Biochemical and in silico molecular study of caffeic acid-O-methyltransferase enzyme associated with lignin deposition in tall fescue.

Caffeic acid-O-methyltransferase (COMT), an important enzyme governing the process of lignification in plants, functions at the level of caffeic acid methylation along with 3-O-methylation of monolignol precursors. The present investigation was carried out to decipher the role of COMT in tall fescue lignification and to clone and characterize the COMT gene. The study on COMT activity variation at different growth stages of tall fescue exhibited a significant increase in activity over all the growth stages of tall fescue. A significant relative increase of 47.8% was observed from the first vegetative to reproductive stage. COMT activity exhibited a strong positive correlation with lignin content suggesting it to be an important enzyme of tall fescue lignification. Amplification and sequencing of tall fescue COMT gene resulted in an amplicon of size 1662 (Accession No.-MW442832) and an ORF of 346 amino acids. The deduced protein was hydrophobic, thermally stable and acidic with molecular formula C1679H2623N445O482S20, molecular mass 37.4 kDa and theoretical pI of 6.12. The protein possesses a conserved dimerization domain with a highly conserved SAM binding site. The COMT protein was found to be a homo-dimer with 1 catalytic SAH/SAM ligand per monomer interacting with 14 amino acid residues within 4 Å region.

Cloning and in silico characterization of cinnamyl alcohol dehydrogenase gene involved in lignification of Tall fescue (Festuca arundinacea Schreb.).

Tall fescue, a promising temperate forage grass of Himalayan region, possesses extraordinary property of rapid growth with high biomass production, but its poor digestibility due to higher lignin content limits its utilization in livestock feeding. The lignification in Tall fescue is under the control of enzymatic cascade of different regulatory enzymes. Cinnamyl alcohol dehydrogenase (CAD) is a crucial regulatory enzyme that catalyzes the last step of monolignol biosynthesis and is a potential candidate for altering the content and types of lignin, and hence increasing the digestibility of fodder crops. Hence, the present investigation was conducted on isolation, cloning and characterization of CAD gene from Tall fescue. Isolation and amplification of CAD gene resulted in an amplicon of 1521 bp. The CAD gene sequence was submitted to NCBI database with an accession number MW442831. Translation of the CAD gene sequence exhibited an ORF of 361 amino acids. The deduced CAD protein was predicted to be hydrophobic, acidic and thermally stable with molecular formula C1712H2734N460O520S23, molecular mass of 38.82 kDa, theoretical pI of 5.60 and 3 strong transmembrane helices. The CAD protein was predicted to have a dimer forming behavior with putative NAD(P) binding site between amino acids 48 and 301, putative substrate-binding site between amino acids 48 and 301, catalytic zinc-binding site between amino acids 48 and 164 and structural zinc-binding site between amino acid residue 101 and 115. A conserved 189GLGGVG194 motif is the binding site for NADP(H). The conserved motif pattern of CAD's zinc catalytic center was found to be 69GHEVVGEV(X)EVG(X)2V83. The zinc-binding site was found to be conserved between amino acid 89 and 115 and was found to be 89G(X)2VG(X)G(X)2VGXC(X)2C(X)2C(X)5QYC115. The deciphered sequence and putative protein information might be useful in subsequent research in lignin bioengineering for enhanced digestibility, biomass conversion as well as impact of lignin on cell wall mechanics.

Literature Review of the Efficacy of High-Volume Hemofiltration in Critically Ill Pediatric Patients.

BACKGROUND: Pediatric sepsis is a significant public health issue. This condition is exacerbated by rising serum creatinine and inflammatory cytokines that lead to deleterious effects upon the body. The current standard of care involves the use of continuous kidney replacement therapy to remove harmful cytokines until the body returns to homeostasis. In order to promote faster clearance and reduced stay in the ICU, high-volume hemofiltration (HVHF) has shown promise. However, there is a paucity of studies to fully elucidate its benefits. METHODS: A literature search was done using PubMed/ MEDLINE and Embase. The literature was reviewed by two independent reviewers, who independently assessed the quality of randomized controlled trials by using the Cochrane risk of bias tool for RCTs and Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized controlled trials. Data were combined from studies with a similar design. RESULTS: The primary endpoint of all-cause mortality was found to be reduced by 40% across all of the pooled studies. For secondary endpoints, significant reductions of serum creatinine were found. Additionally, duration of ICU stays and treatment course was found to be significantly shorter in HVHF patients than the current standard of care. The rate of adverse effects was analyzed, and there was no difference in the proportion of patients developing hypokalemia, hyperkalemia, hypernatremia, or hyponatremia. The proportion of patients developing hyperglycemia was higher in patients undergoing HVHF, whereas the proportions of patients developing bleeding were significantly less in patients undergoing HVHF. One study reported a total number of adverse events between the two groups which were significantly lesser in patients undergoing HVHF. CONCLUSION: HVHF shows promise as a modality to treat pediatric patients with sepsis. In order to confirm the benefits of this modality, future studies need significantly more patients for analysis.

Dichlorophene activates aryl hydrocarbon receptor (AhR) and indoleamine 2, 3-dioxygenase 1 (IDO1) to mediate splenotoxicity in rat.

Dichlorophene (DCP) is a halogenated phenolic compound, widely used as fungicide, bactericide and antiprotozoan and also exhibit therapeutic application in several pathological conditions. Taking account of broad use of DCP, its possible effect on spleen (an important immune organ) was investigated in this study. Male albino rats were treated with graded doses of DCP (10%, 20% and 30% of LD50) and spleen and blood were obtained at 24, 48 and 72 hours post treatment. Oxidative stress parameters, proinflammatory cytokines and protein expression of aryl hydrocarbon receptor (AhR), indoleamine-2, 3-Dioxygenase 1 (IDO1) and nuclear factor erythroid 2-related factor 2 (Nrf2) were measured along with histopathological evaluation of spleen. In the present study, DCP perturbs redox status of splenocytes of rats as evidenced by excess ROS generation, lipid peroxidation and nitric oxide production simultaneously with reduction of antioxidant level [glutathione (GSH)] and inhibition of antioxidative enzymes [superoxide dismutase (SOD) and catalase (CAT)]. Two important proinflammatory cytokines, IL-6 and TNF-α were found to be elevated upon DCP treatment. Moreover, DCP also caused activation of AhR and IDO1 with simultaneous down regulation of Nrf2. All these effects of DCP were found to be dose and duration dependent. DCP also affects the spleen micro-architecture in the present study and these alterations were more prominent in high dose group at 72 hours post treatment. Taken together, all these results suggested that DCP induces oxidative stress and also increases proinflammatory cytokine levels to mount its toxic effect on spleen.

Multi-residue determination of pesticides in vegetables and assessment of human health risks in Western Himalayan region of India.

This study was aimed to determine pesticides concentrations in fresh vegetables and assess human health risks in North-Western Himalayan region of India. Vegetable samples (n = 300) collected randomly from different agro-climatic zones were analyzed for 19 pesticides using gas chromatography. Pesticide residues were detected in 116 samples, of which 49 samples exceeded maximum permissible limits established by European Commission. Hexaconazole was most frequently detected in 9.3% samples followed by aldrin (8.3%), alachlor (5.3%), bifenthrin (4.3%), chlorpyrifos (3.7%), metribuzin (2.7%), ß-endosulfan, ethion, ß-HCH (2%, each), γ-HCH (1.3%), α-HCH, δ-HCH, malathion, heptachlor (1%, each), and α-endosulfan, pendimethalin in 0.7% samples. Human health risk assessment revealed that the percent contribution to acceptable daily intakes of pesticides via dietary intake of vegetables ranged from 0.014 to 39.4% in children and 0.003 to 9.85% in adults. Although hazard index values were < 1 but considering the concentrations of detected pesticide in samples, children were found to be at more risk. Since pragmatic investigations on occurrence of pesticides in vegetables and human health risk assessment from study area have not yet been worked out, so, this study highlights the importance of adopting good agricultural practices, awareness on food safety, monitoring of harmful chemicals in food commodities, and execution of food safety regulations to safeguard environmental and human health.

Transmission Dynamics of Clostridioides difficile in 2 High-Acuity Hospital Units.

BACKGROUND: The key epidemiological drivers of Clostridioides difficile transmission are not well understood. We estimated epidemiological parameters to characterize variation in C. difficile transmission, while accounting for the imperfect nature of surveillance tests. METHODS: We conducted a retrospective analysis of C. difficile surveillance tests for patients admitted to a bone marrow transplant (BMT) unit or a solid tumor unit (STU) in a 565-bed tertiary hospital. We constructed a transmission model for estimating key parameters, including admission prevalence, transmission rate, and duration of colonization to understand the potential variation in C. difficile dynamics between these 2 units. RESULTS: A combined 2425 patients had 5491 admissions into 1 of the 2 units. A total of 3559 surveillance tests were collected from 1394 patients, with 11% of the surveillance tests being positive for C. difficile. We estimate that the transmission rate in the BMT unit was nearly 3-fold higher at 0.29 acquisitions per percentage colonized per 1000 days, compared to our estimate in the STU (0.10). Our model suggests that 20% of individuals admitted into either the STU or BMT unit were colonized with C. difficile at the time of admission. In contrast, the percentage of surveillance tests that were positive within 1 day of admission to either unit for C. difficile was 13.4%, with 15.4% in the STU and 11.6% in the BMT unit. CONCLUSIONS: Although prevalence was similar between the units, there were important differences in the rates of transmission and clearance. Influential factors may include antimicrobial exposure or other patient-care factors.

Reproductive toxic potential of phthalate compounds - State of art review.

Phthalates are pervasive compounds, and due to the ubiquitous usage of phthalates, humans or even children are widely exposed to them. Since phthalates are not chemically bound to the plastic matrix, they can easily leach out to contaminate the peripheral environment. Various animal and human studies have raised vital health concern including developmental and reproductive toxicity of phthalate exposure. The present review is based upon the available literature on phthalates with respect to their reproductive toxic potential. Common reproductive effects such as declined fertility, reduced testis weight, variations in accessory sex organs and several female reproductive disorders appeared to be largely associated with the transitional phthalates. Among the higher molecular weight phthalates (≥ C7), di-isononyl phthalate (DINP) produces some minor effects on development of male reproductive tract and among low molecular weight phthalates (≤C3), di-methyl (DMP) and di-isobutyl (DIBP) phthalate produce some adverse effects on male reproductive system. Whereas transitional phthalates such as di-butyl phthalate, benzyl butyl phthalate, and di-(2-ethylhexyl) phthalate have shown adverse effects on female reproductive system. Owing to these, non-toxic alternatives to phthalates may be developed and use of phthalates could be rationalized as an important issue where human reproduction system is involved. Though, more epidemiological studies are needed to substantiate the reported findings on phthalates.

Current practice patterns, challenges, and educational needs of asthma care providers in the United States.

OBJECTIVE: For severe, uncontrolled asthma (SUA), a gap exists between recent scientific advances and their incorporation into clinical practice. Using a Knowledge-to-Action Framework, new knowledge can be translated into evidence-based interventions to improve outcomes. The AstraZeneca U.S. PRECISION initiative aims to apply this Framework to improve recognition and management of SUA. The study objective was to identify factors contributing to gaps in care for patients with SUA. Results from a needs assessment survey of U.S. pulmonologists and allergists/immunologists were assessed within the Knowledge-to-Action Framework to advance bench-to-bedside care. METHODS: Pulmonologists and allergists/immunologists from across the United States were invited to complete a customized, quantitative severe asthma survey in person at the 2017 American Thoracic Society annual meeting or via the Internet. Responses were summarized descriptively, and chi-squared tests evaluated associations between variables of interest. RESULTS: Overall, 140 U.S. providers responded, most of whom were pulmonologists (84%). Most (60%) practiced in a community-based setting; 40% practiced at an academic medical center. Key challenges to providing care for patients with severe asthma included insurance company requirements and identification of the pathophysiology of an individual patient's severe asthma. Traditional measures of asthma-related morbidity were ranked as highly important by significantly more respondents compared with assessment of biomarkers (p < 0.0001). Respondents generally valued online virtual self-education. CONCLUSIONS: Survey results identified unmet needs for the identification and management of patients with SUA and opportunities to improve patient outcomes through evidence-based management of SUA, including testing for biologic eligibility and subsequent use of biologic therapies.

Variation Among Primary Care Physicians in 30-Day Readmissions.

Background: Whether readmission rates vary by primary care physician (PCP) is unknown, although federal policy holds PCPs accountable for reducing readmissions. Objective: To determine whether 30-day readmission rates vary by PCP. Design: Retrospective cohort study using marginal models and multilevel logistic regression with 100% of data on Texas Medicare claims from 2008 to 2015. Setting: Texas. Participants: Patients discharged alive between 1 January 2008 and 30 November 2015 who had a PCP in the prior year and whose PCP had at least 50 admissions in the study period. Measurements: Readmission within 30 days of discharge. Follow-up visits with a PCP within 7 days of discharge were also measured. Results: Between 2012 and 2015, the mean risk-standardized rate of 30-day readmissions was 12.9%. Of 4230 PCPs, 1 had a readmission rate that was significantly higher than the mean and none had a significantly lower rate. The 10th and 90th percentiles of PCP readmission rates were 12.4% and 13.4%, respectively, each only 0.5 percentage point different from the mean. The 99th percentile of PCP readmission rates was 14.0%, 1.1 percentage points higher than the mean. Detecting a 1.1-percentage point difference from the mean adjusted readmission rate would require more than 3500 admissions per PCP per year. Limitations: Only fee-for-service Medicare patients in a single state were included. The authors could not account for confounders not included in Medicare databases or classify readmissions as avoidable. Conclusion: Variation in readmission rates among PCPs is very low. Programs holding PCPs accountable for readmissions may prove ineffective. Primary Funding Source: National Institutes of Health.

Very Early Versus Early Readmissions in General Surgery Patients.

BACKGROUND: Hospital readmission rates are an important quality metric. A readmission very soon after discharge may be related to a different cause than readmissions that occur later in the first 30 d. MATERIALS AND METHODS: The National Surgical Quality Improvement Program data sets from 2014 to 2015 were used to identify patients undergoing general surgery procedures. Demographics, comorbidities, and morbidity were analyzed. Stepwise regression was used to determine statistical predictors for any readmission. The final model variables were a combination of selected clinical variables and statistically significant variables. Multinomial logistic regression was then used with these variables to develop models for "very early" (days 0-3 after discharge) and "early" (days 4-30) readmissions. RESULTS: A total of 744,492 patients were included with 5.9% readmitted within 30 d and 1.5% readmitted within 3 d of discharge (26.1% of all readmissions). Significant risk factors for any readmission included ≥3 comorbidities, major surgery (operative time >1 h, length of stay greater >2 d), and American Society of Anesthesiologists class ≥3. When examining "very early" readmissions, the greatest risk factor was experiencing a severe complication (≥Grade III) before discharge. CONCLUSIONS: Readmissions within 3 d of discharge constitute a large portion of all 30 d readmissions. The greatest risk factor for "very early" readmission was a severe complication before discharge. Better understanding of the reason for this association is needed to develop effective prevention strategies.

Targeting mitochondria with folic acid and vitamin B12 ameliorates nicotine mediated islet cell dysfunction.

Nicotine, one of the well-known highly toxic components of cigarette smoke, causes a number of adverse health effects and diseases. Our previous study has shown that nicotine induces reactive oxygen species (ROS) in islet cell and disrupts islet cell mitochondrial membrane potential (ΔΨm). However, supplementation with folic acid and vitamin B12 were found effective against nicotine induced changes in pancreatic islet cells. But the toxicological effects and underlying mechanisms of nicotine-induced mitochondrial dysfunction is still unknown. In this study, nicotine exposure decreases mitochondrial enzymes (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, aconitase, malate dehydrogenase) activities by increasing cytosolic Ca2+ level which may contribute to increased mitochondrial ROS production by raising its flow to mitochondria. This in turn produces malondialdehyde and nitric oxide (NO) with a concomitant decrease in the activities of antioxidative enzymes and glutathione levels leading to loss of ΔΨm. Simultaneously, nicotine induces pancreatic islet cell apoptosis by modulating ΔΨm via increased cytosolic Ca2+ level, altered Bcl-2, Bax, cytochrome c, caspase-9, PARP expressions which were prevented by the supplementation of folic acid and vitamin B12 . In conclusion, nicotine alters islet cell mitochondrial redox status, apoptotic machinery, and enzymes to cause disruption in the ΔΨm and supplementation of folic acid and vitamin B12 possibly blunted all these mitochondrial alterations. Therefore, this study may help to determine the pathophysiology of nicotine-mediated islet cell mitochondrial dysfunction.

Inhibition of catalase activity with 3-amino-1,2,4-triazole intensifies bisphenol A (BPA)-induced toxicity in granulosa cells of female albino rats.

Exposure to bisphenol A (BPA), an endocrine disruptor and environmental toxicant, is associated with adverse estrogenic effects in both humans and wildlife species. Because the effects of BPA on the ovary at the cellular level are incompletely understood, the present study was designed to investigate the underlying mechanism of granulosa cell injury following BPA exposure. Eight-week-old female Wistar rats were treated with BPA (25 mg/kg BW/day for 9 days, intraperitonially) with or without pretreatment of the catalase-specific blocker 3-amino-1,2,4-triazole (ATZ; 1 g/kg BW/day for 5 days, intraperitonially). Different oxidative and antioxidant stress parameters, pro-inflammatory cytokines, and hormonal levels were measured. Catalase expression in isolated granulosa cells was analyzed by Western blot. There were noticeable increases in both nitric oxide and lipid peroxidation levels in the granulosa cells of the BPA-treated group with or without pretreatment with ATZ. Compared with the controls, BPA exposure resulted in a significant increase in pro-inflammatory cytokine levels that was further increased following pretreatment with ATZ. Results of the hormonal assays clearly showed a significant decrease in both estrogen and progesterone levels. In contrast, there was a significant increase in both serum follicle-stimulating hormone and luteinizing hormone levels following BPA exposure, with or without ATZ pretreatment. Results of Western blot analysis demonstrated decreased expression of catalase in the BPA-treated group and a further decrease in expression in the group treated with both BPA and ATZ. Our data suggest that catalase plays a role in mediating reproductive damage to granulosa cells exposed to BPA.

Novel 3-methylindoline inhibitors of EZH2: Design, synthesis and SAR.

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.

Large inter annual variation in air quality during the annual festival 'Diwali' in an Indian megacity.

A network of air quality and weather monitoring stations was established under the System of Air Quality Forecasting and Research (SAFAR) project in Delhi. We report observations of ozone (O3), nitrogen oxides (NOx), carbon monoxide (CO) and particulate matter (PM2.5 and PM10) before, during and after the Diwali in two consecutive years, i.e., November 2010 and October 2011. The Diwali days are characterised by large firework displays throughout India. The observations show that the background concentrations of particulate matter are between 5 and 10 times the permissible limits in Europe and the United States. During the Diwali-2010, the highest observed PM10 and PM2.5 mass concentration is as high as 2070µg/m3 and 1620µg/m(3), respectively (24hr mean), which was about 20 and 27 times to National Ambient Air Quality Standards (NAAQS). For Diwali-2011, the increase in PM10 and PM2.5 mass concentrations was much less with their peaks of 600 and of 390µg/m(3) respectively, as compared to the background concentrations. Contrary to previous reports, firework display was not found to strongly influence the NOx, and O3 mixing ratios, with the increase within the observed variability in the background. CO mixing ratios showed an increase. We show that the large difference in 2010 and 2011 pollutant concentrations is controlled by weather parameters.

A qualitative evaluation of geographical localization of hospitalists: how unintended consequences may impact quality.

BACKGROUND: Geographical localization of hospitalist teams to nursing units may have an impact on the quality of inpatient care. The perceptions of individuals who provide patient care in a localized model of care have not been adequately studied. OBJECTIVE: To determine the impact of geographic localization of hospitalist teams by evaluating the perceptions of hospitalists (faculty and physician assistants) localized to a single nursing unit and the nurses who staffed that unit. DESIGN: Focus group study. SUBJECTS: Six hospitalist faculty and three hospitalist physician assistants who provided patient care while localized to a single nursing unit, as well as 29 nurses who staffed the nursing unit where localization occurred. MAIN MEASURES: Themes that emerged from grounded theory analysis of focus group transcripts. KEY RESULTS: Participants perceived an overall positive impact of localization on the quality of patient care they provide and their workflow. The positive impact was mediated through proximity to patients and between members of the healthcare team, as well as through increased communication, decreased wasted time and increased teamwork. The participants also identified increased interruptions, variability in patient flow, mismatches in specialization and perverse incentives as mediating factors leading to unintended consequences. A model emerged that can inform future deployment and evaluation of localization interventions. CONCLUSIONS: Geographical localization of hospitalist teams is perceived to be desirable by both hospitalists and nurses. Others who attempt localization could use our conceptual model as a guide to maximize the benefit and minimize the unintended consequences of this intervention.

Variation in the risk of readmission among hospitals: the relative contribution of patient, hospital and inpatient provider characteristics.

BACKGROUND: The risk of readmission varies among hospitals. This variation has led the Centers of Medicare and Medicaid services to reduce payments to hospitals with excess readmissions. The contribution of patient characteristics, hospital characteristics and provider type to the variation in risk of readmission among hospitals has not been determined. OBJECTIVE: To describe the variation in risk of readmission among hospitals and partition it by patient characteristics, hospital characteristics and provider type. DESIGN: Retrospective research design of 100% Texas Medicare data using multilevel, multivariable models. SUBJECTS: A total of 514,064 admissions of Medicare beneficiaries to 272 hospitals in Texas for medical diagnoses during the years 2008 and 2009. MAIN MEASURES: Using hierarchical generalized linear models, we describe the hospital-specific variation in risk of readmission that is attributable to patients characteristics, hospital characteristics and provider type by measuring the variance and intraclass correlation coefficients. KEY RESULTS: Of the total variation in risk of readmission, only a small amount (0.84%) is attributed to hospitals. In further analyses modeling the components of this variation among hospitals, differences in patient characteristics in the hospitals explained 56.2% of the variation. Hospital characteristics and the type of provider explained 9.3% of the variation among hospitals and 0.08% of the total variation in risk of readmission. CONCLUSIONS: Patient characteristics are the largest contributor to variation in risk of readmission among hospitals. Measurable hospital characteristics and the type of inpatient provider contribute little to variation in risk of readmission among hospitals.

Centella asiatica mitigates the detrimental effects of Bisphenol-A (BPA) on pancreatic islets.

Bisphenol-A (BPA) is widely used in food packaging and household products, leading to daily human exposure and potential health risks including metabolic diseases like type 2 diabetes mellitus (T2DM). Understanding BPA's mechanisms and developing intervention strategies is urgent. Centella asiatica, a traditional herbal medicine containing pentacyclic triterpenoids, shows promise due to its antioxidant and anti-inflammatory properties, utilized for centuries in Ayurvedic therapy. We investigated the effect of Centella asiatica (CA) ethanol extract on BPA-induced pancreatic islet toxicity in male Swiss albino mice. BPA administration (10 and 100 µg/kg body weight, twice daily) for 21 days caused glucose homeostasis disturbances, insulin resistance, and islet dysfunction, which were partially mitigated by CA supplementation (200 and 400 mg/kg body weight). Additionally, heightened oxidative stress, elevated levels of proinflammatory cytokines, loss of mitochondrial membrane potential (MMP), abnormal cell cycle, and increased apoptosis were implicated in the detrimental impact of BPA on the endocrine pancreas which were effectively counteracted by CA supplementation. In summary, CA demonstrated a significant ability to mitigate BPA-induced apoptosis, modulate redox homeostasis, alleviate inflammation, preserve MMP, and regulate the cell cycle. As a result, CA emerged as a potent agent in neutralizing the diabetogenic effects of BPA to a considerable extent.

Hotspot driven air pollution during crop residue burning season in the Indo-Gangetic Plain, India.

Intensive crop residue burning (CRB) in northern India triggers severe air pollution episodes over the Indo-Gangetic Plain (IGP) each year during October and November. We have quantified the contribution of hotspot districts (HSDs) and total CRB to poor air quality over the IGP. Initially, we investigated the spatiotemporal distribution of CRB fire within the domain and pinpointed five HSD in each Punjab and Haryana. Furthermore, we have simulated air quality and quantified the impact of CRB using the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem), incorporating recent anthropogenic emissions (EDGAR v5) and biomass burning emissions (FINN v2.4) inventories, along with MOZART-MOSAIC chemistry. The key finding is that HSDs contributed ∼80% and ∼50% of the total fire counts in Haryana and Punjab, respectively. The model effectively captured observed PM2.5 concentrations, with a normalized mean bias (NMB) below 0.2 and R-squared (R2) exceeding 0.65 at the majority of validation sites. However, some discrepancies were observed at a few sites in Delhi, Punjab, Haryana, and West Bengal. The National Capital Region experienced the highest PM2.5 concentrations, followed by Punjab, Haryana, Uttar Pradesh, Bihar, and West Bengal. Moreover, HSDs were responsible for about 70% of the total increase in CRB-induced PM2.5 in the western, central, and eastern cities, and around 50% in the northern cities. By eliminating CRB emissions across the domain, we could potentially save approximately 18,000 lives annually. Policymakers, scientists, and institutions can leverage the framework to address air pollution at national and global scales by targeting source-specific hotspots. This approach, coupled with appropriate technological and financial solutions, can contribute to achieving climate change and sustainable development goals.

Variation in length of stay and outcomes among hospitalized patients attributable to hospitals and hospitalists.

BACKGROUND: There have been no prior population-based studies of variation in performance of hospitalists. OBJECTIVE: To measure the variation in performance of hospitalists. DESIGN: Retrospective research design of 100 % Texas Medicare data using multilevel, multivariable models. SUBJECTS: 131,710 hospitalized patients cared for by 1,099 hospitalists in 268 hospitals from 2006-2009. MAIN MEASURES: We calculated, for each hospitalist, adjusted for patient and disease factors (case mix), their patients' average length of stay, rate of discharge home or to skilled nursing facility (SNF) and rate of 30-day mortality, readmissions and emergency room (ER) visits. KEY RESULTS: In two-level models (admission and hospitalist), there was significant variation in average length of stay and discharge location among hospitalists, but very little variation in 30-day mortality, readmission or emergency room visit rates. There was stability over time (2008-2009 vs. 2006-2007) in hospitalist performance. In three-level models including admissions, hospitalists and hospitals, the variation among hospitalists was substantially reduced. For example, hospitals, hospitalists and case mix contributed 1.02 %, 0.75 % and 42.15 % of the total variance in 30-day mortality rates, respectively. CONCLUSIONS: There is significant variation among hospitalists in length of stay and discharge destination of their patients, but much of the variation is attributable to the hospitals where they practice. The very low variation among hospitalists in 30-day readmission rates suggests that hospitalists are not important contributors to variations in those rates among hospitals.