Evaluation of the pharmacodynamic interaction effect of augmentation agents with clozapine in patients with treatment-resistant schizophrenia: A simulation study of clinical data.

INTRODUCTION: The aim of the study was to evaluate interaction effect of various augmentation strategies with clozapine in patients with Treatment-resistant schizophrenia. METHODS: Data was extracted for change in positive and negative syndrome scale (PANSS) or brief psychiatric rating scale (BPRS) scores for monotherapy with various antipsychotic agents alone and their combination with clozapine. Individual patient data was generated using simulation of data (factorial trial framework) from published clinical trials for sample sizes from eight to 400 to evaluate interaction effect through linear modeling. Dose equivalents were calculated, and best fit models were determined for simulated data. RESULTS: The polynomial model was found to be the best fit for the simulated data to determine interaction effect of combination. The clozapine augmentation with risperidone and ziprasidone was found to be antagonistic, whereas it was additive for haloperidol, aripiprazole, and quetiapine. A synergistic effect was observed for ECT combined with clozapine (Interaction effect: -7.62; p <0.001). A sample size of 250-300 may be sufficient to demonstrate a clinically significant interaction in future trials. CONCLUSION: Clozapine may be augmented with electroconvulsive therapy, leading to the enhancement of antipsychotic effect. Though some antipsychotics like aripiprazole demonstrate additive effects, they may also add to the adverse effects.

Fluorescent Labeling and Imaging of IL-22 mRNA-Loaded Lipid Nanoparticles.

Lipid nanoparticle (LNP)-based drug delivery systems (DDSs) are widely recognized for their ability to enhance efficient and precise delivery of therapeutic agents, including nucleic acids like DNA and mRNA. Despite this acknowledgment, there is a notable knowledge gap regarding the systemic biodistribution and organ accumulation of these nanoparticles. The ability to track LNPs in vivo is crucial for understanding their fate within biological systems. Fluorescent labeling of LNPs facilitates real-time tracking, quantification, and visualization of their behavior within biological systems, providing valuable insights into biodistribution, cellular uptake, and the optimization of drug delivery strategies. Our prior research established reversely engineered LNPs as an exceptional mRNA delivery platform for treating ulcerative colitis. This study presents a detailed protocol for labeling interleukin-22 (IL-22) mRNA-loaded LNPs, their oral administration to mice, and visualization of DiR-labeled LNPs biodistribution in the gastrointestinal tract using IVIS spectrum. This fluorescence-based approach will assist researchers in gaining a dynamic understanding of nanoparticle fate in other models of interest. Key features • This protocol is developed to assess the delivery of IL-22 mRNA to ulcerative colitis sites using lipid nanoparticles. • This protocol uses fluorescent DiR dye for imaging of IL-22 mRNA-loaded lipid nanoparticles in the gastrointestinal tract of mice. • This protocol employs the IVIS spectrum for imaging.

Augmentation Strategies for Partial or Non-responders to Clozapine in Patients with Schizophrenia: A Bayesian Network Meta-analysis of Randomized Controlled Trials.

Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/ non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (-5.2 [95%CrI: -7.7, -2.7]) and memantine (-2.1 [95%CrI: -4.0, -0.19]] were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.

Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross-sectional study.

INTRODUCTION: The debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM. METHODS: The present cross-sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non-remission on Young's mania rating scale (YMRS). RESULTS: The intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non-remission, but the comparison between the two ROC analyses was not statistically significant. CONCLUSION: Free valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring.

Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol.

BACKGROUND: Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. The present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). METHODS AND ANALYSIS: A randomised, double-blind, add-on, placebo-controlled, group sequential design clinical trial will be conducted on patients with MDD who will be randomly assigned to the control and the test group in a 1:1 ratio. Patients in the test group will get dextromethorphan 30 mg once daily, whereas patients in the control group will receive a placebo once daily as an add-on to ongoing SSRI treatment for 8 weeks. All patients will be evaluated for the primary outcome (change in the Montgomery-Åsberg Depression Rating Scale score) and secondary outcomes (treatment response rate, remission rate, Clinical Global Impression, serum brain-derived neurotrophic factor, serum dextromethorphan and treatment-emergent adverse events) over the period of 8 weeks. Intention-to-treat analysis will be done for all parameters using suitable statistical tools. ETHICS AND DISSEMINATION: This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR's ethical guidelines for biomedical research on human subjects (2017). Written informed consent will be obtained from the participants before recruitment. The results of this study will be published in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05181527.

Unleashing the Potential of Oral Deliverable Nanomedicine in the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), marked by chronic gastrointestinal tract inflammation, poses a significant global medical challenge. Current treatments for IBD, including corticosteroids, immunomodulators, and biologics, often require frequent systemic administration through parenteral delivery, leading to nonspecific drug distribution, suboptimal therapeutic outcomes, and adverse effects. There is a pressing need for a targeted drug delivery system to enhance drug efficacy and minimize its systemic impact. Nanotechnology emerges as a transformative solution, enabling precise oral drug delivery to inflamed intestinal tissues, reducing off-target effects, and enhancing therapeutic efficiency. The advantages include heightened bioavailability, sustained drug release, and improved cellular uptake. Additionally, the nano-based approach allows for the integration of theranostic elements, enabling simultaneous diagnosis and treatment. Recent preclinical advances in oral IBD treatments, particularly with nanoformulations such as functionalized polymeric and lipid nanoparticles, demonstrate remarkable cell-targeting ability and biosafety, promising to overcome the limitations of conventional therapies. These developments signify a paradigm shift toward personalized and effective oral IBD management. This review explores the potential of oral nanomedicine to enhance IBD treatment significantly, focusing specifically on cell-targeting oral drug delivery system for potential use in IBD management. We also examine emerging technologies such as theranostic nanoparticles and artificial intelligence, identifying avenues for the practical translation of nanomedicines into clinical applications.

Efficacy and Safety of Anti-CGRP Monoclonal Antibodies in Prevention of Chronic Migraine: A Bayesian Network Meta-analysis.

Due to the unmet needs in the management of migraine, a primary headache, and disabling disorder, the past decade has focused on developing monoclonal antibodies (mAbs) against the calcitonin-gene-related peptide (CGRP) as migraine prophylactic agents. The objective of the study was to evaluate the efficacy and safety of various anti-CGRP mAbs in the prevention of chronic migraine. Network meta-analysis (NMA) was performed using the Bayesian framework to estimate the efficacy and safety of mAbs after performing a literature search in PubMed, MEDLINE, Cochrane database, and International Clinical Trial Registry Platform (ICTRP). The outcomes calculated were in terms of mean difference (MD) or odds ratio (OR) with a 95% credible interval (95%CrI). Network graphs were constructed and node-split analysis was done to analyze the inconsistency. The NMA included a total of 10 clinical trials. Galacanezumab (120 mg) (MD: -2.7; 95%CrI: -4.8 to -0.83) was found to be better than other mAbs in terms of the difference in mean migraine days (MMD). Fremanezumab quarterly dose administration showed the best response (OR: 2.9; 95%CrI: 1.9 to 4.6) in terms of responder rate. Eptinezumab was found to be safer (OR: 0.88; 95%CrI: 0.61-1.3) as compared to other mAbs in terms of the rate of adverse events. Fremanezumab (quarterly) ranked better in terms of response rate, and eptinezumab was found to be the safest in the prophylactic management of migraine. Galacenequmab was better at reducing MMD. Further studies are needed to evaluate the long-term safety, efficacy, and use of mAbs in migraine patients.

Efficacy of pharmacological agents for the management of treatment-resistant schizophrenia: a network meta-analysis.

OBJECTIVE: The present network meta-analysis (NMA) was conducted to compare and generate evidence for the most efficacious treatment among available pharmacological interventions for treatment-resistant schizophrenia (TRS). METHODS: Reviewers extracted data from 47 studies screened from PubMed/MEDLINE, Embase, Cochrane databases and clinical trial registries fulfilling the eligibility criteria. Random effects Bayesian NMA was done with non-informative priors. Network geometry was visualized, and node splitting was done for the closed triangles. Standardized mean difference and 95% credible interval(95%CrI) were reported for the reduction in symptom severity scores. The probability of each intervention for each rank was plotted. Meta-regression was done for the duration of the therapy. RESULTS: Augmentation of antipsychotics with escitalopram (SMD: -1.7[95%CrI: -2.8, -0.70]), glycine (SMD: -1.2 [95%CrI: -2.2, -0.28]) and Yokukansan (SMD: -1.3 [95%CrI: -2.4, -0.24]) shows a statistically significant reduction in symptom severity when compared to clozapine. As per surface under cumulative ranking curve analysis, escitalopram in combination with antipsychotics appeared to be the best intervention with moderate certainty of evidence. There was no significant effect of the duration of therapy on the treatment effects. CONCLUSION: Escitalopram augmentation of antipsychotics appears to be the most efficacious treatment with moderate certainty of evidence among the available pharmacological interventions. PROSPERO REGISTRATION: CRD42022380292.

Efficacy and Safety of Fezolinetant for the Treatment of Menopause-Associated Vasomotor Symptoms: A Meta-analysis.

OBJECTIVE: To evaluate the efficacy and adverse events of fezolinetant for treating vasomotor symptoms (VMS) of menopause. DATA SOURCES: PubMed/MEDLINE, ClinicalTrials.gov , EMBASE, Cochrane Database, Scopus, and WHO International Clinical Trials Registry Platform were searched through June 2023 for publications and randomized controlled trials on fezolinetant compared with placebo in menopausal women who experienced moderate-to-severe VMS. METHODS OF STUDY SELECTION: Our literature search identified 330 articles, of which five studies with six reports were included in our meta-analysis per our eligibility criteria. TABULATION, INTEGRATION, AND RESULTS: The risk of bias was evaluated using Cochrane's RoB 2 (Risk of Bias version 2) tool, quality of evidence was graded using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, and outcome measures data for effect size were pooled in random-effects model and rated. A total of 2,168 participants from five randomized clinical trials (six reports) were included. Fezolinetant significantly lowered VMS frequency, with pooled mean difference of 2.62 (95% CI, 1.84-3.41). The pooled mean difference for fezolinetant compared with placebo for the MENQOL (Menopause-Specific Quality of Life) measure was -0.60 (95% CI, -0.92 to -0.28), and the mean percentage improvement in VMS frequency was 22.51% (95% CI, 15.35-29.67). Fezolinetant was associated with improvement in sleep quality when compared with placebo. CONCLUSION: Fezolinetant is effective in lowering moderate-to-severe VMS frequency and sleep disturbances in postmenopausal women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023427616.

Efficacy and safety of V1a receptor antagonists in autism spectrum disorder: A meta-analysis.

This meta-analysis has evaluated the efficacy and safety of V1a receptor antagonists in ASD compared to placebo. The reviewers extracted data from four relevant clinical trials after a literature search on databases and clinical trial registries. Quality assessment was done using the risk of bias assessment tool, and the random-effects model was used to estimate effect size. Subgroup analysis, meta-regression and sensitivity analysis were done. PRISMA guidelines were followed in the selection, analysis and reporting of findings. V1a receptor antagonists did not reduce Vineland II Adaptive behaviour composite score significantly (SMD: 0.14; 95% CI: -0.06-0.35; p = 0.16; PI: -0.44-0.73), communication domain subscale score and socialization domain subscale score. The change in daily living skills domain subscale score was significant and favourable for V1a receptor antagonists (SMD: 0.15; 95% CI: 0.03-0.26; p = 0.01). The subgroup analysis revealed a significant improvement in Vineland II Adaptive behaviour composite score with doses <10 mg (SMD: 0.45; 95% CI: 0.11-0.78; p = 0.009). Meta-regression does not show a significant association between SMD of ASD symptom score reduction with the duration and dose of V1a receptor antagonist therapy. Treatment-emergent adverse effects were not serious and dose dependent. Low doses (<10 mg) of V1a receptor antagonist may be effective in reducing the core symptoms of ASD compared to placebo; however, future active-controlled clinical trials are necessary to generate conclusive evidence.

Performance of the transoesophageal echocardiography probe as an oesophageal temperature monitor in patients undergoing cardiac surgery with cardiopulmonary bypass: a prospective observational study.

OBJECTIVES: Core temperature monitoring is critical during cardiopulmonary bypass (CPB). In this prospective observational study, we investigated the performance of the transoesophageal echocardiography (TOE) probe for core (oesophageal) temperature monitoring during CPB. METHODS: Thirty adult patients, 18-70 years of either gender, undergoing cardiac surgery with CPB were enrolled. All patients received a reusable nasopharyngeal probe for monitoring core temperatures. In addition, the oesophageal temperatures were monitored with the TOE probe. The arterial outlet temperatures at the membrane oxygenator were also monitored and taken as the reference standard. Monitoring was performed every 5 min until 20 min, and then at 30 min during both the cooling and rewarming periods. RESULTS: During cooling, the oesophageal and nasopharyngeal temperatures lagged behind the arterial outlet temperatures. However, the intra-class correlation of the oesophageal temperatures with the arterial outlet temperatures was better (range 0.58-0.74) than the correlation of the nasopharyngeal temperatures with the arterial outlet temperatures (range 0.46-0.62). During rewarming, the performance of the TOE probe was significantly superior to the nasopharyngeal probe. After 15 and 20 min of rewarming, there was a difference of ∼1°C between the oesophageal and nasopharyngeal temperatures. At 30 min of rewarming, the oesophageal and the arterial outlet temperatures were similar, while the nasopharyngeal temperatures still lagged by 0.5°C. Bias was significantly less both during cooling and warming between the oesophageal temperatures and arterial outlet temperatures. CONCLUSIONS: Performance of the TOE probe as an oesophageal temperature probe is superior to the nasopharyngeal probe during CPB. CLINICAL TRIAL REGISTRATION NUMBER: CTRI no 2020/10/028228; ctri.nic.in.

Pharmacological augmentation of serotonin reuptake inhibitors in patients with obsessive-compulsive disorder: A network meta-analysis.

OBJECTIVES: The augmentation of serotonin reuptake inhibitors (SRIs) can be achieved by add-on therapy with different pharmacological agents in obsessive-compulsive disorder (OCD) for a better clinical outcome. This network meta-analysis (NMA) was conducted to evaluate and compare the effects of available augmentation agents for SRIs in OCD. METHOD: The data was extracted from 59 relevant clinical trials after a literature search on MEDLINE/PubMed, Scopus, Cochrane databases and clinical trial registries. PRISMA guidelines were followed in data extraction, analysis and reporting. Random effects Bayesian NMA was done to pool the effects across the interventions for the change in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scoring from baseline to the end of the study. Network graph was built, consistency model was run, node splitting analysis was performed, treatments were ranked as per SUCRA score and meta-regression was done for refractoriness to SRIs and duration of augmentation therapy as the predictor variables. RESULTS: The drugs showing significant reduction in YBOCS scoring were pregabalin (MD:-8.1;95% CrI: -16, -0.43), memantine (MD:-6.2;95% CrI: -9.9, -2.3), lamotrigine (MD:-6;95% CrI: -12, -0.47), ondansetron (MD:-5.7;95% CrI: -11, -0.67), granisetron (MD:-5.6;95% CrI: -11, -0.44), aripiprazole (MD:-5.4;95% CrI:-9.1, -1.6), risperidone (MD:-3.3;95% CrI: -6.4, -0.20) and topiramate (MD:-5.3;95% CrI: -9.6, -0.97). The node-split analysis showed that direct and indirect pooled effect sizes for all comparisons were comparable. Meta-regression showed a statistically non-significant association between YBOCS score reduction with the duration of augmentation therapy, but significant with SRI-refractory status. Finally, the results were sorted based on certainty of evidence. CONCLUSION: Memantine was found to be most effective augmentation agent for SRIs in OCD, followed by lamotrigine, ondansetron and granisetron with moderate certainty of evidence. The augmentation agents showed better symptom reduction in patients with SRI-refractory OCD in comparison to non-refractory OCD. PROSPERO REGISTRATION: CRD42022360110.

Study of Correlation between Serum Osteoprotegerin, TNF-Alfa, and Biomarkers of Bone Metabolism in Patients with Treatment-Naive Graves' Disease-A Cross-Sectional Study.

Objectives: Primary - a study of the correlation between serum osteoprotegerin (OPG), and biomarkers of bone metabolism in patients with treatment-naive Graves' disease (GD). Secondary - serum level of OPG, TNF-alfa, and biomarkers of bone metabolism in patients three months after treatment of GD with methimazole (MMI). Materials and Methods: A total of thirty-five treatment-naive newly diagnosed GDs were recruited for the study, most of them female. All patients started with MMI for treatment and various blood parameters were measured at baseline and three months after treatment. Measurements: Serum calcium (Ca), phosphorus (P), bone-specific alkaline phosphatase (B-ALP), OPG, TNF-alfa, and urine deoxypyridinoline (U-DPD) along with serum-free T3 and T4, thyroid-stimulating hormone (TSH) and thyroid receptor antibody (TR-ab) were analysed at baseline and three months after MMI treatment. All the patients had euthyroid at three months of MMI treatment. Results: Mean serum OPG (0.94 ± 1.39 vs. 0.63 ± 0.27 ng/ml; P = 0.262) level at baseline and after treatment with MMI did not show any significant change. Mean TSH level (0.207 ± 0.59 vs. 1.00 ± 1.95, P = 0.025) was significantly low at baseline than after treatment; FT4 (5.9 ± 5.22 v 1.77 ± 1.89 ng/dl; P < 0.001), FT3 (12.19 ± 6.91 vs. 4.99 ± 3.55 pg/ml; P < 0.001), and TNF-alfa values decreased significantly after treatment, however, PTH (58.09 ± 28.75 vs. 75.57 ± 41.50; P < 0.026) increased significantly after treatment. Discussion: There is no correlation of OPG with thyroid hormone profile, TSH, thyroid receptor antibody (TR-ab), and bone metabolic parameters such as serum Ca, P, B-ALP, TNF-alfa, and U-DPD in our study. Mean TNF-alfa decreased significantly (393.43 ± 270.473 vs. 139.34 ± 101.264 pg/ml; P = 0.001) level after treatment with MMI. TNF-alfa was positively correlated with TR-ab (r = 0.374; P = 0.027) and B-ALP (r = 0.388; P = 0.021). Conclusion: The bone turnover marker in GD seems to be mediated other than OPG. We observed an increase in circulating TNF-alfa in GD with a significant decrease after treatment. TNF-alfa could be a marker of GD activity as evidenced by a close positive correlation with TR-ab, a sensitive marker of GD autoimmunity. TNF-alfa could be a factor associated with bone turnover markers in GD despite its euthyroid state.

Perioperative mortality and morbidity of hip fractures among COVID-19 infected and non-infected patients: A systematic review and meta-analysis.

PURPOSE: Hip fractures among elderly patients are surgical emergencies. During COVID-19 pandemic time, many such patients could not be operated at early time because of the limitation of the medical resources, the risk of infection and redirection of medical attention to a severe infective health problem. METHODS: A search of electronic databases (PubMed, Medline, CINAHL, EMBASE and the Cochrane Central Register of Controlled Trials) with the keywords "COVID", "COVID-19″, "SARS-COV-2", "Corona", "pandemic", "hip fracture", "trochanteric fracture" and "neck femur fracture" revealed 64 studies evaluating treatment of hip fracture in elderly patients during COVID-19 pandemic time. The 30-day mortality rate, inpatient mortality rate, critical care/special care need, readmission rate and complications rate in both groups were evaluated. Data were analyzed using Review Manager (RevMan) V.5.3. RESULTS: After screening, 7 studies were identified that described the mortality and morbidity in hip fractures in both COVID-19 infected (COVID-19 +) and non-infected (COVID-19 -) patients. There were significantly increased risks of 30-day mortality (32.23% COVID-19 + death vs. 8.85% COVID-19 - death) and inpatient mortality (29.33% vs. 2.62%) among COVID-19 + patients with odds ratio (OR) of 4.84 (95% CI: 3.13 - 7.47, p < 0.001) and 15.12 (95% CI: 6.12 - 37.37, p < 0.001), respectively. The COVID-19 + patients needed more critical care admission (OR = 5.08, 95% CI: 1.49 - 17.30, p < 0.009) and they remain admitted for a longer time in hospital (mean difference = 3.6, 95% CI: 1.74 - 5.45, p < 0.001); but there was no difference in readmission rate between these 2 groups. The risks of overall complications (OR = 17.22), development of pneumonia (OR = 22.25), and acute respiratory distress syndrome/acute respiratory failure (OR = 32.96) were significantly high among COVID-19 + patients compared to COVID-19 - patients. CONCLUSIONS: There are increased risks of the 30-day mortality, inpatient mortality and critical care admission among hip fracture patients who are COVID-19 +. The chances of developing pneumonia and acute respiratory failure are more in COVID-19 + patients than in COVID-19 ‒ patients.

Effect of Colchicine in Reducing Inflammatory Biomarkers and Cardiovascular Risk in Coronary Artery Disease: A Meta-analysis of Clinical Trials.

BACKGROUND: Colchicine's role in reducing inflammation and cardiovascular adverse events despite standard care in coronary artery disease (CAD) is controversial. STUDY QUESTION: Can colchicine reduce inflammation [high-sensitivity C-reactive protein (hs-CRP)] in CAD? DATA SOURCES: PubMed, Cochrane Library, and Trial registries. STUDY DESIGN: The meta-analysis included 15 studies using add-on colchicine in patients with CAD. The outcomes evaluated were hs-CRP, white blood cell and neutrophil count, a composite end point of major cardiovascular events, myocardial infarction (MI), cardiovascular and all-cause mortality, and gastrointestinal adverse events. The analysis was performed using a random-effects model to calculate pooled mean difference and odds ratio (OR). RESULTS: The meta-analysis revealed a mean reduction of 0.36 mg/L in hs-CRP levels [95% confidence interval (CI): -0.51 to -0.20] with add-on colchicine. The mean white blood cell reduction of 371.75 per µL (95% CI: -544.27 to -199.24) and the mean neutrophil reduction also favored the add-on colchicine group. There was a reduction in composite end point of major cardiovascular events [OR, 0.65 (95% CI: 0.51-0.83)] and MI [OR, 0.77 (95% CI: 0.63-0.95)] with add-on colchicine therapy. There was no reduction in cardiovascular/overall mortality. Gastrointestinal adverse events were less with low-dose colchicine than those with high dose. CONCLUSION: Add-on colchicine has reduced the inflammation in CAD as implicated by a decrease in inflammatory markers. It has also lowered the incidence of MI but not mortality. With this present trend, the authors recommend further trials to validate the effectiveness of add-on colchicine in the secondary prevention of CAD.

Chemotherapy-induced hand foot syndrome: comparative efficacy and safety of pharmacological prophylaxis - systematic review and Bayesian network meta-analysis.

BACKGROUND: Hand-foot syndrome (HFS) is one of the most common toxicities experienced by patients receiving systemic chemotherapy agents such as capecitabine and multikinase inhibitors such as sorafenib. Several randomised controlled trials (RCTs) have investigated the efficacy and safety of prophylactic agents such as pyridoxine, celecoxib, urea cream and cystine/theanine in managing HFS. This network meta-analysis (NMA) evaluated data from high-quality trials to provide strong evidence in forming recommendations to prevent systemic cancer therapy-induced HFS. OBJECTIVE: To examine the comparative efficacy and safety of interventions for preventing systemic chemotherapy-induced HFS in patients with cancer. METHODS: We searched PubMed, Embase and clinical trial registry for RCTs of interventions for preventing HFS. Bayesian NMA was performed to estimate the OR with 95% credible intervals (CrI) from both direct and indirect evidence. The outcome measures were the incidence of HFS (grade ≥1) and moderate to severe HFS (grade ≥2). Adverse drug reactions were discussed descriptively. RESULTS: A total of 15 RCTs with 2715 patients with 12 prophylactic strategies were included. The analysis showed only celecoxib could significantly prevent the incidence of moderate to severe HFS (grade ≥2) (OR 0.29, 95% CrI 0.13 to 0.68). But none of the preventive interventions could prevent the incidence of HFS (grade ≥1). CONCLUSION: Only celecoxib (200 mg two times per day) showed significant prevention of the incidence of moderate to severe HFS. Pyridoxine (400 mg once daily) and urea cream (10%) have to be evaluated further in larger randomised trials.

Timeline of changes in spike conformational dynamics in emergent SARS-CoV-2 variants reveal progressive stabilization of trimer stalk and enhanced NTD dynamics

SARS-CoV-2 emergent variants are characterized by increased transmissibility and each show multiple mutations predominantly localized to the spike (S) protein. Here, amide hydrogen/deuterium exchange mass spectrometry has been applied to track correlative changes in S dynamics from multiple SARS-CoV-2 variants. Our results highlight large differences across variants at two loci with impacts on S dynamics and stability. A significant enhancement in stabilization first occurred with the emergence of D614G S followed by smaller, progressive stabilization in Omicron BA.1 S traced through Alpha S and Delta S variants. Stabilization preceded progressive enhancement in dynamics in the N-terminal domain, wherein Omicron BA.1 S showed the largest magnitude increases relative to other preceding variants. Changes in stabilization and dynamics resulting from specific S mutations detail the evolutionary trajectory of S protein in emerging variants. These carry major implications for SARS-CoV-2 viral fitness and offer new insights into variant-specific therapeutic development.

Impact of limb length discrepancy on functional outcome in total knee arthroplasty patients: a prospective cohort study.

BACKGROUND: Limb length alteration following total knee arthroplasty (TKA) has been under-reported. Few studies have shown a significant association between limb length discrepancy (LLD) and poor functional outcome. This prospective study evaluated the impact of radiographic and perceived LLD on functional outcome in TKA. The variables affecting LLD were also evaluated. METHODS: The preoperative and postoperative limb lengths of TKA patients (112 knees, 81 patients, KL grade ≥ 3) were measured in full-length digital radiographs. The Hip-Knee-Ankle (HKA) angles were also measured. The functional outcome (Western Ontario and McMaster Universities Arthritis Index) and perception about LLD were evaluated after six months. RESULTS: The mean preoperative radiographic LLD in the unilateral and bilateral TKA groups was 0.75 cm ± 0.60 cm and 0.58 cm ± 0.52 cm (P = 0.197), respectively. Similarly, postoperative LLD was 0.76 cm ± 0.85 cm in the unilateral group and was 0.59 cm ± 0.92 cm (P = 0.402) in the bilateral group. Only 19.7% of patients had postoperative radiographic LLD of ≥ 10 mm, and 80.2% of patients had LLD of < 10 mm. The functional outcome was significantly affected when LLD exceeded 10 mm (correlation coefficient 0.54, P < 0.001). Linear regression analysis revealed no significant effects of age, sex, height, weight, BMI, preoperative LLD and difference in deformity between the limbs on postoperative LLD. 34.5% of patients perceived LLD in the preoperative period, which decreased to 3.7% in the postoperative period. Perceived LLD did not correlate to radiographic LLD and functional outcome. CONCLUSIONS: There is no significant difference in radiographic LLD between unilateral and bilateral TKA. The functional outcome is adversely affected by radiographic LLD of ≥ 10 mm. Age, sex, BMI, preoperative LLD and difference in deformity angle do not affect the LLD. About one-third of patients perceive LLD in the preoperative period, which improves significantly after TKA. LEVELS OF EVIDENCE: II.

Awareness, attitude, and practice of materiovigilance among medical professionals at a tertiary care institute of national importance: A cross-sectional study.

Background: Medical faculty and residents have a key role in the reporting of adverse events associated with medical devices. However, at present, there are no published data regarding their knowledge, attitude, and practice about materiovigilance in India. Materials and Methods: This was a cross-sectional questionnaire-based survey done among medical faculty and residents of a tertiary care institution of national importance. The questionnaire consists of 15 questions pertaining to knowledge, attitude, and practice of materiovigilance. Results: The questionnaire was administered to 138 medical faculty and residents, out of which 105 responded constituting a 76% response rate. The mean knowledge score of medical faculty and residents was 2.09 ± 1.06 and 2.07 ± 1.02, respectively, and the difference between the two groups was not statistically significant (P = 0.9). The majority of the participants (92.63%) believed that medical device can cause adverse events; however, very few of them (20.13%) have reported it during their practice. Conclusion: Requisite knowledge and appropriate attitude are essential for developing healthy practice toward reporting of adverse events associated with medical devices. Our study revealed that the knowledge gap exists among medical professionals about the reporting of adverse events and the materiovigilance program. A continuous effort is required to make them aware of the materiovigilance by conducting various training programs such as continuous medical education and workshops by the coordinators of the medical device adverse events monitoring center.

Comparative Study of the Effects of Azilsartan and Telmisartan on Insulin Resistance and Metabolic Biomarkers in Essential Hypertension Associated With Type 2 Diabetes Mellitus.

Introduction The complex interplay between the autonomic nervous system, renin-angiotensin-aldosterone system (RAAS), and immunity contributes to the pathogenesis of hypertension in diabetes mellitus. The objective of this study was to investigate and compare the effect of azilsartan and telmisartan on insulin resistance and metabolic biomarkers in patients with both hypertension and type 2 diabetes mellitus. Methods The present study was a prospective, randomized, active-controlled, open-label, parallel-group clinical trial. Patients with grade I or II essential hypertension with type 2 diabetes mellitus were randomized into two groups of 25 patients each. Baseline evaluation of homeostasis model assessment-insulin resistance (HOMA-IR), plasma glucose, insulin, leptin and adiponectin levels, and systolic and diastolic blood pressure (SBP and DBP) of patients was done. Patients were reassessed after 12 weeks of drug therapy with azilsartan 40 mg OD (once daily) or telmisartan 40 mg OD. Results The mean changes in HOMA-IR from the baseline at the end of 12 weeks of treatment were 0.15 (-0.64, 0.94.52) in the azilsartan group and 0.32 (-0.61, 1.26) in the telmisartan group. The mean difference in the changes from the baseline in HOMA-IR between the two groups was 0.3 (-0.87, 1.48), which was not statistically significant. No statistically significant changes were observed between the two groups in metabolic biomarkers (leptin: -0.84, CI: -4.83 to 3.14, and adiponectin: -0.12, CI: -0.62 to 0.37). Systolic (SBP) and diastolic blood pressure (DBP) decreased at the end of the 12-week treatment in both the groups; however, there was no significant difference between the two groups (SBP: -2.6, CI: -10.35 to 5.1, and DBP: -3.0, CI: -7.7 to 1.7). Conclusion Neither azilsartan nor telmisartan had any significant effects on insulin resistance and metabolic biomarkers after 12 weeks of drug therapy in hypertension patients associated with type 2 diabetes mellitus. However, they showed a comparable antihypertensive effect. The adverse effects observed were mild in nature, and their incidence was comparable between the two groups.