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Approximately 3 billion people worldwide cook with solid fuels, such as wood, charcoal, and agricultural residues. These fuels, also used for residential heating, are often combusted in inefficient devices, producing carbonaceous emissions. Between 2.6 and 3.8 million premature deaths occur as a result of exposure to fine particulate matter from the resulting household air pollution (Health Effects Institute, 2018a; World Health Organization, 2018). Household air pollution also contributes to ambient air pollution; the magnitude of this contribution is uncertain. Here, we simulate the distribution of the two major health-damaging outdoor air pollutants (PM2:5 and O3) using state-of-thescience emissions databases and atmospheric chemical transport models to estimate the impact of household combustion on ambient air quality in India. The present study focuses on New Delhi and the SOMAARTH Demographic, Development, and Environmental Surveillance Site (DDESS) in the Palwal District of Haryana, located about 80 km south of New Delhi. The DDESS covers an approximate population of 200 000 within 52 villages. The emissions inventory used in the present study was prepared based on a national inventory in India (Sharma et al., 2015, 2016), an updated residential sector inventory prepared at the University of Illinois, updated cookstove emissions factors from Fleming et al. (2018b), and PM2:5 speciation from cooking fires from Jayarathne et al. (2018). Simulation of regional air quality was carried out using the US Environmental Protection Agency Community Multiscale Air Quality modeling system (CMAQ) in conjunction with the Weather Research and Forecasting modeling system (WRF) to simulate the meteorological inputs for CMAQ, and the global chemical transport model GEOS-Chem to generate concentrations on the boundary of the computational domain. Comparisons between observed and simulated O3 and PM2:5 levels are carried out to assess overall airborne levels and to estimate the contribution of household cooking emissions.

Air quality in rural India is impacted by residential cooking and heating with biomass fuels. In this study, emissions of CO, CO2, and 76 volatile organic compounds (VOCs) and fine particulate matter (PM2.5) were quantified to better understand the relationship between cook fire emissions and ambient ozone and secondary organic aerosol (SOA) formation. Cooking was carried out by a local cook, and traditional dishes were prepared on locally built chulha or angithi cookstoves using brushwood or dung fuels. Cook fire emissions were collected throughout the cooking event in a Kynar bag (VOCs) and on polytetrafluoroethylene (PTFE) filters (PM2.5). Gas samples were transferred from a Kynar bag to previously evacuated stainless-steel canisters and analyzed using gas chromatography coupled to flame ionization, electron capture, and mass spectrometry detectors. VOC emission factors were calculated from the measured mixing ratios using the carbon-balance method, which assumes that all carbon in the fuel is converted to CO2, CO, VOCs, and PM2.5 when the fuel is burned. Filter samples were weighed to calculate PM2.5 emission factors. Dung fuels and angithi cookstoves resulted in significantly higher emissions of most VOCs (p < 0.05). Utilizing dung-angithi cook fires resulted in twice as much of the measured VOCs compared to dung-chulha and 4 times as much as brushwood-chulha, with 84.0, 43.2, and 17.2g measured VOCkgg fuel carbon, respectively. This matches expectations, as the use of dung fuels and angithi cookstoves results in lower modified combustion efficiencies compared to brushwood fuels and chulha cookstoves. Alkynes and benzene were exceptions and had significantly higher emissions when cooking using a chulha as opposed to an angithi with dung fuel (for example, benzene emission factors were 3.18gkgg fuel carbon for dung-chulha and 2.38gkgg fuel carbon for dung-angithi). This study estimated that 3 times as much SOA and ozone in the maximum incremental reactivity (MIR) regime may be produced from dung-chulha as opposed to brushwood-chulha cook fires. Aromatic compounds dominated as SOA precursors from all types of cook fires, but benzene was responsible for the majority of SOA formation potential from all chulha cook fire VOCs, while substituted aromatics were more important for dung-angithi. Future studies should investigate benzene exposures from different stove and fuel combinations and model SOA formation from cook fire VOCs to verify public health and air quality impacts from cook fires.

Emissions of airborne particles from biomass burning are a significant source of black carbon (BC) and brown carbon (BrC) in rural areas of developing countries where biomass is the predominant energy source for cooking and heating. This study explores the molecular composition of organic aerosols from household cooking emissions with a focus on identifying fuel-specific compounds and BrC chromophores. Traditional meals were prepared by a local cook with dung and brushwood-fueled cookstoves in a village in Palwal district, Haryana, India. Cooking was done in a village kitchen while controlling for variables including stove type, fuel moisture, and meal. Fine particulate matter (PM2.5) emissions were collected on filters, and then analyzed via nanospray desorption electrospray ionization-high-resolution mass spectrometry (nano-DESI-HRMS) and high-performance liquid chromatography-photodiode array-high-resolution mass spectrometry (HPLC-PDA-HRMS) techniques. The nano-DESI-HRMS analysis provided an inventory of numerous compounds present in the particle phase. Although several compounds observed in this study have been previously characterized using gas chromatography methods a majority of the species in the nano-DESI spectra were newly observed biomass burning compounds. Both the stove (chulha or angithi) and the fuel (brushwood or dung) affected the composition of organic aerosols. The geometric mean of the PM2.5 emission factor and the observed molecular complexity increased in the following order: brushwood-chulha (7.3±1.8 g kg-1 dry fuel, 93 compounds), dung-chulha (21.1±4.2 g kg-1 dry fuel, 212 compounds), and dung-angithi (29.8±11.5 g kg-1 dry fuel, 262 compounds). The mass-normalized absorption coefficient (MACbulk) for the organic-solvent extractable material for brushwood PM2.5 was 3.7±1.5 and 1.9±0.8m2 g-1 at 360 and 405 nm, respectively, which was approximately a factor of two higher than that for dung PM2.5. The HPLC-PDA-HRMS analysis showed that, regardless of fuel type, the main chromophores were CxHyOz lignin fragments. The main chromophores accounting for the higher MACbulk values of brushwood PM2.5 were C8H10O3 (tentatively assigned to syringol), nitrophenols C8H9NO4, and C10H10O3 (tentatively assigned to methoxycinnamic acid).

© 2015 Public Health Services, US Dept of Health and Human Services. All rights reserved.Background: With 40% of the world’s population relying on solid fuel, household air pollution (HAP) represents a major preventable risk factor for COPD (chronic obstru

Background: More than two-fifths of the world's population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD) among women in developing countries. Objective:

Stable-isotope ratios of carbon (13C/12C; δ13C) and nitrogen (15N/14N; δ15N) in animal tissues are analyzed to estimate animal foraging ecology because these ratios reflect those of an animal's diet. This reflection is generally indirect, as stable-isotope ratios change with trophic level. These differences, called discrimination factors (reported as Δ), vary considerably by species and tissue. Variations in discrimination factors used in stableisotope mixing models can lead to inaccurate estimates of diets. Therefore, determining accurate discrimination factors specific to species and tissue is important. We established the Δ13C and Δ15N values between diet and blood and feathers from chicks and juveniles of the California Condor (Gymnogyps californianus). Hatchlings were fed rats for 76-119 days, whereas juveniles were fed dairy calves for 64 days. The mean Δ13C and Δ15N values ( ± SD) between chick feathers and rat muscle were 0.4 ± 0.4‰ and 3.1 ± 0.2‰, respectively; those between chicks' whole blood and rat muscle were -0.7 ± 0.1‰ and 1.7 ± 0.1‰, respectively. The mean Δ13C and Δ15N values between juvenile condors' plasma and calf muscle were 0.9 ± 0.2‰ and 3.3 ± 0.7‰, respectively; those between juveniles' red blood cells and calf muscle were 0.3 ± 0.3‰ and 1.8 ± 0.1‰, respectively; and those between juveniles' whole blood and calf muscle were 0.3 ± 0.3‰ and 1.9 ± 0.2‰, respectively. We report the first discrimination factors for the Cathartidae (New World vultures), and our findings will have important applications in studies of the critically endangered California Condor's foraging ecology. © The Cooper Ornithological Society 2013.

The PHENIX experiment at RHIC has a unique large rapidity coverage (1.2 < |y| < 2.2) for heavy flavor studies in heavy-ion collisions. This kinematic region has a smaller particle density and may undergo different nuclear effects before and after the hard process when compared to mid-rapidity production. The latest PHENIX runs contain a large data set which allows, for the first time, the study of heavy flavor and J/ψ flow at the large rapidity region in Au+Au collisions at √SNN =200 GeV. This measurement has the potential to reveal a medium evolution distinct from that known at mid-rapidity.

BACKGROUND: Implicit memory cannot be consciously recalled but may be revealed by changes in behavior. There is evidence for implicit memory formation during anesthesia in adults, but several studies in children have found no evidence for implicit memory. This may be due to insensitive testing. Also many of these tests were undertaken under controlled conditions. It remains unknown whether implicit memory is formed during routine pediatric anesthesia. The aim of this study was to determine whether there is evidence of implicit memory formation during routine anesthesia in children, using a degraded auditory stimulus recognition task. METHODS: Three hundred and twelve children, aged 5-12 yr, were randomly assigned to be played either a sheep sound or white noise continuously through headphones during general anesthesia. No attempt was made to standardize the anesthetic. On recovery, children were played a sheep sound degraded by a white noise mask that progressively decreased over 60 s, with the outcome being the time taken to correctly recognize the sheep sound. RESULTS: Three hundred children completed the task. A comparison of the distribution of recognition times between the two groups found little evidence that exposure to a sheep sound during anesthesia was associated with postoperative time to recognition of a degraded sheep sound (hazard ratio 1.14, 95% CI of 0.90-1.43, P = 0.28). CONCLUSION: No implicit memory formation during routine anesthesia was demonstrated in children. It is increasingly likely that the potential clinical implications of implicit memory formation are less of a concern for pediatric anesthetists. [ABSTRACT FROM AUTHOR]

Background: In Nepal, tuberculosis (TB) is a major problem. Worldwide, six previous epidemiologic studies have investigated whether indoor cooking with biomass fuel such as wood or agricultural wastes is associated with TB with inconsistent results. Objectives: Using detailed information on potential confounders, we investigated the associations between TB and the use of biomass and kerosene fuels. Methods: A hospital-based case-control study was conducted in Pokhara, Nepal. Cases (n = 125) were women, 20-65 years old, with a confirmed diagnosis of TB. Age-matched controls (n = 250) were female patients without TB. Detailed exposure histories were collected with a standardized questionnaire. Results: Compared with using a clean-burning fuel stove (liquefied petroleum gas, biogas), the adjusted odds ratio (OR) for using a biomass-fuel stove was 1.21 [95% confidence interval (CI), 0.48-3.05], whereas use of a kerosene-fuel stove had an OR of 3.36 (95% CI, 1.01-11.22). The OR for use of biomass fuel for heating was 3.45 (95% CI, 1.44-8.27) and for use of kerosene lamps for lighting was 9.43 (95% CI, 1.45-61.32). Conclusions: This study provides evidence that the use of indoor biomass fuel, particularly as a source of heating, is associated with TB in women. It also provides the first evidence that using kerosene stoves and wick lamps is associated with TB. These associations require confirmation in other studies. If using kerosene lamps is a risk factor for TB, it would provide strong justification for promoting clean lighting sources, such as solar lamps. [ABSTRACT FROM AUTHOR]

Exposure to household wood smoke from cooking is a risk factor for chronic obstructive lung disease among women in developing countries. The Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) is a randomized intervention trial evaluating the respiratory health effects of reducing indoor air pollution from open cooking fires. A total of 504 rural Mayan women in highland Guatemala aged 15-50 years, all using traditional indoor open fires, were randomized to either receive a chimney woodstove (plancha) or continue using the open fire. Assessments of chronic respiratory symptoms and lung function and individual measurements of carbon monoxide exposure were performed at baseline and every 6 months up to 18 months. Use of a plancha significantly reduced carbon monoxide exposure by 61.6%. For all respiratory symptoms, reductions in risk were observed in the plancha group during follow-up; the reduction was statistically significant for wheeze (relative risk = 0.42, 95% confidence interval: 0.25, 0.70). The number of respiratory symptoms reported by the women at each follow-up point was also significantly reduced by the plancha (odds ratio = 0.7, 95% confidence interval: 0.50, 0.97). However, no significant effects on lung function were found after 12-18 months. Reducing indoor air pollution from household biomass burning may relieve symptoms consistent with chronic respiratory tract irritation. [ABSTRACT FROM AUTHOR]

Abstract Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1), a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions. Methods A femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into Rag2-/-;γc-/- mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT). Results PCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into Rag2-/-;γc-/- mice. Xenograft tumors expressed human prostate specific antigen (PSA) in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture. Conclusions PCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely resembled the bone lesions in the patient. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study metastatic disease in the bone and to develop novel therapies for inhibiting prostate cancer growth in the bone-niche.

Abstract Background Silencing of genes inserted near telomeres provides a model to investigate the function of heterochromatin. We initiated a study of telomeric silencing in Neurospora crassa, a fungus that sports DNA methylation, unlike most other organisms in which telomeric silencing has been characterized. Results The selectable marker, hph, was inserted at the subtelomere of Linkage Group VR in an nst-1 (neurospora sir two-1) mutant and was silenced when nst-1 function was restored. We show that NST-1 is an H4-specific histone deacetylase. A second marker, bar, tested at two other subtelomeres, was similarly sensitive to nst-1 function. Mutation of three additional SIR2 homologues, nst-2, nst-3 and nst-5, partially relieved silencing. Two genes showed stronger effects: dim-5, which encodes a histone H3 K9 methyltransferase and hpo, which encodes heterochromatin protein-1. Subtelomeres showed variable, but generally low, levels of DNA methylation. Elimination of DNA methylation caused partial derepression of one telomeric marker. Characterization of histone modifications at subtelomeric regions revealed H3 trimethyl-K9, H3 trimethyl-K27, and H4 trimethyl-K20 enrichment. These modifications were slightly reduced when telomeric silencing was compromised. In contrast, acetylation of histones H3 and H4 increased. Conclusion We demonstrate the presence of telomeric silencing in Neurospora and show a dependence on histone deacetylases and methylation of histone H3 lysine 9. Our studies also reveal silencing functions for DIM-5 and HP1 that appear independent of their role in de novo DNA methylation.

Abstract Background Soluble fibers lower serum lipids, but are difficult to incorporate into products acceptable to consumers. We investigated the physiological effects of a concentrated oat β-glucan on cardiovascular disease (CVD) endpoints in human subjects. We also compared the fermentability of concentrated oat β-glucan with inulin and guar gum in a model intestinal fermentation system. Methods Seventy-five hypercholesterolemic men and women were randomly assigned to one of two treatments: 6 grams/day concentrated oat β-glucan or 6 grams/day dextrose (control). Fasting blood samples were collected at baseline, week 3, and week 6 and analyzed for total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glucose, insulin, homocysteine and C-reactive protein (CRP). To estimate colonic fermentability, 0.5 g concentrated oat β-glucan was incubated in a batch model intestinal fermentation system, using human fecal inoculum to provide representative microflora. Fecal donors were not involved with the β-glucan feeding trial. Inulin and guar gum were also incubated in separate serum bottles for comparison. Results Oat β-glucan produced significant reduction from baseline in total cholesterol (-0.3 ± 0.1 mmol/L) and LDL cholesterol (-0.3 ± 0.1 mmol/L), and the reduction in LDL cholesterol were significantly greater than in the control group (p = 0.03). Concentrated oat β-glucan was a fermentable fiber and produced total SCFA and acetate concentrations similar to inulin and guar gum. Concentrated oat β-glucan produced the highest concentrations of butyrate at 4, 8, and 12 hours. Conclusion Six grams concentrated oat β-glucan per day for six weeks significantly reduced total and LDL cholesterol in subjects with elevated cholesterol, and the LDL cholesterol reduction was greater than the change in the control group. Based on a model intestinal fermentation, this oat β-glucan was fermentable, producing higher amounts of butyrate than other fibers. Thus, a practical dose of β-glucan can significantly lower serum lipids in a high-risk population and may improve colon health.

Abstract Background Recently a hyperthermic rat hippocampal slice model system has been used to investigate febrile seizure pathophysiology. Our previous data indicates that heating immature rat hippocampal slices from 34 to 41°C in an interface chamber induced epileptiform-like population spikes accompanied by a spreading depression (SD). This may serve as an in vitro model of febrile seizures. Results In this study, we further investigate cellular mechanisms of hyperthermia-induced initial population spike activity. We hypothesized that GABAA receptor-mediated 30–100 Hz γ oscillations underlie some aspects of the hyperthermic population spike activity. In 24 rat hippocampal slices, the hyperthermic population spike activity occurred at an average frequency of 45.9 ± 14.9 Hz (Mean ± SE, range = 21–79 Hz, n = 24), which does not differ significantly from the frequency of post-tetanic γ oscillations (47.1 ± 14.9 Hz, n = 34) in the same system. High intensity tetanic stimulation induces hippocampal neuronal discharges followed by a slow SD that has the magnitude and time course of the SD, which resembles hyperthermic responses. Both post-tetanic γ oscillations and hyperthermic population spike activity can be blocked completely by a specific GABAA receptor blocker, bicuculline (5–20 μM). Bath-apply kynurenic acid (7 mM) blocks synaptic transmission, but fails to prevent hyperthermic population spikes, while intracellular diffusion of QX-314 (30 mM) abolishes spikes and produces a smooth depolarization in intracellular recording. Conclusion These results suggest that the GABAA receptor-governed γ oscillations underlie the hyperthermic population spike activity in immature hippocampal slices.

OBJECTIVE: Trials of environmental risk factors and acute lower respiratory infections (ALRI) face a double challenge: implementing sufficiently sensitive and specific outcome assessments, and blinding. We evaluate methods used in the first randomized exposure study of pollution indoors and respiratory effects (RESPIRE): a controlled trial testing the impact of reduced indoor air pollution on ALRI, conducted among children 90% of children meeting ALRI criteria, of whom about 70% attended a physician. Referrals for cough without respiratory signs and self-referrals contributed 19.0% and 17.9% of physician-diagnosed ALRI cases respectively. Intervention group attendance following ALRI referral was 7% higher than controls, a trend also seen in compliance with RSV tests and CXR. There was no evidence of bias by intervention status in fieldworker classification or physician diagnosis. Incidence of fieldworker ALRI (1.12 episodes/child/year) is consistent with high sensitivity and low specificity; incidence of physician-diagnosed ALRI (0.44 episodes/child/year) is consistent with comparable studies. CONCLUSION: The combination of case-finding methods achieved good sensitivity and specificity, but intervention cases had greater likelihood of reaching the physician and being investigated. There was no evidence of bias in fieldworkers classifications despite lack of concealment at home visits. Pulse oximetry offers practical, objective severity assessment for field studies of ALRI. Copyright © 2007 World Health Organization [ABSTRACT FROM AUTHOR]

Reduction of indoor air pollution (IAP) exposure from solid fuel use is a potentially important intervention for childhood pneumonia prevention. This review updates a prior meta-analysis and investigates whether risk varies by etiological agent and pneumonia severity among children aged less than 5 years who are exposed to unprocessed solid fuels. Searches were made of electronic databases (including Africa, China and Latin America) without language restriction. Search terms covered all sources of IAP and wide-ranging descriptions of acute lower respiratory infections, including viral and bacterial agents. From 5317 studies in the main electronic databases (plus 307 African and Latin American, and 588 Chinese studies, in separate databases), 25 were included in the review and 24 were suitable for meta-analysis. Due to substantial statistical heterogeneity, random effects models were used. The overall pooled odds ratio was 1.78 (95% confidence interval, CI: 1.45-2.18), almost unchanged at 1.79 (95% CI: 1.26-2.21) after exclusion of studies with low exposure prevalence (< 15%) and one high outlier. There was evidence of publication bias, and the implications for the results are explored. Sensitivity subanalyses assessed the impact of control selection, adjustment for confounding, exposure and outcome assessment, and age, but no strong effects were identified. Evidence on respiratory syncytial virus was conflicting, while risk for severe or fatal pneumonia was similar to or higher than that for all pneumonia. Despite heterogeneity, this analysis demonstrated sufficient consistency to conclude that risk of pneumonia in young children is increased by exposure to unprocessed solid fuels by a factor of 1.8. Greater efforts are now required to implement effective interventions. [ABSTRACT FROM AUTHOR]

Breast cancer is a significant health challenge worldwide and is the most frequently diagnosed cancer among women globally. This review provides a comprehensive overview of breast cancer biology, genomics, and microbial dysbiosis, focusing on its various subtypes and racial differences. Breast cancer is primarily classified into carcinomas and sarcomas, with carcinomas constituting most cases. Epidemiology and breast cancer risk factors are important for public health intervention. Staging and grading, based on the TNM and Nottingham grading systems, respectively, are crucial to determining the clinical outcome and treatment decisions. Histopathological subtypes include in situ and invasive carcinomas, such as invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). The review explores molecular subtypes, including Luminal A, Luminal B, Basal-like (Triple Negative), and HER2-enriched, and delves into breast cancer's histological and molecular progression patterns. Recent research findings related to nuclear and mitochondrial genetic alterations, epigenetic reprogramming, and the role of microbiome dysbiosis in breast cancer and racial differences are also reported. The review also provides an update on breast cancer's current diagnostics and treatment modalities.

There are substantial challenges in studying human transgenerational epigenetic outcomes resulting from environmental conditions. The task requires specialized methods and tools that incorporate specific knowledge of multigenerational relationship combinations of probands and their ancestors, phenotype data for individuals, environmental information of ancestors and their descendants, which can span historical to present datasets, and informative environmental data that chronologically aligns with ancestors and descendants over space and time. As a result, there are few epidemiologic studies of potential transgenerational effects in human populations, thus limiting the knowledge of ancestral environmental conditions and the potential impacts we face with modern human health outcomes. In an effort to overcome some of the challenges in studying human transgenerational effects, we present two transgenerational study designs: transgenerational space-time cluster detection and transgenerational case-control study design. Like other epidemiological methods, these methods determine whether there are statistical associations between phenotypic outcomes (e.g., adverse health outcomes) among probands and the shared environments and environmental factors facing their ancestors. When the ancestor is a paternal grandparent, a statistically significant association provides some evidence that a transgenerational inheritable factor may be involved. Such results may generate useful hypotheses that can be explored using epigenomic data to establish conclusive evidence of transgenerational heritable effects. Both methods are proband-centric: They are designed around the phenotype of interest in the proband generation for case selection and family pedigree creation. In the examples provided, we incorporate at least three generations of paternal lineage in both methods to observe a potential transgenerational effect.

Objective: To ascertain how an instrumental variables (IV) model can improve upon the estimates obtained from traditional cost-of-illness (COI) models that treat health conditions as predetermined., Study Setting and Design: A simulation study based on observational data compares the coefficients and average marginal effects from an IV model to a traditional COI model when an unobservable confounder is introduced. The two approaches are then applied to real data, using a kinship-weighted family history as an instrument, and differences are interpreted within the context of the findings from the simulation study., Data Sources and Analytic Sample: The case study utilizes secondary data on type 2 diabetes mellitus (T2DM) status to examine healthcare costs attributable to the disease. The data come from Utah residents born between 1950 and 1970 with medical insurance coverage whose demographic information is contained in the Utah Population Database. Those data are linked to insurance claims from Utah's All-Payer Claims Database for the analyses., Principal Findings: The simulation confirms that estimated T2DM healthcare cost coefficients are biased when traditional COI models do not account for unobserved characteristics that influence both the risk of illness and healthcare costs. This bias can be corrected to a certain extent with instrumental variables. An IV model with a validated instrument estimates that 2014 costs for an individual age 45-64 with T2DM are 27% (95% CI: 2.9% to 51.9%) higher than those for an otherwise comparable individual who does not have T2DM., Conclusions: Researchers studying the COI for chronic diseases should assess the possibility that traditional estimates may be subject to bias because of unobserved characteristics. Doing so may be especially important for prevention and intervention studies that turn to COI studies to assess the cost savings associated with such initiatives., (© 2024 The Author(s). Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Activity-dependent protein synthesis is crucial for long-lasting forms of synaptic plasticity. However, our understanding of translational mechanisms controlling GABAergic synapses is limited. One distinct form of inhibitory long-term potentiation (iLTP) enhances postsynaptic clusters of GABA A Rs and the primary inhibitory scaffold, gephyrin, to promote sustained synaptic strengthening. While we previously found that persistent iLTP requires mRNA translation, the mechanisms controlling plasticity-induced gephyrin translation remain unknown. We identify miR153 as a novel regulator of Gphn mRNA translation which controls gephyrin protein levels and synaptic clustering, ultimately impacting inhibitory synaptic structure and function. iLTP induction downregulates miR153, reversing its translational suppression of Gphn mRNA and promoting de novo gephyrin protein synthesis and synaptic clustering during iLTP. Finally, we find that reduced miR153 expression during iLTP is driven by an excitation-transcription coupling pathway involving calcineurin, NFAT and HDACs, which also controls the miRNA-dependent upregulation of GABA A Rs. Together, we delineate a miRNA-dependent post-transcriptional mechanism that controls the expression of the key synaptic scaffold, gephyrin, and may converge with parallel miRNA pathways to coordinate gene upregulation to maintain inhibitory synaptic plasticity., (© 2024. The Author(s).)

Introduction: Clinical notes, biomarkers, and neuroimaging have proven valuable in dementia prediction models. Whether commonly available structured clinical data can predict dementia is an emerging area of research. We aimed to predict gold-standard, research-based diagnoses of dementia including Alzheimer's disease (AD) and/or Alzheimer's disease related dementias (ADRD), in addition to ICD-based AD and/or ADRD diagnoses, in a well-phenotyped, population-based cohort using a machine learning approach., Methods: Administrative healthcare data (k = 163 diagnostic features), in addition to census/vital record sociodemographic data (k = 6 features), were linked to the Cache County Study (CCS, 1995-2008)., Results: Among successfully linked UPDB-CCS participants (n = 4206), 522 (12.4%) had incident dementia (AD alone, AD comorbid with ADRD, or ADRD alone) as per the CCS "gold standard" assessments. Random Forest models, with a 1-year prediction window, achieved the best performance with an Area Under the Curve (AUC) of 0.67. Accuracy declined for dementia subtypes: AD/ADRD (AUC = 0.65); ADRD (AUC = 0.49). Accuracy improved when using ICD-based dementia diagnoses (AUC = 0.77)., Discussion: Commonly available structured clinical data (without labs, notes, or prescription information) demonstrate modest ability to predict "gold-standard" research-based AD/ADRD diagnoses, corroborated by prior research. Using ICD diagnostic codes to identify dementia as done in the majority of machine learning dementia prediction models, as compared to "gold-standard" dementia diagnoses, can result in higher accuracy, but whether these models are predicting true dementia warrants further research., (© 2024. The Author(s).)

Food motivation varies between individuals, affecting body weight and risk for eating disorders. Prior neuroimaging studies in youth and adults have revealed functional and structural alterations in the anterior cingulate cortex [ACC] in those with obesity and disordered eating but have not investigated their neurochemical underpinnings. In a sample of 37 children aged 4 to 13 years old, we used Magnetic Resonance Spectroscopy [MRS] to assess levels of γ-aminobutyric acid [GABA] - the major inhibitory neurotransmitter in the human brain - quantified relative to creatine in a 27-ml voxel including the dorsal ACC. We used the CEBQ to assess trait food motivation. In analyses adjusting for age, lower GABA+/Cr levels in the dorsal ACC were associated with higher trait enjoyment of food. Higher enjoyment of food scores were in turn associated with higher energy intake during an ad libitum test meal and during a postprandial task assessing intake in the absence of hunger, and higher body weight. Our results indicate a role for GABA function in the dorsal ACC in determining individual variation in food motivation in children., (© 2024. The Author(s).)

Background: Anorexia nervosa (AN) is a mental and behavioral health condition characterized by an intense fear of weight or fat gain, severe restriction of food intake resulting in low body weight, and distorted self-perception of body shape or weight. While substantial research has focused on general anxiety in AN, less is known about eating-related anxiety and its underlying neural mechanisms. Therefore, we sought to characterize anxiety-to-eat in AN and examine the neurometabolic profile within the dorsal anterior cingulate cortex (dACC), a brain region putatively involved in magnifying the threat response., Methods: Women seeking inpatient treatment for AN and women of healthy weight without a lifetime history of an eating disorder (healthy controls; HC) completed a computer-based behavioral task assessing anxiety-to-eat in response to images of higher (HED) and lower (LED) energy density foods. Participants also underwent magnetic resonance spectroscopy of the dACC in a 3 Tesla scanner., Results: The AN group reported greater anxiety to eat HED and LED foods relative to the HC group. Both groups reported greater anxiety to eat HED foods relative to LED foods. The neurometabolite myo-inositol (mI) was lower in the dACC in AN relative to HC, and mI levels negatively predicted anxiety to eat HED but not LED foods in the AN group only. mI levels in the dACC were independent of body weight, body mass, and general anxiety., Conclusions: These findings provide critical new insight into the clinically challenging feature and underlying neural mechanisms of eating-related anxiety and indicate mI levels in the dACC could serve as a novel biomarker of illness severity that is independent of body weight to identify individuals vulnerable to disordered eating or eating pathology as well as a potential therapeutic target.

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABA A receptor (GABA A R) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABA A R clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca 2+ -permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca 2+ -signaling, likely downstream of TRPM2 activation, upregulates Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)