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The aim of the present study was to investigate the effects of multicomponent training on adropin, endothelial function, insulin resistance, and sleep quality in overweight older adults. In this randomized controlled study, 40 overweight older adults were randomly divided into training and control groups. The multicomponent training program including aerobic, resistance, and balance exercise was followed for 8 weeks, 3 days a week. Study variables were measured 48 hr before and after the intervention. After 8 weeks of multicomponent training, adropin (p =.01), nitric oxide (p =.01), and maximal oxygen uptake (VO2max; p =.002) increased, and glucose (p =.001), insulin (p =.001), insulin resistance (p =.01), systolic blood pressure (p =.01), and sleep disorders (p =.01) decreased significantly. Also, Pearson's test results showed a significant inverse relationship between adropin level (p =.01 and r = −.55) and glucose (p =.01 and r = −.51) with sleep disorders. It seems that multicomponent training increases adropin and improves insulin resistance, endothelial function, and sleep quality in older adults. [ABSTRACT FROM AUTHOR]

Clinical Scenario: Ankle sprains are one of the most common injuries in athletics, and many lead to recurrent sprains, chronic ankle instability, and persistent symptoms. Treatment improvements are needed. Platelet-rich plasma (PRP) involves formulating autologous plasma with higher platelet concentration to be injected in the desired tissue. There is currently high-quality evidence supporting the use of PRP with lateral epicondylitis and knee osteoarthritis to accelerate the healing process and decrease pain. Clinical Question: Does the injection of PRP relieve pain faster and improve function compared with no injection or placebo in patients with a lateral ankle sprain? Summary of Key Findings: A computerized search yielded 191 studies; of these, 3 studies fit the inclusion and exclusion criteria. PRP injection reduces pain and increases function after lateral ankle sprain 5 to 8 weeks after intervention. Clinical Bottom Line: The use of PRP after lateral ankle sprain to decrease pain and increase function is supported with moderate evidence. Strength of Recommendation: Based on the Strength of Recommendation Taxonomy, evidence from the included studies is considered as level B, reflecting limited quality patient-oriented evidence. [ABSTRACT FROM AUTHOR]

The two‐trials rule for drug approval requires "at least two adequate and well‐controlled studies, each convincing on its own, to establish effectiveness." This is usually implemented by requiring two significant pivotal trials and is the standard regulatory requirement to provide evidence for a new drug's efficacy. However, there is need to develop suitable alternatives to this rule for a number of reasons, including the possible availability of data from more than two trials. I consider the case of up to three studies and stress the importance to control the partial Type‐I error rate, where only some studies have a true null effect, while maintaining the overall Type‐I error rate of the two‐trials rule, where all studies have a null effect. Some less‐known P$$ P $$‐value combination methods are useful to achieve this: Pearson's method, Edgington's method and the recently proposed harmonic mean χ2$$ {\chi}^2 $$‐test. I study their properties and discuss how they can be extended to a sequential assessment of success while still ensuring overall Type‐I error control. I compare the different methods in terms of partial Type‐I error rate, project power and the expected number of studies required. Edgington's method is eventually recommended as it is easy to implement and communicate, has only moderate partial Type‐I error rate inflation but substantially increased project power. [ABSTRACT FROM AUTHOR]

Background: Histology has prognostic value in ulcerative colitis (UC). However, direct comparisons of histological endpoints are lacking. Aim: To perform a network meta‐analysis (NMA) to compare histological endpoints with biologics and small molecules. Methods: We searched four databases up until July 2024 for randomised controlled trials (RCTs) on advanced therapies for moderate‐to‐severe UC reporting histological endpoints. Outcomes included histological improvement or remission, and histo‐endoscopic improvement after induction or during maintenance. We used a random‐effects frequentist model and have reported outcomes as relative risk and 95% confidence interval. We estimated relative drug efficacy with the P‐score. We conducted subgroup analysis by trial phase and evaluated risk of bias and evidence certainty. Results: We included 24 RCTs (15 therapies, 8874 patients). Nineteen provided data on induction and 10 on maintenance; outcome definitions were similar. Etrasimod 2 mg/day ranked highest in achieving histologic improvement (P‐score 0.98) and remission (P‐score 0.90) following induction. Globally, guselkumab 200–400 mg ranked first for histo‐endoscopic improvement, while etrasimod 2 mg/day and upadacitinib 45 mg/day were superior in the subgroup analysis. During maintenance, upadacitinib 30 mg/day was superior in achieving histologic improvement and remission (P‐score 0.88 for both) and histo‐endoscopic improvement (P‐score 0.94). Etrasimod 2 mg/day ranked second for histologic remission (P‐score 0.70) and histo‐endoscopic improvement (P‐score 0.73), while mirikizumab 200 mg/month ranked second for histologic improvement. Conclusion: These results support the ability of small molecules to achieve stringent endpoints in moderate‐to‐severe UC. Histological outcome data for biologics was sparser, particularly during maintenance. Head‐to‐head RCTs are imperative to better inform clinical practice. [ABSTRACT FROM AUTHOR]

The emergence of biological agents and small molecule drugs has revolutionized the treatment landscape for psoriasis, yet there remains a lack of systematic reviews elucidating the efficacy and safety of drugs for patients with psoriasis and mental disorders (MDs). The aim was to systemically evaluate the efficacy and safety of FDA-approved psoriasis drugs on MD symptoms and MD drugs on psoriasis symptoms. We conducted comprehensive literature searches of the PubMed, Embase, and Cochrane Library from inception to March 24, 2024, identifying 116 relevant studies for inclusion. Our review encompasses 62 clinical trials and 54 case reports/series. Analyses of clinical trials revealed a positive impact of psoriasis drugs on MD, with notable exceptions including lithium and benzodiazepine receptor agonists, which exhibited adverse effects on psoriasis. Furthermore, analysis of case reports/series highlighted the efficacy of drugs such as apremilast, etanercept, infliximab, and secukinumab in ameliorating MD symptoms, contrasting with detrimental effects observed with methotrexate (MTX), cyclosporine, adalimumab, and secukinumab. Notably, tumor necrosis factor alpha (TNF-α) inhibitors and interleukin inhibitors demonstrated superior efficacy compared to conventional treatments. In the anxiety group, secukinumab showed the largest effective size as assessed by the Hospital Anxiety and Depression Scale - Anxiety (HADS-A) index; In the depression group, ixekizumab showed the largest effective size assessed by the 16-item Quick Inventory of Depressive Symptomology – Self-Report (QIDS-SR16) index. The extracted data cannot be meta-analyzed, as the measurement scale is not uniform. This systematic review provides robust evidence regarding treatment options for individuals with psoriasis and MD, emphasizing the potential benefits of specific drugs in managing both conditions concurrently. • In general, psoriasis drugs (conventional drugs, small molecule drugs, TNF-α inhibitors, IL inhibitors) all have a positive effect on MD. • TNF-α and IL inhibitors demonstrated superior efficacy compared to conventional treatments, particularly in patients with highly inflammatory conditions. • In the anxiety group, secukinumab showed the largest effective size as assessed by the HADS-A index; In the depression group, ixekizumab showed the largest effective size assessed by the QIDS-SR16 index. • MD drugs included gabapentin and paroxetine showed positive effect on psoriasis while lithium and BZRAs were reported to induce psoriasis. [ABSTRACT FROM AUTHOR]

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The US Food and Drug Administration recognizes the unmet medical need for antibacterial drugs to treat serious bacterial diseases caused by resistant pathogens for which effective therapies are limited or lacking. The agency also recognizes that designing and conducting clinical trials to assess the safety and efficacy of drugs to treat resistant infections is challenging, especially for drugs only active against a single or a few bacterial species, and that a more flexible development program might be appropriate. In this article, we discuss several regulatory considerations for flexible development programs for antibacterial drugs intended to meet an unmet medical need. As an example, we use the recent approval of sulbactam for injection and durlobactam for injection (XACDURO) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. [ABSTRACT FROM AUTHOR]

Background: Many morphological and histological changes take place in aging skin. Topical tretinoin is the gold standard anti-aging agent used to reduce signs of aging through stimulation of epidermal growth and differentiation and inhibition of collagenase. Objective: The aim of this systematic review is to summarize studies evaluating the efficacy of tretinoin compared with other topical medications and cosmeceuticals in reducing the appearance of skin aging. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. The literature search was conducted using the PubMed and Embase databases from conception to December 2023. Studies were included if they compared anti-aging outcomes of topical medications with those of topical tretinoin (also called all-trans retinoic acid and retinoic acid). Studies were excluded if they compared non-topical anti-aging treatments with tretinoin or were conducted on animal models. Results: The literature search resulted in 25 studies that met all inclusion and exclusion criteria. The most common study comparators to tretinoin included other forms of vitamin A. Outcomes were reported on the basis of visual reduction of aging signs, histological assessment of the epidermis and dermis, and protein expression. Although comparators to tretinoin had variable efficacy (greater in 7 studies, equivalent in 13 studies, and less in 3 studies), most studies found the comparator to be less irritating and better tolerated by patients than tretinoin. Discussion: Tretinoin is currently the gold standard therapy for the treatment of photoaging, but its poor tolerability often limits its use. Unfortunately, given that most studies comparing topical therapies with tretinoin are of poor quality and/or demonstrate bias, there is a lack of substantial evidence to support an alternative first-line therapy. However, given there are some data to support the efficacy of retinoid precursors, namely retinaldehyde, pro-retinal nanoparticles, and conjugated alpha-hydroxy acid and retinoid (AHA-ret), these agents can be considered a second-line option for anti-aging treatment in patients who cannot tolerate tretinoin. [ABSTRACT FROM AUTHOR]

Alopecia areata is a common autoimmune disorder characterized by non-scarring hair loss on the scalp or other hair-bearing surface. In recent years, Janus kinase (JAK) inhibitors have shown promise in the treatment of alopecia areata by disrupting the signaling pathways involved in immune-mediated hair follicle damage. However, some patients with alopecia areata exhibit insufficient responses to JAK inhibitors. This review aims to explore the predictive factors for poor responses to JAK inhibitors in patients with alopecia areata and to discuss alternative treatment strategies in such cases. Patients with a longer duration of the current episode and higher baseline severity are at an increased risk of inadequate JAK inhibitor responses. Oral administration rather than topical application, and extended treatment durations, correlate with a favorable response. Notably, the poor response to JAK inhibitors in alopecia areata may be related to the amount and functional depletion of regulatory T cells resulting from an augmented T helper-2-type immune response. For patients with poor responses to JAK inhibitors, treatment adjustments may include increasing the dosage, extending the treatment duration, combination therapies, or switching to alternative JAK inhibitors. For patients with atopic comorbidities or psychological problems, it is important to select corresponding treatment options to optimize patient outcomes. Further research is needed to establish more reliable predictors and improve overall patient care. [ABSTRACT FROM AUTHOR]

Objectives: Previous evidence suggests that bisphosphonates (BPs) may lower the risk of recurrent fractures and enhance functional recovery in patients with fractures. However, there has been controversy regarding the optimal timing of treatment initiation for patients with fragility fractures. We conducted a meta-analysis to evaluate the available evidence on the use of BPs during the perioperative period and compared it to both non-perioperative periods and non-usage. Methods: Electronic searches were performed using PubMed, EMBASE, Web of Science and the Cochrane Library published before February 2023, without any language restrictions. The primary outcomes included fracture healing rate, healing time, and new fractures. We also examined a wide range of secondary outcomes. Random effects meta-analysis was used. Results: A total of 19 clinical trials involving 2543 patients were included in this meta-analysis. When comparing patients with non-perioperative BPs use in 4-6 weeks and approximately 10-12 weeks post-surgically, the overall risk ratios (RRs) of perioperative BPs use for healing rate were 1.06 (95% CI: 0.81, 1.38, p=0.69) and 1.02 (95% CI: 0.94, 1.11, p=0.65), respectively, suggesting no difference in healing rate between perioperative and non-perioperative BP initiation. For healing time, the overall mean difference between perioperative and non-perioperative periods was -0.19 week (95% CI: -1.03, 0.64, p=0.65) at approximately 10-12 weeks, indicating no significant impact of perioperative BP initiation on healing time. In terms of new fractures, the overall RR with BP use was 0.35 (95% CI: 0.17-0.73, p=0.005), when compared to patients without BPs use. This suggests a protective impact of BP use against new fractures compared to patients without BP use. Perioperative BP use was associated with a markedly higher likelihood of having adverse experiences, including fever (RR: 23.78, 95% CI: 8.29, 68.21, p< 0.001), arthralgia (RR: 10.20, 95% CI: 2.41, 43.16, p=0.002), and myalgia (RR: 9.42, 95% CI: 2.54, 34.87, p< 0.001), compared with non-BPs use. Conclusions: Treatment with BP during the perioperative period does not affect the healing process and has positive effects on therapy for patients with fragility fractures. These compelling findings underscore the potential efficacy of BP use during the perioperative period as a viable treatment option for patients with fragility fractures. [ABSTRACT FROM AUTHOR]

Summary: This 78-week (18-month) study conducted in 479 postmenopausal women with osteoporosis evaluated the efficacy, pharmacodynamics, pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P41 relative to US reference denosumab. CT-P41 had equivalent efficacy and pharmacodynamics to US-denosumab, with similar pharmacokinetics and comparable safety and immunogenicity profiles. Purpose: To demonstrate equivalence of candidate biosimilar CT-P41 and US reference denosumab (US-denosumab) in postmenopausal women with osteoporosis. Methods: This 78-week (18-month), double-blind, randomized, active-controlled Phase 3 study (NCT04757376) comprised two treatment periods (TPs). In TPI, patients (N = 479) were randomized 1:1 to 60 mg subcutaneous CT-P41 or US-denosumab. At Week 52, those who had received CT-P41 in TPI continued to do so. Those who had received US-denosumab were randomized (1:1) to continue treatment or switch to CT-P41 in TPII. The primary efficacy endpoint was percent change from baseline in lumbar spine bone mineral density at Week 52. Efficacy equivalence was concluded if associated 95% confidence intervals (CI) for least squares (LS) mean group differences fell within ± 1.503%. The primary pharmacodynamic (PD) endpoint was area under the effect curve for serum carboxy-terminal cross-linking telopeptide of type I collagen through the first 26 weeks, with an equivalence margin of 80–125% (for 95% CIs associated with geometric LS mean ratios). Results: Equivalence was demonstrated for CT-P41 and US-denosumab with respect to primary efficacy (LS mean difference [95% CI]: − 0.139 [− 0.826, 0.548] in the full analysis set and − 0.280 [− 0.973, 0.414] in the per-protocol set) and PD (geometric LS mean ratio [95% CI]: 94.94 [90.75, 99.32]) endpoints. Secondary efficacy, PD, pharmacokinetics, and safety results were comparable among all groups up to Week 78, including after transitioning to CT-P41 from US-denosumab. Conclusions: CT-P41 was equivalent to US-denosumab in women with postmenopausal osteoporosis, with respect to primary efficacy and PD endpoints. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA). Methods: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. Results: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. Conclusions: This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management. [ABSTRACT FROM AUTHOR]

Objectives. To investigate characteristics of data reported in US medical cannabis registries across states. Methods. Data included 2021 medical cannabis registry reports from 34 states, Puerto Rico, and the District of Columbia (hereafter, states) with active medical cannabis programs. The data from the reports were manually coded into domains and subcategories, including information related to patients (e.g., number, demographics), authorizing clinicians, sales (e.g., content, revenue), license tracking, and health and safety outcomes. Results. Among 36 states, 97% reported total patient number and 75% reported number of authorizing clinicians. Least reported subcategories included patient race/ethnicity (8%), adverse events (11%), therapeutic benefits (6%), and product recalls (6%). States that recently legalized medical cannabis (2013–2018) reported a higher number of subcategories overall, with a median of 11 versus 8 for early adopting states (1996–2012). More medical-use states reported data on authorizing clinicians compared with nonmedical adult-use states but were otherwise similar. Conclusions. Medical cannabis state registries generally reported data on consumers, clinicians, and sales rather than health and safety outcomes. More comprehensive and uniform medical cannabis public health surveillance is needed. (Am J Public Health. 2024;114(S8):S685–S693. https://doi.org/10.2105/AJPH.2024.307728) [ABSTRACT FROM AUTHOR]

Purpose Evidence has suggested that clevidipine may provide faster blood pressure (BP) reduction with less volume than nicardipine in stroke and cardiothoracic surgery patients, but its use in hypertensive crises has not been well established. The primary objective of this study was to compare the treatment success of clevidipine and nicardipine in hypertensive crisis. Methods This was a multicenter, retrospective cohort study including patients who received either clevidipine or nicardipine for treatment of hypertensive crisis. The primary outcome was the time from infusion start to attainment of goal BP, defined as the higher value of the guideline-directed 25% reduction in BP or the physician-ordered goal. Secondary outcomes were the time from infusion start to guideline-directed 25% reduction in BP, drug and total volume intake, the time from order entry to BP goal attainment, the number of BP and heart rate excursions, intensive care unit (ICU) length of stay, and study medication cost. Results In total, 182 patients were included in the study (103 receiving nicardipine and 79 receiving clevidipine). Time to goal BP was similar between the groups (35 vs 33 minutes for clevidipine vs nicardipine, respectively; P = 0.37). Time to guideline-directed 25% reduction was also similar (P = 0.42). Volume from study drug was significantly less with clevidipine (222 vs 518 mL; P = 0.01); however, the total volume received in the ICU was similar (3,370 vs 3,383 mL; P = 0.43). Percent time in the goal BP range was similar (43.1% vs 42.3%). The cost of clevidipine was $199.37 per vial (based on the average wholesale price as of June 2023). This cost was 682% higher than that for a bag of nicardipine. Conclusion Time to goal BP was similar for clevidipine and nicardipine in this population. Any decreases in medication-associated volume with clevidipine were no longer evident when all volume sources were considered. These results show that clevidipine may not provide meaningful benefit in this heterogenous population. The difference in cost does not seem justified given the lack of improvement in clinically relevant outcomes. [ABSTRACT FROM AUTHOR]

Context Polyphenols are plant-based compounds with potential anti-inflammatory, antioxidant, and anti-obesogenic properties. However, their effects on health outcomes remain unclear. Objective To evaluate the effects of polyphenols on anthropometric and cardiometabolic markers. Data Sources Six electronic databases—namely, EMBASE, CINAHL, PubMed, Scopus, The Cochrane Library (reviews only), and Web of Science—were searched for relevant systematic reviews with meta-analyses (SRMAs). Data Extraction Three reviewers performed the data extraction via a data-extraction Microsoft Excel spreadsheet. Data Analysis An umbrella review and meta-analysis of existing SRMAs was conducted. Eighteen SRMAs published from 2015 to 2023, representing 445 primary studies and 838 unique effect sizes, were identified. Meta-analyses were conducted using random-effects models with general inverse variance. Polyphenol-containing foods were found to significantly improve weight (-0.36 kg; 95% confidence interval [CI]: −0.62, 0.77 kg; P  < 0.01, I 2 = 64.9%), body mass index (−0.25 kg/m2; 95% CI: −0.34, −0.17 kg/m2; P  < 0.001, I 2 = 82.4%), waist circumference (−0.74 cm; 95% CI: −1.34, −0.15 cm; P  < 0.01, I 2 = 99.3%), low-density-lipoprotein cholesterol (−1.75 mg/dL; 95% CI: −2.56, −0.94; P  < 0.001, I 2 = 98.6%), total cholesterol (−1.23 mg/dL; 95% CI: −2.00, −0.46; P  = 0.002, I 2 = 94.6%), systolic blood pressure (−1.77 mmHg; 95% CI: −1.77, −0.93 mmHg; P  < 0.001, I 2 = 72.4%), diastolic blood pressure (−1.45 mmHg; 95% CI: −2.09, −0.80 mmHg; P  < 0.001, I 2 = 61.0%), fat percentage (−0.70%; 95% CI: −1.03, −0.36%; P  < 0.001, I 2 = 52.6%), fasting blood glucose (−0.18 mg/dL; 95% CI: −0.35, −0.01 mg/dL; P  = 0.04, I 2 = 62.0%), and C-reactive protein (CRP; including high-sensitivity-CRP [hs-CRP]) (−0.2972 mg/dL; 95% CI: −0.52, −0.08 mg/dL; P  = 0.01, I 2 = 87.9%). No significant changes were found for high-density-lipoprotein cholesterol (−0.12 mg/dL; 95% CI: −1.44, 0.69; P  = 0.67, I 2 = 89.4%) and triglycerides (−1.29 mg/dL; 95% CI: −2.74, 0.16; P  = 0.08, I 2 = 85.4%). Between-study heterogeneity could be explained by polyphenol subclass differences. Conclusion The findings of this umbrella review support the beneficial effects of polyphenols on anthropometric and metabolic markers, but discretion is warranted to determine the clinical significance of the magnitude of the biomarker improvements. Systematic Review Registration International Prospective Register of Systematic Reviews no. CRD42023420206. [ABSTRACT FROM AUTHOR]

Pegmolesatide, a synthetic, polyethylene-glycolylated, peptide-based erythropoiesis-stimulating agent (ESA), has been recently approved in China. Pegmolesatide is derived from the structure of endogenous erythropoietin (EPO), a natural product in mammals. This study compared the in vitro effects and selectivity of pegmolesatide to those of recombinant EPO and carbamylated EPO (CEPO) through computer-aided analyses and biological tests. The findings indicate that pegmolesatide exhibited the same stimulating effect on erythropoiesis as EPO with fewer side effects than EPO and CEPO. [ABSTRACT FROM AUTHOR]

Scutellarin, one of natural flavonoids from Scutellaria barbata D. Don and Erigeron breviscapus (vant) Hand.-Mazz. Modern pharmacological studies have shown that scutellarin has a good anti-tumor effect. According to the literature review at home and abroad, scutellarin can inhibit the growth and metastasis of tumor cells, block the cell cycle at various stages, induce apoptosis and autophagy, interfere with tumor metabolism, reverse drug resistance of tumor cells and enhance the sensitivity of chemotherapy drugs. In this paper, the anti-tumor mechanism of scutellarin was reviewed, and the shortcomings of current studies and future research directions were analyzed, so as to provide a basis for further exploration of the anti-tumor potential of scutellarin and its further development and utilization. [ABSTRACT FROM AUTHOR]

Chemotherapeutics are most often used to treat cancer, but side effects, drug resistance, and toxicity often compromise their effectiveness. In contrast, phytocompound plumbagin possesses a distinct pleiotropic nature, targeting multiple signaling pathways, such as ROS generation, cell death, cellular proliferation, metastasis, and drug resistance, and is shown to enhance the efficacy of chemotherapeutic drugs. Plumbagin has been shown to act synergistically with various chemotherapeutic drugs and enhance their efficacy in drug-resistant cancers. The pleiotropic nature is believed to be due to plumbagin's unique structure, which contains a naphthoquinone ring and a hydroxyl group responsible for plumbagin's various biological responses. Despite limitations such as restricted bioavailability and delivery, recent developments aim to address these challenges and harness the potential of plumbagin as an anticancer therapeutics. This review delves into the structural aspect of the plumbagin molecule contributing to its pleiotropic nature, explores the diverse mechanism that it targets, and discusses emerging strategies to overcome its limitations. [ABSTRACT FROM AUTHOR]

Summary: Objective: To summarize the literature on pharmacotherapy for managing paediatric obesity. Methods: A systematic review and meta‐analysis were conducted of randomized controlled trials (RCTs) with <18‐year‐olds of pharmacotherapeutic agents published up to November 2022. Estimates of effect for outcomes were presented relative to minimal important differences and GRADE certainty of evidence. We examined data on patient/proxy‐reported outcome measures (PROMs), cardiometabolic risk factors, anthropometry and adverse events (AEs). Results: Overall, 35 RCTs were included. Trials examined metformin (n = 26), glucagon‐like peptide‐1 receptor agonists (GLP1RAs) (n = 7) and a lipase inhibitor (orlistat; n = 2). Intervention duration varied (3−24 months). Metformin had little to no benefit on PROMs (e.g., health‐related quality of life [HRQoL]; 6 RCTs), moderate reductions in triglycerides, a moderate decline in insulin resistance, a small to moderate decline in BMI z‐score (BMIz) and a moderate increase in mild to moderate gastrointestinal AEs. Response to GLP1RAs was heterogeneous and results of subgroup analysis demonstrated variability of impact. Liraglutide (2 RCTs) resulted in a small reduction in HOMA‐IR and BMIz, but little to no benefit on other outcomes. Exenatide (4 RCTs) had a moderate reduction on blood pressure and a small decrease in BMIz with little to no benefit on other outcomes. Semaglutide (1 RCT) had a small benefit on HRQoL, a small reduction on SBP, a moderate reduction on total cholesterol and LDL‐cholesterol, a large reduction on triglyceride, and a very large decline in BMIz accompanied by a small increase in mild to moderate gastrointestinal AEs. Orlistat had a moderate reduction in DBP and little to no benefit in other outcomes measured, but had a very large increased risk of mild to moderate gastrointestinal AEs. Serious AEs were rare and for interventions with sufficent AE reporting, were considered not likely attributable to the interventions. Conclusion: Few studies examined the impact of pharmacotherapy on PROMs. There is evidence that metformin and GLP1RAs lead to important improvements in cardiometabolic and anthropometric outcomes while accompanied by mild to moderate AEs. Long‐term effectiveness and safety of GLP1RAs remain to be evaluated. [ABSTRACT FROM AUTHOR]

Summary: Anti‐obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long‐term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end‐points, secondary end‐points, eligibility criteria, trial run‐in and follow‐up phases, use of active comparators and guidelines for down‐titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end‐points, emphasis was placed on moving away from BMI z‐score as a primary outcome, incorporating multiple alternative BMI‐related outcomes and measuring adiposity/body fat as a prominent secondary end‐point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run‐in phases was discussed. It was also underscored that designing trials with extended follow‐up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo‐controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down‐titration to avoid excessive weight reduction when applicable. [ABSTRACT FROM AUTHOR]

Summary: Background: Up to 50% of adolescents who undergo metabolic and bariatric surgery (MBS) have obesity 3 years post‐MBS, placing them at continued risk for the consequences of obesity. Objectives: We conducted an open‐label, 16‐week pilot study of liraglutide in adolescents with obesity after sleeve gastrectomy (SG) to investigate liraglutide effects on weight and body mass index (BMI) post‐SG. Methods: Adolescents aged 12–20.99 years with obesity and a history of SG ≥1 year prior were enrolled. Liraglutide was initiated at 0.6 mg/day, escalated weekly to a maximum of 3 mg/day, with treatment duration 16 weeks. Fasting laboratory assessments and an oral glucose tolerance test were performed at baseline and end‐treatment. Results: A total of 43 participants were screened, 34 initiated liraglutide (baseline BMI 41.2 ± 7.7 kg/m2), and 31 (91%) attended the end‐treatment visit. BMI decreased by 4.3% (p < 0.001) with liraglutide. Adolescents who had poor initial response to SG (<20% BMI reduction at BMI nadir) had less weight loss with liraglutide. Fasting glucose and haemoglobin A1C concentrations significantly decreased. There were no serious treatment‐emergent adverse events reported. Conclusions: Liraglutide treatment was feasible and associated with a BMI reduction of 4.3% in adolescents who had previously undergone SG, quantitatively similar to results obtained in adolescents with obesity who have not undergone MBS. [ABSTRACT FROM AUTHOR]

Summary: Background: There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. Aims: To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). Methods: An extensive review of the published literature. Results: TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure‐response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non‐TNF inhibitors demonstrate less robust exposure‐response relationships, and TDM may not prove as beneficial. Conclusions: In the treat‐to‐target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control. [ABSTRACT FROM AUTHOR]

In 2020, the number of deaths caused by lung cancer worldwide reached 1,796,144, making it the leading cause of cancer‐related deaths. Cyclooxygenase‐2/prostaglandin endoperoxide synthase 2 (COX‐2/PTGS2) is overexpressed in lung cancer, which promotes tumor proliferation, invasion, angiogenesis, and resistance to apoptosis. Here, we report that the oligonucleotide drug HQi‐sRNA‐2 from Traditional Chinese Medicine Huangqin targeting COX‐2/PTGS2 significantly inhibited proliferation, migration, and invasion and induced apoptosis in the human lung cancer cell line NCI‐H460. Oral delivery of HQi‐sRNA‐2 bencaosomes prolonged survival, reduced tumor burden, and maintained weight in a spontaneous mouse lung cancer model. Compared with paclitaxel, HQi‐sRNA‐2 may be less toxic and have approximately equal efficacy in reducing tumor burden. Our previous studies reported that herbal small RNAs (sRNAs) are functional medical components. Our data suggest that sphingosine (d18:1)‐HQi‐sRNA‐2 bencaosomes, targeting COX‐2/PTGS2 and downregulating the PI3K and AKT signaling pathways, may provide novel therapeutics for lung cancer. [ABSTRACT FROM AUTHOR]

The aim of this trial was to assess the effectiveness of Sediflù, a medical device containing active herbal ingredients, on nocturnal and diurnal persistent coughs in children, with a duration of 3 to 7 days. Children with a dry and/or productive cough were enrolled in this prospective, interventional, multicenter, placebo-controlled, double-blind, randomized clinical study. Clinical efficacy was assessed through the evaluation of the soothing action of Sediflù against dry and/or productive coughing, both at night and during the day, and other effects of coughing associated with quality of sleep: frequency, child's quality of sleep, parental quality of sleep and severity. Treatment with Sediflù improved both night-time and day-time cough scores from day 2. The diurnal score also improved significantly in the Sediflù group at days 3 and 7. Sediflù syrup can be considered a valid treatment for cough management in younger children with upper respiratory tract infections, shortening the cough duration. [ABSTRACT FROM AUTHOR]

Purpose: Based on the comparison of ramucirumab monoclonal antibody with control treatments in randomized controlled trials, this study aims to elucidate the role of ramucirumab monoclonal antibody in cancer therapy and its potential side effects, providing scientific evidence for clinical treatment. Methods: PubMed, Embase, Cochrane, and Web of Science were searched systematically to obtain the trials on ramucirumab in the treatment of gastric or gastroesophageal junction (GEJ) adenocarcinoma up to April 13, 2023. We included randomized controlled trials (RCTs) evaluating the efficacy and safety of ramucirumab as monotherapy and in combination with other chemotherapy agents as interventions for treating gastric or gastroesophageal junction (GEJ) adenocarcinoma. Results: After screening 2200 studies, we finally included 8 eligible studies (involving a total of 3,283 participants). Meta-analysis results showed that compared to the control group, ramucirumab monotherapy significantly improved overall survival (OS) (hazard ratio [HR] = 0.77, 95% confidence interval [CI] [0.67, 0.89]) and progression-free survival (PFS) (HR = 0.48, 95% CI [0.40, 0.58]). Similar results were obtained for ramucirumab combined with paclitaxel. In the treatment combining ramucirumab with paclitaxel, compared to monotherapy, three severe adverse reactions (grade ≥ 3) were observed with significantly increased risks (OR > 2). These include proteinuria (OR = 5.37, 95% CI [1.22, 23.54]), hypertension (OR = 4.02, 95% CI [2.63, 6.14]), and gastrointestinal perforation (OR = 4.64, 95% CI [1.00, 21.60]). Subgroup analysis further indicated that ramucirumab is effective in both non-East Asian and East Asian populations, with East Asian patients more prone to developing proteinuria, while having a lower incidence of hypertension. Additionally, ramucirumab demonstrated comparable efficacy between first-line and second-line treatments, with a higher incidence of proteinuria observed in second-line therapy. Conclusion: Ramucirumab significantly improves the prognosis of patients with gastric or gastroesophageal junction adenocarcinoma. When used in combination with paclitaxel, close monitoring of adverse reactions such as proteinuria (especially in East Asian populations), hypertension (especially in non-East Asian populations), and gastrointestinal perforation is essential. [ABSTRACT FROM AUTHOR]

The translation of in vitro potency of a candidate drug, as determined by traditional pharmacology metrics (such as EC50/IC50 and KD/Ki values), to in vivo efficacy and safety is challenging. Residence time, which represents the duration of drug‐target interaction, can be part of a more comprehensive understanding of the dynamic nature of drug‐target interactions in vivo, thereby enabling better prediction of drug efficacy and safety. As a consequence, a prolonged residence time may help in achieving sustained pharmacological activity, while transient interactions with shorter residence times may be favourable for targets associated with side effects. Therefore, integration of residence time into the early stages of drug discovery and development has yielded a number of clinical candidates with promising in vivo efficacy and safety profiles. Insights from residence time research thus contribute to the translation of in vitro potency to in vivo efficacy and safety. Further research and advances in measuring and optimizing residence time will bring a much‐needed addition to the drug discovery process and the development of safer and more effective drugs. In this review, we summarize recent research progress on residence time, highlighting its importance from a translational perspective. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is the sixth most common type of cancer worldwide, and head and neck squamous cell carcinoma (HNSCC) accounts for 90% of HNC cases. Furthermore, HNSCC accounts for 400,000 cancer-associated deaths worldwide each year. However, at present there is an absence of a versatile biomarker that can be used for diagnosis, prognosis evaluation and as a therapeutic target for HNSCC. In the present study, bioinformatics analysis was used to assess the relationship between hub genes and the clinical features of patients with HNSCC. The findings from the bioinformatics analysis were then verified using clinical samples and in vitro experiments. A total of 51 overlapping genes were identified from the intersection of differentially expressed genes and co-expressed genes. The top 10 hub genes were obtained from a protein-protein interaction network of overlapping genes. Among the hub genes, only secretoglobin family 1A member 1 (SCGB1A1) was significantly associated with both overall and disease-free survival. Specifically, upregulated SCGB1A1 expression levels were associated with prolonged overall and disease-free survival. Moreover, the SCGB1A1 expression levels were negatively correlated with drug sensitivity. Notably, it was demonstrated that SCGB1A1 was involved in tumor immunoreaction by affecting the infiltration of cells and checkpoint regulation of immune cells. Additionally, it was shown that SCGB1A1 regulated multiple key cancer-related signaling pathways, including extracellular matrix receptor interaction, transforming growth factor-β and tumor metabolism signaling pathways. Based on the results of the present study, SCGB1A1 may serve as a novel biomarker for predicting the diagnosis, prognosis and therapeutic effectiveness of certain drugs in patients with HNSCC. Moreover, SCGB1A1 may serve as a potential therapeutic target for the management of HNSCC. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a common allergic skin disease characterized by eczema, dryness, and severe itching, which has a significant impact on patients' quality of life. Its pathogenesis involves immune dysregulation and impaired skin barrier function. In this study, the therapeutic potential of Ampelopsis brevipedunculata (Maxim.) Trautv for alleviating atopic dermatitis symptoms was investigated using the NC/Nga mouse model. A. brevipedunculata (Maxim.) Trautv was effective in attenuating the atopic dermatitis-like epidermal thickening and the immune cell infiltration in the skin lesions induced by the atopic dermatitis ointment. Additionally, A. brevipedunculata (Maxim.) Trautv suppressed the production of inflammatory mediators and chemokines associated with atopic dermatitis progression. In addition, A. brevipedunculata (Maxim.) Trautv exhibited restorative effects on skin barrier dysfunction by increasing the expression of key barrier proteins. Mechanistically, A. brevipedunculata (Maxim.) Trautv modulated the mitogen-activated protein kinase pathway and inhibited nuclear factor-kappa B activation. These findings highlight the potential of A. brevipedunculata (Maxim.) Trautv as a promising therapeutic agent for treating atopic dermatitis and provide insight into its mechanisms of action. [ABSTRACT FROM AUTHOR]

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400–1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789–796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753–779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15–29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE. [ABSTRACT FROM AUTHOR]

Objective: Cleft lip repair (CLR) can be complicated by hypertrophic scar or keloid. Botulinum toxin type A (BTA) may improve postoperative scarring by reducing muscle tension and cytokine activity at the scar site. This systematic review analyzes the available evidence regarding the effect of BTA on scar quality after CLR. Design: The search was conducted in 6 different databases in accordance with PRISMA guidelines (PubMed, Scielo, Embase, Scopus, Web of Science, and Cochrane) using "botulinum toxin" and "cleft lip" as keywords. Setting: Academic hospital Patients: Exclusive to patients who underwent CLR and BTA injection Outcome measures: Mean visual analog scores (VAS), mean Vancouver scar scale (VSS), scar width, and BTA or CLR-related complications. Results: Five studies for a total of 216 patients met inclusion criteria. Four studies reported on primary CLR during infancy while 1 study recruited older patients seeking revision. All patients had BTA (range: 1-2 units/kg) injected in the orbicularis oris muscle. One study documented BTA injections in additional perioral muscles. All 4 studies that measured scar width and had a saline control arm found a significant decrease in width with BTA injection. Improvement of VAS and VSS with BTA was reported in 3 of 5 studies and 2 of 5 studies, respectively. There were no reports of complications associated with BTA or CLR. Conclusion: The existing studies support the use of BTA injection to improve scar quality following CLR with low concern for complication. Further investigations with a greater number of patients are necessary. [ABSTRACT FROM AUTHOR]

Objective: To determine the efficacy of hyaluronic acid (HLA) lip filler to correct subtle cleft lip asymmetries in adults using a validated patient reported outcome measure (PROM). Design: Prospective cross sectional. Setting: UK National Health Service. Patients, Participants: Over 18 years old with repaired cleft lip and dissatisfaction of their lip appearance. Interventions: HLA lip filler injection. Main Outcome Measures: A validated, cleft specific PROM, the lip module of CLEFT-Q™ prior to treatment and again after six weeks. Results: 24 patients included. A mean total CLEFT-Q™ score pre-procedure was 14.9 (Stand deviation (SD) = 4.91) and 24 (SD = 6.08) post-procedure. Difference in mean total score pre- and post-procedure were statically significant (P =.0001) in all domains on the CLEFT-Q™. No adverse outcomes. Conclusion: HLA filler to correct subtle cleft lip asymmetries in adults is a simple low risk technique, which can significantly improve the patient's perception of lip appearance. Conclusion: HLA lip filler to correct subtle cleft lip asymmetries in adults is a simple technique, low risk procedure which can significantly improve the patient's perception of lip appearance. [ABSTRACT FROM AUTHOR]

Product adherence is critical to obtaining objective estimates of efficacy of pre-exposure prophylactic interventions against HIV-1 infection. With imperfect adherence, intention-to-treat analyses assess the collective effects of complete, sub-optimal and non-adherence, providing a biased and attenuated estimate of the average causal effect of an intervention. Using data from the MTN-020/ASPIRE phase III trial evaluating HIV-1 efficacy of the dapivirine vaginal ring, we conducted per-protocol, and adherence-adjusted causal inference analyses using principal stratification and marginal structural models. We constructed two adherence cut offs of ≥ 0.9 mg (low cutoff) and > 4.0 mg (high cutoff) that represent drug released from the ring over a 28-day period. The HIV-1 efficacy estimate (95% CI) was 30.8% (3.6%, 50.3%) (P = 0.03) from the per-protocol analysis, and 53.6% (16.5%, 74.3%) (P = 0.01) among the highest predicted adherers from principal stratification analyses using the low cutoff. Marginal structural models produced efficacy estimates (95% CIs) ranging from 48.8 (21.8, 66.4) (P = 0.0019) to 56.5% (32.8%, 71.9%) (P = 0.0002). Application of adherence-adjusted causal inference methods are useful in interpreting HIV-1 efficacy in secondary analyses of PrEP clinical trials. [ABSTRACT FROM AUTHOR]

Adherence drives efficacy in PrEP clinical trials. We compared drug concentrations and self-reported adherence in HPTN069/ACTG5305, a double-blinded, randomized trial of the safety and tolerability of candidate PrEP regimens that included maraviroc (MVC), tenofovir (TDF), and emtricitabine (FTC). Plasma drug concentrations and self-reported adherence by computer-assisted self-interview (CASI) were assessed at study weeks 24 and 48. Descriptive statistics and a generalized linear model were used to assess the association between selected demographic factors, self-report of daily medication adherence and plasma drug concentrations consistent with daily adherence. Among 718 paired observations from 370 participants, 43% (306/718) reported daily adherence by CASI, 65% (467/718) had drug concentrations consistent with daily adherence and 11% (81/718) had CASI responses that reported daily adherence despite having drug concentrations consistent with less-than-daily adherence. In adjusted analyses, participants who were assigned male at birth (aOR 1.42 [95% CI 1.02, 1.97]), older (5-year increments aOR 1.10 [95% CI 1.09, 1.11]), White (aOR 2.2 [95% CI 1.88, 2.56]), had advanced education (aOR 3.89 [95% CI 2.97, 5.09]), were employed (aOR 1.89 [95% CI 1.50, 2.40]), or partnered/married (aOR 2 [95% CI 1.72, 2.32]) were more likely to have drug concentrations consistent with daily adherence. Participants who were not employed (aOR 2.7 [95% CI 1.31, 5.55]) or who were single/not partnered (aOR 2.33 [CI 95% 1.25, 4.34]) were more likely to have drug concentrations that did not reflect daily adherence despite self-reported PrEP adherence. These findings support the need for ongoing adherence counseling in clinical trials of new PrEP regimens. [ABSTRACT FROM AUTHOR]

Synovial sarcoma (SS) is identified as a sarcoma with monomorphic blue spindle cells that display variable epithelial differentiation and is characterized by the SS18::SSX fusion gene. SS accounts for approximately 5–10% of all soft tissue sarcomas, making it a relatively common type within this group of tumors. Since SS is generally sensitive to chemotherapy, the standard treatment for SS includes extensive surgical resection, complemented by neoadjuvant chemotherapy with several approved anticancer drugs. However, in advanced and metastatic cases, the efficacy of these drugs is limited, resulting in poor prognoses. This underscores the need for innovative therapeutic strategies. Patient-derived cancer cell lines are essential tools for basic and preclinical research, yet only four SS cell lines are publicly available. To facilitate the studies of SS, we have developed a novel SS cell line, named NCC-SS6-C1, derived from surgically excised tumor tissue of an SS patient. NCC-SS6-C1 cells preserve the SS18::SSX1 fusion gene, consistent with the genetic characteristics of the original tumor. The cells exhibit continuous proliferation, invasiveness, and the ability to form spheroids. Additionally, we confirmed that this cell line was useful for evaluating the efficacy of anticancer drugs. Our results suggest that NCC-SS6-C1 is a useful tool for basic and pre-clinical studies of SS. [ABSTRACT FROM AUTHOR]

Bone defects resulting from trauma, disease, or congenital abnormalities represent a significant clinical challenge, necessitating advanced regenerative therapies. This study presents the development and formulation of a drug-loaded hydrogel as a novel approach for bone regeneration. The hydrogel matrix is engineered to provide structural support and controlled release of therapeutic agents to enhance bone healing. Various biocompatible polymers and crosslinking strategies are investigated to optimize the hydrogel's mechanical properties, degradation kinetics, and drug release profiles. Furthermore, the study explores the efficacy of different drugs, growth factors, and osteoinductive molecules in promoting osteogenesis and bone tissue regeneration within the hydrogel scaffold. The developed drug-loaded hydrogel holds promise as a versatile platform for addressing diverse bone defects and advancing the field of regenerative orthopedics. [ABSTRACT FROM AUTHOR]

Numerous clinical trials for myasthenia gravis (MG) treatment have been conducted recently, with satisfactory cognitive and clinical results. However, due to the limited evidence for direct comparison of the safety and effectiveness of various drugs, there is a need for further exploration of the advantages and disadvantages of different monoclonal antibodies and immunosuppressants. Thus, in the present network meta-analysis (NMA), we aimed to compare the efficacy and safety of immunosuppressants and monoclonal antibodies in treating MG. We systematically searched for randomized controlled trials published in PubMed, Embase, Web of Science, and the Cochrane Library between January 1, 2000 and March 6, 2024. Statistical analyses were performed using R software (version 4.2.3), JAGS, and STATA (version 15.0). The surface under the cumulative ranking curve (SUCRA) value was calculated to assess the potential efficacy of each drug and the likelihood of adverse events (AEs), with higher SUCRA values indicating better efficacy or a lower likelihood of AEs. This NMA included 21 randomized controlled trials involving 13 drugs and 1,657 patients. Based on changes in Quantitative MG and MG Composite scores, batoclimab was most likely to exert the best therapeutic effects, with SUCRA values of 99% and 92%, respectively. Rozanolixzumab performed better than the other drugs in terms of the MG Activities of Daily Living score (85%). Eculizumab exhibited the highest potential in reducing the 15-item revised version of the MG Quality of Life score (96%). Regarding safety, belimumab had the highest SUCRA value (85%), demonstrating the lowest likelihood of AEs. In conclusion, all immunosuppressants and monoclonal antibodies analyzed in this study were more effective than the placebo in treating MG, with rozanolixzumab and batoclimab potentially being the most effective. Regarding safety, rozanolixzumab exhibited a higher likelihood of AEs than did placebo. The conclusions guide the clinical selection of effective drugs and offer insights for future drug experiments. [ABSTRACT FROM AUTHOR]

Introduction: In recent decades, an increase in the incidence of type 2 diabetes mellitus (T2DM) in children and adolescents has been observed. Pediatric‐onset T2DM differs from the adult‐onset form, particularly regarding the durability of glycemic control and earlier appearance of complications. However, the scarcity of approved treatments and comprehensive studies on T2DM management in youth persists. Ongoing clinical trials seek to ascertain the efficacy and safety of sodium‐glucose cotransporter 2 inhibitors (SGLT2i) in patients aged between 10 and 24 years with T2DM. Therefore, we aimed to perform a meta‐analysis exploring the efficacy and safety of SGLT2i in pediatric patients and young adults with T2DM. Methods: We searched PubMed, Embase, Cochrane, and Web of Science for randomized controlled clinical trials on the efficacy and safety of SGLT2i in children, adolescents, and young adults with T2DM compared with placebo. Statistical analysis was performed using RevMan 5.4 and R statistical software 4.2.1. Heterogeneity was assessed with I2 statistics. Results: We included three studies totaling 334 patients followed for 37.79 weeks. Reduction in HbA1C (MD = −0.93; 95% CI = −1.36 to −0.49; p < 0.0001; I2 = 0%) was significantly higher in SGLT2i group compared with placebo. The proportion of patients requiring rescue or discontinuation of study medication due to lack of efficacy was statistically lower in SGLT2i group compared with placebo (RR = 0.64; 95% CI = 0.43–0.94; p = 0.02; I2 = 0%). SGLT2i and placebo were similar in terms of any adverse event (RR = 1.10; 95% CI = 0.96–1.27; p = 0.17; I2 = 0%), serious side effects (RR = 1.06; 95% CI = 0.44–2.57; p = 0.90; I2 = 0%), and individual adverse effects. Conclusion: In children, adolescents, and young adults with T2DM, SGLT2i appears to be effective and safe for glycemic control. [ABSTRACT FROM AUTHOR]

Individuals with epilepsy are at risk of developing preictal, ictal, postictal and interictal psychoses. Antipsychotic drugs (APDs) are the main class of drugs used to treat psychosis and schizophrenia. The efficacy and safety of APDs as a treatment for epileptic psychosis is not well understood. This systematic review aimed to assess the effectiveness and adverse effects of APDs for treating psychosis in people with epilepsy. We adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines. We searched MEDLINE, Embase, PsycInfo, and AMED (Allied and Complementary Medicine) from database inception to June 20, 2023. We contacted experts in the field and performed citation searches to identify additional records. Title, abstract, full‐text review, and data analysis were conducted in duplicate, with conflicts resolved by discussion among authors. Given the considerable heterogeneity of study designs, meta‐analysis was not deemed appropriate; instead, the results were tabulated in a narrative synthesis. The Joanna Briggs Institute Risk of Bias tool and GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework were used to assess study quality. We identified 13 studies with a total of 1180 participants. In the four case series included, the psychotic symptoms of 25 of 28 patients treated with APDs partially improved or fully resolved. Three of the four cohort studies reported an association between antipsychotic use and longer duration of psychotic episodes, two found similar results in both APD and non‐APD groups, and two did not report control psychosis outcomes. When reported, seizure frequency was observed to remain unchanged or decrease following APD treatment. The evidence on the effectiveness of antipsychotics in the treatment of psychosis in epilepsy is inconclusive and may reflect confounding by indication. However, most studies suggest that antipsychotics were not associated with a marked worsening in seizure frequency. It remains unclear whether antipsychotics should be used in epilepsy, and well‐controlled cohort studies and randomized controlled trials are necessary to draw definitive conclusions. [ABSTRACT FROM AUTHOR]

Cisplatin (DDP) is a potent chemotherapeutic drug, which can regulate tumor cell apoptosis by up-regulating caspase-3 activity. Thus, monitoring caspase-3 activity in breast cancer cells can directly illustrate the efficiency of DDP treatment. In this study, by using reduced graphene oxide (rGO) as a quencher of a fluorescence labeled peptide, we developed an "off to on" method to monitor the effect of DDP on caspase-3 in breast cancer cells. In this method, the rGO quenched fluorescence with an ultra-high level of efficiency. Caspase-3 hydrolyzed the polypeptide probe, generating two segments of different lengths. The release of a short segment marked with fluorophores led to the recovery of the fluorescence signal (Ex/Em = 450/521 nm). Under the optimal conditions, the linear range of caspase-3 was 0.4–7 U mL−1 and the limit of detection was 0.33 U mL−1. The upregulating effect of DDP on intracellular caspase-3 activity was visualized with the "off to on" method and flow cytometry assay showed that caspase-3 activity increased along with the apoptosis rate of tumor cells. The above results show the practical application of the method for evaluating the efficacy of drugs against cancer cells. [ABSTRACT FROM AUTHOR]

It would be clinically valuable if the efficacy of antiarrhythmic drugs could be simulated in advance. We developed a digital twin to predict amiodarone efficacy in high-risk atrial fibrillation (AF) patients post-ablation. Virtual left atrium models were created from computed tomography and electroanatomical maps to simulate AF and evaluate its response to varying amiodarone concentrations. As the amiodarone concentration increased in the virtual setting, action potential duration lengthened, peak upstroke velocities decreased, and virtual AF termination became more frequent. Patients were classified into effective (those with virtually terminated AF at therapeutic doses) and ineffective groups. The one-year clinical outcomes after AF ablation showed significantly better results in the effective group compared to the ineffective group, with AF recurrence rates of 20.8% vs. 45.1% (log-rank p = 0.031, adjusted hazard ratio, 0.37 [0.14-0.98]; p = 0.046). This study highlights the potential of a digital twin-guided approach in predicting amiodarone's effectiveness and improving personalized AF management. Clinical Trial Registration Name: The Evaluation for Prognostic Factors After Catheter Ablation of Atrial Fibrillation: Cohort Study, Registration number: NCT02138695. The date of registration: 2014-05. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02138695. [ABSTRACT FROM AUTHOR]

Background: Effective endodontic treatment requires the use of a root canal sealer with optimal properties to ensure a hermetic seal, prevent reinfection, and promote healing. Despite the availability of various sealers, a standardized evaluation system still needs to be improved. Objectives: To develop a Clinical Utility Index (CUI) that systematically evaluates and ranks root canal sealers based on their sealing ability, antimicrobial efficacy, flow rate, and solubility. Methods: The CUI was developed through a structured process involving expert identification, panel discussions, and the establishment of scoring criteria. Five sealers were evaluated (Sealers A, B, C, D, and E). Mean values for the core properties were calculated, and sealers were ranked accordingly. The total CUI for each sealer was computed based on the assigned scores for each property. Results: Sealer B achieved the highest CUI at 95%, demonstrating superior performance across all core properties. Sealer C followed with a CUI of 80%, while Sealer A ranked third with 60%. Sealers D and E showed the lowest performance, with CUIs of 30% and 35%, respectively, highlighting deficiencies in multiple properties. Discussion: The CUI provides a comprehensive evaluation framework for root canal sealers, facilitating informed decision-making by practitioners. Sealer B's high CUI underscores the importance of balancing sealing ability, antimicrobial effect, flow rate, and solubility. The results align with existing literature emphasizing the critical role of these properties in endodontic success. Conclusion: The CUI offers a robust and balanced method for evaluating root canal sealers, aiding in selecting the most suitable sealer based on empirical data. Future research should refine the index and validate its applicability in diverse clinical scenarios to enhance endodontic treatment outcomes. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive antitumor clinical outcomes. However, the limited response rates suggest the incomplete understanding of PD-L1 regulation. Here, we demonstrate that vacuole protein sorting 11 and 18 (VPS11/18), two key players in vesicular trafficking, positively regulate PD-L1 and confer resistance to immune checkpoint blockade therapy. VPS11/18 interact with PD-L1 in endosome recycling accompanied by promoting PD-L1 glycosylation and protein stability. VPS18 deficiency enhances antitumor immune response. Pharmacological inhibition by VPS18 inhibitor RDN impaired PD-L1 member trafficking and protein stability. Combination treatment of RDN and anti-cytotoxic T lymphocyte-associated antigen 4 synergistically enhances antitumor efficacy in aggressive and drug-resistant tumors. RDN exerted lung-preferred distribution and good bioavailability, suggesting a favorable drug efficacy. Together, our study links VPS18/11-mediated trans-Golgi network recycling of PD-L1 and points to a promising treatment strategy for the enhancement of antitumor immunity. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is an acute infection of the lung parenchyma acquired outside the hospital or other healthcare settings, typically affecting previously healthy individuals. This intersociety consensus aims to provide evidence-based recommendations for the antibiotic treatment of mild to moderate CAP in previously healthy children in Italy. A systematic review was conducted to identify the most recent and relevant evidence. Embase, Scopus, PubMed, and Cochrane databases were systematically screened, with a date restriction from 2012 to April 2024, but without language limitations. The review included studies conducted in high-income countries on antibiotic therapy in children over 3 months of age diagnosed with mild-moderate CAP. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods. The final recommendations were obtained through a Delphi consensus of an expert panel. Amoxicillin is the first-line treatment if the child is at least immunized against Haemophilus influenzae type b (low/very low quality of evidence, strong recommendations), while amoxicillin-clavulanate or second- or third-generation cephalosporins should be prescribed for those unimmunized or with incomplete immunization coverage for both H. influenzae type b and Streptococcus pneumoniae (low/very low quality of evidence, strong recommendations). Macrolides should be considered in addition to amoxicillin in children over 5 years old, if symptoms persist and the clinical condition remains good after 48 h of therapy (low/very low quality of evidence, strong recommendations). The dosage of amoxicillin is 90 mg/kg/day divided in three doses, although two doses could be considered to improve compliance (moderate quality of evidence, weak recommendations). A five-day duration of therapy is recommended, with clinical monitoring and re-assessment approximately 72 h after the start of antibiotic treatment to evaluate symptom resolution (moderate quality of evidence, strong recommendations). To improve the management of CAP in pediatric patients, we have developed this consensus based on a thorough review of the best available evidence and extensive discussions with an expert panel. However, further efforts are needed. Future research should focus on enhancing diagnostic accuracy, optimizing antibiotic utilization, comparing the efficacy of different antibiotic regimens, and determining the optimal dosage and duration of treatment in different setting. [ABSTRACT FROM AUTHOR]

Background: We aimed to study the impact of biological therapies in Saudi Arabia on patients with severe asthma (SA) combined with chronic rhinosinusitis (CRS) in terms of clinical outcomes. Methods: This is a retrospective observational cohort research that was undertaken at the severe asthma clinics of the Armed Forces Hospital of the Southern Region (AFHSR) and King Khalid University Hospital, Abha, from March to September 2022 to delineate the effects of 3 biological therapies (dupilumab, benralizumab, and omalizumab) in adults with SA and concomitant CRS. Clinical outcomes assessed included asthma exacerbation frequency, hospitalization rates, use of oral corticosteroids (OCs), and the asthma control test (ACT) scores before and 1 year after biological therapies. Results: Eighty patients were enrolled, with a mean age of 46.68. There were 45 (56%) females and 35 (44%) males. There was a notifiable decrease in the frequency of exacerbations and hospitalization and in the number of patients who received OCs after 6 and 12 months of biological therapies compared to pre-biological therapies, respectively (p < 0.001 each), while there was a significant increase in the ACT scores at 6 and 12 months post-biological therapies, compared to pre-biological therapies, respectively (p < 0.001). These significant differences were maintained with all the 3 biologics used. Conclusions: Results from the first study from two large Saudi Arabian tertiary centers for patients with SA and CRS agree with and support those of worldwide real-life ones. One-year follow-up showed the effectiveness of the 3 drugs in terms of reduced frequency of asthma hospitalizations and exacerbations, the use of OCs, and improved ACT scores. Further prospective multicenter studies are warranted. [ABSTRACT FROM AUTHOR]

The number of quantitative systems pharmacology (QSP) submissions to the U.S. Food and Drug Administration has continued to increase over the past decade. This report summarizes the landscape of QSP submissions as of December 2023. QSP was used to inform drug development across various therapeutic areas and throughout the drug development process of small molecular drugs and biologics and has facilitated dose finding, dose ranging, and dose optimization studies. Though the majority of QSP submissions (>66%) focused on drug effectiveness, QSP was also utilized to simulate drug safety including liver toxicity, risk of cytokine release syndrome (CRS), bone density, and others. This report also includes individual contexts of use from a handful of new drug applications (NDAs) and biologics license applications where QSP modeling was used to demonstrate the utility of QSP modeling in regulatory drug development. According to the models submitted in QSP submissions, an anonymous case was utilized to illustrate how QSP informed development of a bispecific monoclonal antibody with respect to CRS risk. QSP submissions for informing pediatric drug development were summarized along with highlights of a case in inborn errors of metabolism. Furthermore, simulations of response variability with QSP were described. In summary, QSP continues to play a role in informing drug development. [ABSTRACT FROM AUTHOR]

Background: Depression affects approximately 280 million individuals globally and it is a leading cause of disability. Despite effective medication options, 50% of patients prematurely discontinue antidepressants within 6 months. We sought to understand patients' perspectives regarding their needs and expectations related to antidepressants. Objectives: To identify and describe enablers and barriers that influence adult patients' medication adherence in depression treatment and to explore patients' educational needs on initiating or continuing antidepressant therapy. Methods: Qualitative descriptive study was conducted using individual, semi-structured interviews of adult patients with depression who were prescribed an antidepressant within 3 months of study recruitment at an urban primary care clinic in Toronto, Canada. Thirteen participants were interviewed. Interviews were recorded and transcribed verbatim for inductive thematic analysis. Results: Six themes emerged: safety and effectiveness of antidepressant, understanding of depression and its management, medication administration, healthcare experiences in the treatment of depression, and social influences and relationships. Barriers to adherence included adverse effects of antidepressants, preference for non-pharmacological therapies, uncertainty about therapeutic effects, and social stigma. In contrast, enablers were positive responses from antidepressants, fear of relapse, reminder aids, established routine, and a trusting patient-provider relationship. Participants desired access to reliable, evidence-based, and personalized educational information delivered through verbal, written, and digital formats to support antidepressant adherence. Conclusion: To overcome the identified barriers, educational strategies should involve both patients and their prescribers to identify patient-specific needs and treatment goals, engage in shared decision-making, and maintain consistent follow-up to support antidepressant adherence. [ABSTRACT FROM AUTHOR]

Background: No clinical trials have evaluated the antimicrobial activity and substantivity of gel formulations containing chlorhexidine (CHX) and cymenol. Objective: To compare the in situ antimicrobial effect and substantivity of a new 0.20% CHX + cymenol gel (test) with the current 0.20% CHX gel formulation (control) on salivary flora and dental plaque biofilm up to seven hours after a single application. Methods: A randomised-crossover clinical trial was conducted with 29 orally healthy volunteers participating in the development of Experiments 1 (saliva) and 2 (dental plaque biofilm). All subjects participated in both experiments and were randomly assigned to receive either the test or control gels. Samples were collected at baseline and five minutes and one, three, five, and seven hours after a single application of the products. The specimens were processed using confocal laser scanning microscopy after staining with the LIVE/DEAD® BacLight™ solution. Bacterial viability (BV) was quantified in the saliva and biofilm samples. The BV was calculated using the DenTiUS Biofilm software. Results: In Experiment 1, the mean baseline BV was significantly reduced five minutes after application in the test group (87.00% vs. 26.50%; p < 0.01). This effect was maintained throughout all sampling times and continued up to seven hours (40.40%, p < 0.01). The CHX control followed the same pattern. In Experiment 2, the mean baseline BV was also significantly lower five minutes after applying the test gel for: (1) the total thickness of biofilm (91.00% vs. 5.80%; p < 0.01); (2) the upper layer (91.29% vs. 3.94%; p < 0.01); and (3) the lower layer (86.29% vs. 3.83%; p < 0.01). The reduction of BV from baseline was observed for the full-thickness and by layers at all sampling moments and continued seven hours after application (21.30%, 24.13%, and 22.06%, respectively; p < 0.01). Again, the control group showed similar results. No significant differences between test and control gels were observed in either saliva or dental plaque biofilm at any sampling time. Conclusions: A 0.20% CHX + cymenol gel application demonstrates potent and immediate antimicrobial activity on salivary flora and de novo biofilm. This effect is maintained seven hours after application. Similar effects are obtained with a 0.20% CHX-only gel. [ABSTRACT FROM AUTHOR]

Background: Solid tumors often develop hypoxic regions, leading to aggressive behavior and increased drug resistance. Methods: The chemical composition of Cymbopogon citratus essential oil (EO) was analyzed using GC-MS. Alginate nanoparticles containing the EO and its primary component, citral, were synthesized via the ionic gelation method. Encapsulation was confirmed using ATR-FTIR analysis. The anticancer efficacy of C. citratus EO, citral, and their respective alginate nanoparticles was evaluated under normoxic (21% oxygen) and hypoxic (1% oxygen) conditions on breast cancer (MDA-MB-231) and melanoma (A-375) cell lines. Additionally, qPCR and flow cytometry were used to assess apoptosis gene expression ratios (Bax/Bcl-2) and levels of apoptosis. Results: Citral (80.98%) was identified as the major component of the EO. Alginate nanoparticles containing C. citratus EO and citral (C. citratus-AlgNPs and citral-AlgNPs) were synthesized with particle sizes of 195 ± 4 nm and 222 ± 9 nm, and zeta potentials of -22 ± 3 mV and − 17 ± 1 mV, respectively. Both samples demonstrated significantly greater efficacy under hypoxic conditions. Citral and C. citratus-AlgNPs had IC50 values of 27 (19–39) µg/mL and 25 (4-147) µg/mL, respectively, against MDA-MB-231 and A-375 cells. Flow cytometry showed increased apoptosis under hypoxic conditions, with the highest rates observed for citral-AlgNPs and C. citratus-AlgNPs (84 ± 5 and 92 ± 5% in MDA-MB-231 and A-375 cells, respectively). Conclusion: This study demonstrates that alginate nanoparticles enhance the anticancer activity of C. citratus-AlgNPs and citral, particularly under hypoxic conditions, highlighting their potential for hypoxia-targeted cancer therapies. [ABSTRACT FROM AUTHOR]

Migraine is a chronic, recurrent neurovascular disorder characterized by episodes closely associated with neurovascular hypersensitivity. Oxidative stress can worsen the hypersensitive state of the central nervous system, which in turn can trigger pro-inflammatory factors that result in neurogenic inflammation. Topiramate is frequently used as a preventative measure for migraines, but there is currently little empirical data to support its efficacy through pathways related to neurogenic inflammation and oxidative stress. This review provides an overview of current knowledge regarding the etiology, inducements, pathophysiology, and available treatments for migraine, with a focus on the clinical and experimental evidence of neurogenic inflammation and oxidative stress in migraine. It also delves into the antioxidant and anti-inflammatory qualities of topiramate, clarifying the possible ways in which topiramate affects these pathways to lessen migraine symptoms. [ABSTRACT FROM AUTHOR]

The increasing threat of antibiotic resistance and shrinking treatment options for infections have pushed mankind into a difficult position. The looming threat of the return of the pre-antibiotic era has caused a sense of urgency to protect and conserve the potency of antibiotic therapy. One of the perverse effects of antibiotic resistance is the dissemination of its causative agents from non-clinically important strains to clinically important strains and vice versa. The popular saying "Prevention is better than cure" is appropriate for tackling antibiotic resistance. On the one hand, new and effective antibiotics are required; on the other hand, better measures for the use of antibiotics, along with increased awareness in the general public related to antibiotic use, are essential. Awareness, especially of appropriate antibiotic use, antibiotic resistance, its dissemination, and potential threats, can help greatly in controlling the use and abuse of antibiotics, and the containment of antibiotic resistance. Antibiotic drugs' effectiveness can be enhanced by producing novel antibiotic analogs or adding adjuvants to current antibiotics. Combinatorial therapy of antibiotics has proven successful in treating multidrug-resistant (MDR) bacterial infections. This review aims to highlight the current global situation of antibiotic resistance and discuss the methods used to monitor, prevent, inhibit, or reverse bacterial resistance mechanisms in the fight against antibiotic resistance. [ABSTRACT FROM AUTHOR]