Exploring aryl hydrocarbon receptor (AhR) as a target for Bisphenol-A (BPA)-induced pancreatic islet toxicity and impaired glucose homeostasis: Protective efficacy of ethanol extract of Centella asiatica.

The estrogenic impact of Bisphenol-A (BPA), a widely recognized endocrine disruptor, causes disruption of pancreatic ß-cell function through estrogen receptors (ERs). While BPA's binding affinity for ERs is significantly lower than that of its natural counterpart, estrogen, recent observations of BPA's affinity for aryl hydrocarbon receptor (AhR) in specific cellular contexts have sparked a specific question: does AhR play a role in BPA's toxicological effects within the endocrine pancreas? To explore this question, we investigated BPA's (10 and 100 µg/ kg body weight/day for 21 days) potential to activate AhR within pancreatic islets and assessed the protective role of ethanol extract of Centella asiatica (CA) (200 and 400 mg/kg body weight/day for 21 days) against BPA-mediated toxicity in mouse model. Our results indicate that BPA effectively triggers the activation of AhR and modulates its target genes within pancreatic islets. In contrast, CA activates AhR but directs downstream pathways differentially and activates Nrf2. Additionally, CA was observed to counteract the disruption caused by BPA in glucose homeostasis and insulin sensitivity. Furthermore, BPA-induced oxidative stress and exaggerated production of proinflammatory cytokines were effectively counteracted by CA supplementation. In summary, our study suggests that CA influenced AhR signaling to mitigate the disrupted pancreatic endocrine function in BPA exposed mice. By shedding light on how BPA interacts with AhR, our research provides valuable insights into the mechanisms involved in the diabetogenic actions of BPA.

Postoperative Fracture Risk in Giant Cell Tumor: A Case Report and Review of Literature.

Giant cell tumor (GCT) of the proximal femur poses various challenges in its management and recurrence. We present a rare case of GCT of proximal femur in which recurrence and coxa vara deformity were encountered after index surgery. Management of the recurrence was done with intramedullary fixation with extended curettage and bone grafting. Different aspects of management such as the role of defect size, adjuvants, bone cement/bone graft, implants, and bisphosphonates have been highlighted in this article.

Cystic Diseases of the Kidneys: From Bench to Bedside.

Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet-Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel-Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual.

Molecular dissection of cellular response of pancreatic islet cells to Bisphenol-A (BPA): A comprehensive review.

Bisphenol A (BPA) is an endocrine disrupting chemical which poses great concern because of its high proportionate industrial production, omnipresent human exposure and budding toxic consequences in human. A plethora of previous studies has connected BPA to a variety of negative health outcomes and diabetes mellitus is among the first bencher. However, there is disagreement over the degree of toxic effects generated by low and high doses of BPA and critical period of exposure. Furthermore, the safe level of BPA determined by classical toxicological studies does not protect pancreatic islet cells from low dose effects of BPA. Thus, the extremities of toxic effects on pancreatic islets associated with BPA exposure are complicated and contentious. In this review, we highlighted different cellular and molecular pathways targeted by BPA to mediate its action on pancreatic islets with consideration of both low and high dose effects. Besides estrogen receptor α and ß, BPA also uses non canonical membrane bound estrogen receptor and G-protein coupled estrogen receptor to confer its toxic effects. In doing so, BPA modulates ion channels, and transcription factors; causes aggregation of human islet amyloid polypeptide, endoplasmic reticulum and mitochondrial stress; and results in activation of NFκB in pancreatic ß cells. BPA also renders a major shift in ß to α cell ratio in islets causing deregulated glucagon secretion. Hence, understanding of various mechanisms of BPA action on the pancreatic islets will provide meaningful insights in recognizing the risk posed by exposure to low and high doses of BPA.

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.

Clinical Dilemma of Corneal Opacity, Very Low High-density Lipoprotein, and Nephrotic Syndrome: Mystery Revealed.

Lecithin-cholesterol acyltransferase (LCAT) is a liver enzyme necessary for the formation of cholesteryl esters in plasma from free cholesterol. The rare autosomal recessive disease resulting from familial deficiency of this enzyme can lead to nephropathy with kidney involvement generally being the most common cause of death. In addition, the disease process can engender corneal opacity, very low high-density lipoprotein, normochromic anemia, and nephropathy. We present this case of a 35-year-old male who initially visited for a second opinion for renal failure and nephrotic range proteinuria. He underwent renal biopsy which displayed focal segmental glomerulosclerosis-type injury pattern and was started on futile high-dose steroid therapy. A second renal biopsy coincided with the development of corneal opacity leading to a confirmatory testing of LCAT deficiency through biochemistry panel.

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.

Proximal Femoral Nail versus Proximal Femoral Nail Antirotation: Functional and Radiological Outcome in Intertrochanteric Fractures of Femur.

Introduction Newer implant designs such as Proximal Femoral Nail (PFN) and Proximal Femoral Nail Antirotation (PFN-A) have shown promising results in the treatment of intertrochanteric fractures. Despite the availability of various implants for the treatment of these fractures, there is no common consensus as to which implant would be ideal. Therefore, there is a need for further clinical trials to establish the biomechanical and functional outcome superiority of implants such as PFN and PFN-A, especially among osteoporotic patients. Aim To compare the functional and radiological outcomes in intertrochanteric patients treated with PFN and PFN-A. Methodology A total of 152 intertrochanteric fracture patients were included in this retrospective study, 94 in the PFN group and 58 in the PFN-A group. The postoperative radiological outcome was assessed and compared using parameters such as tip-apex distance (TAD), Cleveland index, neck-shaft angle, and type of reduction. Operative time for the procedure, pre and postoperative hemoglobin levels were recorded and compared. Fracture union rates were compared at six weeks and six months. Functional outcome was compared between the two groups at follow-up period of 6 months using Harris Hip Score (HHS) and pre and postoperative Parker Palmer Mobility Score (PPS). Complication rates were compared between the two groups. Also, osteoporotic patients were evaluated using the same parameters. Results The radiological parameters were similar in both groups. There was a shorter operative time and better hemoglobin levels after surgery in the PFN-A group. The complication rate in the PFN group was 7.4% when compared to the PFN-A group which was just 1.7%. The functional outcome based on HHS and PPS was alike in the two groups. In osteoporotic patients randomized based on Singh's index, better union rates were observed in the PFN-A group and a higher complication rate was seen in the PFN group. Conclusion Cephalomedullary nailing using PFN-A is superior to PFN in terms of a lesser procedure time, minimal blood loss, and fewer complications even among osteoporotic patients. The radiological specifications such as neck-shaft angle post-surgery, reduction type, TAD, and Cleveland index is of paramount importance which is established in this study.

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.

Association between duration of coal dust exposure and respiratory impairment in coal miners of West Bengal, India.

Purpose. The prevalence and severity of respiratory disorders are very high among coal miners as continuous exposure of workers in such an environment leads to accumulation of dust in the lungs. This study was designed to assess the prevalence of lung function impairment and to determine whether there is any correlation between dust exposure duration and lung function indices. Materials. Two hundred and thirty underground coal dust-exposed workers and 130 age-matched non-exposed workers were recruited from an underground mine in West Bengal, India. A spirometry test was performed for lung function and also basic information on personnel's dust exposure, smoking and respiratory morbidity was collected. Student's t test, Pearson's correlation coefficient (r), uncorrected Pearson's χ2 test and Fischer's exact test were performed for statistical analysis. Results. Lung function indices were significantly (p < 0.050) impaired between the exposed (43.91%) and non-exposed (23.85%) groups. In addition, highly significant decrements in the pulmonary volumes of exposed subjects were also noted. Furthermore, a high negative correlation was observed between spirometric results and exposure time in the exposed group compared with the non-exposed group. Conclusion. This study suggested a positive relationship between exposure time and lung function deterioration.

Association Between Environmental Factors and Toxigenic Clostridioides difficile Carriage at Hospital Admission.

Importance: Clostridioides difficile infection is the most frequent health care-associated infection in the United States. However, exposure to this organism might occur outside the health care setting. Objective: To examine whether exposure to environmental factors, such as livestock farms, is associated with a higher probability of being colonized with C difficile at hospital admission. Design, Setting, and Participants: This retrospective cohort study was conducted from May 1, 2017, to June 30, 2018, at a teaching-affiliated hospital in Milwaukee, Wisconsin. All consecutive patients underwent C difficile screening using a nucleic acid amplification test at hospital admission. Data analyses were performed from July 2018 to October 2019. Exposures: The distances from patient residence to the nearest livestock farms, meat processing plants, raw materials services, and sewage facilities were measured in addition to risk factors previously evaluated in other studies. Main Outcomes and Measures: The main outcome was a positive result on C difficile screening tests performed within 72 hours of hospital admission. Results: A total of 3043 patients admitted to the hospital were included in the final analysis. Of those, 1564 (51.4%) were women and 2074 (68.9%) were white, with a mean (SD) age of 62.0 (15.9) years; 978 patients (32.1%) were admitted to hematology-oncology units. At first admission, 318 patients (10.4%) were detected through testing as C difficile carriers. Multivariable logistic regression analyses were performed on a stratified sample of patients based on hematology-oncology admission status. These analyses indicated that although patients admitted to hematology-oncology units were 35% more likely to be colonized with C difficile, no significant association existed between their sociodemographic and economic characteristics or health care and environmental exposures and the likelihood of a positive C difficile test result. In contrast, among patients admitted to non-hematology-oncology units, comorbidities increased the likelihood for colonization by more than 4 times; women had 60% greater colonization than men, and a history of recent hospitalization (ie, within the preceding 6 months) increased the likelihood of colonization by 70%. Residential proximity to livestock farms were all significantly associated with a higher likelihood of a positive C difficile test result. Residential proximity to livestock farms more than doubled the probability of C difficile colonization in patients admitted to non-hematology-oncology units. Conclusions and Relevance: A shorter distance between residence and livestock farms was associated with C difficile colonization. Knowledge of the epidemiology of C difficile in the community surrounding the hospital is important, as it has potential implications for the incidence of hospital-onset C difficile infection.

Cold stress modulates redox signalling in murine fresh bone marrow cells and promotes osteoclast transformation.

Context: Alteration of redox signalling and RANK-L expression in FBMCs of mice exposed to different intensities of cold stress (15 °C, 8 °C and 4 °C) were studied.Objective: To understand the effects of varying intensities of cold stress on murine FBMCs and its impact on osteoclastogenesis.Materials and methods: FBMCs were isolated from mice exposed to different intensities of cold stress and used for immunoblotting and biochemical assays. Bone histometry was also done.Results: Different intensities of cold stress perturb redox signalling in FBMCs and alters bone histometry. Higher RANK-L expressions were noted in FBMCs of mice exposed to 8 °C and 4 °C as compared with 15 °C.Discussion and conclusion: Cold stress boosts free radical production in FBMC's, which might enhance RANK-L expression, an indicator of osteoclastogenesis. Thus, we speculate that stronger cold stress (8 °C and 4 °C) contributes to the development of early bone loss.

Radioprotective effect of ethanolic extract of Alocasia indica on γ-irradiation-induced reproductive alterations in ovary and uterus.

Evaluation of the modulatory effect of ethanolic extract of Alocasia indica tuber (EEAIT) against γ-irradiation induced ovarian and uterine toxicity. Extract preparation was done by 80% hydro-ethanol using Soxhlet apparatus. EEAIT was administered to female Swiss albino mice (n = 5) daily (200 and 400 mg/kg body weight/d) for 7 days before γ-irradiation exposure (2.9 Gy). FSH, LH, estrogen, progesterone, cytokine levels, and oxidative stress parameters were measured after 24 hours of γ-irradiation. Histology, folliculogenesis, viability of granulosa cells, ROS measurement by flow cytometry, western blot of P450scc, P45017A1, 3ß HSD and SF 1 were also performed. In addition, fertility status was assessed by fecundability and fecundity. The results showed that EEAIT exhibit a strong radioprotective activity by reducing the oxidative stress and thereby restored the ovarian and uterine alterations. EEAIT also improved the abnormality in follicle development, restored altered gonadal hormones and cytokines levels, increase the fertility status, reducing ROS level of granulosa cells with increasing granulosa cells viability and steroidogenic enzyme activity as compared to control. So EEAIT showed a radioprotective effect on γ-irradiation induced ovarian and uterine damage. Our results suggested that Alocasia indica tuber can be a potential radioprotector to prevent female infertility.

Combined effect of coal dust exposure and smoking on the prevalence of respiratory impairment among coal miners of West Bengal, India.

Accelerating prevalence of coal workers pneumoconiosis is considered as a serious occupational health problem. This cross-sectional study was designed to determine the prevalence of lung function impairment of underground coal miners in West Bengal, India. A total of 230 underground coal dust-exposed subjects and 130 nonexposed subjects were examined for lung function test and also information on sociodemographic characteristics, addiction, respiratory morbidity, personnel protective equipment and dust exposure were collected. Lung function impairment was significantly higher in exposed group than nonexposed group and personnel dust exposure level were exceeded above the NIOSH recommended level. In addition, respiratory ailments were found to be higher in exposed group than the nonexposed group. So, this study has established the need for an advanced understanding of the quantifiable and measurable remedies for protection of lung disorder of coal mine workers.

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.

Immediate impact of healthcare-facility-onset Clostridium difficile laboratory-identified events reporting methodology change on standardized infection ratios.

In 2018, the Clostridium difficile LabID event methodology changed so that hospitals doing 2-step tests, nucleic acid amplification test (NAAT) plus enzyme immunofluorescence assay (EIA), had their adjustment modified to EIA-based tests, and only positive final tests (eg, EIA) were counted in the numerator. We report the immediate impact of this methodological change at 3 Milwaukee hospitals.

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.

Variations in 30-day readmissions and length of stay among spine surgeons: a national study of elective spine surgery among US Medicare beneficiaries.

OBJECTIVE Pay-for-performance programs are targeting hospital readmissions. These programs have an underlying assumption that readmissions are due to provider practice patterns that can be modified by a reduction in reimbursement. However, there are limited data to support the role of providers in influencing readmissions. To study this, the authors examined variations in readmission rates by spine surgeon within 30 days among Medicare beneficiaries undergoing elective lumbar spine surgery for degenerative conditions. METHODS The authors applied validated ICD-9-CM algorithms to 2003-2007 Medicare data to select beneficiaries undergoing elective inpatient lumbar spine surgery for degenerative conditions. Mixed models, adjusting for patient demographics, comorbidities, and surgery type, were used to estimate risk of 30-day readmission by the surgeon. Length of stay (LOS) was also studied using these same models. RESULTS A total of 39,884 beneficiaries were operated on by 3987 spine surgeons. The mean readmission rate was 7.2%. The mean LOS was 3.1 days. After adjusting for patient characteristics and surgery type, 1 surgeon had readmission rates significantly below the mean, and only 5 surgeons had readmission rates significantly above the mean. In contrast, for LOS, the patients of 288 surgeons (7.2%) had LOS significantly lower than the mean, and the patients of 397 surgeons (10.0%) had LOS significantly above the mean. These findings were robust to adjustments for surgeon characteristics and clustering by hospital. Similarly, hospital characteristics were not significantly associated with readmission rates, but LOS was associated with hospital for-profit status and size. CONCLUSIONS The authors found almost no variations in readmission rates by surgeon. These findings suggest that surgeon practice patterns do not affect the risk of readmission. Likewise, no significant variation in readmission rates by hospital characteristics were found. Strategies to reduce readmissions would be better targeted at factors other than providers.

Association of Hospitalist Years of Experience With Mortality in the Hospitalized Medicare Population.

Importance: Substantial numbers of hospitalists are fresh graduates of residency training programs. Current data about the effect of hospitalist years of experience on patient outcomes are lacking. Objective: To describe the association of hospitalist years of experience with 30-day mortality and hospital mortality of their patients. Design, Setting, and Participants: We used a 5% sample of national Medicare data of patient and hospital characteristics to build a multilevel logistic regression model to predict mortality as a function of years of experience of the hospitalists. We created 2 cohorts. The first was a cross-sectional cohort of 21 612 hospitalists working between July 1, 2013, and June 30, 2014, with a 5-year look-back period to assess their years of prior experience as a hospitalist, and the second was a longitudinal cohort of 3860 hospitalists in their first year of practice between July 1, 2008, and June 30, 2011, who continued practicing hospital medicine for at least 4 years. Main Outcomes and Measures: Thirty-day postadmission mortality adjusted for patient and hospital characteristics in a 3-level logistic regression model. Hospital mortality was a secondary outcome. Results: Among 21 612 hospitalists caring for Medicare inpatients from July 1, 2013, to June 30, 2014, 5445 (25%) had 1 year of experience or less, while 11 596 (54%) had 4 years of experience or more. We then identified 3860 physicians in their first year as hospitalists who continued to practice as hospitalists for 4 years. There was a significant association between hospitalist experience and mortality. Observed 30-day mortality was 10.50% for patients of first-year hospitalists vs 9.97% for patients of hospitalists in their second year. The mortality odds for patients of second-year hospitalists were 0.90 (95% CI, 0.84-0.96) compared with patients of first-year hospitalists. Observed hospital mortality was 3.33% for patients cared for by first-year hospitalists vs 2.96% for second-year hospitalists. (odds ratio, 0.84; 95% CI, 0.75-0.95). For both 30-day and hospital mortality, there was little change in odds of mortality between the second year and subsequent years of experience. Conclusions and Relevance: Patients cared for by hospitalists in their first year of practice experience higher mortality. Early-career hospitalists may require additional support to ensure optimal outcomes for their patients.

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.