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Abstract: In the present study, apparent diffusivity of hydrogen at different temperatures in 9Cr-1MoVNbN steel was determined using the data obtained from the measurement of hydrogen evolved from specimens charged with hydrogen. Cylindrical specimens of the 9Cr-1MoVNbN steel in normalized condition were charged with hydrogen electrochemically to saturation level. Hot extraction technique was used for collection of hydrogen evolved from the specimens at different temperatures in a chamber. Subsequently, measurement of evolved hydrogen was carried out using a Nafion based proton-exchange-membrane hydrogen sensor (PEMHS). Using these data in the diffusion equation for a finite cylinder, apparent diffusivity of hydrogen in steel was determined at temperatures in the range of 25–400 °C. Hydrogen lost from the specimens prior to start of the collection of hydrogen evolved was estimated. Apparent diffusivity data, earlier obtained, were revised by considering this lost hydrogen in the estimation. Apparent diffusivities calculated using this method agreed well with the values reported in the literature. [Copyright &y& Elsevier]

Abstract: Photo-assisted hydrogen generation studies of platinum loaded titanium (IV) oxide nanotubes suspended in ethanol–water mixture were carried out at room temperature. The TiO2 nanotubes synthesized by rapid breakdown anodization technique were loaded with Pt nanoparticles by chemical reduction of aqueous chloroplatinic acid solution using sodium borohydride. The chemisorption (active) surface area of the synthesized nanocomposites for hydrogen was measured by pulse chemisorption method using temperature programmed desorption reduction oxidation equipment and found to decrease with increase in platinum loading in the range 1–10wt%. The platinum supported nanotube composites were characterized for phase and morphology by XRD, TEM and SEM. The hydrogen generated by the photocatalytic reduction of water from water–ethanol mixture at different wavelengths of incident light, using the Pt-TiO2 nanocomposite photocatalyst, was determined by using a proton exchange membrane based hydrogen meter. The highest hydrogen generation efficiency was observed at 1–2.5wt% of Pt loading. The maximum photocatalytic hydrogen generation of 0.03mol/h/g of Pt-TiO2 was observed with a 64W UV light source (λ =254nm). The photoluminescence property of the Pt loaded TiO2 has been correlated with the hydrogen generation efficiency and the reaction mechanism briefly discussed. [Copyright &y& Elsevier]

Statins are the most prescribed drug for regulating the high cholesterol level in the blood, which can lead to severe complications, such as cardiovascular diseases and other health complications. A wide range of analytical techniques have been employed for the quantification of statins from various origins, including fermentation derived (lovastatin, pravastatin, and compactin), semi-synthetic (simvastatin), and synthetic (atorvastatin, rosuvastatin, and fluvastatin) routes. The presence of more than one structural form and structural analogue generated in the biosynthesis pathway, as well as reaction intermediates and macromolecules in the clinical sample, complicates the quantification of statins. Furthermore, significant concentrations of statins in environmental samples pose serious health and ecology hazards, and estimating statins in those diluted samples is extremely difficult. On the other hand, the: cost, accurate estimation of the desired one from other structural forms, sample complexity, time, limits of detection and quantification, were major criteria distinguishing the usability of each technique. As a result, the current manuscript focuses on analytical techniques such as molecular spectroscopy (normal and derivatives UV-Visible spectrophotometer), chromatography (TLC, HP-TLC, HPLC, GC, swing column, micellar, and supercritical fluid), mass spectroscopy (HPLC-MS/MS and GC-MS/MS), sequential flow injection, capillary electrophoresis, and cyclic voltammetry, as well as their: optimal operating conditions, limits of detection and quantification, advancements, and limitations. Furthermore, various online and offline sample preparations (precipitation, solid phase extraction, liquid-liquid extraction, and micellar extraction) have been highlighted as an essential pretreatment technique to avoid the interference caused by structural analogues and other macromolecules. The greener and more sustainable concepts used in analytical approaches for the quantification statins are also highlighted with current advancements.

Background: Cardiovascular diseases (CVDs) are the leading cause of cardiac arrest (CA), which are presented as sudden cardiac arrest (SCA) and sudden cardiac death (SCD). To assess the impact of CPR duration on the functional outcome, level of independence, and survival among patients with in-hospital cardiac arrest (IHCA)., Material and Methods: This prospective longitudinal pilot study was conducted at a tertiary care hospital in South India. Data were collected using consecutive sampling techniques from nine patients with IHCA, and outcomes were measured using the cerebral performance category (CPC) and Katz level of independence (LOI) during the immediate post-CPR, 30 th day, and 90 th day. Based on the principles of pilot study design, descriptive statistics was used to analyze the results. Inferential statistics analysis was not applicable based on the sample size of the pilot study., Results: Nine patients were included in this pilot study. The mean and median age of the patients were 48.11 ± 8.66 (46, IQR, 32-67 years) and 77.8% were male patients. The primary medical diagnosis was cardiology and neurology conditions among 44.4% and 22.2% of patients. The mean and median CPR duration was 12.11 ± 4.59 minutes (IQR, 8-15.50) and 44.4% achieved a return of spontaneous circulation (ROSC) with a mean ROSC time of 5.56 ± 7.418. The mean CPC score in the immediate post-CPR period and 30 th day was 4 ± 1.732 and 4.56 ± 1.33, with mortality of 66.7% and 33.3% survivors in the immediate post-CPR period. While the mean LOI score among the survivors during the immediate post-CPR and 30 th day was zero and four. which highlights the complete dependency of patients during the immediate post-CPR with significant improvement by the 30 th day and unchanged until the 90 th day., Conclusions: The overall mortality and survival were 88.8% and 11.1%, respectively, by the 90 th day. The pilot study is feasible at the end of the study. However, due to the difficulty in obtaining CA, an additional tertiary hospital was included in the larger study., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Education and Health Promotion.)

Asthma remains a prevalent condition among all age groups globally. First-line treatment requires the delivery of medications into the distal respiratory tract via inhalers. Using appropriate inhaler techniques is a significant challenge in achieving disease control. A variety of inhalers are available for treating asthma, and selecting the appropriate inhaler type for any given patient is crucial to achieving and maintaining symptomatic control. This review will discuss the anatomy and physiology behind drug delivery via inhalers, the types of inhalers currently available for use, nebulizers, and future directions in the delivery of inhaled medications for asthma.

Background and aims Laryngoscopy and intubation cause an increased sympatho-adrenergic pressor response, which can be detrimental to patients with coronary artery disease, hypertension, etc. Various drugs and manoeuvres have been tried to reduce the pressor response with acceptable results but the quest for the ideal drug still continues. Hence, we planned to compare the effects of magnesium sulfate with paracetamol and fentanyl with lignocaine on attenuating the hemodynamic responses due to direct laryngoscopy and intubation and to note the complications of these drugs. Methods We studied 60 adult patients of the American Society of Anaesthesiologists (ASA) physical status I and II of either sex, scheduled for elective surgery under general anaesthesia. The patients were randomly divided into two groups. Group A received 25 mg/kg magnesium sulphate mixed with paracetamol 1 gram IV (100 ml) given over 10 minutes before induction and Group B received 2 mcg/kg fentanyl and 1.5 mg/kg lignocaine, 3 minutes before intubation. All patients were uniformly pre-medicated, induced, and intubated as per standard protocol. Heart rate (HR) and systemic arterial pressures were recorded at baseline, after study drug infusion, after induction, and 1, 3, 5, 10, and 15 mins after intubation. Hemodynamic parameters were compared using repeated measures analysis of variance (ANOVA). In the post-hoc tests, p value < 0.05 was considered statistically significant. Results We observed the mean pre-op HR (p = 0.161) and mean HR one-minute post-induction (p = 0.144). The percentage change from baseline at one-minute post-induction was 9.7 in Group A and 15.2 in Group B. We observed the mean pre-op mean arterial pressure (MAP) (p = 0.119) and mean MAP one minute post-induction (p = 0.585). The percentage change from baseline at one-minute post-induction was 3.3 in Group A and 2.8 in Group B. The percentage change from baseline was found to be within 15%, for HR in Group A and for systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP in Group B. However, there was no statistically significant difference (p > 0.05) between the mean HR, SBP, DBP, and MAP between the time points. Conclusion In our study, both the combinations of drugs, magnesium sulphate with paracetamol (Group A drugs) and fentanyl with lignocaine (Group B drugs) were found to be equally effective (i.e. neither group was superior to the other) in attenuating the hemodynamic response to laryngoscopy and intubation., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. PIMS Institute Ethics Committee (IEC) issued approval IEC: RC/19/112, CTRI/2019/12/022315, 11/12/2019. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Murugesan et al.)

The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic codeletion along with PTEN on chromosome 10q in approximately 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low-SCD expression. Although this SCD-deficient subset was refractory to SCD inhibitors, the subset of PTEN wild-type melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low oleic acid custom diet was combined with an SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wild-type melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T-cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment. Significance: Blockade of endogenous production of fatty acids essential for melanoma combined with restriction of dietary intake blocks tumor growth and enhances response to immunotherapy, providing a rational drug-diet treatment regimen for melanoma., (©2024 American Association for Cancer Research.)

Background: The kallikrein kinin system (KKS) is an established pharmacological target for the treatment and prevention of attacks in hereditary angioedema (HAE). Proteolytic activities of FXIIa and single-chain Factor XII (FXII) zymogen contribute to KKS activation and thereby may play roles in both initiating and propagating HAE attacks. In this report, we investigated the effects of potent small molecule FXIIa inhibitors on FXIIa and single chain FXII enzymatic activities, KKS activation, and angioedema in mice. Methods: We examined the effects of 29 structurally distinct FXIIa inhibitors on enzymatic activities of FXIIa and a mutant single chain FXII with R334A, R343A and R353A substitutions (rFXII-T), that does not undergo zymogen conversion to FXIIa, using kinetic fluorogenic substrate assays. We examined the effects of a representative FXIIa inhibitor, KV998086, on KKS activation and both carrageenan- and captopril-induced angioedema in mice. Results: FXIIa inhibitors designed to target its catalytic domain also potently inhibited the enzymatic activity of rFXII-T and the pIC 50 s of these compounds linearly correlated for rFXIIa and rFXII-T ( R 2 = 0.93). KV998086, a potent oral FXIIa inhibitor (IC 50 = 7.2 nM) inhibited dextran sulfate (DXS)-stimulated generation of plasma kallikrein and FXIIa, and the cleavage of high molecular weight kininogen (HK) in human plasma. KV998086 also inhibited rFXII-T mediated HK cleavage ( p < 0.005) in plasma from FXII knockout mice supplemented with rFXII-T and stimulated with polyphosphate or DXS. Orally administered KV998086 protected mice from 1) captopril-induced Evans blue leakage in colon and laryngotracheal tissues and 2) blocked carrageenan-induced plasma HK consumption and paw edema. Conclusion: These findings show that small molecule FXIIa inhibitors, designed to target its active site, also inhibit the enzymatic activity of FXII zymogen. Combined inhibition of FXII zymogen and FXIIa may thereby suppress both the initiation and amplification of KKS activation that contribute to hereditary angioedema attacks and other FXII-mediated diseases., Competing Interests: AC, NM, HE, DL, NB, SP, SH, and EF are employees of KalVista Pharmaceuticals. ED was an employee of KalVista Pharmaceuticals at the time of the study. DG has received consultants fees from Anthos Therapeutics, Bristol-Myers Squibb, Ionis, and Janssen., (Copyright © 2023 Clermont, Murugesan, Edwards, Lee, Bayliss, Duckworth, Pethen, Hampton, Gailani and Feener.)

Background: As an illustrative example of COVID-19 pandemic community-based participatory research (CBPR), we describe a community-academic partnership to prioritize future research most important to people experiencing high occupational exposure to COVID-19 - food service workers. Food service workers face key challenges surrounding (1) health and safety precautions, (2) stress and mental health, and (3) the long-term pandemic impact., Method: Using CBPR methodologies, academic scientists partnered with community stakeholders to develop the research aims, methods, and measures, and interpret and disseminate results. We conducted a survey, three focus groups, and a rapid qualitative assessment to understand the three areas of concern and prioritize future research., Results: The survey showed that food service employers mainly supported basic droplet protections (soap, hand sanitizer, gloves), rather than comprehensive airborne protections (high-quality masks, air quality monitoring, air cleaning). Food service workers faced challenging decisions surrounding isolation, quarantine, testing, masking, vaccines, and in-home transmission, described anxiety, depression, and substance use as top mental health concerns, and described long-term physical and financial concerns. Focus groups provided qualitative examples of concerns experienced by food service workers and narrowed topic prioritization. The rapid qualitative assessment identified key needs and opportunities, with help reducing in-home COVID-19 transmission identified as a top priority. COVID-19 mitigation scientists offered recommendations for reducing in-home transmission., Conclusions: The COVID-19 pandemic has forced food service workers to experience complex decisions about health and safety, stress and mental health concerns, and longer-term concerns. Challenging health decisions included attempting to avoid an airborne infectious illness when employers were mainly only concerned with droplet precautions and trying to decide protocols for testing and isolation without clear guidance, free tests, or paid sick leave. Key mental health concerns were anxiety, depression, and substance use. Longer-term challenges included Long COVID, lack of mental healthcare access, and financial instability. Food service workers suggest the need for more research aimed at reducing in-home COVID-19 transmission and supporting long-term mental health, physical health, and financial concerns. This research provides an illustrative example of how to cultivate community-based partnerships to respond to immediate and critical issues affecting populations most burdened by public health crises., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Asthma is a heterogenous disorder characterized by presence of different phenotypes and endotypes. Up to 10% of the individuals suffer from severe asthma and are at increased risk of morbidity and mortality. Fractional exhaled nitric oxide (FeNO) is a cost-effective, point of care biomarker that is used to detect type 2 airway inflammation. Guidelines have proposed to measure FeNO as an adjunct to diagnostic evaluation in individuals with suspected asthma and to monitor airway inflammation. FeNO has lower sensitivity, suggesting that it may not be a good biomarker to rule out asthma. FeNO may also be used to predict response to inhaled corticosteroids, predict adherence and deciding on biologic therapy. Higher levels of FeNO have been associated with lower lung function and increased risk for future asthma exacerbations and its predictive value increases when combined with other standard measurements of asthma assessment.

Background: Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE., Methods: Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial., Results: KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a K i of 3.02 nM. The association constant (K on ) of KVD900 for PKa is >10 × 10 6  M -1  s -1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage., Conclusion: KVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks., (© 2022 KalVista Pharmaceuticals, Inc. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Imparting quality healthcare to the critically ill patient is associated with competence, compassion, and excellent care by healthcare professionals. It includes the development and widespread application of evidence-based interventions, following guidelines, and protocol-based care on ventilator-associated bundle approach to ensure the delivery of care to prevent ventilator-associated problems., Materials and Methods: Quantitative evaluative approach, pre-experimental research, one group pre- and post-test design by the convenient method of sampling 70 staff nurses were selected. A self-structured compliance checklist was used to collect the data., Results: The level of compliance with handwashing revealed that all the samples 70 (100) have complied with the handwashing technique during the clean and sterile procedure on the patient in all three shifts and 30 (42.9%) subjects were very good in following the handwashing in the morning compared to evening and night. With regard to inserting the catheter into the ET tube gently by using an aseptic technique to perform endotracheal suctioning, 28 (40%) samples had carried out in all three shifts respectively and 50 (71.4%) were good in adhering in following all the steps. In relation to cuff pressure monitoring, it was carried out by 63 (90%) of the samples and around 43 (61.4%) subjects were found to be good in all the three shifts, respectively., Conclusion: Healthcare professionals need to adopt the protocols and policies. Implementation appropriately helps in the prevention of ventilator-associated problems, and quality care will be improved., How to Cite This Article: Murugesan N, Natesan G, Felix AJW. A Study to Assess the Compliance on Hand Hygiene during Bundle of Care Interventions among Healthcare Professionals Working in ICU of a Tertiary Care Hospital. Indian J Crit Care Med 2022;26(9):1006-1010., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2022; The Author(s).)

Background: The coronavirus disease 2019 (COVID-19) pandemic has spread globally leading to over 3,700,000 deaths. As COVID-19 cases stabilized, the re-opening of endoscopy centers potentially exposed patients and healthcare workers to viral infection. This study aims to determine risk of COVID-19 exposure among patients undergoing outpatient endoscopies in a tertiary care setting during the COVID-19 pandemic., Methods: Patients undergoing outpatient endoscopy were contacted post-procedure for any new COVID-19 symptoms or COVID-19 test results. Patient experiences and perception of personal safety were also determined., Results: Of the 1,584 patients who completed elective endoscopy, 996 (62.9%) completed the survey. Two patients were diagnosed with COVID-19 within 14 days of procedure. The majority (99.7%) felt safe during their procedure and apprehension regarding endoscopy decreased over time., Conclusion: Thus, the risk of COVID-19 transmission during outpatient endoscopy is extremely low when following recommended society guidelines. Patients felt safe during the procedure and experienced less fear of exposure over time., Competing Interests: None to declare., (Copyright 2022, Manski et al.)

Background: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin., Objective: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults., Methods: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 × 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals., Results: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC 0-24 ) of 18,600 (22.5) h⋅ng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours., Conclusion: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves near-complete PKa inhibition and is generally safe and well tolerated., Gov Identifier: NCT04349800., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study is part of a multicountry matched-cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI) of children exposed to invasive group B Streptococcus (iGBS). The specific objective of this paper is to compare NDI across domains of iGBS survivors with a matched non iGBS group in our population., Methods: Survivors of iGBS in a South Indian hospital were identified and recruited between January 2020 and April 2021. Cases were compared with age- and gender-matched non iGBS children. Participants were assessed using Bayley Scales of Infant and Toddler Development-3rd edition (BSID-III), Wechsler Preschool and Primary Scale of Intelligence-4th edition (WPPSI-IV), Wechsler Intelligence Scale for Children-5th edition (WISC-V), Child Behavior Checklist (CBCL), and Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2), depending on age., Results: Our cohort comprised 35 GBS-exposed and 65 matched non iGBS children, aged 1-14 years. The iGBS-exposed group had 17 (48.6%) children with impairment in ≥1 domain compared to 25 (38%) in the non iGBS group (unadjusted OR, 1.51; 95% CI, .65-3.46), 9 (26%) children with "multi-domain impairment" compared to 10 (15.4%) in the non iGBS group (unadjusted OR, 1.90; 95% CI, .69-5.24), and 1 (2.9%) child with moderate to severe impairment compared to 3 (4.6%) in the non iGBS group (unadjusted OR, .60; 95% CI, .06-6.07). In the iGBS group, more children had motor impairments compared with the non iGBS group (unadjusted OR, 10.7; 95% CI, 1.19-95.69; P = .034)., Conclusions: Children with iGBS seem at higher risk of developing motor impairments compared with a non iGBS group., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

We reported that histone H3 lysine (K) 4 methyltransferase, KMT2D , serves as a potent tumor-suppressor in melanoma, which was identified via in vivo epigenome-focused RNA interference (RNAi) screen. KMT2D -deficient tumors show substantial reprogramming of key metabolic pathways including glycolysis via reduction of H3K4me1 (Histone H3K4 mono-methylation)-marked active enhancers, conferring sensitivity to inhibitors of glycolysis and IGFR (Insulin Growth Factor Receptor) pathway., Competing Interests: No potential conflicts of interest were disclosed., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21 , which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Our studies in primary human adipocytes show that naringenin, a citrus flavonoid, increases oxygen consumption rate and gene expression of uncoupling protein 1 (UCP1), glucose transporter type 4, and carnitine palmitoyltransferase 1 β (CPT1 β ). We investigated the safety of naringenin, its effects on metabolic rate, and blood glucose and insulin responses in a single female subject with diabetes. The subject ingested 150 mg naringenin from an extract of whole oranges standardized to 28% naringenin three times/day for 8 weeks, and maintained her usual food intake. Body weight, resting metabolic rate, respiratory quotient, and blood chemistry panel including glucose, insulin, and safety markers were measured at baseline and after 8 weeks. Adverse events were evaluated every 2 weeks. We also examined the involvement of peroxisome proliferator-activated receptor α (PPAR α ), peroxisome proliferator-activated receptor γ (PPAR γ ), protein kinase A (PKA), and protein kinase G (PKG) in the response of human adipocytes to naringenin treatment. Compared to baseline, the body weight decreased by 2.3 kg. The metabolic rate peaked at 3.5% above baseline at 1 h, but there was no change in the respiratory quotient. Compared to baseline, insulin decreased by 18%, but the change in glucose was not clinically significant. Other blood safety markers were within their reference ranges, and there were no adverse events. UCP1 and CPT1β mRNA expression was reduced by inhibitors of PPAR α and PPAR γ , but there was no effect of PKA or PKG inhibition. We conclude that naringenin supplementation is safe in humans, reduces body weight and insulin resistance, and increases metabolic rate by PPAR α and PPAR γ activation. The effects of naringenin on energy expenditure and insulin sensitivity warrant investigation in a randomized controlled clinical trial.

Objectives: Over the last two decades, various studies have evaluated the impact of weekend admission to the hospital on inpatient mortality. Our study sought to identify whether or not the "weekend effect" was true for patients with Intracranial Hemorrhage (ICH) admitted to United States hospitals and whether or not the introduction of comprehensive stroke centers (CSCs) made an impact on the "weekend effect" for ICH., Patients and Methods: Searched the Nationwide Inpatient Sample for the ICH discharges between 2006 and 2014. Multivariate regression analysis was performed to evaluate the factors that impacted in-hospital mortality. Additional subgroup analysis was performed based on two time periods, before CSCs (2006-2009) and afterward (2010-2014)., Results: 146,587 discharges with ICH were reported by the NIS with 37,471 (25.6%) weekend admissions. The weekday admission cohort was 50.6% male with a mean age of 67.1 years. There was a total of 35,362 deaths among ICH admissions. The in-hospital mortality rate was significantly higher for weekend admissions compared to that of weekday admissions (25.2% vs. 23.8%, p < 0.001). Multivariate analysis of mortality for the 2006-2009 subgroup demonstrated a statistically significant higher odds of death with weekend admission (OR = 1.15, 95% CI [1.10, 1.20], p = 0) but not for the 2010-2014 subgroup (OR = 1.03, 95% CI [0.99, 1.07], p = 0.09)., Conclusion: Our study showed that in-hospital mortality was found to be increased for patients with ICH admitted on a weekend; however, this association was lost after the initiation of CSCs. Further prospective studies are warranted to gain a better understanding regarding this association., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The plasma kallikrein-stimulated generation of bradykinin (BK) has been implicated in diabetic macular edema (DME). This study characterizes the effects of BK on the ultrastructure and proteome of the rat retina. The effects of intravitreal injection of BK on retinal thickness and vascular ultrastructure in Sprague Dawley rats were analyzed and compared with the effects of VEGF using spectral-domain optical coherence tomography. At 24 h post intravitreal injection of BK or saline vehicle retina were harvested and solubilized proteins were analyzed by mass spectrometry-based proteomics. Proteins were identified using X!Tandem and spectral counts were used as a semiquantitative measurement of protein abundance. Proteins identified from retinal extracts were annotated by Gene Ontology (GO) slim terms and compared with a human DME vitreous proteome. Intravitreal injection of BK and VEGF induced transient increases in retinal thickness of 46 μm (24.6%, p = 0.015) and 39 μm (20.3%, p = 0.004), respectively at 24 h, which were resolved to baseline thicknesses at 96 h post injection. BK and VEGF also increased retinal vessel diameters and tortuosity at 24 h post intravitreal injection. Proteomic analyses identified 1757 non-redundant proteins in the rat retina, including 1739 and 1725 proteins from BK- and saline control-injected eyes, respectively. Eighteen proteins, including two proteins associated with intercellular junctions, filamin A and actinin alpha 4, were decreased by at least 50% (p < 0.05) in retina from BK-injected eyes compare with retina from eyes injected with saline. In addition, 32 proteins were increased by > 2-fold (p < 0.05) in retina from BK-injected eyes. Eight proteins, including complement C3, were identified to be increased in both BK-stimulated rat retina and in human DME vitreous. Western blot analysis showed that Complement 3 levels in vitreous from BK-injected eyes in rats and clinical DME samples were increased by 6.6-fold (p = 0.039) and 4.3-fold (p = 0.02), compared with their respective controls. In summary, this study identifies protein changes in rat retina that are associated with BK-induced retinal thickening, including 8 proteins that were previously reported to be increased in the human DME vitreous proteome., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Living systems are constantly under different combinations of competing gradients of chemical, thermal, pH, and mechanical stresses allied. The present work is about competing chemical and thermal gradients imposed on E. coli in a diffusive stagnant microfluidic environment. The bacterial cells were exposed to opposing and aligned gradients of an attractant (1 mM sorbitol) or a repellant (1 mM NiSO 4 ) and temperature. The effects of the repellant/attractant and temperature on migration behavior, migration rate, and initiation time for migration have been reported. It has been observed that under competing gradients of an attractant and temperature, the nutrient gradient (gradient generated by cells itself) initiates directed migration, which, in turn, is influenced by temperature through the metabolic rate. Exposure to competing gradients of an inhibitor and temperature leads to the imposed chemical gradient governing the directed cell migration. The cells under opposing gradients of the repellant and temperature have experienced the longest decision time (∼60 min). The conclusion is that in a competing chemical and thermal gradient environment in the range of experimental conditions used in the present work, the migration of E. coli is always initiated and governed by chemical gradients (either generated by the cells in situ or imposed upon externally), but the migration rate and percentage of migration of cells are influenced by temperature, shedding insights into the importance of such gradients in deciding collective dynamics of such cells in physiological conditions.

Aims: The aims were to assess effect of a short training programme on non-communicable diseases (NCDs), particularly diabetes on school teachers and also on students who were in turn educated by them. Lifestyle changes made by both groups were assessed 6months later., Methods: Graduate teachers (n=1017) from 2 districts in Tamilnadu, India were trained using audio visual aids in batches of 100, on healthy lifestyle practices, prevention and management of diabetes. Pre and post training knowledge scores were assessed using questionnaires. Each teacher was requested to impart similar education to 100 high school students within 3months. Impact of the training on teachers and students was assessed using questionnaires 6months later. Feedback from the students' parents was also collected., Results: A total of 1017 teachers (men: 33.8%, women: 66.2%, urban: 68.8%, rural: 31.1%) were trained. Among them, 651 (men: 31.3%, women: 68.7%) responded for impact evaluation. Changes in knowledge and attitude were reported by 93.7% of teachers. Improvement in lifestyle of the students was assessed by 587 teachers, 60.4% of the students avoided junk foods, 57.5% advised their family members on diabetes. Outdoor games were played by 50.8% of the students. Improvement in knowledge, changes in lifestyle and a positive attitude towards health care delivery were achieved among teachers and students through this training programme., Conclusions: Significant improvement in health perception among the teachers and students occurred even with a short training. It has demonstrated that non-medical personnel like teachers are efficient in disseminating health information on lifestyle diseases especially diabetes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Bacteria responds to changing chemical and thermal environment by moving towards or away from a particular location. In this report, we looked into thermal gradient generation and response of E. coli DH5α cells to thermal gradient in the presence and in the absence of spherical gold nanoparticles (size: 15 to 22 nm) in a static microfluidic environment using a polydimethylsiloxane (PDMS) made microfluidic device. A PDMS-agarose based microfluidic device for generating thermal gradient has been developed and the thermal gradient generation in the device has been validated with the numerical simulation. Our studies revealed that the presence of gold nanoparticles, AuNPs (0.649 μg/mL) has no effect on the thermal gradient generation. The E. coli DH5α cells have been treated with AuNPs of two different concentrations (0.649 μg/mL and 0.008 μg/mL). The thermotaxis behavior of cells in the presence of AuNPs has been studied and compared to the thermotaxis of E.coli DH5α cells in the absence of AuNPs. In case of thermotaxis, in the absence of the AuNPs, the E. coli DH5α cells showed better thermotaxis towards lower temperature range, whereas in the presence of AuNPs (0.649 μg/mL and 0.008 μg/mL) thermotaxis of the E. coli DH5α cells has been inhibited. The results show that the spherical AuNPs intervenes in the themotaxis of E. coli DH5α cells and inhibits the cell migration. The reason for the failure in thermotaxis response mechanism may be due to decreased F-type ATP synthase activity and collapse of membrane potential by AuNPs, which, in turn, leads to decreased ATP levels. This has been hypothesized since both thermotaxis and chemotaxis follows the same response mechanism for migration in which ATP plays critical role.

Purpose: Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema., Methods: Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy., Results: Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice., Conclusions: Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.

This study characterizes the kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma prekallikrein (PPK) and plasma kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Retinal ischemia and hemorrhage are hallmarks of worsening diabetic retinopathy, which can lead to neovascularization, macular edema, and severe vision loss. Although diabetes alters expression of clotting factors and their activities, and increases retinal microthromboses, the effects of thrombotic processes on the pathogenesis of diabetic retinopathy are not fully understood. In addition to the roles of coagulation and fibrinolytic cascades in thrombosis and hemostasis, components in these systems also mediate multiple effects on the vasculature that promote inflammation. Plasma kallikrein, thrombin, and urokinase are increased in diabetic retinopathy, and exert proinflammatory effects that contribute to retinal vascular dysfunction. The accumulation and activation of these and additional coagulation factors in the vitreous due to hemorrhage and chronic retinal injury in the diabetic retina may contribute to worsening of retinal inflammation and capillary dysfunction, which lead to retinal ischemia and edema. Further understanding of the role for specific coagulation factors in diabetic retinopathy may suggest new therapeutic opportunities for this vision-threatening disease., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Nontraumatic subarachnoid hemorrhage (SAH) in a dialysis patient is an uncommon occurrence and is often associated with high mortality. We report for the first time in India, a case of spontaneous nontraumatic, nonaneurysmal SAH without any cerebrovascular malformation in a maintenance hemodialysis patient, following a session of hemodialysis. The dialysis prescription needs to be modified in these patients, in order to prevent worsening of cerebral edema and progression of hemorrhage. Where available, continuous forms of renal replacement therapies, with regional anticoagulation seem to be the best option for such patients, till neurologic stabilization is achieved.

Motile bacteria respond to changing chemical environment by moving towards or away from a particular location. Bacterial migration under chemical gradient is one of the most studied areas in biomedical field. In this work we looked into how bacterial cells respond to sudden change in the microfluidic chemical environment. E. coli DH5α cells were subjected to an attractant gradient (0.1 mM sorbitol--attractant to E. coli cells) and after 120 min the same cells were exposed to an inhibitor (0.1 mM NiSO4) gradient in the same microfluidic device. Our studies revealed that when the E. coli DH5α cells were exposed to 0.1 mM sorbitol, they showed faster chemotaxis towards the attractant (0.1 mM sorbitol) and achieved steady state by 60 min. When we replaced 0.1 mM sorbitol with 0.1 mM NiSO4 in the device we found that that the E. coli DH5α cells started responding to change in chemical environment within 10 min and achieved steady state at the end of 60 min. This shows that the bacterial cells respond to change in local chemical environment is within few minutes.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.