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Background: Evidence shows that diabetes raises the probability of contracting COVID-19 and associated complications. We hypothesize that metformin, being pleiotropic, may improve COVID-19 in diabetics., Methods: A retrospective cohort study was conducted with 421 COVID-19 patients with diabetes, hospitalized between 1st April 2020 and 31st March 2022 in a tertiary-care hospital. Patients with metformin or its combination constituted the study cohort (SC; n  = 221), while other antidiabetics constituted the reference cohort (RC; n  = 200)., Results: SC and RC were matched for mean age ± SD (SC: 53.3 ± 5.7 vs. RC: 54.3 ± 8.2 years). The mean length of hospitalization (days) was significantly shorter in SC (9.0 ± 5.7) than in RC (12.7 ± 6) ( p  < 0.02). Metformin use was associated with reduction in mortality risk (OR: 0.106, 95% CI = 0.039-0.287; p  < 0.001). Moreover, SC also improved levels of LDH (OR: 0.243, 95% CI = 0.104-0.566; p  < 0.001), CRP (OR: 0.281, 95% CI = 0.120-0.659; p  < 0.004), and D-dimer (OR: 0.220, 95% CI = 0.089-0.539; p  < 0.001) than RC. The calculated number needed to treat for metformin was 3.1., Conclusion: Metformin users have a decrease in hospital stay and mortality rates and improvement in LDH, CRP, and D-dimer levels. Therefore, metformin might protect against mortality in COVID-19 with diabetes.

Introduction: Plasma inclusive resuscitation (PIR) uses fresh frozen plasma as an adjunct to crystalloid in the management of burn shock and has potential benefits over other colloids. Yet, safety concerns for transfusion-related acute lung injury (TRALI) exist. The aim of this study evaluated the association between TRALI and PIR in a cohort of severely burn-injured patients using the updated Canadian Blood Services Consensus definitions., Methods: Burn-injured patients requiring PIR at a burn center from 2018 to 2022 were retrospectively reviewed. To assess for TRALI, data related to acute hypoxemia, bilateral pulmonary edema, left atrial hypertension, and changes to respiratory status up to 6 h after PIR were recorded. To identify other risks and benefits associated with PIR timing, resuscitative volumes and outcomes were compared between early (0-8 h) and late PIR (8-24 h) initiation., Results: Of the 88 patients included for study, no patient developed TRALI type I or II under the updated definitions. Early (n = 39) compared to late PIR (n = 49) was associated with a higher percent total body surface area (TBSA, 36.3%, 26.0%, P = 0.01). The predicted 24-h volume was higher for early PIR (10.1 L, 6.3 L, P = 0.049), but the observed 24-h volume (cc/kg/%TBSA) was not significantly different (5.2, 5.3, P = 0.62)., Conclusions: In a cohort of severely burn-injured patients undergoing PIR, no patient developed TRALI type I or type II under the updated Canadian Blood Services Consensus definitions. Earlier use of PIR was not associated with higher resuscitative volumes despite higher TBSA. Further studies are necessary to better ascertain the potential risks and benefits associated with PIR., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Dynamically titrated crystalloids are the standard of care for burn shock resuscitation. There are theoretical concerns that the adjunctive use of allogeneic plasma may perturb the patient's coagulation and inflammation status deleteriously. It was hypothesized that plasma-inclusive resuscitation (PIR) would not be associated with prothrombotic changes relative to baseline after thermal injury., Methods: Patients admitted to a regional burn center who were treated with PIR as part of their burn resuscitation were enrolled. Whole blood samples were analyzed prospectively via rapid thromboelastography and rotational thromboelastometry to assess for coagulopathy at four time points throughout their acute burn resuscitation. The mixed-effect model for repeated measures followed by Tukey's post hoc test for comparisons was used to examine group differences., Results: There were 35 patients in the analysis. Most were male (74.3%) with a median age of 43 y (32-55), concomitant inhalation injury of 28.6%, total body surface area burn size of 34% (27%-48.5%), and the overall mortality of the cohort was 28.6%. There were no transfusion reactions or thrombotic events. There were no differences in thromboelastography or rotational thromboelastometry parameters overall or when stratified by mortality, total body surface area burn, and inhalation injury. There were no significant differences between the fibrinolytic phenotypes over time., Conclusions: Data suggest that PIR was not associated with prothrombotic or lytic changes in burn patients relative to baseline. Further research is needed to confirm these findings and evaluate efficacy of PIR in acute burn resuscitation., (Published by Elsevier Inc.)

Background: The efficacy and safety of the ultrathin BioMime sirolimus-eluting coronary stent (SES) system in treating single or multiple de novo native coronary lesions, in-stent restenosis, and bifurcation lesions have been evidenced at 1 year., Aims: We sought to investigate the long-term safety and efficacy of the BioMime SES in a real-world population with obstructive coronary artery disease (CAD)., Methods: The prospective, single-arm, multicentre meriT-2 trial enrolled 250 patients from 11 sites across India. The safety endpoint was the cumulative frequency of major adverse cardiovascular events (MACE) at 5 years, defined as a composite of cardiac death, myocardial infarction (MI), emergent coronary artery bypass grafting or clinically indicated target lesion revascularisation (CI-TLR). Stent thrombosis (ST) was evaluated according to the Academic Research Consortium definitions., Results: A total of 214 (85.6%) subjects completed the 5-year follow-up. The mean age of patients was 57.44±10.75 years, and 82.71% were males. A total of 308 lesions were treated with BioMime SES. Most of the lesions were localised in the left anterior descending artery (45.46%) and were type B2 lesions (44.81%). The cumulative MACE rate at 5 years was 8.9% (n=19), including 0.9% cardiac deaths, 1.9% MI and 6.1% CI-TLR. The rate of ST was only 0.5%. The Kaplan-Meier survivor analysis revealed actuarial survivorship of 95.6% for the intention-to-treat population (n=250) over 5 years., Conclusions: The long-term clinical outcomes of the meriT-2 trial established the safety and efficacy of the ultrathin-strut biodegradable-polymer-based BioMime SES with satisfactory clinical outcomes at 5 years., Competing Interests: A. Thakkar and U. Chandra are full-time employees of Meril Life Sciences Pvt. Ltd. U. Kaul is the Editor-in-Chief of AsiaIntervention. The other authors have no conflicts of interest to declare. The Guest Editor has no relevant conflicts of interest to declare.

Introduction: Literature examining the impact of obesity on burn injury remains mixed. Previous examination of the National Burn Repository, now the BCQP, in obesity-related burn research is limited. The aim of this work was to provide an assessment of the BCQP dataset to examine the effect of obesity on burn-related outcomes., Materials and Methods: A retrospective review of the BCQP dataset from 2015-2018 was conducted. The primary outcome measure was mortality. Secondary outcomes included overall length of stay (LOS), ICU LOS, and total hospital costs. Patients were grouped as obese or non-obese and were further stratified by total body surface area burned (TBSA) for comparison purposes. Multiple logistic regression (MLG) was used to compare the effect of several independent variables on mortality, ICU LOS > 7days, hospital LOS > 10 days, and total hospital costs > $200,000., Results: Of 41,031 patients in the analysis, 3845 (9.37 %) were obese. Obese patients had a higher mean TBSA (p = 0.01), longer overall LOS (p < 0.001), ICU LOS (p < 0.001), and total hospital costs (p < 0.001). MLG found obesity to be an independent predictor of ICU LOS > 7 days, hospital LOS > 10 days, and total hospital costs > $200,000. Obesity was not an independent predictor of mortality in burn patients, even when stratified by burn size., Conclusions: The presence of obesity in this dataset was not found to be a predictor of mortality for any burn size, but was a predictor of overall LOS, ICU LOS, and total hospital costs. Including obesity-related variables in databases may improve analysis in obesity-related burn research., Competing Interests: Declaration of Competing Interest The authors have no financial or personal relationships with other people or organizations to report that could inappropriately influence this work. The authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Background: Children with nephrotic syndrome experience many side effects and frequent relapses when treated with steroids and other drugs. Mycophenolic acid (MPA) is one of the effective and least toxic drug for the treatment of nephrotic syndrome. This drug needs to be monitored for maximal efficacy and minimal toxicity. The therapeutic reference range for this drug is not established for the aforementioned patient population of Indian origin., Materials and Methods: In this observational study, children with nephrotic syndrome on mycophenolate mofetil were followed up for a minimum duration of three months. Following this, their clinical status (relapse/remission) was determined and the mycophenolate exposure was measured for over 12 hours., Results: A total of 34 participants were included, with 17 (50%) in relapse. Median MPA Area under the curve over 12 hours (AUC0-12h) (36.5 µg·h/ml) in the remission group differed significantly compared to that in the relapse group (17.2 µg·h/ml)., Conclusion: Higher exposure to MPA AUC0-12h is associated with clinical remission of pediatric nephrotic syndrome., Competing Interests: There are no conflicts of interest., (© 2024 Indian Journal of Nephrology | Published by Scientific Scholar.)

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM&#95;021082.4):c.1048C>G) and rs13397109 ((NM&#95;004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: Sepsis and septic shock are major healthcare problems that need early and appropriate management., Objectives: To evaluate the association of daily cefepime pharmacokinetic/pharmacodynamic (PK/PD) parameters with change in Sequential Organ Failure Assessment (SOFA) score and vasopressors requirement., Design Setting and Participants: This is a retrospective study. Adult ICU patients who received cefepime for Gram-negative pneumonia or bloodstream infection (BSI) and had cefepime concentrations measured were included. Daily cefepime exposure was generated and PK/PD parameters calculated for patients. Repeated-measures mixed-effect modeling was used to evaluate the impact of PK/PD on the outcomes., Main Outcomes and Measures: Change in daily SOFA score and vasopressors requirement., Results: A total of 394 and 207 patients were included in the SOFA and vasopressors analyses, respectively. The mean (±sd) age was 55 years (19) and weight 81 kg (29). For the change in SOFA score, daily SOFA score, mechanical ventilation, renal replacement therapy, and number of vasopressors were included. In the vasopressors analysis, daily SOFA score, day of therapy, and hydrocortisone dose were significant covariates in the final model. Achieving cefepime concentrations above the minimum inhibitory concentration (MIC) (T >MIC ) for 100% of the dosing interval was associated with 0.006 µg/kg/min decrease in norepinephrine-equivalent dose. Cefepime PK/PD did not have an impact on the daily change in SOFA score., Conclusions and Relevance: Achieving 100% T >MIC was associated with negligible decrease in vasopressors requirement in ICU patients with Gram-negative pneumonia and BSI. There was no impact on the change in SOFA score., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: To evaluate the association between early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters and therapy outcomes in bloodstream infection (BSI)., Methods: Adult patients who received cefepime, meropenem, or piperacillin/tazobactam for BSI and had concentrations measured were included. Beta-lactam exposure was generated and the time that free concentration remained above the minimum inhibitory concentration (fT >MIC ) and four multiples of MIC (fT >4 × MIC ) were calculated for times 0-24 h and 0-7 days of therapy. Multiple regression analysis was performed to evaluate the impact of PK/PD on microbiological and clinical outcomes., Results: A total of 204 patients and 213 BSI episodes were included. The mean age was 58 years and weight 83 kg. Age, Sequential Organ Failure Assessment (SOFA) score, haemodialysis, Pitt bacteraemia score, and hours of empiric antibiotic therapy were significantly associated with certain outcomes and retained in the final model. In multiple regression analysis, fT >4 × MIC at 0-24 h and 0-7 days was a significant predictor of negative blood culture on day 7 (P=0.0161 and 0.0068, respectively). In the time-to-event analysis, patients who achieved 100% fT >4 × MIC at 0-24 h and 0-7 days had a shorter time to negative blood culture compared with those who did not (log-rank P=0.0004 and 0.0014, respectively). No significant associations were identified between PK/PD parameters and other outcomes, including improvement in symptoms at day 7 and 30-day mortality., Conclusion: Early and cumulative achievement of fT >4 × MIC was a significant predictor of microbiological outcome in patients with BSI., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Adequate colistin exposure is important for microbiological clearance. This study was performed in critically ill patients >18 years old to develop a simplified nonparametric pharmacokinetic (PK) model of colistin for routine clinical use and to determine the role of dose optimization. The Non-Parametric Adaptive Grid algorithm within the Pmetrics software package for R was used to develop a PK model from 47 patients, and external validation of the final model was performed in 13 patients. A 1-compartment multiplicative gamma error model with 0-order input and first-order elimination of colistin was developed with creatinine clearance and serum albumin as covariates on elimination rate constant. An R 2 for observed vs individual predicted colistin concentrations of 0.92 was obtained in the validation cohort. High interindividual variability in colistin steady-state area under the plasma concentration-time curve (AUC) from from 120 hours to 144 hours (coefficient of variation = 80.1%) and a high interoccasion variability (median coefficient of variation of AUC from time 0 to hours predicted every 8 hours for initial 96 hours after starting colistin = 23.8) was predicted in patients who received this antibiotic for a period of over 152 hours (n = 22). With the model-suggested dose regimen, only 20% of simulated profiles achieved AUC from time 0 to 24 hours in the range of 50 to 60 mg • h/L due to high variability in population PK. In this group of patients, steady-state colistin concentrations were predicted to be achieved >96 hours after initiation of colistimethate sodium. This study advocates the need for early and repeated therapeutic drug monitoring and dose optimization in critically ill patients to achieve adequate therapeutic concentration of colistin., (© 2022, The American College of Clinical Pharmacology.)

Aim: This study aimed to identify DPYD  variants and the related but previously unexplored phenotype (plasma uracil, dihydrouracil [DHU], and the DHU-to-uracil ratio) in a healthy adult Indian population. Methods: Healthy adult volunteers (n = 100) had their uracil and DHU levels measured and were genotyped for selected variants. Results: Among the nine variants studied, c.1906-14763G>A and c.85T>C were the most prevalent. Participants with any of the variants except for c.85T>C and c.1627A>G had a significantly lower DHU-to-uracil ratio and those with c.1905+1G>A variant had significantly increased uracil concentration compared with wild-type. Conclusion: Participants with five variants were identified as having altered phenotypic measures, and 40% of the intermediate metabolizers had their phenotype in the terminal population percentiles.

A significant proportion of patients with Rhino-orbito-cerebral mucormycosis (ROCM) develop oroantral fistulas. Due to the unclear efficacy of crushed delayed-release posaconazole tablets (DRPT) via nasogastric tube in this group of patients, clinicians often use inferior alternatives like posaconazole suspension. In this prospective study, we report good plasma concentrations (median, 2,639 ng/mL; interquartile range [IQR], 1,690 to 3,575 ng/mL; and range, 1,004 to 4,835ng/mL) and complete cure and survival at 3 and 6 months in 19 such patients.

Background and aims The second wave of coronavirus disease 2019 (COVID-19) has been devastating in India and many developing countries. The mortality reported has been 40% higher than in the first wave, overwhelming the nation's health infrastructure. Despite a better understanding of the disease and established treatment protocols including steroids and heparin, the second wave was disastrous. Subsequent waves have the potential to further cripple healthcare deliveries, also affecting non-COVID-19 care across many developing economies. It is then important to identify and triage high-risk patients to best use the limited resources. Routine tests such as neutrophil and monocyte counts have been identified but have not been successfully validated uniformly, and their utility is still being understood in COVID-19. Various predictive models that are available require online resources and calculators and additionally await validation across all populations. These, although useful, might not be available or accessible across all institutions. It is then important to identify easy-to-use scores that utilize tests done routinely. In identifying with this goal, we did a retrospective review of the institutional database to identify potential predictors of intensive care unit (ICU) admission and mortality in patients hospitalized during the second wave who accessed healthcare at our academic setup. Results Three predictors of mortality and four predictors of ICU admission were identified. Absolute neutrophil count was a common predictor of both ICU admission and mortality but with two separate cut points. An absolute neutrophil count of >4,200 predicted need for ICU admission (odds ratio (OR): 3.1 (95% confidence interval (CI): 2.0, 4.8)), and >7,200 predicted mortality (adjusted OR: 4.2 (95% CI: 1.9, 9.4)). We observed that a blood urea level greater than 45 was predictive of needing ICU care (adjusted OR: 8.0 (95% CI: 3.7, 17.6)). In our dataset, serum ferritin of >500 was predictive of ICU admission (adjusted OR: 2.7 (95% CI: 1.2, 5.9)). We noted a right shift of partial pressure (p50 is the oxygen tension at which hemoglobin is 50% saturated) (p50c) in SARS-CoV-2 as a predictor of ICU care (OR: 2.6 (95% CI: 1.7, 3.9)) when partial pressure is >26.5. In our analysis, a serum protein of less than 7 g/dL (OR: 2.8 (95% CI: 1.7, 4.4)) was a predictive variable for ICU admission. An LDH value of >675 was predictive of severity with a need for ICU admission (OR: 9.2 (95% CI: 5.4, 15.5)) in our series. We then assigned a score to each of the predictive variables based on the adjusted odds ratio. Conclusion We identified a set of easy-to-use predictive variables and scores to recognize the subset of patients hospitalized with COVID-19 with the highest risk of death or clinical worsening requiring ICU care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Philip et al.)

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are the most common intensive care unit (ICU) infections. We aimed to evaluate the association of early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters with therapy outcomes in pneumonia. Adult ICU patients who received cefepime, meropenem, or piperacillin-tazobactam for HAP or VAP and had its concentration measured were included. Beta-lactam exposure was generated for every patient for the entire duration of therapy, and the time free concentration remained above the MIC ( f T >MIC ) and the time free concentration remained above four multiples of the MIC ( f T >4×MIC ) were calculated for time frames of 0 to 24 h, 0 to 10 days, and day 0 to end of therapy. Regression analyses and machine learning were performed to evaluate the impact of PK/PD on therapy outcomes. A total of 735 patients and 840 HAP/VAP episodes (47% HAP) were included. The mean age was 56 years, and the mean weight was 80 kg. Sequential organ failure assessment (SOFA), hemodialysis, age, and weight were significantly associated with the clinical outcomes and kept in the final model. In the full cohort including all pneumonia episodes, PK/PD parameters at different time windows were associated with a favorable composite outcome, clinical cure, and mechanical ventilation (MV)-free days. In patients who had positive cultures and reported MICs, almost all PK/PD parameters were significant predictors of therapy outcomes. In the machine learning analysis, PK/PD parameters ranked high and were the primary overall predictors of clinical cure. Early target attainment and cumulative target attainment have a great impact on pneumonia outcomes. Beta-lactam exposure should be optimized early and maintained through therapy duration.

Background: Serial monitoring of tacrolimus and serum creatinine after renal transplantation is of vital importance. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the estimation of tacrolimus and creatinine, obtained from dried blood spots (DBS) or by volumetric absorptive microsampling (VAMS) was validated and the two sampling strategies were compared with traditional venous sampling., Methods: The LC-MS/MS assay was validated using a shared extract for the estimation of tacrolimus and creatinine from DBS and VAMS independently. The relationship between the concentrations in DBS/VAMS specimens and in venous samples was assessed using Passing-Bablok (PB) analysis and the bias between the two methods was determined by the Bland Altman (BA) analysis., Results: The imprecision and bias of tacrolimus and creatinine estimated from DBS and VAMS samples was <12% and was independent of the hematocrit (Hct). Samples were stable for five days at ambient temperature. From the PB regression analysis, correction equations were generated for the prediction of tacrolimus and creatinine values from DBS and VAMS samples. In a separate cohort of patients for validation, the corrected DBS and VAMS concentrations had a mean (95% CI) bias for tacrolimus of -0.64 (-2.98 to 1.70)% and -0.92 (-3.69 to 1.85)% respectively and for creatinine of 1.00 (-2.73 to 4.72)% and -0.71 (-3.74 to 2.32)% respectively. Using DBS and VAMS respectively, for tacrolimus, 91.8 and 89.8% of patient values and for creatinine, 69.4 and 81.6% of patient values were within the limits of clinical acceptance (within 15% agreement against the venous samples)., Conclusion: We conclude that VAMS is the preferred single sampling option for estimating tacrolimus and creatinine in renal transplant patients., (Copyright © 2022 The Canadian Society of Clinical Chemists. All rights reserved.)

Abstract: Individualization of vancomycin dosing based on therapeutic drug monitoring (TDM) data is known to improve patient outcomes compared with fixed or empirical dosing strategies. There is increasing evidence to support area-under-the-curve (AUC24)-guided TDM to inform vancomycin dosing decisions for patients receiving therapy for more than 48 hours. It is acknowledged that there may be institutional barriers to the implementation of AUC24-guided dosing, and additional effort is required to enable the transition from trough-based to AUC24-based strategies. Adequate documentation of sampling, correct storage and transport, accurate laboratory analysis, and pertinent data reporting are required to ensure appropriate interpretation of TDM data to guide vancomycin dosing recommendations. Ultimately, TDM data in the clinical context of the patient and their response to treatment should guide vancomycin therapy. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology, the IATDMCT Anti-Infectives Committee, provides recommendations with respect to best clinical practice for vancomycin TDM., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The spread of misinformation in social media has become a severe threat to public interests. For example, several incidents of public health concerns arose out of social media misinformation during the COVID-19 pandemic. Against the backdrop of the emerging IS research focus on social media and the impact of misinformation during recent events such as the COVID-19, Australian Bushfire, and the USA elections, we identified disaster, health, and politics as specific domains for a research review on social media misinformation. Following a systematic review process, we chose 28 articles, relevant to the three themes, for synthesis. We discuss the characteristics of misinformation in the three domains, the methodologies that have been used by researchers, and the theories used to study misinformation. We adapt an Antecedents-Misinformation-Outcomes (AMIO) framework for integrating key concepts from prior studies. Based on the AMIO framework, we further discuss the inter-relationships of concepts and the strategies to control the spread of misinformation on social media. Ours is one of the early reviews focusing on social media misinformation research, particularly on three socially sensitive domains; disaster, health, and politics. This review contributes to the emerging body of knowledge in Data Science and social media and informs strategies to combat social media misinformation., Competing Interests: Conflict of interestOn behalf of two authors, the corresponding author states that there is no conflict of interest in this research paper., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022.)

Competing Interests: The authors declare no conflict of interest.

Aims: 5-Fluorouracil (5-FU) is widely used in combination chemotherapy, and literature suggests pharmacokinetic-guided dosing to improve clinical efficacy and reduce toxicity. This study aimed to determine the pharmacokinetic exposure of both 5-FU and its metabolite, 5,6-dihydrofluorouracil (DHFU), in patients with gastrointestinal malignancy and to establish a simplified strategy to assist in therapeutic drug management for dose optimization., Methods: This was a prospective, observational study, performed in 27 patients diagnosed with gastrointestinal malignancy who were prescribed 5-FU. Multiple samples were collected per patient over the slow bolus (15-20 min) and continuous infusion period (over 44 h) in doses 1 and 3, and the concentrations of 5-FU and DHFU were measured., Results: A higher proportion of patients had exposures within the therapeutic range in dose 3 (50%) as compared to dose 1 (37.5%) with 5-FU. There was an association between delayed time to maximum concentration of DHFU and a high maximum concentration of 5-FU. A limited sampling strategy was developed with 4 samples, 2 during the bolus period and 2 during the continuous period (at 18 h and the end of infusion), which accurately predicted the total area under the curve of 5-FU., Conclusion: Using body surface area-based dosing with 5-FU, 50-60% of patients were outside of the therapeutic range. In the absence of genotype testing, measurement of the metabolite DHFU could be a phenotypical measure of dihydropyrimidine dehydrogenase enzyme activity. A limited sampling strategy was developed in patients who were prescribed a combination regimen of slow bolus, followed by a 44-hour continuous infusion of 5-FU to assist in the therapeutic drug management of patients., (© 2020 The British Pharmacological Society.)

Objective: Adequate data on fentanyl pharmacokinetics in neonates are lacking. The study was performed to compare serum concentrations and clinical outcome between continuous infusion (CI) and intermittent bolus (IB) doses of fentanyl for analgesia and sedation in neonates., Methods: In this open-label randomised controlled trial, neonates requiring 24-48 hours of mechanical ventilation and fentanyl administration were recruited. In CI regimen, 1 mcg/kg loading dose was followed by 1 mcg/kg/hour infusion. In IB regimen, 1mcg/kg/dose was administered every 4 hours.Maximum six blood samples were collected in 48 hours from each baby at prespecified time points for estimating serum fentanyl concentration. Secondary outcomes were pain scores (Neonatal Infant Pain Scale and Neonatal Pain, Agitation and Sedation Scale for acute and ongoing pain, respectively) and incidence of adverse effects of fentanyl., Results: 100 neonates were recruited, 53 in CI and 47 in IB group. In CI regimen, median (IQR) serum fentanyl concentration was 0.42 (0.35, 0.46) to 0.61 (0.47, 0.89) ng/mL throughout the infusion period. In IB regimen, median (IQR) peak concentration ranged from 2.21 (1.82, 3.55) to 3.61 (2.91, 4.51) ng/mL and trough concentration 0.41 (0.33, 0.48) to 0.97 (0.56, 1.25) ng/mL for various doses.Median (IQR) peak concentration (C max , 3.06 (1.09, 4.50) vs 0.78 (0.49, 1.73) ng/mL; p<0.001) was significantly higher and area under concentration-time curve (AUC 0-24 , 19.6 (10.4, 33.5) vs 13.2 (10.8, 22.6) µg·hour/L; p=0.12) was higher (though not statistically significant) in IB than CI regimen. Pain scores and adverse effects were comparable between the two regimens., Conclusion: CI regimen of fentanyl produces steady serum concentrations, whereas IB regimen produces wide fluctuations in serum concentration with high-peak concentrations. A serum fentanyl concentration of 0.4-0.6 ng/mL produces adequate analgesia and sedation in neonates., Trial Registration Number: CTRI/2014/11/005190., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens., Methods: Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model., Results: Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg -1 , was found to provide adequate drug exposure in most children., Conclusions: The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin., (© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2-16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (C max ), the area under the concentration-time curve from 0-6 h (AUC 0-6h ) and treatment outcome were determined. Ninety-two percent of patients had an INH C max  > 3 µg/mL. Seventy-seven percent of patients had a RIF C max  < 8 µg/mL and 28% of patients had a RIF AUC 0-24h  < 13 mg ⋅ h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses., (Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Context: Kv7 potassium channels are expressed in several types of smooth muscles and could mediate physiological responses in the tissues expressed. Flupirtine is an analgesic that acts by opening Kv7 potassium channels. It has been shown to inhibit the contractility of several types of isolated smooth muscle., Aims: This study investigated the ability of flupirtine to inhibit the spontaneous contractility of isolated distal caprine (goat) ureter., Settings and Design: Spontaneous contractility of the isolated goat ureter was recorded using a physiograph., Materials and Methods: The ability of 1, 3, 10, 30, and 90 μM concentrations of flupirtine maleate to inhibit the spontaneous contractility of isolated distal goat ureter was investigated. The ability of the nonspecific potassium channel blocker 4-aminopyridine (4-AP; 1 mM) and the specific Kv7 channel blocker XE-991 (100 μM) to reverse the inhibitory effect of flupirtine on ureteric contractility was also investigated., Statistical Analysis Used: Both parametric and nonparametric statistical tests were used., Results: At 10, 30, and 90 μM concentrations, flupirtine significantly inhibited the spontaneous contractility of the isolated goat ureter. The EC 50 of flupirtine for a contact period of 10 min was 17.7 μM. The inhibitory effect of flupirtine on ureteric contractility was significantly reversed by 4-AP and XE-991., Conclusions: Flupirtine inhibits the spontaneous contractility of the isolated goat ureter by opening Kv7 channels., Competing Interests: There are no conflicts of interest.

Context: Benidipine is a calcium channel blocker that blocks all the major types (L, N, and T) of calcium channels. It has been shown to inhibit the contractility of many isolated smooth muscles but not isolated ureter., Aims: This study evaluated the ability of benidipine to inhibit the spontaneous contractility of isolated proximal and distal caprine (goat) ureter., Settings and Design: Spontaneous contractility of isolated goat ureter was recorded using a physiograph., Materials and Methods: Benidipine at concentrations in the range of 1 nM to 10 μM was analyzed for its inhibitory effects on the spontaneous contractility of the isolated proximal and distal caprine ureter., Statistical Analysis Used: Both parametric and nonparametric statistical tests were used., Results: The EC 50 of benidipine for inhibiting contractility in the distal ureter was found to be 54.68 nM. Benidipine was found to have a greater inhibitory effect on the distal ureter than on the proximal ureter. It was also found to inhibit amplitude of spontaneous ureteric contractility more readily than the frequency of spontaneous ureteric contractility., Conclusions: These results suggest that benidipine has differential inhibitory effects on the spontaneous contractility of the isolated ureter. Benidipine could be useful in the management of clinical conditions like ureteric colic due to its inhibitory effects on the contractility of the ureter., Competing Interests: There are no conflicts of interest.

We use a liquid crystal variable retarder (LCVR) for polarization modulation of the input beam in a polarimeter intended for solar observations. It is known that the retardance of LCVR depends on the voltage and temperature. Voltage at a constant temperature is used for fast modulation. However, fluctuations in the temperature reduce the accuracy in the polarimetric measurements. In order to understand these, we have performed calibration of the LCVR with respect to temperature and estimated the different parameters, critical exponent (β), maximum retardance (δ 0 ), and order parameter (S) of the liquid crystal using Haller's approximation. We also study the dependence of these parameters with voltage. It is observed that the change in order parameter with change in temperature varies linearly with voltage in the range of 1-7 V.

Background & Aims: Although Absorb Bioresorbable Vascular Scaffolds (A-BVS) are routinely used in the Asia-Pacific, there is little information on patient selection or deployment technique here. This document investigates the experiences of leading interventional cardiologists from the Asia-Pacific region with a focus on patient characteristics, deployment techniques and management., Methods and Results: A detailed questionnaire was distributed to 28 highly-experienced interventional cardiologists ('Authors') from 13 Asia-Pacific countries. The results were discussed at a meeting on patient selection, technical consideration, deployment practices and patient management. Potential patient benefits of Absorb compared to metallic DES, the learning curve for patient selection and preparation, device deployment, and subsequent patient management approaches are presented., Conclusions: Current practices are derived from guidelines optimized for European patients. Differences in approach exist in the Asia-Pacific context, including limited access to imaging and frequency of occurrence of complex lesions. Nevertheless, the use of the Absorb BVS ('Absorb') in certain Asia-Pacific countries has flourished and practices here are continuing to mature., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population., Methods: This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem., Results: A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat., Conclusions: This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.

Many people over the years have studied the Bible from a medical point of view offering diagnoses for the symptoms and signs that appear to have afflicted numerous individuals in the Bible. We review the biblical characters in the Old Testament and offer newer insights to their neurological diseases. We first look at the battle between Goliath and David. Interestingly, Goliath probably suffered from acromegaly. We propose autism as a diagnosis for Samson which would precede the first known case of autism by centuries. Isaac was a diabetic, and he probably had autonomic neuropathy. Few verses from the books of I Samuel, Psalms, and Ezekiel reveal symptoms suggestive of stroke. Jacob suffered from sciatica, and the child of the Shunnamite woman in II Kings had a subarachnoid hemorrhage. These instances among others found in the Old Testament of the Bible offer newer insights on the history of current neurological diseases.

Experimental determination of the electro-optic coefficient r13 of a lithium niobate crystal is described. The crystal in this experiment is z cut, used as a substrate for a Fabry-Perot etalon. I computed the r13 coefficient from the measured voltage tuning curve of the Fabry-Perot etalon. It is find that the measured value of r13 is lower than most of the reported values in literature.