These results will be used to develop best practices for the clinical adoption of DPYD testing to prevent severe and fatal toxicity in cancer patients receiving FP chemotherapy.

Yttrium-90 Anti-CD25-BEAM-Conditioning for Autologous Hematopoietic Cell Transplantation in Peripheral T Cell Lymphoma.

Peripheral T cell lymphomas (PTCL) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemosensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCL. In this phase 1 clinical trial, we tested the addition of beta-emitting 90Y-labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, melphalan) as conditioning for AHCT in patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5 and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure [median time of death 17 mo (range: 9-21 mo)] post-AHCT. Median follow-up was 24 mo (range: 9-26 mo) overall and 24 mo (range: 13-26 mo) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% CI: 34-77%) and 68% (95% CI: 42-84%), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.clinicaltrials.gov as # NCT02342782.

Perinatal optimisation for periviable birth and outcomes: a 4-year network analysis (2018-2021) across a change in national guidance.

Introduction: The British Association of Perinatal Medicine (BAPM) released their revised framework for extremely preterm infant management in 2019. This revised framework promotes consideration of perinatal optimisation and survival-focused care from 22 weeks gestation onwards. This was a departure from the previous BAPM framework which recommended comfort care as the only recommended management for infants <23 + 0 weeks. Methods: Our study evaluates the clinical impact that this updated framework has had across the Northwest of England. We utilised anonymised network data from periviable infants delivered across the region to examine changes in perinatal optimisation practices and survival outcomes following the release of the latest BAPM framework. Results: Our data show that after the introduction of the updated framework there has been an increase in perinatal optimisation practices for periviable infants and an 80% increase in the number of infants born at 22 weeks receiving survival-focused care and admission to a neonatal unit. Discussion: There remain significant discrepancies in optimisation practices by gestational age, which may be contributing to the static survival rates that were observed in the lowest gestational ages.

A 7-month multi-disciplinary healthy lifestyle intervention effectively improved cardiometabolic risk profile of firefighters.

OBJECTIVE: We investigated the effect of a 7-month healthy lifestyle intervention on cardiometabolic risk factors (CMRF) among male career military firefighters (FFs). METHODS: 49 FFs participated in a 7-month workplace multi-disciplinary healthy lifestyle intervention designed to reduce CMRF through exercise, diet, and improved sleep. Medical assessments, accelerometry, and surveys at the beginning and end determined program effectiveness. RESULTS: At the end of the intervention period, there was a significant improvement in measures of body composition and blood glucose. The prevalence of hypertension also decreased significantly (p < 0.01). The 57% of participants who fully adhered to the program had significantly greater improvements across multiple CMRF. Participants increased their physical activity and improved their diet following the intervention. CONCLUSION: This healthy lifestyle intervention was effective in changing behavior and lowering cardiometabolic risk among FFs.

Predicting consequences of COVID-19 control measure de-escalation on nosocomial transmission and mortality: a modelling study in a French rehabilitation hospital.

INTRODUCTION: Infection control measures are effective for nosocomial COVID-19 prevention but bear substantial health-economic costs, motivating their "de-escalation" in settings at low risk of SARS-CoV-2 transmission. Yet consequences of de-escalation are difficult to predict, particularly in light of novel variants and heterogeneous population immunity. AIM: To estimate how infection control measure de-escalation influences nosocomial COVID-19 risk. METHODS: An individual-based transmission model was used to simulate SARS-CoV-2 outbreaks and control measure de-escalation in a French long-term care hospital with multi-modal control measures in place (testing and isolation, universal masking, single-occupant rooms). Estimates of COVID-19 case fatality rates (CFRs) from reported outbreaks were used to quantify excess COVID-19 mortality due to de-escalation. RESULTS: In a population fully susceptible to infection, de-escalating both universal masking and single rooms resulted in hospital-wide outbreaks of 114 (95% CI: 103-125) excess infections, compared with five (three to seven) excess infections when de-escalating only universal masking or 15 (11-18) when de-escalating only single rooms. When de-escalating both measures and applying CFRs from the first wave of COVID-19, excess patient mortality ranged from 1.57 (1.41-1.71) to 9.66 (8.73-10.57) excess deaths/1000 patient-days. By contrast, when applying CFRs from subsequent pandemic waves and assuming susceptibility to infection among 40-60% of individuals, excess mortality ranged from 0 (0-0) to 0.92 (0.77-1.07) excess deaths/1000 patient-days. CONCLUSIONS: The de-escalation of bundled COVID-19 control measures may facilitate widespread nosocomial SARS-CoV-2 transmission. However, excess mortality is probably limited in populations at least moderately immune to infection and given CFRs resembling those estimated during the 'post-vaccine' era.

Proposing a new history of grief's medicalisation: A critical discourse analysis.

Conceptualisations of grief have transformed significantly in recent decades, from an experience accepted and expressed in community spaces to a diagnosable clinical phenomenon. Narratives of this transformation tend to focus on grief's relationship to major depression, or on recent nosological changes. This paper examines the possibility of a new narrative for medicalisation by grounding in the networks of language and power created around 'grief' through a critical discourse analysis of psy-discipline articles (n = 70) published between 1975 and 1995. Focusing on shifts in definitions of, methods used to approach, and rationales motivating study of the experience, it posits that the psy-disciplines exerted exclusive expertise over grief decades before its creation as a diagnosis. By reconceptualising grief in the terms of psy-specific symptoms and functional performance and by approaching it with the decontextualising and interventionist methods of an increasingly scientific psy-discipline, the psy-community medicalised grief between 1975 and 1995. Identifying neoliberal and other cultural influences shaping this process of medical construction and reconsidering narratives of grief's history mindful of the powers exerted in medicalisation, this paper establishes that these moments played a critical role in the development of the present's grief.

Telomere dynamics during hibernation in a tropical primate.

Hibernation is a widespread metabolic strategy among mammals for surviving periods of food scarcity. During hibernation, animals naturally alternate between metabolically depressed torpor bouts and energetically expensive arousals without ill effects. As a result, hibernators are promising models for investigating mechanisms that buffer against cellular stress, including telomere protection and restoration. In non-hibernators, telomeres, the protective structural ends of chromosomes, shorten with age and metabolic stress. In temperate hibernators, however, telomere shortening and elongation can occur in response to changing environmental conditions and associated metabolic state. We investigate telomere dynamics in a tropical hibernating primate, the fat-tailed dwarf lemur (Cheirogaleus medius). In captivity, these lemurs can hibernate when maintained under cold temperatures (11-15 °C) with limited food provisioning. We study telomere dynamics in eight fat-tailed dwarf lemurs at the Duke Lemur Center, USA, from samples collected before, during, and after the hibernation season and assayed via qPCR. Contrary to our predictions, we found that telomeres were maintained or even lengthened during hibernation, but shortened immediately thereafter. During hibernation, telomere lengthening was negatively correlated with time in euthermia. Although preliminary in scope, our findings suggest that there may be a preemptive, compensatory mechanism to maintain telomere integrity in dwarf lemurs during hibernation. Nevertheless, telomere shortening immediately afterward may broadly result in similar outcomes across seasons. Future studies could profitably investigate the mechanisms that offset telomere shortening within and outside of the hibernation season and whether those mechanisms are modulated by energy surplus or crises.

geoFOR: A collaborative forensic taphonomy database for estimating the postmortem interval.

Accurately assessing the postmortem interval (PMI), or the time since death, remains elusive within forensic science research and application. This paper introduces geoFOR, a web-based collaborative application that utilizes ArcGIS and machine learning to deliver improved PMI predictions. The geoFOR application provides a standardized, collaborative forensic taphonomy database that gives practitioners a readily available tool to enter case information that automates the collection of environmental data and delivers a PMI prediction using statistically robust methods. After case submission, the cross-validating machine learning PMI predictive model results in a R² value of 0.82. Contributors receive a predicted PMI with an 80% confidence interval. The geoFOR database currently contains 2529 entries from across the U.S. and includes cases from medicolegal investigations and longitudinal studies from human decomposition facilities. We present the overall findings of the data collected so far and compare results from medicolegal cases and longitudinal studies to highlight previously poorly understood limitations involved in the difficult task of PMI estimation. This novel approach for building a reference dataset of human decomposition is forensically and geographically representative of the realities in which human remains are discovered which allows for continual improvement of PMI estimations as more data is captured. It is our goal that the geoFOR data repository follow the principles of Open Science and be made available to forensic researchers to test, refine, and improve PMI models. Mass collaboration and data sharing can ultimately address enduring issues associated with accurately estimating the PMI within medicolegal death investigations.

Enhancing the Standardized Field Sobriety Test to detect cannabis impairment: An observational study.

OBJECTIVE: The purpose of this study was to explore various tests of impairment that could potentially be added to the Standardized Field Sobriety Test (SFST) to enhance its sensitivity to identify drivers whose abilities are adversely affected by cannabis. METHODS: An observational study was conducted in which participants were invited to use their own cannabis at the research facility. Once prior to cannabis use and at four times during the 150 min after cannabis use, participants performed the three tests of the Standardized Field Sobriety Test (SFST) (i.e., Horizontal Gaze Nystagmus, Walk and Turn, and One Leg Stand) as well as the Modified Romberg Balance and Finger to Nose tests. In addition, assessments were made of physiological indicators (i.e., eyelid, leg and body tremors, rebound dilation, lack of convergence) and vital signs (pulse, blood pressure and body temperature). Participants also completed a digit-symbol substitution task at each testing interval. With the exception of vital signs and the digit symbol task, all tests and assessments were administered and scored by certified Drug Recognition Experts using the standard procedures of the Drug Evaluation and Classification Program. RESULTS: Twenty minutes after vaping cannabis (mean THC concentration = 6.34 ng/mL), participants displayed performance deficits on a variety of tasks; 67% met the criterion for suspected impairment on the SFST. Addition of the Finger-to-Nose (FTN) test along with observations of head movements and jerks (HMJ) increased the percentage of participants who met the criterion for suspected impairment by 33% and improved the sensitivity of the test from 0.67 to 0.88. CONCLUSIONS: The results of this study support supplementing the SFST with the Finger-to-Nose test and observations of HMJ to assist in the detection of drivers who are adversely affected by the use of cannabis. The observational study design and the use of assessors who were not blinded as to the use of cannabis by participants limits the strength of the evidence. Further research, including randomized trials and field studies of drivers, is required to confirm and validate this enhanced version of the SFST.

Prenatal cortisol exposure impairs adrenal function but not glucose metabolism in adult sheep.

Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose-insulin dynamics and pituitary-adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1-2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic-euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary-adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.

Pharmacogenomic testing in oncology: a health system's approach to identify oncology provider perspectives.

Aim: Identify oncology healthcare providers' attitudes toward barriers to and use cases for pharmacogenomic (PGx) testing and implications for prescribing anticancer and supportive care medications. Materials & methods: A questionnaire was designed and disseminated to 71 practicing oncology providers across the MedStar Health System. Results: 25 of 70 (36%) eligible oncology providers were included. 88% were aware of PGx testing and 72% believed PGx can improve care. Of providers who had ordered a medication with PGx implications in the past month, interest in PGx for anticancer (90-100%) and supportive care medications (>75%) was high. Providers with previous PGx education were more likely to have ordered a test (odds ratio: 7.9; 95% CI: 1.1-56; p = 0.0394). Conclusion: Oncology provider prescribing practices and interest in PGx suggest opportunities for implementation.

Phosphorus release and recovery by reductive dissolution of chemically precipitated phosphorus from simulated wastewater.

Chemically mediated recovery of phosphorous (P) as vivianite from the sludges generated by chemical phosphorus removal (CPR) is a potential means of enhancing sustainability of wastewater treatment. This study marks an initial attempt to explore direct P release and recovery from lab synthetic Fe-P sludge via reductive dissolution using ascorbic acid (AA) under acidic conditions. The effects of AA/Fe molar ratio, age of Fe-P sludge and pH were examined to find the optimum conditions for Fe-P reductive solubilization and vivianite precipitation. The performance of the reductive, chelating, and acidic effects of AA toward Fe-P sludge were evaluated by comparison with hydroxylamine (reducing agent), oxalic acid (chelating agent), and inorganic acids (pH effect) including HNO3, HCl, and H2SO4. Full solubilization of Fe-P sludge and reduction of Fe3+ were observed at pH values 3 and 4 for two Fe/AA molar ratios of 1:2 and 1:4. Sludge age (up to 11 days) did not affect the reductive solubilization of Fe-P with AA addition. The reductive dissolution of Fe-P sludge with hydroxylamine was negligible, while both P (95 ± 2%) and Fe3+ (90 ± 1%) were solubilized through non-reductive dissolution by oxalic acid treatment at an Fe/oxalic acid molar ratio 1:2 and a pH 3. With sludge treatment with inorganic acids at pH 3, P and Fe release was very low (<10%) compared to AA and oxalic acid treatment. After full solubilization of Fe-P sludge by AA treatment at pH 3 it was possible to recover the phosphorus and iron as vivianite by simple pH adjustment to pH 7; P and Fe recoveries of 88 ± 2% and 90 ± 1% respectively were achieved in this manner. XRD analysis, Fe/P molar ratio measurements, and magnetic attraction confirmed vivianite formation. PHREEQC modeling showed a reasonable agreement with the measured release of P and Fe from Fe-P sludge and vivianite formation.

Understanding the mechanism by which Gd(III) coiled coils achieve magnetic resonance relaxivity - a study into the water coordination chemistry.

A class of Gd(III) coiled coils achieve high MRI relaxivity, in part due to their slow rotational correlation time. However, extending their length is unable to further enhance performance, as the mechanism by which relaxivity is achieved is dominated by the presence of three inner sphere waters in rapid exchange, through an associative mechanism.

Evaluation of food security status, psychological well-being, and stress on BMI and diet-related behaviors among a sample of college students.

OBJECTIVES: The purpose of this study was to evaluate food insecurity on body mass index (BMI) and diet-related behaviors among college students and whether psychological well-being (PWB) and stress levels mediate this relationship. STUDY DESIGN: This was a cross-sectional study. METHODS: Data from 1439 students from the American College Health Association National College Health Assessment III (Fall 2020) were used. Food security status was evaluated by the USDA Six-Item Short Form. PWB was measured using the Diener Flourishing Scale. Diet-related behaviors included the average servings of fruits, vegetables, and sugar-sweetened beverages consumed per day. Stress was measured by self-reported levels. Regression model analysis evaluated the influence of food security status, PWB, and stress levels on BMI. PWB and stress were also tested as mediators in the relationship between food insecurity and BMI. RESULTS: Among our sample of college students, 44.54% (n = 641) were food insecure, and 55.46% (n = 798) were food secure. Multiple regression analysis showed that higher food insecurity, older age, full-time enrollment status, and fifth-year student status were positively associated with a higher BMI score (P < 0.05). Results from mediation models revealed that PWB, but not stress, mediated the relationship between food security and BMI among Black/African American students. Regarding diet-related behaviors, high stress levels mediated the relationship between food insecurity and sugar-sweetened beverage intake among students. CONCLUSIONS: Food insecurity appears to influence BMI in college students. This relationship seems to be mediated by disrupted PWB and a higher intake of sugar-sweetened beverages due to stress.

How have mathematical models contributed to understanding the transmission and control of SARS-CoV-2 in healthcare settings? A systematic search and review.

Since the onset of the COVID-19 pandemic, mathematical models have been widely used to inform public health recommendations regarding COVID-19 control in healthcare settings. The objective of this study was to systematically review SARS-CoV-2 transmission models in healthcare settings, and to summarize their contributions to understanding nosocomial COVID-19. A systematic search and review of published articles indexed in PubMed was carried out. Modelling studies describing dynamic inter-individual transmission of SARS-CoV-2 in healthcare settings, published by mid-February 2022 were included. Models have mostly focused on acute-care and long-term-care facilities in high-income countries. Models have quantified outbreak risk, showing great variation across settings and pandemic periods. Regarding surveillance, routine testing rather than symptom-based was highlighted as essential for COVID-19 prevention due to high rates of silent transmission. Surveillance impacts depended critically on testing frequency, diagnostic sensitivity, and turn-around time. Healthcare re-organization also proved to have large epidemiological impacts: beyond obvious benefits of isolating cases and limiting inter-individual contact, more complex strategies (staggered staff scheduling, immune-based cohorting) reduced infection risk. Finally, vaccination impact, while highly effective for limiting COVID-19 burden, varied substantially depending on assumed mechanistic impacts on infection acquisition, symptom onset and transmission. Modelling results form an extensive evidence base that may inform control strategies for future waves of SARS-CoV-2 and other viral respiratory pathogens. We propose new avenues for future models of healthcare-associated outbreaks, with the aim of enhancing their efficiency and contributions to decision-making.

Urbanisation and Declining Suicide Rates in China Between 2005 and 2017.

BACKGROUND: Worldwide suicide rates have declined since 2000s, with China being the primary contributor. This study aimed to investigate whether urbanisation is associated with decreasing suicide rates in China. METHODS: Suicide rates and economic indicators of 31 provinces, municipalities, and autonomous regions of China between 2005 and 2017 were analysed. Poisson random intercept models were used to determine associations between suicide rates, urbanicity, sexes, and gross regional product (GRP). RESULTS: Between 2005 and 2017, suicide rates in 31 provinces, municipalities, and autonomous regions of China continued to decrease. Urbanicity and GRP were associated with decreased suicide rates among Chinese males and females. An increase in urbanicity by 1% was associated with a 2.2% decrease in suicide rates (p < 0.001). The most urbanised and populous cities (Beijing, Shanghai, Tianjin) had the lowest suicide rates. Urbanicity was associated with a greater decline in suicide rates among females, compared with males. Association between increased urbanicity and reduced suicide rates was independent of GRP. CONCLUSION: Urbanisation was associated with declining suicide rates in China; this association was stronger among females than males.

Reducing Vocal Fatigue While Preserving Realism During Video Game Voice-Overs Using the Vocal Combat Technique: A Randomized Controlled Trial.

OBJECTIVE: Vocal Combat Technique (VCT) teaches indirect and direct behavioral voice techniques to voice-over artists performing in violent video games. Although previous work on VCT has shown promise for mitigating dysphonia symptoms, a randomized clinical trial has yet to be undertaken. Therefore, we completed a randomized, controlled trial between a group of experienced video game voice-over actors receiving VCT and a control group comparison. METHODS: A total of 24 video game voice-over actors completed this study. Participants were randomly assigned to receive VCT or indirect vocal hygiene training prior to completing an intensive 1-hour video game voice recording session. The primary outcome was a change in Voice Handicap Index-10 (VHI-10) preperformance/postperformance. Secondary measures included a modified version of the Evaluation of the Ability to Sing Easily (m-EASE), the Vocal Tract Discomfort Scale (VTDS), and questions regarding return to work. Participants were also rated on the realism of their vocal performance by a blinded video game director. RESULTS: The VCT group showed a significantly smaller change in VHI-10 and m-EASE scores postperformance, and a higher increased likelihood to return to work compared to the control group. There were no group differences for VTDS or realism ratings. Four participants from the control group exhibited outlier behavior with more pronounced phonotraumatic symptoms following performance than all other participants. CONCLUSIONS: VCT shows evidence of mitigating symptoms of dysphonia while preserving the realism of the vocal performance. More work is needed to understand performers at risk for more severe vocal symptoms following extreme voice-over work, so as to target them for preventative techniques and voice preservation.

Developmental Manganese Exposure Causes Lasting Attention Deficits Accompanied by Dysregulation of mTOR Signaling and Catecholaminergic Gene Expression in Brain Prefrontal Cortex.

Elevated manganese (Mn) exposure is associated with attentional deficits in children, and is an environmental risk factor for attention deficit hyperactivity disorder (ADHD). We have shown that developmental Mn exposure causes lasting attention and sensorimotor deficits in a rat model of early childhood Mn exposure, and that these deficits are associated with a hypofunctioning catecholaminergic system in the prefrontal cortex (PFC), though the mechanistic basis for these deficits is not well understood. To address this, male Long-Evans rats were exposed orally to Mn (50 mg/kg/d) over PND 1-21 and attentional function was assessed in adulthood using the 5-Choice Serial Reaction Time Task. Targeted catecholaminergic system and epigenetic gene expression, followed by unbiased differential DNA methylation and gene regulation expression transcriptomics in the PFC, were performed in young adult littermates. Results show that developmental Mn exposure causes lasting focused attention deficits that are associated with reduced gene expression of tyrosine hydroxylase, dopamine transporter, and DNA methyltransferase 3a. Further, developmental Mn exposure causes broader lasting methylation and gene expression dysregulation associated with epigenetic regulation, inflammation, cell development, and hypofunctioning catecholaminergic neuronal systems. Pathway enrichment analyses uncovered mTOR and Wnt signaling pathway genes as significant transcriptomic regulators of the Mn altered transcriptome, and Western blot of total, C1 and C2 phospho-mTOR confirmed mTOR pathway dysregulation. Our findings deepen our understanding of the mechanistic basis of how developmental Mn exposure leads to lasting catecholaminergic dysfunction and attention deficits, which may aid future therapeutic interventions of environmental exposure associated disorders. Significance Statement: Attention deficit hyperactivity disorder (ADHD) is associated with environmental risk factors, including exposure to neurotoxic agents. Here we used a rodent model of developmental manganese (Mn) exposure producing lasting attention deficits to show broad epigenetic and gene expression changes in the prefrontal cortex, and to identify disrupted mTOR and Wnt signaling pathways as a novel mechanism for how developmental Mn exposure may induce lasting attention and catecholaminergic system impairments. Importantly, our findings establish early development as a critical period of susceptibility to lasting deficits in attentional function caused by elevated environmental toxicant exposure. Given that environmental health threats disproportionately impact communities of color and low socioeconomic status, our findings can aid future studies to assess therapeutic interventions for vulnerable populations.