Population Pharmacokinetics and Limited Sampling Strategy of Mycophenolate Mofetil for Indian Patients with Lupus Nephritis.

BACKGROUND: Mycophenolic acid is widely used to treat lupus nephritis (LN). However, it exhibits complex pharmacokinetics with large interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model and a 3-sample limited sampling strategy (LSS) to optimize therapeutic drug monitoring in Indian patients with LN. METHODS: Five blood samples from each LN patient treated with mycophenolic acid were collected at steady-state predose and 1, 2, 4, and 6 hours postdose. Demographic parameters were tested as covariates to explain interindividual variability. PopPK analysis was performed using Monolix and the stochastic approximation expectation-maximization algorithm. An LSS was derived from 500 simulated pharmacokinetic (PK) profiles using maximum a posteriori Bayesian estimation to estimate individual PK parameters and area under the curve (AUC). The LSS-calculated AUC was compared with the AUC calculated using the trapezoidal rule and all the simulated samples. RESULTS: A total of 51 patients were included in this study. Based on the 245 mycophenolic acid concentrations, a 1-compartmental model with double absorption using gamma distributions best fitted the data. None of the covariates improved the model significantly. The model was internally validated using diagnostic plots, prediction-corrected visual predictive checks, and bootstrapping. The best LSS included samples at 1, 2, and 4 hours postdose and exhibited good performances in an external dataset (root mean squared error, 21.9%; mean bias, -4.20%). CONCLUSIONS: The popPK model developed in this study adequately estimated the PK of mycophenolic acid in adult Indian patients with LN. This simple LSS can optimize TDM based on the AUC in routine practice.

Scedosporium Infection in Recipients of Kidney Transplants from Deceased Near-Drowning Donor.

Scedosporium aurianticum infection developed in 2 recipients of kidney transplants in India, acquired from the same deceased near-drowning donor. Given the substantial risk for death associated with Scedosporium infection among solid-organ transplant recipients, safety protocols for organ transplantation from nearly drowned donors should be thoroughly revaluated and refined.

Therapeutic drug monitoring in India: A strength, weakness, opportunity and threats analysis.

Over the last three to four decades, Therapeutic Drug Monitoring (TDM) has shaped itself as therapeutic drug management, an integral component of precision medicine. The practice of TDM is not extensive in India, despite being one of the fastest-growing economies in the world. It is currently limited to a few academic medical centres and teaching hospitals. Apart from the immunosuppressive drugs, several other therapeutic areas, such as anticancer, antifungal, antibiotic and antitubercular, have demonstrated great potential to improve patient outcomes in Indian settings. Factors such as the higher prevalence of nutritional deficiencies, tropical diseases, widespread use of alternative medicines, unalike pharmacogenomics and sparse population-specific data available on therapeutic ranges of several drugs make the population of this subcontinent unique regarding the relevance of TDM. Despite the impact of TDM in clinical science and its widespread application, TDM has failed to receive the attention it deserves in India. This review intends to bring out a strength, weakness, opportunity and threats (SWOT) analysis for TDM in India so that appropriate steps for fostering the growth of TDM could be envisioned. The need of the hour is the creation of a cooperative group including all the stakeholders, such as TDM professionals, clinicians and the government and devising a National Action Plan to strengthen TDM. Nodal TDM centres should be established, and pilot programmes should be rolled out to identify the thrust areas for TDM in the country, capacity building and creating awareness to integrate TDM into mainstream clinical medicine.

Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19.

ABSTRACT: Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.

Evolving Role of Pharmacogenetic Biomarkers to Predict Drug-Induced Hematological Disorders.

ABSTRACT: Drug-induced hematological disorders constitute up to 30% of all blood dyscrasias seen in the clinic. Hematologic toxicity from drugs may range from life-threatening marrow aplasia, agranulocytosis, hemolysis, thrombosis to mild leukopenia, and thrombocytopenia. Pathophysiologic mechanisms underlying these disorders vary from an extension of the pharmacological effect of the drug to idiosyncratic and immune-mediated reactions. Predicting these reactions is often difficult, and this makes clinical decision-making challenging. Evidence supporting the role of pharmacogenomics in the management of these disorders in clinical practice is rapidly evolving. Despite the Clinical Pharmacology Implementation Consortium and Pharmacogenomics Knowledge Base recommendations, few tests have been incorporated into routine practice. This review aims to provide a comprehensive summary of the various drugs which are implicated for the hematological adverse events, their underlying mechanisms, and the current evidence and practical recommendations to incorporate pharmacogenomic testing in clinical care for predicting these disorders.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia.

OBJECTIVES: To assess the effects of phosphodiesterase inhibitors (PDEI) compared to placebo and other standard of care drugs i.e alpha blockers (AB) and 5-alpha reductase inhibitors (5-ARI) in men with LUTS consistent with benign prostatic hyperplasia (BPH). METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). Citation tracking and hand-searching of abstracts and conference proceedings was done. We also attempted to contact the study authors in case additional information was needed. Randomised controlled trials (RCT) comparing PDEI versus placebo, AB, or 5-ARI used for at least four weeks in men with BPH-LUTS were included. Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AE). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long-term (12 weeks or longer) results separately. RESULTS: We included a total of 16 randomised trials in this review. Primary outcomes: PDEI versus placebo: PDEI may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI versus AB: PDEI and AB probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AE (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI and AB versus AB : The combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AE may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AE per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks. PDEI and AB versus PDEI alone: The combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AE. Study results were limited to a treatment duration of four weeks. PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AE. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AE (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AE per 1000 participants (95% CI 43 fewer to 98 more per 1000). We found no trials comparing other combinations of treatments or comparing different PDEI for BPH-LUTS. CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AE. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AE. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB or PDEI combined with 5-ARI compared to ARI with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.

Persistent Muscle Twitching With Phenobarbitone in a Preterm Neonate-Lack of Response or Manifestation of Toxicity?

BACKGROUND: Phenobarbitone is frequently used for the treatment of seizures in neonates, but it has a narrow therapeutic index. CASE PRESENTATION: A 28-week preterm infant born of vaginal delivery developed signs and symptoms suggestive of ventriculitis on day 9. After an episode of clonic seizures on day 11, phenobarbitone was administered intravenously at a loading dose of 20 mg/kg followed by maintenance doses of 6 mg/kg per day in 2 divided doses for 5 days. Due to suspected recurrence of seizures, a mini-loading dose of 10 mg/kg was administered on day 16; after which the child became unresponsive, hypotonic, and comatose with generalized slowing on electroencephalography. Pupils were dilated and fixed, and deep tendon reflexes were absent. Spontaneous respiration was depressed which resulted in ventilatory support. While awaiting the therapeutic drug monitoring results, 2 additional doses of 5 mg/kg of phenobarbitone were administered due to the persistence of muscle twitching. The phenobarbitone level (164 mcg/mL) was alarmingly above the normal range, warranting immediate discontinuation of the drug. This led to reduction in the plasma phenobarbitone levels into the therapeutic range (37 mcg/mL) over the next 10 days with subsequent improvement in the neurological status and respiration. CONCLUSIONS: Phenobarbitone levels are reported to be greater in preterm infants as compared to term infants. Persistence of seizures and muscle twitching on phenobarbitone could either be due to a lack of response or a manifestation of drug toxicity. This case underlies the importance of therapeutic drug monitoring, which can distinguish between the 2 causes, thus enabling the clinician to make an appropriate decision.

Efficacy of tamsulosin and tadalafil in relieving benign prostatic hyperplasia related symptoms: A randomized double blind placebo controlled cross-over study.

INTRODUCTION: Tadalafil and Tamsulosin have both been approved for use in the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). This study compared the differential effects of these two on BPH-LUTS using a cross over study design. METHODS: Men ≥45 years of age, with an International Prostate Symptom Score (IPSS) ≥8 due to BPH-LUTS were included. The patients were randomized into sequence AB (tadalafil 10 mg OD followed by tamsulosin 0.4 mg OD) or BA in a double blind manner. All patients received a placebo lead-in period for 2 weeks, followed by an active drug for 6 weeks; placebo wash out for 4 weeks and then crossed over to second active drug for another 6 weeks. IPSS scores, Uroflowmetry parameters and International Index of Erectile Function-5 scores were recorded. RESULTS: Out of the 40 patients, 36 completed the study. Demographic and baseline characteristics were comparable between the two groups (AB and BA). No significant placebo effects were observed. Tadalafil and tamsulosin significantly improved the total IPSS score and quality of life (P < 0.05) as compared to the baseline. However, there were no significant differences between the two drugs with respect to extent of observed effect and which drug was prescribed 1st in the sequence respectively (P > 0.05). Significant period effect was observed (P < 0.05) i.e., the symptoms did not return to the baseline before the second treatment. Half of the nonresponders to either of the drugs responded when the drug was changed to the other. Tadalafil showed better improvement in EF score as compared to Tamsulosin. CONCLUSION: Both Tadalafil and Tamsulosin improved LUTS and erectile function and those patients who did not respond to Tadalafil showed improvement with Tamsulosin and vice-a-versa.

Efficacy and safety of programmed cell death-1/programmed cell death ligand-1 inhibitors in advanced urothelial malignancy: A systematic review and meta-analysis.

INTRODUCTION: Programmed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings. METHODS: Extensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis. RESULTS: Ten nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1-21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3-14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9-27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5-2.9 vs. 2.0-2.7 months and 7.9-18.2 vs. 15.9 months) and second-line chemotherapy (3.3-4.0 months and 7.4-8 months). Odds of achieving ORR was 0.10 (95% CI 0.03-0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19-0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible. CONCLUSIONS: PD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.

Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) refers to non-malignant enlargement of the prostate gland that may cause bothersome lower urinary tract symptoms (LUTS). Alpha-blockers (ABs) and 5-alpha reductase inhibitors (5-ARIs) are the mainstay of medical treatment. Recently, phosphodiesterase inhibitors (PDEIs) that so far have been used mainly to treat erectile dysfunction were introduced to treat male LUTS. OBJECTIVES: To assess the effects of PDEIs compared to placebo and other standard of care drugs (ABs and 5-ARIs) in men with LUTS consistent with BPH. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). We performed citation tracking and handsearching of abstracts and conference proceedings. We also contacted study authors to ask for additional information. SELECTION CRITERIA: We considered for inclusion in this systematic review randomised controlled trials (RCTs) comparing PDEIs versus placebo, ABs, or 5-ARIs for at least four weeks in men with BPH-LUTS. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AEs). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long-term (12 weeks or longer) results separately. MAIN RESULTS: We included a total of 16 randomised trials in this review. The results for primary outcomes are as follows.PDEI versus placebo: PDEIs may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI versus AB: PDEIs and ABs probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AEs (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI and AB versus AB alone: the combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AEs may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AEs per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks.PDEI and AB versus PDEI alone: the combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AEs. Study results were limited to a treatment duration of four weeks.PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AEs. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AEs (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AEs per 1000 participants (95% CI 43 fewer to 98 more per 1000).We found no trials comparing other combinations of treatments or comparing different PDEI agents. AUTHORS' CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AEs. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AEs. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB alone or PDEI combined with 5-ARI compared to ARI alone with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.

A mobile application-based post-stroke care strategy for survivors and their caregivers for prevention and management of post-stroke complications - "Stroke Home Care:" Development and feasibility.

Objectives: In developing nations such as India, a disparity exists between the available resources for stroke rehabilitation and the substantial burden of stroke cases. Consequently, the provision of cost-effective and multidisciplinary post-stroke rehabilitation care to stroke survivors becomes of paramount importance. The utilization of mobile applications (apps) for stroke care has been on the rise, offering a personalized and pragmatic solution with the potential for wider reach in settings constrained by limited resources. To address the unmet needs in the prevention and management of post-stroke complications, we conceptualized a strategy known as a mobile application-based post-stroke care strategy for both survivors and their caregivers. Materials and Methods: The scope of the app's focus was determined based on the incidence of post-stroke complications within a prospective cohort of stroke patients, in conjunction with existing literature. An initial "web-based mobile app" prototype was crafted to align with the identified focus area. Before the development of the final app version, a feasibility study was conducted involving 30 participant dyads (comprising a patient and a caregiver). Content validity was evaluated by a panel of 20 stroke experts encompassing neurologists, nurses, physiotherapists, and psychologists. Results: The "Stroke Home Care" (SHC) mobile app was conceived as a web-based educational tool aimed at preventing and managing post-stroke complications. It seeks to train caregivers of immobile stroke patients in the administration of preventive and therapeutic care procedures, thereby potentially enhancing survivors' quality of life and alleviating caregivers' burden. The feasibility and validity studies indicated "high satisfaction" levels among most caregivers and experts (>75%), with the remainder expressing "satisfaction" and no "dissatisfaction" regarding app utilities. Stroke experts unanimously deemed the app "appropriate", with consensus on contents, video quality, video length, and voice clarity. Caregivers reported "satisfactory" user experiences, encountering no issues during app installation or operation. Suggestions from both caregivers and experts were integrated into the final app version. Conclusion: The "SHC" app represents a feasible and well-received innovation tailored for the use by caregivers of stroke survivors. Consequently, the initial feasibility of the developed app serves as a precursor to a randomized controlled clinical trial aimed at substantiating its effectiveness within the post-stroke survivor and caregiver population. Notably, within resource-constrained contexts, this app has the potential to be a pivotal tool for post-stroke care.

Effect of Postmeal Fast-Acting Insulin Aspart Injection on the Frequency of Hypoglycemia among Pre-School Children with Type 1 Diabetes: An Open-Label, Cross-Over, Randomized Control Trial.

OBJECTIVES: To study the effect of postmeal Fast-acting insulin Aspart (Fiasp®) on the frequency of hypoglycemia compared to premeal injection among preschool children with type 1 diabetes. METHODS: A single-center trial was conducted among 65 pre-school children (6 mo to 6 y) with Type 1 diabetes for at least 6 mo, on multiple daily insulin injections. Children were randomized to receive their meal bolus postmeal or premeal for the first 3 mo, followed by cross-over at 3 mo. The two groups were compared at the end of 6 mo for the change in frequency of hypoglycemia and hyperglycemia, HbA1c, glycemic variability, and parental satisfaction. Ten children (5 in each group) underwent pharmacokinetic studies. The trial was approved by Institutional Ethics Committee and registered with the Controlled Trial Registry of India vide no CTRI/2020/10/028750. RESULTS: Fifty-four children completed the study, with 27 children in each group. There were no significant differences in the frequency of clinical (p = 0.921), severe (p = 0.167) or serious (p = 0.753) hypoglycemia in the two groups. There were no differences in secondary outcome parameters and pharmacokinetics. CONCLUSIONS: The premeal or postmeal injection of Fiasp® does not affect the frequency of hypoglycemia or other glycemic control parameters among pre-school children with Type 1 diabetes. TRIAL REGISTRATION: The trial is registered with the Controlled Trial Registry of India vide no CTRI/2020/10/028750.

Comparison of alternate-day atorvastatin treatment to daily treatment in maintaining LDL-cholesterol targets in patients with variable coronary risk profile.

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity of atorvastatin lasts upto 20-30 hours. This study aimed at comparing the maintenance of National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) goal by the alternate-day therapy to daily treatment. This randomized, open-label trial included 300 patients of dyslipidemia or coronary artery disease on stable doses of atorvastatin. These patients met their respective NCEP-ATPIII cholesterol goals and were randomized to receive the same doses of atorvastatin every day (QD) or every other day (QOD) in a 1:1 ratio for 12 weeks. The efficacy criteria were (1) proportion of patients maintaining the low-density lipoprotein-cholesterol (LDL-C) goal, (2) comparison of changes in the total cholesterol, LDL-C, high-density lipoprotein cholesterol, and triglyceride levels from baseline. The proportions of patients maintaining their LDL-C goals in QD and QOD groups at 6 weeks were 83.9% (60.3-97.5) versus 70.9% (59.3-82.5) (P < 0.01) and at 12 weeks were 84.6% (70.9-98.3) versus 73.8% (63.8-83.8) (P < 0.05). Per-protocol analysis showed 95.5% (80.0-111.0) versus 79.1% (66.2-92.0) (P < 0.001) patients at 6 weeks and 91.9% (82.0-106.8) versus 77.4% (64.8-90) (P < 0.05) patients at 12 weeks had maintained their LDL-C goals in the QD and QOD groups. A significant increase was observed in the levels of total cholesterol, LDL-C, and triglyceride at 6 and 12 weeks compared with baseline values in the QOD group. Alternate-day treatment of atorvastatin was inferior to daily treatment in maintaining the NCEP-ATPIII goal.

Quantifying prognosis severity of COVID-19 patients from deep learning based analysis of CT chest images.

The COVID-19 pandemic has affected all the countries in the world with its droplet spread mode. The colossal amount of cases has strained all the healthcare systems due to the serious nature of infections especially for people with comorbidities. A very high specificity Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) test is the principal technique in use for diagnosing the COVID-19 patients. Also, CT scans have helped medical professionals in patient severity estimation & progression tracking of COVID-19 virus. In study we present our own extensible COVID-19 viral infection tracking prognosis technique. It uses annotated dataset of CT chest scan slice images created with the help of medical professionals. The annotated dataset contains bounding box coordinates of different features for COVID-19 detection like ground glass opacities, crazy paving pattern, consolidations, lesions etc. We qualitatively identify the severity of the patient for later prognosis stages in our study to assist medical staff for patient prioritization. First we detected COVID-19 positive patients with pre-trained Siamese Neural Network (SNN) which obtained 87.6% accuracy, 87.1% F1-Score & 95.1% AUC scores. These metrics were achieved after removal of 40% quantitatively highly similar images from the COVID-CT dataset. This reduced dataset was further medically annotated with COVID-19 features for bounding box detection. After this we assigned severity scores to detected COVID-19 features and calculated the cumulative severity score for COVID-19 patients. For qualitative patient prioritization with prognosis clinical assistance information, we finally converted this score into a multi-classification problem which obtained 47% weighted-average F1-score.

Pharmacometabolomics-guided clozapine therapy in treatment resistant schizophrenia: Preliminary exploration of future too near.

AIM: To study the association of clozapine pharmacometabolomics and clozapine response in Asian patients with treatment-resistant schizophrenia (TRS). METHOD: A cross-sectional study was performed on 50 consecutive TRS patients following up in psychiatry department of the tertiary care hospital. Demographic details, response assessment, were collected on the case record form. A blood sample was also collected for trough concentration assessment of drug and its metabolites. Clozapine (CLZ) the parent drug and its two major metabolites - Clozapine N oxide (CNO) and N-Desmethyl clozapine (N-DSMC) levels were assessed using a high-performance liquid chromatography method. Clozapine responders and nonresponders patients were classified based upon Andreasen criteria. RESULTS: The average trough concentration of CNO, N-DSMC, and CLZ were 123 ± 76.04, 171.93 ± 93.24, 229.27 ± 124.25 ng/ml, respectively. The two patient subgroups did not differ for CLZ, CNO, and N-DSMC concentrations statistically. However, clozapine nonresponse was associated with a higher CLZ/N-DSMC ratio (p = 0.03) and clozapine dose (p = 0.01). The receiver operator characteristic curve showed that the cut-off CLZ/N-DSMC ratio of 1.54 with a sensitivity of 85% and a positive predictive value of 84% for identifying nonresponders. CONCLUSION: CLZ/N-DSMC ratio and clozapine dose were identified as significant variables for future dose optimization algorithms. Pharmacometabolomics-guided clozapine therapy has the potential to revolutionize TRS management.

Cyclophosphamide, hydroxycyclophosphamide and carboxyethyl phosphoramide mustard quantification with liquid chromatography mass spectrometry in a single run human plasma samples: A rapid and sensitive method development.

A novel method for simultaneous quantification of cyclophosphamide along with its two major metabolites namely 4-hydroxycyclophosphamide (HCy) and carboxyethyl phosphoramide mustard (CEPM) in a single sample run was demonstrated in the present study. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument was used for analysis. Semicarbazide was used as a stabilizing agent for HCy whereas ifosfamide, hexamethyl phosphoramide mustard and deuterated CEPM were the internal standards for quantification of Cy, HCy and CEPM respectively. Chromatographic separation was achieved by Chromsystems C18 reverse-phase column (50 mm × 4.6 mm, particle size 3.2 µm). The mobile phase was composed of eluent A (2 mM ammonium acetate in water with 2% formic acid) and eluent B (100 % acetonitrile). The flow rate was 1 ml/min. Linearity of the assay was assured in the range of 19.53 ng/ml to 10,000 ng/ml concentration in human plasma, which is adequate for pharmacokinetic studies of any dose Cy used clinically. The quality control(QC) accuracy was between 99.58% and 101.62%, 97.85% to 103.53% and 99.64% to 100.10% for Cy, HCy and CEPM respectively. Precision limits for QC samples were between 3.9% and 9.4%, 5.2% to 8.9% and 1.8% to 9.2% respectively. The analytical method was validated in ten leukaemia patients undergoing haploidentical hematopoietic cell transplantation.

U-DAVIS-Deep Learning Based Arm Venous Image Segmentation Technique for Venipuncture.

Arm Venous Segmentation plays a crucial role in smart venipuncture. The difficulties faced in locating veins for intravenous procedures can be diminished using computer vision for vein imaging. To facilitate this, a high-resolution dataset consisting of arm images was curated and has been presented in this study. Leveraging the ability of Near Infrared Imaging to easily detect veins, ambient lighting conditions were created inside a small enclosure to capture the images. The acquired images were annotated to create the corresponding masks for the dataset. To extend the scope and assert the usability of the dataset, the images, and corresponding masks were used to train an image segmentation model. In addition to using basic preprocessing and image augmentation based techniques, a U-Net based algorithmic architecture has been used to facilitate the task of segmentation. Subsequently, the results of performing image segmentation after applying the preprocessing methods have been compared using various evaluation metrics and have been visualised in the study. Furthermore, the possible applications of the presented dataset have been investigated in the study.

Effectiveness and Safety of Nitrazepam in Children with Resistant West Syndrome.

OBJECTIVES: To study the effectiveness, tolerability, and safety of oral nitrazepam in children with resistant West syndrome (WS). METHODS: This prospective observational study was conducted at a tertiary care hospital in North India from January 2019 to October 2020. Children with WS resistant to standard therapy were enrolled within 7 d of initiation of nitrazepam and prospectively followed-up for cessation of spasms and adverse events. RESULTS: Forty-one children with resistant WS initiated on nitrazepam therapy were evaluated. The median age at onset of spasms was 6 mo (Q1, Q3: 4, 8). There was a preponderance of male gender (71%) and structural causes (78%). More than half of the enrolled children had failed four or more antiseizure medications (ASM) for epileptic spasms. The study participants had a long lead-time-to-treatment (LTTT) for the initial standard therapy (median: 2 mo; Q1, Q3: 1, 5) and nitrazepam (median: 11 mo; Q1, Q3: 8, 16). Nitrazepam was instituted as monotherapy in 7 (17%) children and as an adjunct in the rest. Twenty-one (51%) children achieved persistent cessation of epileptic spasms. However, the electroclinical response was observed in 17 (42%) children. Drowsiness, sialorrhea, and decreased appetite were the most commonly observed adverse events. Most adverse events were mild to moderate in severity and did not require dose reduction or change of medication. There was no significant difference between the responders and nonresponders in terms of LTTT, age at onset, or etiology. CONCLUSIONS: Nitrazepam is a safe and feasible treatment alternative in children with resistant WS resulting in persistent cessation of spasms and electroclinical response in nearly half of patients.