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Pancreatic cancer is lethal due to poor prognosis with 5-year survival rate lesser than 5 %. Gemcitabine is currently used to treat pancreatic cancer and development of chemoresistance is a major obstacle to overcome pancreatic cancer. Nicotine is a known inducer of drug resistance in pancreatic tumor micro-environment. Present study evaluates chemoresistance triggered by nicotine while treating with gemcitabine and chemosensitization using Embelin. Embelin is a naturally occurring benzoquinone from Embelia ribes possessing therapeutic potency. To develop nicotine-induced chemo-resistance, pancreatic cancer cells PANC-1 and MIA PaCa-2 were continuously treated with nicotine followed by exposure to gemcitabine. Gemcitabine sensitivity assay and immunoblotting was performed to assess the chemo-resistance. Antiproliferative assays such as migration assay, clonogenic assay, Mitochondrial Membrane Potential (MMP) assay, dual staining assay, comet assay, Reactive Oxygen Species (ROS) assay, cell cycle analysis and immunoblotting assays were performed to witness the protein expression involved in chemoresistance and chemosensitization. Epithelial to mesenchymal transition was observed in nicotine induced chemoresistant cells. Gemcitabine sensitivity assay revealed that relative resistance was increased to 6.26 (p < 0.0001) and 6.45 (p < 0.0001) folds in resistant PANC-1 and MIA PaCa-2 compared to parental cells. Protein expression studies confirmed resistance markers like hENT1 and dCK were downregulated with subsequent increase in RRM1 expression in resistant cells. Embelin considerably decreased the cell viability with an IC50 value of 4.03 ± 0.08 µM in resistant PANC-1 and 2.11 ± 0.04 µM in resistant MIA PaCa-2. Cell cycle analysis showed Embelin treatment caused cell cycle arrest at S phase in resistant PANC-1 cells; in resistant MIA PaCa-2 cells there was an escalation in the Sub G1. Embelin upregulated Bax, γH2AX, p53, ERK1/2 and hENT1 expression with concomitant down regulation of Bcl-2 and RRM1. Bioactive molecule embelin, its combination with gemcitabine could provide new vistas to overcome chemo resistance in pancreatic cancer.

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A series of new thiophene analogues with acarbonitrile-basedmoiety were designed and synthesized via structural optimization. The conjugates were assessed for their in-vitro cytotoxic activity against a human pancreatic cancer cell line (Mia PaCa-2) and among them compound 5b showed IC50 value of 13.37 ± 2.37 µM. The compounds 5b (20 µM & 25 µM) and 7c (30 & 35 µM) also showed reduced clonogenicity, enhanced ROS and decreased mitochondrial membrane potential in Mia PaCa-2 cells. Treatment with these compounds also increased apoptotic population as evident with the double staining assay. Among the evaluated series, compounds 5b, 5g, 7c, and 9a attained a greater inhibitory potency than first generation's reversible EGFR inhibitor, Gefitinib. EGFR2 enzyme inhibitory studies revealed that 5b efficiently and arbitrarily suppressed the development of EGFR2 dependent cells and inhibited the enzymatic activity with an IC50 value of 0.68 µM; interestingly, the most effective molecule 5b with N-methyl piperazine substitution, has 1.29-fold greater potency than well-known EGFR inhibitor Gefitinib and increased Gefitinib's anti-growth impact with 2.04 folds greater against Mia PaCa-2. The in-vitro studies were validated with in-silico docking studies wherein compounds 5b and 7c exhibited binding energies of -8.2 and -7.4 Kcal/mol respectively. The present study reveals that tetrahydrobenzothiophene based analogues could be a promising lead for the evolution of potent chemo preventives over pancreatic cancer.

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BACKGROUND: Global data on cardiac surgery centers are outdated and survey-based. In 1995, there were 0.7 centers per million population, ranging from one per 120,000 in North America to one per 33 million in sub-Saharan Africa. This study analyzes the contemporary distribution of cardiac surgery centers and proposes targets relative to countries' cardiovascular disease (CVD) burdens. METHODS: Medical databases, gray literature, and governmental reports were used to identify the most recent post-2010 data that describe the number of centers performing cardiac surgery in each nation. The 2019 Institute for Health Metrics and Evaluation Global Burden of Disease Results Tool provided national CVD burdens. One-third of the CVD burden was assumed to be surgical. Center targets were proposed as the average or half of the average of centers per million surgical CVD patients in high-income countries. RESULTS: 5,111 cardiac surgery centers were identified across 230 nations and territories with available data, equaling 0.73 centers per million population. The median (interquartile range) number of centers ranged from 0 (0-0.06) per million in low-income countries to 0.75 (0-1.44) in high-income countries. Targets were 612.2 (optimistic) or 306.1 (conservative) centers per million surgical CVD incidence. In 2019, low-income, lower-middle-income, and upper-middle-income countries possessed 34.8, 149.0, and 271.9 centers per million surgical CVD incidence. CONCLUSION: Little progress has been made to increase cardiac surgery centers per population despite growing CVD burdens. Today's global cardiac surgical capacity remains insufficient, disproportionately affecting the world's poorest regions.

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Inflammation is a complex biological response involving immune cells to an infection creating injury to the normal tissues. The anti-inflammatory efficacy of embelin, a benzoquinone from the plant Embelia ribes, was screened for antioxidant and anti-inflammatory activity in carrageenan and Freund's adjuvant-induced inflammation models. Embelin exhibited significant dose-dependent antioxidant potential. In carrageenan-induced inflammation, embelin (20 mg/kg) showed an inhibition of oedema by 71.01 ± 0.12% and 81.91 ± 0.67% in Freund's adjuvant-treated chronic inflammation model and resulted in a noticeable increase in adrenal size and restoration of the weight of spleen. Embelin also demonstrated cytoprotective effects on HEK-293 cells under induced oxidative stress. In silico analysis, embelin demonstrated binding energy of - 7.7 kcal/Mol and - 7.0 kcal/Mol with COX1 and COX2 with two hydrogen bonds. These results further prove that embelin could be a promising anti-inflammatory agent and supports the traditional use of Embelia ribes for rheumatism.

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OBJECTIVES: We aimed to identify a threshold number of Clostridioides difficile infections (CDI) for acute-care hospitals (ACHs) to notify public health agencies of outbreaks and we aimed to determine whether thresholds can be used with existing surveillance strategies to further infection reduction goals. DESIGN: Descriptive analysis of laboratory-identified CDI reported to the National Healthcare Safety Network by Colorado and Tennessee ACH inpatient units in 2018. METHODS: Threshold levels of ≥2, ≥3, and ≥4 CDI events per calendar month per unit (unit month) were assessed to identify units that would trigger facility reporting to public health. Values meeting thresholds were defined as alerts. Recurrent alerts were defined as alerts from units meeting the threshold ≥2 times within 12 months. The presence of alerts was compared to the number of excess infections to identify high-burden facilities. RESULTS: At an alert threshold of ≥2 CDI events per unit month, 204 alerts occurred among 43 Colorado ACHs and 290 among 78 Tennessee ACHs. At a threshold of ≥3, there were 59 and 61 alerts, and at a threshold of ≥4, there were 17 and 10 alerts in Colorado and Tennessee, respectively. In both Colorado and Tennessee, at a threshold of ≥3 nearly 50% of alerts were recurrent, and facilities with at least one alert in 2018 accounted for ∼85% of the statewide excess infections. CONCLUSIONS: An alert threshold of ≥3 CDI events per unit month is feasible for rapid identification of outbreaks in ACHs. This threshold can facilitate earlier assessments and interventions in high-burden facilities.

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Recently, Tennessee, USA, has seen an increase in the use of commonly injected drugs, such as heroin and fentanyl. Injection drug use (IDU) practices can lead to life-threatening methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) and other serious diseases. We matched MRSA BSIs identified through the National Healthcare Safety Network to the Tennessee Hospital Discharge Data System to characterize the prevalence, demographics, and clinical characteristics associated with IDU in this disease population. Of the 7,646 MRSA BSIs identified during 2015-2017, we found that 1,839 (24.1%) were IDU-related. IDU-related BSIs increased by 118.9%; the greatest rise occurred among emergency department-onset infections (197.4%). IDU was more often associated with white, female, 18-49-year-old, and uninsured persons (p<0.001). We found >1 additional IDU-related diagnoses in 84.2% of IDU-related BSIs. Targeted harm reduction strategies for persons at high risk of IDU are necessary to reduce MRSA BSIs in acute care settings.

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BACKGROUND: In the United States, surveillance of norovirus gastroenteritis is largely restricted to outbreaks, limiting our knowledge of the contribution of sporadic illness to the overall impact on reported outbreaks. Understanding norovirus transmission dynamics is vital for improving preventive measures, including norovirus vaccine development. METHODS: We analyzed seasonal patterns and genotypic distribution between sporadic pediatric norovirus cases and reported norovirus outbreaks in middle Tennessee. Sporadic cases were ascertained via the New Vaccine Surveillance Network in a single county, while reported norovirus outbreaks from 7 middle Tennessee counties were included in the study. We investigated the predictive value of sporadic cases on outbreaks using a 2-state discrete Markov model. RESULTS: Between December 2012 and June 2016, there were 755 pediatric sporadic norovirus cases and 45 reported outbreaks. Almost half (42.2%) of outbreaks occurred in long-term care facilities. Most sporadic cases (74.9%) and reported outbreaks (86.8%) occurred between November and April. Peak sporadic norovirus activity was often contemporaneous with outbreak occurrence. Among both sporadic cases and outbreaks, GII genogroup noroviruses were most prevalent (90.1% and 83.3%), with GII.4 being the dominant genotype (39.0% and 52.8%). The predictive model suggested that the 3-day moving average of sporadic cases was positively associated with the probability of an outbreak occurring. CONCLUSIONS: Despite the demographic differences between the surveillance populations, the seasonal and genotypic associations between sporadic cases and outbreaks are suggestive of contemporaneous community transmission. Public health agencies may use this knowledge to expand surveillance and identify target populations for interventions, including future vaccines.

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