Evaluation of artificial intelligence-generated drug therapy communication skill competencies in medical education.

AIMS: This study compared three artificial intelligence (AI) platforms' potential to identify drug therapy communication competencies expected of a graduating medical doctor. METHODS: We presented three AI platforms, namely, Poe Assistant©, ChatGPT© and Google Bard©, with structured queries to generate communication skill competencies and case scenarios appropriate for graduating medical doctors. These case scenarios comprised 15 prototypical medical conditions that required drug prescriptions. Two authors independently evaluated the AI-enhanced clinical encounters, which integrated a diverse range of information to create patient-centred care plans. Through a consensus-based approach using a checklist, the communication components generated for each scenario were assessed. The instructions and warnings provided for each case scenario were evaluated by referencing the British National Formulary. RESULTS: AI platforms demonstrated overlap in competency domains generated, albeit with variations in wording. The domains of knowledge (basic and clinical pharmacology, prescribing, communication and drug safety) were unanimously recognized by all platforms. A broad consensus among Poe Assistant© and ChatGPT© on drug therapy-related communication issues specific to each case scenario was evident. The consensus primarily encompassed salutation, generic drug prescribed, treatment goals and follow-up schedules. Differences were observed in patient instruction clarity, listed side effects, warnings and patient empowerment. Google Bard did not provide guidance on patient communication issues. CONCLUSIONS: AI platforms recognized competencies with variations in how these were stated. Poe Assistant© and ChatGPT© exhibited alignment of communication issues. However, significant discrepancies were observed in specific skill components, indicating the necessity of human intervention to critically evaluate AI-generated outputs.

Leveraging artificial intelligence to detect ethical concerns in medical research: a case study.

BACKGROUND: Institutional review boards (IRBs) have been criticised for delays in approvals for research proposals due to inadequate or inexperienced IRB staff. Artificial intelligence (AI), particularly large language models (LLMs), has significant potential to assist IRB members in a prompt and efficient reviewing process. METHODS: Four LLMs were evaluated on whether they could identify potential ethical issues in seven validated case studies. The LLMs were prompted with queries related to the proposed eligibility criteria of the study participants, vulnerability issues, information to be disclosed in the informed consent document (ICD), risk-benefit assessment and justification of the use of a placebo. Another query was issued to the LLMs to generate ICDs for these case scenarios. RESULTS: All four LLMs were able to provide answers to the queries related to all seven cases. In general, the responses were homogeneous with respect to most elements. LLMs performed suboptimally in identifying the suitability of the placebo arm, risk mitigation strategies and potential risks to study participants in certain case studies with a single prompt. However, multiple prompts led to better outputs in all of these domains. Each of the LLMs included all of the fundamental elements of the ICD for all case scenarios. Use of jargon, understatement of benefits and failure to state potential risks were the key observations in the AI-generated ICD. CONCLUSION: It is likely that LLMs can enhance the identification of potential ethical issues in clinical research, and they can be used as an adjunct tool to prescreen research proposals and enhance the efficiency of an IRB.

Artificial intelligence and medical education: application in classroom instruction and student assessment using a pharmacology & therapeutics case study.

BACKGROUND: Artificial intelligence (AI) tools are designed to create or generate content from their trained parameters using an online conversational interface. AI has opened new avenues in redefining the role boundaries of teachers and learners and has the potential to impact the teaching-learning process. METHODS: In this descriptive proof-of- concept cross-sectional study we have explored the application of three generative AI tools on drug treatment of hypertension theme to generate: (1) specific learning outcomes (SLOs); (2) test items (MCQs- A type and case cluster; SAQs; OSPE); (3) test standard-setting parameters for medical students. RESULTS: Analysis of AI-generated output showed profound homology but divergence in quality and responsiveness to refining search queries. The SLOs identified key domains of antihypertensive pharmacology and therapeutics relevant to stages of the medical program, stated with appropriate action verbs as per Bloom's taxonomy. Test items often had clinical vignettes aligned with the key domain stated in search queries. Some test items related to A-type MCQs had construction defects, multiple correct answers, and dubious appropriateness to the learner's stage. ChatGPT generated explanations for test items, this enhancing usefulness to support self-study by learners. Integrated case-cluster items had focused clinical case description vignettes, integration across disciplines, and targeted higher levels of competencies. The response of AI tools on standard-setting varied. Individual questions for each SAQ clinical scenario were mostly open-ended. The AI-generated OSPE test items were appropriate for the learner's stage and identified relevant pharmacotherapeutic issues. The model answers supplied for both SAQs and OSPEs can aid course instructors in planning classroom lessons, identifying suitable instructional methods, establishing rubrics for grading, and for learners as a study guide. Key lessons learnt for improving AI-generated test item quality are outlined. CONCLUSIONS: AI tools are useful adjuncts to plan instructional methods, identify themes for test blueprinting, generate test items, and guide test standard-setting appropriate to learners' stage in the medical program. However, experts need to review the content validity of AI-generated output. We expect AIs to influence the medical education landscape to empower learners, and to align competencies with curriculum implementation. AI literacy is an essential competency for health professionals.

Indications, success, and adverse event rates of pediatric endoscopic retrograde cholangiopancreatography (ERCP): a systematic review and meta-analysis.

BACKGROUND: To improve knowledge on endoscopic retrograde cholangiopancreatography (ERCP) in children, we aimed to study the proportion of indications, success rate and complication of ERCP. METHODS: We performed a systematic search of all articles published up to December 2022 in the following databases: Cochrane Library, PubMed (MEDLINE) and Scopus. The meta-analysis was performed using a random-effects model. Heterogeneity was determined by the I2 statistics and the Cochrane Q test. The included data were analyzed to identify the proportion of indications, success rate and complications of ERCP in children. RESULTS: Based on data from 52 studies with a total of 5624 participants, the most common indications for ERCP in children were biliary [48% (95% CI: 0.40 - 0.57; I2 = 98.17%, P < 0.001)] and both biliary and pancreatic [41% (95% CI: 0.33 - 0.49; I2 = 98.27%, P < 0.001)]. The success rate of ERCP was 95% (95% CI: 0.94 - 0.96; I2 = 82.53%, P < 0.001) with the overall complication rate of 7% (95% CI: 0.05 - 0.09; I2 = 82.06%, P < 0.001). The pooled estimate for the incidence of post ERCP pancreatitis was 4% (95% CI: 0.03 - 0.06; I2 = 85.46%, P < 0.001) and the bleeding was 0% (95% CI: 0.0 - 0.0; I2 = 28.21%, P = 0.03). CONCLUSIONS: ERCP appears to be performed safely in children with a similar success rate as in the adult population.

Disinformation about COVID-19 Preventions and Treatments: Analysis of USFDA Warning Letters.

COVID-19 poses a challenge beyond the virus itself, in that lockdown has been associated increased use of the internet and social media. Disinformation about prevention and treatment strategies for COVID-19 can have lethal consequences. The United States Food and Drug Administration (USFDA) is currently monitoring the compliance of manufacturing firms as well as medicinal product advertisers to the Federal Food, Drug, and Cosmetic Act, 21 USC § 321(h) regulations. In the event of noncompliance in the form of advertising products without prior USFDA approval for specific indications, doses, or route of administration, warning letters (WLs) are issued. WLs are intended to address the concerns identified by USFDA and encourage the recipient to take corrective steps to avoid similar instances in the future. We analyzed 182 WLs that were issued for noncompliance with drugs/devices related to either treatment, prevention, or testing of COVID-19 infections. The medicinal product website was identified as the major source of disinformation, followed by disseminated information on Facebook, Twitter, and Instagram. Nearly four-fifths were related to drugs, followed by devices and biologicals. Several biologicals, as well as allopathic, herbal, and non-herbal drugs were identified in the WLs. We observed that noncompliance with the USFDA regulations in terms of advertising a variety of products for prevention and treatment of COVID-19 infection was widely prevalent. More efforts are required by the respective national drug regulatory authorities to initiate or continue their monitoring of disinformation that may have lethal consequences.

Oral side effects of locally delivered nicotine replacement therapy: A meta-analysis of randomized controlled trials.

BACKGROUND: Nicotine replacement therapy is the first choice pharmacotherapy for smoking cessation. Oral side effects caused due to NRT lead to discontinuation of treatment. The objective of this meta-analysis was to look for the certainty of evidence on the number of patients that reported oral side effects due to the use of NRT. METHOD: Eligible studies were selected and data extraction was carried out independently into a pre-tested data extraction form. Risk of bias was assessed using Cochrane Tool. The heterogeneity between the studies was assessed using Chi-square and I2 tests. Mean difference and Odds ratio at 95% confidence interval were the effect estimates. GRADE working group approach was used to assess the quality of evidence. RESULTS: Twenty-eight studies were included with moderate to low risk of bias. The pooled estimates revealed a statistically significant number of patients developed mouth or throat irritation (2.54 [1.23, 5.25]), or oral soreness (2.22 [1.40, 3.55]) or gastric reflux or vomiting (1.97 [1.34, 2.90]) due to NRT. CONCLUSION: It is important to understand that significant implications are caused due to NRT, on oral health. All patients on NRT must adhere to their regular dentist visits and must check their oral mucosa before initiating NRT.

Evaluation of urinary acetaminophen metabolites and its association with the genetic polymorphisms of the metabolising enzymes, and serum acetaminophen concentrations in preterm neonates with patent ductus arteriosus.

Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolised by conjugation and partly by Cytochrome P450 (CYP) enzymes.We carried out the present study to identify the principal urine metabolites of acetaminophen (glucuronide/sulphate) in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen, and to evaluate the prevalence of single nucleotide polymorphisms (SNPs) in the key CYP enzymes (CYP1A2*3, CYP1A2*4, CYP1A2*1C, CYP1A2*1K, CYP1A2*6, CYP2D6*10, CYP2E1*2, CYP2E1*5B, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, and CYP3A5*11) and their effect on urinary metabolites and serum acetaminophen concentrations.Nineteen (32.8%) neonates had heterozygous CYP1A2*1C, two (3.3%) with heterozygous CYP1A2*1K, 15 (27.8%) and two (3.7%) had heterozygous and homozygous CYP2D6*10, two (3.7%) had heterozygous CYP2E1*5B, seven (12.3%) and three (5.3%) had heterozygous and homozygous CYP3A4*1B, and three (5.5%) had CYP3A5*7 amongst the study population. Acetaminophen sulphate predominated over glucuronide metabolite at all time points. Postnatal days of life was significantly associated with an increase in the urine acetaminophen metabolites with decreased serum acetaminophen concentrations.A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed in our neonatal population. Population pharmacokinetic-pharmacodynamic modelling incorporating genetic and metabolite data is urgently needed for implementation of precision medicine in this vulnerable population.

A network meta-analysis of CYP2C9, CYP2C9 with VKORC1 and CYP2C9 with VKORC1 and CYP4F2 genotype-based warfarin dosing strategies compared to traditional.

WHAT IS KNOWN AND OBJECTIVES: Variations in genotypes were observed in randomized clinical trials (RCTs) that evaluated genotype-based warfarin dosing. We carried out a network meta-analysis to assess whether any clinically significant differences exist between RCTs evaluating CYP2C9 with VKORC1, with CYP2C9 alone and CYP2C9, VKORC1, with CYP4F2 dosing strategies. METHODS: Electronic records were searched for RCTs comparing genotype-based warfarin with traditional-dosing strategies. Key outcomes included were the time to first therapeutic international normalized ratio (INR); time to stable INR or warfarin dose; percent time in therapeutic range (TTR); and the proportion of patients with supra-therapeutic INR. Weighted mean differences (WMD) and odds ratios (OR) with 95% confidence intervals (95% CI) were the effect estimates. RESULTS AND DISCUSSION: Twenty-six studies (7898 patients) were included. CYP2C9-based warfarin dosing was associated with a shorter time to first therapeutic INR (WMD: -2.73, 95% CI: -3.41, -2.05) and stable INR/warfarin dose (WMD: -8.1, 95% CI: -12.54, -3.66). CYP2C9 and VKORC1 were observed with a shorter time to first therapeutic INR (WMD: -1.92, 95% CI: -3.23, -0.61) and stable INR/warfarin dose (WMD: -4.6, 95% CI: -6.87, -2.34) along with a longer TTR (%) (WMD: 3.91, 95% CI: 1.18, 6.63). CYP2C9, VKORC1 and CYP4F2 were observed with a reduced proportion of patients with supra-therapeutic INR (OR: 0.68, 95% CI: 0.49, 0.93). Trial sequential analysis confirms the superior benefits of CYP2C9 with VKORC1 genotype. WHAT IS NEW AND CONCLUSION: The present evidence is supportive of personalizing warfarin dose based only on CYP2C9 and VKORC1 genotypes compared to traditional strategies. More RCTs are needed to delineate any benefit for adding CYP4F2 to provide sufficient power for pooled analysis. No convincing evidence exists supporting the role of CYP2C9 alone.

Does fasting during Ramadan influence the therapeutic effect of warfarin?

WHAT IS KNOWN AND OBJECTIVES: The changes in the therapeutic effect of warfarin during Ramadan fasting are controversial. Hence, we carried out the present study to assess if there are any alterations in the anticoagulation response to warfarin and identify the associated risk factors. METHODS: Patients receiving warfarin for at least 1 year were included in the present study. Their demographic details, warfarin doses, prothrombin time-international normalized ratio (PT-INR) values and concomitant diseases/drugs were retrieved. The dates of Ramadan periods for the calendar years were obtained, and these periods were considered as Ramadan periods. One month before the start dates of Ramadan was considered as pre-Ramadan, and 1 month later than the last dates was considered as post-Ramadan periods. Warfarin sensitivity index (WSI), PT-INR category and time spent in therapeutic range (TTR) were assessed. National Institute of Clinical Health Excellence (NICE) criteria for anticoagulation status were adhered to where TTR (%) <65 was considered as poor anticoagulation. RESULTS AND DISCUSSION: One hundred and eighty-three patients were recruited. No significant differences were observed in warfarin doses between the study participants between pre-Ramadan, Ramadan and post-Ramadan periods. Significantly more numbers of PT-INR tests were carried out during Ramadan compared with pre- and post-Ramadan periods. A higher WSI was akin to PT-INR, and lower intra-individual variability was observed in middle-aged and older adults in the post-Ramadan period. Significantly fewer patients had their PT-INR in the therapeutic range and more in the subtherapeutic range during Ramadan periods. Greater proportion of patients had PT-INR in the supratherapeutic range during post-Ramadan periods, particularly the elderly. Although 38.3% had poor anticoagulation status overall, 92.4% met the NICE criteria for poor anticoagulation during the 3 months (pre-Ramadan, Ramadan and post-Ramadan periods). WHAT IS NEW AND CONCLUSION: Ramadan fasting influences the therapeutic effect of warfarin in terms of lowered TTR (%), reduced proportion of patients achieving therapeutic PT-INR and increased risk of poor anticoagulation control. Greater caution is required during the post-Ramadan period, particularly in the elderly category as they are more prone for over-anticoagulation and consequently the risk of bleeding.

Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

WHAT IS KNOWN AND OBJECTIVES: Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15 mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. METHODS: Preterm neonates (≤37 weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. RESULTS: Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. WHAT IS NEW AND CONCLUSION: Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

Effectiveness of a Daily Rounding Checklist on Processes of Care and Outcomes in Diverse Pediatric Intensive Care Units Across the World.

BACKGROUND: Implementation of checklists has been shown to be effective in improving patient safety. This study aims to evaluate the effectiveness of implementation of a checklist for daily care processes into clinical practice of pediatric intensive care units (PICUs) with limited resources. METHODS: Prospective before-after study in eight PICUs from China, Congo, Croatia, Fiji, and India after implementation of a daily checklist into the ICU rounds. RESULTS: Seven hundred and thirty-five patients from eight centers were enrolled between 2015 and 2017. Baseline stage had 292 patients and post-implementation 443. The ICU length of stay post-implementation decreased significantly [9.4 (4-15.5) vs. 7.3 (3.4-13.4) days, p = 0.01], with a nominal improvement in the hospital length of stay [15.4 (8.4-25) vs. 12.6 (7.5-24.4) days, p = 0.055]. The hospital mortality and ICU mortality between baseline group and post-implementation group did not show a significant difference, 14.4% vs. 11.3%; p = 0.22 for each. There was a variable impact of checklist implementation on adherence to various processes of care recommendations. A decreased exposure in days was noticed for; mechanical ventilation from 42.6% to 33.8%, p < 0.01; central line from 31.3% to 25.3%, p < 0.01; and urinary catheter from 30.6% to 24.4%, p < 0.01. Although there was an increased utilization of antimicrobials (89.9-93.2%, p < 0.01). CONCLUSIONS: Checklists for the treatment of acute illness and injury in the PICU setting marginally impacted the outcome and processes of care. The intervention led to increasing adherence with guidelines in multiple ICU processes and led to decreased length of stay.

Topical corticosteroids for phimosis in children: a network meta-analysis of randomized clinical trials.

BACKGROUND: Corticosteroids and hyaluronidase are trialed for treating phimosis in children. We carried out the present network meta-analysis to compare the therapeutic effect of these drugs. METHODS: Electronic databases were searched for appropriate randomized clinical trials. Odds ratio (OR) with 95% confidence intervals (95% CI) was used as the effect estimate. A random-effects model was used for generating the pooled estimates. Rankogram plot was used for ranking the drugs. MAIN OUTCOME MEASURES: Proportions of patients with remission (partial/complete) and with complete remission. RESULTS: Mometasone (OR 6.53, 95% CI 2.85, 14.96), betamethasone/hyaluronidase (OR 12.1, 95% CI 4.27, 34.49), triamcinolone (OR 19.15, 95% CI 4.47, 81.96), dexamethasone (OR 21.38, 95% CI 5.71, 79.98), betamethasone (OR 23.02, 95% CI 6.92, 79.54), hydrocortisone (OR 23.2, 95% CI 5.91, 91.02) and methylprednisolone (OR 50.47, 95% CI 4.45, 572.72) were observed with significantly higher proportions of patients with remission (partial/complete) compared to placebo. Dexamethasone, triamcinolone, betamethasone, betamethasone/hyaluronidase, clobetasol, mometasone, and hydrocortisone were observed with significantly higher proportions of patients with complete remission compared to placebo. Beclomethasone was not observed to be superior to either placebo or other drugs. Rankogram plot revealed methylprednisolone followed by hydrocortisone had the maximum statistical probability of being 'the best' in the pool for remission and betamethasone followed by hydrocortisone for complete remission. CONCLUSION: Topical methylprednisolone, hydrocortisone, and betamethasone were observed with better clinical resolution of phimosis compared to other corticosteroids. Very high potent corticosteroids like beclomethasone and clobetasol were not observed with superior benefits compared to other corticosteroids. Considering low-potency, hydrocortisone shall be preferred until further evidence emerges.

Cerumenolytics with or without manual extraction for impacted earwax: A network meta-analysis of randomised clinical trials.

BACKGROUND: Many different substances for cerumenolysis have been evaluated in clinical trials. We carried out a systematic review and network meta-analysis to compare their effectiveness. METHODS: Electronic databases were searched for randomised clinical trials conducted in patients with impacted cerumen evaluating cerumenolytics. The primary outcome was the proportion of patients with wax clearance using manual techniques. Rankogram plot was used to assess the "best" cerumenolytic. Odds ratio (OR) with 95% confidence intervals (95% CI) was the effect estimate. RESULTS: Twenty-six studies were included in the systematic review and 25 in the meta-analysis. Sodium bicarbonate (OR: 2.68, 95% CI: 1.2, 6.1) and paradichlorobenzene (OR: 30.9, 95% CI: 5.9, 161.3) were associated with significantly greater proportions of patients with wax clearance following syringing compared to normal saline. Rankogram plot revealed paradichlorobenzene to have the highest probability of being the "best" cerumenolytic. Chlorobutanol was observed to be significantly better than normal saline in adults as well as following single application. Following multiple applications, glycerol, docusate sodium, hydrogen peroxide, oil, paradichlorobenzene, hydrogen peroxide/glycerol and arachis oil/chlorobutanol/paradichlorobenzene were observed with significant cerumenolytic activities. Urea/hydrogen peroxide/glycerol was observed with a significant cerumenolytic activity without the need for further interventions such as syringing/aspiration/suction. CONCLUSION: We observed several cerumenolytics to be effective in the treatment of impacted earwax when accompanied by additional manual techniques such as syringing/aspiration/suction.

Clinical audit of gentamicin use by Bayesian pharmacokinetic approach in critically ill children.

INTRODUCTION: Critically ill children tend to have altered gentamicin pharmacokinetics (PK); and so we carried out an audit of gentamicin use using the estimated peak concentrations (Cmax), trough concentrations (Cmin) and area-under-the-concentration-time curve (AUCs) by Bayesian approach. METHODS: Critically ill children with at least one serum gentamicin concentrations available were recruited. We used multiple models Bayesian adaptive control to estimate Cmax, and AUC0-t following each dose. Pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria was used to identify the incidence of acute kidney injury (AKI). RESULTS: Seventy-three children (961 doses and 143 concentrations) were analysed. AUC0-24 was observed to be higher in earlier age groups with a steady decline in older children. Similar changes were observed in Cmax, Cmin and AUC0-24 at steady state. Significantly higher proportions of children in the other age groups were estimated to have Cmax between 5 and 10 mg/L compared to neonates. Neonates had a higher risk of Cmax above 10 mg/L. Patients with augmented renal clearance exhibited lower AUC0-24 and reduced proportion achieving the target AUC0-24 levels. Nearly one-third of children were observed to meet the pRIFLE criteria for AKI. CONCLUSION: We observed higher initial doses and peak concentrations of gentamicin in neonates and infants compared to older age groups in critically ill children. Uniformity in the paediatric-specific standard treatment guidelines for gentamicin is the need of the hour.

Drug-Induced Liver Injury in Critically Ill Children Taking Antiepileptic Drugs: A Retrospective Study.

BACKGROUND: Antiepileptic drugs are among the leading causes of drug-induced liver injury (DILI). Due to critical illness, children admitted to intensive care units are more prone to DILI. OBJECTIVE: We attempted to elucidate the association between antiepileptic drug use and the associated factors resulting in DILI in a pediatric intensive care unit of a tertiary care hospital. METHODS: We carried out an observational retrospective study on children receiving antiepileptic drugs. Details on their demographic characteristics, drugs, serum levels of antiepileptic drugs and liver function tests, and hospital stay were recorded. Council for International Organizations of Medical Sciences definitions were adhered to when defining DILI. LiverTox (https://livertox.nih.gov) and DILIrank were used to assess the risks of hepatotoxicity of the concomitant drugs. Regression models were developed for predicting DILI. RESULTS: Five out of 9 patients taking phenobarbitone (55.6%), 9 out of 12 taking phenytoin monotherapy (75%), 7 out of 10 taking phenytoin/phenobarbitone (70%), all 3 receiving phenytoin/phenobarbitone/valproate sodium, and 1 with phenytoin/carbamazepine developed DILI either in the form of hepatocellular injury or liver biochemical test abnormalities. None of the patients had cholestatic or mixed type of liver injury. All the critically ill children received at least 2 concomitant drugs with hepatotoxic potential. Concomitant category B hepatotoxic drugs and toxic drug levels were significantly associated with increased risk of DILI. Similarly, a trend was observed for less-DILI-concern concomitant drug class and toxic drug levels when the drugs were analyzed by DILIrank classification. CONCLUSIONS: A significant proportion of critically ill children taking antiepileptic drugs experience DILI. Guidelines recommending use of drugs with reduced risk of potential hepatotoxicity for various concomitant disease states in such children admitted to intensive care units receiving antiepileptic drugs are urgently needed.

Fluoride varnish versus glutaraldehyde for hypersensitive teeth: a randomized controlled trial, meta-analysis and trial sequential analysis.

OBJECTIVE: Reports indicate Gluma and Duraphat are commonly used in-office agents to treat hypersensitive teeth. Considering this, the aim of this paper is to compare Gluma and Duraphat using a randomized controlled trial, meta-analysis collating evidences from previous studies and trial sequential analysis. MATERIALS AND METHODS: Thirty-eight participants were randomized. Hypersensitivity and visual analog scale (VAS) scores were recorded at baseline, 5 min and 7 days. Oral health-related quality of life (OHIP) questionnaire was administered at baseline and 7 days. Statistical analysis was performed to identify significant differences between the variables. For the meta-analysis, electronic data bases were searched and eligible data was extracted and analysed using RevMan 5.0. Trial sequential analysis was performed using O'Brien-Fleming boundary approach for the primary outcome. RESULTS: Both agents caused significant reduction in hypersensitivity and VAS score at 5 min and 7 days in the randomized trial with no superiority. The quality of life significantly improved in patients treated with both the agents. Four studies including the present trial in meta-analysis and trial sequential analysis indicated that Gluma produced significant reduction in VAS scores at 7 days. CONCLUSION: Gluma produces significant reduction in hypersensitivity at 7 days post treatment compared with Duraphat. There is definite lack of evidence on the long-term effect of these agents. CLINICAL RELEVANCE: This paper provides strong evidence on the use of Gluma for hypersensitive teeth. This also is a way forward to future research on long-term effects, adverse effects and cost-effectiveness studies.

Vasoactive Agents for Hepatorenal Syndrome: A Mixed Treatment Comparison Network Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials.

BACKGROUND: Hepatorenal syndrome (HRS) is a common complication among patients with cirrhosis, primarily attributable to vasodilation of renal vessels. Vasoactive agents are commonly used to treat HRS. The present network meta-analysis compares the vasoactive agents used in HRS. METHODS: We searched electronic databases for appropriate randomized controlled clinical trials in patients with HRS, comparing active interventions with either placebo or standard of care. The primary outcome was complete HRS reversal; secondary outcomes included partial HRS reversal, mortality, adverse events, and cardiovascular adverse events. The data were pooled using a random effects model. We also carried out direct comparisons for the primary outcome with trial sequential analysis. RESULTS: A total of 16 studies were included in the systematic review. Rates of complete HRS reversal were significantly higher with terlipressin and noradrenaline combined with albumin than with placebo (OR 6.65, 95% CI: 2.08-21.31 and 6.81, 95% CI: 1.87-24.83, respectively). No significant differences were observed in terms of mortality, partial HRS reversal, or adverse events for any of the interventions. However, cardiovascular adverse events were significantly higher with continuous-infusion terlipressin/albumin (OR 7.07, 95% CI: 1.23-40.62), bolus terlipressin/albumin (OR 7.39, 95% CI: 1.89, 28.94), octreotide/midodrine/albumin (OR 9.85, 95% CI: 1.1, 88.1), and noradrenaline/albumin (OR 15.24, 95% CI: 2.1, 112.6) than with albumin alone. Trial sequential analyses revealed adequate evidence to conclude that terlipressin combined with albumin was effective in achieving complete HRS reversal. DISCUSSION: Terlipressin combined with albumin shows strong evidence of improving short-term survival in patients with type 1 but not type 2 HRS. Through indirect comparison, noradrenaline with albumin was also associated with significant benefits in terms of HRS reversal.

Growth factors for diabetic foot ulcers: mixed treatment comparison analysis of randomized clinical trials.

AIMS: Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head-to-head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors. METHODS: Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Proportion of patients with complete healing was the primary outcome. Odds ratio (95% confidence interval) was used as the effect estimate and random effects model was used for both direct and indirect comparisons. Markov Chain Monte Carlo simulation was used to obtain pooled estimates. Rankogram was generated based on surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 26 studies with 2088 participants and 1018 events were included. The pooled estimates for recombinant epidermal growth factor (rhEGF), autologous platelet rich plasma (PRP), recombinant human platelet-derived growth factor (rhPDGF) were 5.72 [3.34, 10.37], 2.65 [1.60, 4.54] and 1.97 [1.54, 2.55] respectively. SUCRA for rhEGF was 0.95. Sensitivity analyses did not reveal significant changes from the pooled estimates and rankogram. No differences were observed in the overall risk of adverse events between the growth factors. However, the growth factors were observed to lower the risk of lower limb amputation compared to standard of care. CONCLUSION: To conclude, rhEGF, rhPDGF and autologous PRP significantly improved the healing rate when used as adjuvants to standard of care, of which rhEGF may perform better than other growth factors. The strength of most of the outcomes assessed was low and the findings may not be applicable for DFU with infection or osteomyelitis. The findings of this study needs to be considered with caution as the results might change with findings from head-to-head studies.

Drugs for treating severe hypertension in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials.

AIMS: Several antihypertensive drugs are used in the treatment of severe hypertension in pregnancy. The present study is a network meta-analysis comparing the efficacy and safety of these drugs. METHODS: Electronic databases were searched for randomized clinical trials comparing drugs used in the treatment of severe hypertension in pregnancy. The number of women achieving the target blood pressure (BP) was the primary outcome. Doses required and time taken for achieving the target BP, failure rate, and incidences of maternal tachycardia, palpitation, hypotension, headache, and neonatal death and stillbirth were the secondary outcomes. Mixed treatment comparison pooled estimates were generated using a random-effects model. Odds ratios for the categorical and mean difference for the numerical outcomes were the effect estimates. RESULTS: Fifty-one studies were included in the systematic review and 46 in the meta-analysis. No significant differences in the number of patients achieving target BP was observed between any of the drugs. Diazoxide [-15 (-20.6, -9.4)], nicardipine [-11.8 (-22.3, -1.2)], nifedipine/celastrol [-19.3 (-27.4, -11.1)], nifedipine/vitamin D [-17.1 (-25.7, -9.7)], nifedipine/resveratrol [-13.9 (-22.6, -5.2)] and glyceryl trinitrate [-33.8 (-36.7, -31)] were observed to achieve the target BP (in minutes) more rapidly than hydralazine. Nifedipine required fewer doses than hydralazine for achieving the target BP. Glyceryl trinitrate and labetalol were associated with fewer incidences of tachycardia and palpitation respectively than hydralazine. Trial sequential analysis concluded adequate evidence for hydralazine and nifedipine compared with labetalol. Moderate quality of evidence was observed for direct comparison estimate between labetalol and hydralazine but was either low or very low for other comparisons. CONCLUSION: The present evidence suggests similar efficacy between nifedipine, hydralazine and labetalol in the treatment of severe hypertension in pregnancy. Subtle differences may exist in their safety profile. The evidence is inadequate for other drugs.

Pharmacological interventions for non-alcoholic fatty liver disease: a systematic review and network meta-analysis.

AIM: Several drugs have been used for treating non-alcoholic fatty liver disease (NAFLD). The present study is a network meta-analysis of such drugs. DESIGN, SETTING AND PATIENTS: Randomised clinical trials comparing drug interventions in patients with NAFLD were analysed. OR and weighted mean difference (95 % CI) were the effect estimates for categorical and numerical outcomes, respectively. Random-effects model was used to generate pooled estimates. Surface under the cumulative ranking curve was used to rank the treatments. MAIN OUTCOME MEASURES: Proportion of responders was the primary outcome measure and non-alcoholic steatohepatitis scores, liver enzymes, lipid profile, body mass index, homeostatic model assessment of insulin resistance, intrahepatic fat and adverse events were the key secondary outcomes. RESULTS: 116 studies were included in the systematic review and 106 in the meta-analysis. Elafibranor, gemfibrozil, metadoxine, obeticholic acid, pentoxifylline, pioglitazone, probiotics, telmisartan, vildagliptin and vitamin E significantly increased the response rate than standard of care. Various other drugs were observed to modify the secondary outcomes favourably. Probiotics was found with a better response in children; and elafibranor, obeticholic acid, pentoxifylline and pioglitazone in patients with type 2 diabetes mellitus. The quality of evidence observed was either low or very low. CONCLUSION: In patients with NAFLD, several drugs have been shown to have variable therapeutic benefit. However, the estimates and the inferences should be considered with extreme caution as it might change with the advent of future head-to-head clinical trials.