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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]

In the conducted research study, solubility investigation was performed to elucidate the dissolution rate and behaviour of a drug incorporated within a solid dispersion matrix. The foremost objective was to appraise the impact of formulation parameters on the improvement of drug's solubility, the list of factors influencing the bioavailability. To this end, a systematic series of experiments were undertaken, wherein the drug was co-precipitated with a hydrophilic polymer carrier using various solvent systems and ratios. The resulting solid dispersions were meticulously characterized, employing state-ofthe-art analytical techniques. Subsequently, solubility profiles were generated through equilibrium solubility studies, encompassing a range of pH conditions and temperatures, to comprehensively evaluate the dissolution behaviour of the drug. Based on study, it was concluded that the solubility of Pazopanib Hydrochloride (Pazopanib base) is significantly increased from 0.001 mg/ml to ~8.000 mg/ml. the same was confirmed from the analytical tools. Analytical tools also confirm the conversion of crystalline form to amorphous form. The outcomes of these investigations provide essential insights into the potential utility of solid dispersion systems as a viable strategy for enhancing the solubility and, consequently, the therapeutic efficacy of the drug in question. [ABSTRACT FROM AUTHOR]

Targeted therapy has the potential to be used in the neoadjuvant setting for odontogenic tumors, reducing the morbidities associated with major surgery. In this regard, the aim of this study was to summarize the current evidence on the different forms of targeted therapy, effectiveness, and drawbacks of this course of treatment. Four databases were searched electronically without regard to publication date or language. Grey literature searches and manual searches were also undertaken. Publications with sufficient clinical data on targeted therapy for odontogenic tumors were required to meet the criteria for eligibility. The analysis of the data was descriptive. A total of 15 papers comprising 17 cases (15 ameloblastomas and 2 ameloblastic carcinomas) were included. Numerous mutations were found, with BRAF V600E being most common. Dabrafenib was the most utilized drug in targeted therapy. Except for one case, the treatment reduced the size of the lesion (16/17 cases), showing promise. Most of the adverse events recorded were mild, such as skin issues, voice changes, abnormal hair texture, dry eyes, and systemic symptoms (e.g., fatigue, joint pain, and nausea). It is possible to reach the conclusion that targeted therapy for ameloblastoma and ameloblastic carcinoma may be a useful treatment strategy, based on the findings of the included studies. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of newly introduced ozonated gels compared with conventional chlorhexidine gel in the home management of periodontal patients. Materials and Methods: 30 patients with bilateral periodontal disease (severity I, complexity II) were enrolled (split‐mouth study design). After nonsurgical mechanical periodontal debridement, the teeth were randomly divided into two groups: teeth in the Control group were treated with a chlorhexidine‐based gel to aid oral hygiene maneuvers for 2 weeks after the first visit, while teeth in the Test group were treated in the same way with ozone‐based gels. After the baseline assessment, the follow‐up included assessments at 1, 2, and 6 months. The variables evaluated were clinical attachment loss (CAL), probing pocket depth (PPD), bleeding on probing (BoP), plaque control record (PCR), recession (R), and tooth mobility (TM). Results: For CAL, PPD, BoP, and PCR, significant intragroup differences were found for both groups (p < 0.05), in contrast to intergroup differences (p > 0.05). No significant differences were found for R and TM. Conclusion: Nonsurgical mechanical periodontal debridement with adjunctive use of ozone and chlorhexidine was found to be effective in periodontal treatment. Ozone could be suggested as an alternative to chlorhexidine. [ABSTRACT FROM AUTHOR]

The article discusses a 2024 study on the attitudes of patients 65 years and older on the use of routine clinical data in making treatment decisions. Results show participants' interest in such data and in how drugs work for them, and their concerns on confounders like populations' similarity of conditions with them, and on common minor side effects. Also noted are participants' common view that their physicians determine the evidence's applicability to them, and recommend a medication.

The worldwide HIV cases were 39.0 million (33.1–45.7 million) in 2022. Due to genetic variations, HIV-1 is more easily transmitted than HIV-2 and favours CD4 + T cells and macrophages, producing AIDS. Conventional HIV drug therapy has many drawbacks, including adherence issues leading to resistance, side effects that lower life quality, drug interactions, high costs limiting global access, inability to eliminate viral reservoirs, chronicity requiring lifelong treatment, emerging toxicities, and a focus on managing infections. Conventional dosage forms have bioavailability issues due to intestinal P-glycoprotein (P-gp) efflux, which can reduce anti-retroviral drug efficacy and lead to resistance. Use of phyto-constituents with P-gp regulating actions has great benefits for semi-synthetic modification to create formulations with greater bioavailability and reduced toxicity, which improves drug effectiveness. Lipid-based nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, polymer-based nanocarriers, and inorganic nanoparticles may inhibit P-gp efflux. Employing potent P-gp inhibitors within nanocarriers as a Trojan horse approach can enhance the intracellular accumulation of anti-retroviral drugs (ARDs), which are substrates for efflux transporters. This technique increases oral bioavailability and offers lower-dose options, boosting HIV patient compliance and lowering costs. Molecular docking of the inhibitor with P-gp may anticipate optimum binding and function, allowing drug efflux to be minimised. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to quantitatively compare the efficacy and safety of CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors for ER+/HER2− metastatic breast cancer. Methods: A parametric survival function was used to analyze the time course of overall survival (OS) and progression-free survival (PFS). The objective response rate (ORR) and the incidence of any grade and grade 3–4 adverse events were summarized using the random-effects model of a single-arm meta-analysis. Results: This study included 44 arms from 48 publications, with a total sample size of 7881 patients. Our study revealed that CDK4/6 inhibitors had a median OS of 40.7 months, a median PFS of 14.8 months, and an ORR of 40%, whereas PI3K/AKT/mTOR inhibitors had a median OS of 29.8 months, a median PFS of 8.3 months, and an ORR of 20%. Additionally, this study also found that the proportion of patients with visceral metastases and specific endocrine therapy used in combination significantly impact OS and PFS. In terms of adverse events, CDK4/6 inhibitors exhibited a relatively high incidence of hematological adverse events. Conclusion: Our study provides solid quantitative evidence for the first-line recommendation of CDK4/6 inhibitors combined with endocrine therapy for ER+/HER2− metastatic breast cancer in clinical guidelines. [ABSTRACT FROM AUTHOR]

Purpose: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. Methods: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). Results: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. Conclusion: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG. Methods: This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17. Results: A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43–98%) for objective response rate, 26% (95% CI = 58–96%) for partial response, 21% (95% CI = 15–28%) for minor response, 14% (95% CI = 3–24%) for complete response, 48% (95% CI = 37–59%) for stable disease, and 8% (95% CI = 4–11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = −1 to 9%) for 6-month PFS, 41% (95% CI = 32–50%) for 2-year PFS, and 29% (95% CI = 22–35%) for 3-year PFS. Conclusion: According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib. Methods: The phase 2 trial (ClinicalTrials.gov identifier: NCT03881059) randomly assigned 203 patients with PsA 1:1:1 to placebo, deucravacitinib at 6 mg once daily (QD), or deucravacitinib at 12 mg QD. Serum biomarkers associated with the interleukin 23 (IL‐23) pathway (IL‐17A, β‐defensin [BD‐2], and IL‐19), type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in the Psoriasis Area and Severity Index [PASI75] and ≥20% improvement from baseline in American College of Rheumatology criteria [ACR20] responses) were measured at week 16. Hematologic variables were also assessed. Results: IL‐17A, BD‐2, and IL‐19 had a modest association with PASI scores (r = 0.4, r = 0.56, and r = 0.5, respectively) at baseline. In deucravacitinib groups, IL‐17A, BD‐2, IL‐19, C‐X‐C motif ligand 9 (CXCL9), CXCL10, C‐reactive protein, matrix metalloproteinase 3, and collagen type 4 degradation marker levels were significantly reduced at week 16 versus baseline (P < 0.01); higher levels of IL‐23 pathway–associated biomarkers predicted higher PASI75 and ACR20 response rates in deucravacitinib‐treated patients. Significantly higher PASI75 response rates were seen in patients with high baseline IL‐17A (odds ratio 15.76) and BD‐2 levels (odds ratio 15.41) versus low baseline IL‐17A and BD‐2 levels. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib. Conclusion: Deucravacitinib significantly impacted biomarkers associated with Tyk2 signaling pathways of key inflammatory cytokines, including IL‐23 and type I interferon, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the survival of different biologic or targeted-synthetic disease-modifying antirheumatic drugs (b/tsDMARD) administered after fulfilling difficult-to-treat rheumatoid arthritis (D2TRA) criteria, and to assess factors related to treatment discontinuation. Methods: Retrospective study including D2TRA patients. Drug retention of the b/tsDMARD administered after fulfilling D2TRA was assessed by Kaplan–Meier plots and the log-rank test. Cox hazard models were used to identify factors affecting treatment discontinuation. Results: Of the 122 patients included, 75 maintained active treatment (61.5%) with a subsequent line after D2T compared to 47 (38.5%) who discontinued and required more successive lines of b/tsDMARDs. The median survival of the treatments was 78.3(7.6) months and the treatment after D2T with the better rate of survival was rituximab, followed by JAKi and IL6Ri, while worse survival rates were associated with abatacept and TNFi. Significant differences were noted among b/tsDMARDs (log-rank p < 0.01) and to evaluate these differences, a Cox regression was performed, taking each b/tsDMARD as a reference and comparing it with the others. DAS28 values 6-months after initiation of treatment were higher in those patients who discontinued treatment [4.4(1.2) vs 3.5(1.3), p = 0.01]. The multivariate cox regression model revealed that treatment choice after D2T [HR = 1.26(95%CI 1.06–1.05)] and lower DAS28 values at 6 months [HR = 1.49(95%CI 1.16–1.52)] were independent risk factors associated with treatment discontinuation. Conclusions: Once patients met the D2TRA criteria, the subsequent line of b/tsDMARDs with the best survival rates were rituximab, JAKi and IL6Ri. Moreover, DAS28 at 6-months of treatment after D2T was an independent risk factor for drug discontinuation. Key Points • Rituximab, IL6Ri and JAKi have better retention rates in patients after fulfilling D2TRA criteria • Clinical disease activity in the first six months after fulfillment of D2TRA criteria is an independent risk factor of subsequent treatment survival [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics. [ABSTRACT FROM AUTHOR]

Objective: Following recent changes to the German Narcotics Act, this article examines prehospital analgesia by paramedics using piritramide vs. nalbuphine + paracetamol. Material and methods: Prehospital analgesia administered by paramedics from the Fulda (piritramide) and Gütersloh (nalbuphine + paracetamol) emergency services was compared regarding pain intensity at the beginning and end of the mission, measured using the numeric rating scale (NRS). Additionally, an analysis of the resulting complications was carried out. Results: In this study 2429 administrations of analgesia were evaluated (nalbuphine + paracetamol: 1635, 67.3%, initial NRS: 8.0 ± 1.4, end of NRS: 3.7 ± 2.0; piritramide: 794, 32.7%, initial NRS: 8.5 ± 1.1, end of NRS: 4.5 ± 1.6). Factors influencing NRS change were initial NRS (regression coefficient, RC: 0.7075, 95% confidence interval, CI: 0.6503–0.7647, p < 0.001), treatment with nalbuphine + paracetamol (RC: 0.6048, 95% CI: 0.4396–0.7700, p < 0.001). Treatment with nalbuphine + paracetamol (n = 796 (48.7%)) compared to piritramide (n = 190 (23.9%)) increased the odds of achieving NRS < 4 (odds ratio, OR: 2.712, 95% CI: 2.227–3.303, p < 0.001). Complications occurred in n = 44 (5.5%) with piritramide and in n = 35 (2.1%) with nalbuphine + paracetamol. Risk factors for complications were analgesia with piritramide (OR: 2.699, 95% CI: 1.693–4.301, p < 0.001), female sex (OR: 2.372, 95% CI: 1.396–4.029, p = 0.0014), and age (OR: 1.013, 95% CI: 1.002–1.025, p = 0.0232). Conclusion: Compared with piritramide, prehospital analgesia with nalbuphine + paracetamol has favorable effects in terms of analgesic efficacy and complication rates and should therefore be considered in future recommendations for paramedics. [ABSTRACT FROM AUTHOR]

Objective: To compare the color change, the risk and intensity of tooth sensitivity (TS), and gingival irritation (GI) of at‐home bleaching applied on the buccal surface only or the buccal and lingual surfaces. Materials and Methods: Sixty patients with canines A2 or darker were selected and their superior arches were randomized in two groups: at‐home bleaching on the buccal‐only or on the buccal and lingual surfaces, with 7.5% hydrogen peroxide, for 1 h daily/2 weeks. The color change was evaluated at baseline, 7, 14 days, and 1 month after bleaching using shade guides scales (ΔSGU) and a spectrophotometer (ΔEAB, ΔE00, and ΔWID). Risk and intensity of TS and GI were recorded daily using visual analogic scale (0–10). Patient satisfaction was evaluated with the orofacial esthetics. Paired t‐test, McNemar's, and Wilcoxon signed‐rank test were used for data analysis (α = 5%). Results: Neither the color change nor the risk/intensity of TS was statistically different between groups (p > 0.05). Patient satisfaction increased after bleaching for both groups (p < 0.05). Conclusion: The addition of one contact surface does not result in an increased whitening degree compared to bleaching applied solely on the buccal surface. Clinical Significance: Understanding the influence of surfaces interacting with the bleaching agent is crucial for comprehending the bleaching mechanism and avoiding unnecessary material expenses. Notably, employing the buccal‐only technique is sufficient to achieve the desired efficacy. [ABSTRACT FROM AUTHOR]

Treatment of ocular diseases presents unique challenges and opportunities for the clinician and for the clinical pharmacologist. Ophthalmic pharmaceuticals, typically given as liquids, require consideration of solubility, physiological pH, and osmolarity, as well as sterility and stability, which in turn requires optimal pharmaceutics. Ocular tissue levels are challenging to obtain in humans, and the clinical pharmacokinetics is typically blood levels, which are primarily related to safety, rather than efficacy. The eye is a closed compartment with multiple physiological barriers with esterases and transporters, but relatively little cytochrome oxidases. Delivery routes include topical, intravitreal, and systemic. Patient dosing involves not only adherence issues common to all chronic diseases, but also performance requirements on eye drop instillation. Therapeutically, ocular diseases and their pharmacological treatments include both those analogous to systemic diseases (e.g., inflammation, infection, and neuronal degeneration) and those unique to the eye (e.g., cataract and myopia). [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long‐term efficacy of these treatments. Our analysis aim was to develop a semi‐mechanistic longitudinal exposure‐tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model‐estimated on‐treatment tumor growth rate constant was 1.7‐fold higher for apitolisib compared to everolimus. Estimated half‐life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re‐growth for apitolisib patients likely due to the emergence of resistance. Goodness‐of‐fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size–time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model‐informed drug development for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Objectives: Effective posttonsillectomy analgesia is crucial for patient comfort and recovery. Fentanyl, notable for its potency, rapid action, and lipophilicity, has been successfully used in various procedures through multiple administration routes. However, the use of its nebulized form for posttonsillectomy pain has not been extensively explored. This study sought to compare the analgesic efficacy, onset time, and complications between nebulized and intravenous fentanyl in posttonsillectomy patients. Methods and Methods: In this randomized controlled trial, adult patients who underwent tonsillectomy were assigned to either an intravenous fentanyl group (1 mcg/kg) or a nebulized fentanyl group (4 mcg/kg). In both groups, fentanyl was administered when pain scores exceeded three. Pain levels were monitored every 5 minutes until they fell below four. The study also recorded the duration until the next analgesia request and noted complications (such as respiratory depression, bradycardia, chest tightness, drowsiness, nausea, pruritus, sweating, and flushing) within 24 hours. Patient exclusions were based on predetermined criteria. Results: From an initial cohort of 59 patients, 22 in the intravenous group and 27 in the nebulizer group were eligible for analysis after applying the exclusion criteria. The nebulizer group exhibited a significantly prolonged period before the next analgesia request, with a median of 683.5 minutes (interquartile range 260-1440), in contrast to the 326.7 minutes (145.0-504.7) observed in the intravenous group (P =.009). The time to achieve a pain score less than 4 and the incidence of side effects did not differ significantly between the groups. Conclusion: Nebulized fentanyl provided a longer duration of analgesia than intravenous fentanyl in posttonsillectomy pain management, with similar onset times and side effect profiles. These findings underscore the potential of nebulized fentanyl as an effective alternative for pain control in posttonsillectomy patients. [ABSTRACT FROM AUTHOR]

Background: Palmoplantar pustulosis (PPP), a refractory skin disease characterized by repeated eruptions of sterile pustules and vesicles on palms and/or soles, involves interleukin-17 pathway activation. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, is being investigated for use in PPP treatment. Objective: The aim was to assess the efficacy and safety of brodalumab in Japanese PPP patients with moderate or severe pustules/vesicles. Methods: A phase 3, randomized, double-blind, placebo-controlled trial was conducted between July 2019 and August 2022, at 41 centers in Japan. Patients aged 18–70 years with a diagnosis of PPP for ≥ 24 weeks, a PPP Area Severity Index (PPPASI) score of ≥ 12, a PPPASI subscore of pustules/vesicles of ≥ 2, and inadequate response to therapy were included. Participants were randomized 1:1 to receive brodalumab 210 mg or placebo, subcutaneously (SC) at baseline, weeks 1 and 2, and every 2 weeks (Q2W) thereafter until week 16. Changes from baseline to week 16 in the PPPASI total score (primary endpoint) and other secondary skin-related endpoints and safety endpoints were assessed. Results: Of the 126 randomized patients, 50 of 63 in the brodalumab group and 62 of 63 in the placebo group completed the 16-week period. Reasons for discontinuation were adverse event (n = 6), withdrawal by patient/parent/guardian (n = 3), progressive disease (n = 3), and lost to follow-up (n = 1) in the brodalumab group and Good Clinical Practice deviation (n = 1) in the placebo group. Change from baseline in the PPPASI total score at week 16 was significantly higher (p = 0.0049) with brodalumab (least-squares mean [95% confidence interval {CI}] 13.73 [10.91–16.56]) versus placebo (8.45 [5.76–11.13]; difference [95% CI] 5.29 [1.64–8.94]). At week 16, brodalumab showed a trend of rapid improvement versus placebo for PPPASI-50/75/90 response (≥ 50%/75%/90% improvement from baseline) and Physician's Global Assessment 0/1 score: 54% versus 24.2%, 36.0% versus 8.1%, 16.0% versus 0.0%, and 32.0% versus 9.7%, respectively. Infection was the dominant treatment-emergent adverse event (TEAE); the commonly reported TEAEs were otitis externa (25.4%/1.6%), folliculitis (15.9%/3.2%), nasopharyngitis (14.3%/4.8%), and eczema (14.3%/12.9%) in the brodalumab/placebo groups, respectively. The severity of most TEAEs reported was Grade 1 or 2 and less frequently Grade ≥ 3. Conclusions: Brodalumab SC 210 mg Q2W demonstrated efficacy in Japanese PPP patients. The most common TEAEs were mild infectious events. Trial Registration: NCT04061252 (Date of Trial Registration: August 19, 2019) [ABSTRACT FROM AUTHOR]

With the continued development of biologics for the treatment of psoriasis, some patients have achieved optimal control, but a recommended biologic sequence if a biologic fails to initially improve the skin, termed primary nonresponse, or loses efficacy after initial improvement, termed secondary nonresponse, is still lacking. Primary and secondary nonresponse can occur with any class of biologics, and the type of nonresponse can drive the choice of whether to switch within a biologic class or to a different biologic class. The choice of biologic can also be challenging when managing psoriasis and concomitant psoriatic arthritis, as treatment differs on the basis of the severity of both diseases and further classification of axial and peripheral joint involvement. When choosing a biologic, each patient's comorbidities and preferences are also taken into account to provide the optimal therapy. With this lack of an established biologic sequence after biologic failure, the objective of our review is to define a therapy sequence for the tumor necrosis factor (TNF), interleukin-17 (IL-17), and interleukin-23 (IL-23) inhibitor classes in the treatment of psoriasis and psoriatic arthritis. Our proposed biologic sequence was derived through an analysis of the efficacy of each biologic class, primary and secondary nonresponse rates from clinical trials, and clinical experience with expert opinion. [ABSTRACT FROM AUTHOR]

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response. [ABSTRACT FROM AUTHOR]

The article focuses on the efficacy of intravenous thrombolysis (IVT) with tenecteplase for large vessel occlusion strokes when administered beyond the standard 4.5-hour window and the comparison of tenecteplase to placebo in a Chinese cohort, its potential benefits over traditional treatments.

Purpose: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in managing cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) is evolving. This meta-analysis seeks to explore the influence of SGLT2i on the recurrence of atrial fibrillation (AF) following catheter ablation (CA) in individuals with T2DM qualitatively and quantitatively. Methods: A comprehensive literature search was conducted in electronic databases. Studies meeting predefined criteria were included. Individual patient data (IPD) were used from reconstructed time-to-event data to estimate hazard ratios (HRs) and 95% confidence intervals for AF recurrence. IPD meta-analysis was followed by a direct meta-analysis to assess the risk of AF recurrence. Results: A total of five studies [one randomized controlled trial (RCT) and four cohort studies] were included in this study, and five studies were included in the qualitative analysis, while four studies comprising 1043 patients with T2DM were included in the quantitative analysis. The pooled Kaplan–Meier curve based on reconstructed data showed a significantly lower risk of AF recurrence in the SGLT2i group compared with all antidiabetic drugs (log-rank P = 0.00011) and dipeptidyl-peptidase IV inhibitors (DPP4i) (log-rank P = 0.01). Cox regression analysis showed consistent results. Direct meta-analysis showed that SGLT2i, compared with all antidiabetic medications (HR 0.57, 95% CI [0.44, 0.73], I2) and DPP4i (HR 0.41, 95% CI [0.24, 0.70], I2), was associated with a lower risk of AF recurrence. Conclusions: SGLT2i are associated with a reduced risk of AF recurrence after CA in patients with T2DM. These results suggest that SGLT2i is promising in improving clinical outcomes for this population. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) remains a significant global health issue and is a leading cause of mortality worldwide. Patients with CKD have an increased risk of developing atrial fibrillation (AF) and venous thromboembolism (VTE). While direct oral anticoagulants (DOACs) have become a standard of care for anticoagulation (AC) in patients with AF and VTE, the appropriate use of these agents in comorbid kidney impairment warrants detailed discussion. This scientific narrative review summarizes the effectiveness and safety of apixaban use in patients with renal dysfunction by assessing the current published pharmacokinetic, interventional, observational, and guideline data. Apixaban is a highly selective, orally active, direct inhibitor of factor Xa, with well-established pharmacokinetics and consistent clinical outcomes across a broad range of patient populations, including those with kidney impairment. Overall, the scientific literature has shown that apixaban has a favorable clinical efficacy and safety profile compared with vitamin K antagonists for patients with AF or VTE and comorbid kidney impairment. These data support the approved label dosing strategy of apixaban in reducing the risk of stroke/systemic embolism in patients with nonvalvular AF and in treating VTE across all ranges of kidney function. Both clinician experience and knowledge of patient-specific factors may be required in the management of comorbid patients with advanced CKD or those requiring dialysis, as data on these patients are limited. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease was the leading cause of death worldwide in 2021, with atherosclerotic cardiovascular disease, encompassing hypercholesterolemia, being a major contributing factor. A range of lipid-lowering medications is used for the management of hyperlipidemia, but the use of statins is considered as standard therapy. Unfortunately, some patients do not respond to this therapy, necessitating novel therapeutic approaches. Tafolecimab is a novel proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody that inhibits the binding of PCSK9 with low-density lipoprotein receptors (LDLRs) and increases LDLR recycling, and thus it indirectly lowers circulating low-density lipoprotein cholesterol (LDL-C) levels by increasing LDL-C uptake. The primary objective of this study is to assess the efficacy of tafolecimab in reducing LDL-C levels. Methods: A thorough search was conducted on Medline (PubMed), Cochrane CENTRAL, Scopus, and Google Scholar from inception until December 2023. Review Manager was used for statistical analysis. The random effects model was used to calculate risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs). Heterogeneity was assessed using the Higgins I2 index. The risk of bias was assessed using Cochrane's RoB 2 tool. This review has been registered with PROSPERO (CRD42023471020). Results: A total of four Chinese studies matched the inclusion criteria and were included in this review. A total of 726 patients were included in this review, out of which 476 patients were males. Out of four, three studies that studied the efficacy of 450 mg tafolecimab every 4 weeks in patients (n = 462) as compared to placebo (n = 224) were included in the meta-analysis. According to the pooled results, tafolecimab caused a significant decrease in LDL-C levels from baseline to week 12 as compared to placebo (MD = − 63.78, 95% CI − 65.88 to − 61.68, p value < 0.00001, I2 = 97%). The pooled results showed that more patients achieved ≥ 50% reductions in LDL-C levels (RR = 52.33, 95% CI 18.51–147.95, p value < 0.00001, I2 = 0%) and LDL-C < 1.8 mmol/L (RR = 17.27, 95% CI 9.59–31.11, p value < 0.00001, I2 = 0%) at week 12 in the tafolecimab group than the placebo group. Additionally, tafolecimab also caused a robust decrease in non-HDL-C, apolipoprotein B, and lipoprotein(a) levels from baseline to week 12 compared to placebo. The overall risk of bias was low, as determined by the RoB 2 tool. Conclusions: Tafolecimab showed promising lipid-lowering efficacy and a well-tolerated safety profile. Our findings suggest its potential as an innovative therapeutic option for individuals with hypercholesterolemia; however, significant heterogeneity was observed in some results, making it difficult to come to a firm conclusion. Therefore, large-scale randomized trials are required to confirm our findings, particularly exploring the most effective dosage regimens across varied populations. Registration: PROSPERO identifier number CRD42023471020. [ABSTRACT FROM AUTHOR]

Objective: Metabolic syndrome (MetS) is characterized by the cluster of risk factors associated with diabetes and cardiovascular diseases. Given the influential role of oxidative stress (OxS) in the pathogenesis of MetS and the antioxidant properties of melatonin, our study aims to investigate the impact of melatonin supplementation on OxS biomarkers and serum endothelin-1 (ET-1) levels in patients diagnosed with MetS. Methods: This double-blind, placebo-controlled, randomized clinical trial involved male and female adult participants with MetS. Subjects in the melatonin and control groups were administered 6 mg/day of encapsulated powdered melatonin or placebo (wheat flour), respectively, over a 12-week period. We evaluated serum levels of malondialdehyde (MDA), superoxide dismutase (SOD) activity, and ET-1 in MetS patients, both pre- and post-intervention. Results: Melatonin supplementation significantly decreased serum ET-1 level (1.55 ± 0.24 pg/ml vs. 0.808 ± 0.18 pg/ml; p = 0.04) and MDA (1.326 ± 0.05 μM vs. 1.134 ± 0.05 μM; p = 0.021) in the melatonin group relative to baseline values. Additionally, SOD activity displayed a significant increase (23.64 ± 2.77 U/ml vs. 41.35 ± 1.22 U/ml; p = 0.0001) in the melatonin group when compared to baseline. Conclusion: Our research indicates that 12 weeks of melatonin supplementation in MetS patients leads to a significant reduction in serum ET-1 and MDA levels, alongside an increase in SOD activity levels relative to baseline. However, further comprehensive and well-structured randomized controlled trials are essential for establishing the effects of melatonin supplementation on OxS biomarkers in diverse age demographics. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the effects of sodium-glucose co-transporter inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and dipeptidyl peptidase-4 inhibitors (DPP4i) on individuals subjected to diabetes and COVID-19. Methods: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched to cover studies (except for case reports and review studies) published until August 30, 2022. The primary outcome was the mortality of people with diabetes and COVID-19. The secondary outcomes comprised the requiring intensive care unit (ICU) admission and mechanical ventilation. Two reviewers independently screened studies, abstracted data, and assessed risk-of-bias. Furthermore, the network meta-analyses (NMA) were conducted. Results: A total of 12 trials were involved in the analysis. The OR and 95% CI of mortality for SGLT2i compared with SGLT2i + GLP-1RA and DPP4i reached 0.41 (0.17,0.97) and 0.69 (0.49,0.98), respectively. The OR and 95% CI of requiring mechanical ventilation for SGLT2i compared with the DPP4i reached 0.85 (0.75,0.97). Conclusions: As revealed by the result of this study, SGLT2i is associated with the lower mortality rate in people with diabetes and COVID-19 among novel glucose-lowering drugs. And SGLT2i is linked to lower requiring mechanical ventilation. These findings can have a large impact on clinicians' decisions amid the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Background: The incidence of coagulation of continuous renal replacement therapy circuits remains high. To the best of our knowledge, no scholar has published a protocol to avoid management errors when different types of citrates coexist in the same Intensive Care Unit. Aim: To assess the safety and efficacy of the unification of two protocols with different concentrations of citrate solution. Study Desing: A prospective, quasi‐experimental study was carried out in the intensive care unit of a tertiary referral hospital (in Barcelona, Spain), over 3 years. Consecutive adult patients requiring continuous renal replacement therapy with citrate were included. The sample was divided into two groups, a control group (concentrated citrate) and an intervention group (diluted citrate). The decision to initiate anticoagulation with diluted (18 mmol/L) or concentrated (136 mmol/L) citrate was made based on the machine available and the decision of the doctor responsible for the patient. It was not possible to randomize the sample. Both protocols were matched with a starting citrate dose of 3.5 mmol/L, and a dialysis solution was used. Post‐filter replacement was not used, and the citrate solution was the only fluid administered pre‐filter. Results: The analysis included 59 circuits in the concentrated citrate group and 40 circuits in the diluted citrate group. An increased need for electrolyte replacement was observed in the diluted group (p <.001). The concentrated citrate group had a longer filter life (p <.05), and there was a slight trend toward alkalosis. Conclusion: The diluted citrate group had a higher incidence of electrolyte replacement. The concentrated citrate group had longer circuit lifespan and a trend toward metabolic alkalosis, although this was not statistically significant. If these conclusions are considered, the protocol can be unified. Relevance to Clinical Practice: The present work aims to provide information on the differences in the use of regional anticoagulation with diluted or concentrated citrate. The objective is to pay special attention to aspects that can lead to complications. The unified protocol proposed in this paper could be extrapolated to any machine on the market that uses either of these two types of citrate concentration. [ABSTRACT FROM AUTHOR]

Objective: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. Background: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug‐device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). Methods: The STOP 101 was a Phase 1 open‐label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open‐label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. Results: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9–15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4–17.1) at 5 min post‐dose, persisting up to 30 min post‐dose for systolic BP (6.3 mmHg; 95% CI 3.0–9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9–11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non‐serious, vascular treatment‐emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off‐protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. Conclusion: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV‐related contraindications. [ABSTRACT FROM AUTHOR]

Objective: Research regarding the therapeutic application of psychedelics and psychedelic‐assisted psychotherapy in the treatment of eating disorders (EDs) has begun to emerge. This systematic scoping review aimed to map and synthesise the existing evidence regarding the participant reported efficacy and perspectives concerning psychedelics in the treatment of EDs, and to identify significant research gaps. Method: A systematic search was undertaken across several databases in accordance with Preferred Reporting Items for Systematic reviews and Meta‐Analyses extension for Scoping Reviews guidelines. Results: 1290 publications were identified, 1135 after duplicates removed, with 17 meeting full‐eligibility criteria. Overall, findings suggested that most participants reported experiencing a meaningful reduction in their ED symptoms and having positive experiences or an openness to explore psychedelics as a treatment for ED symptoms, although some noted concerns of adverse effects and the importance of having psychological support to increase safety and efficacy. Conclusions: While preliminary research suggests psychedelics and psychedelic‐assisted psychotherapy may be a viable treatment option for ED symptoms, further research with more robust research designs is required to increase confidence in its efficacy, generalisability, and safety as a therapeutic medium. Highlights: While research regarding the efficacy of psychedelics in the treatment of eating disorders (EDs) is still in its infancy, preliminary findings have been promising.Participants across the included studies reported largely positive experiences and an openness to explore the use of psychedelics and psychedelic‐assisted psychotherapy as a treatment modality for EDs. However, some participants noted concerns about potential adverse effects (AEs) and the importance of ensuring psychological support was provided before, during, and/or after a psychedelic treatment experience.There is currently not enough evidence to determine which psychedelic substances are most efficacious for therapeutic intervention for EDs. Further research is therefore needed, with more robust research methodologies. [ABSTRACT FROM AUTHOR]

The article focuses on evaluating the effectiveness of four clinical drugs—nirmatrelvir (NTV), ensitrelvir (ETV), leritrelvir (LTV), and GC376—against the main protease (Mpro) of SARS-CoV-2 and other coronaviruses. Topics include the impact of mutations on drug resistance, the comparative efficacy of these inhibitors against resistant Mpro mutants, and the role of pharmacokinetics in drug effectiveness.

Objective: The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. Methods: Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose–response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). Results: Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2–3; S23) of ROP progression compared with its administration at earlier stages (stages 0–1; S01). OR values for oral propranolol 1.5 and 2 mg/kg/day given at S23 were 0.13 (95% CrI 0.04–0.37) and 0.16 (95% CrI 0.04–0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02–2.96) and 0.78 (95% CrI 0.14–4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09–1.00) versus an S01 OR of 0.64 (95% CrI 0.21–2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5–2 mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose–response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5 mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02–0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05–0.93) and laser (OR 0.16; 95% CrI 0.02–1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5–1.0 mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5 mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5 mg/kg/day and the highest risk difference for oral propranolol 2.0 mg/kg/day (0.06; 95% CI −0.01 to 0.13). Conclusion: A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies. [ABSTRACT FROM AUTHOR]

Background: Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large‐scale randomised trials have yet investigated this hypothesis. Methods: LENS is a streamlined randomised double‐masked placebo‐controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non‐referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants. Results: Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy. Conclusions: LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid‐2024. Trial Registrations: NCT03439345; ISRCTN15073006; EuDRACT 2016–002656‐24. [ABSTRACT FROM AUTHOR]

Background: As the elderly population continues to grow worldwide, it becomes crucial to explore safe and effective treatment options to manage venous thromboembolic disease in this vulnerable demographic group. Methods: We carried out a retrospective cohort study (January 2017–December 2021) to analyse the efficacy and safety of bemiparin as a treatment for venous thromboembolic disease in 223 patients. We compared patients aged ≥65 years (elderly; n = 153) with patients aged less than 65 years (adults; n = 70) for a combined end point of death, recurrent thromboembolism, and major bleeding at 30 days. Results: Elderly (mean age 79 ± 7.7 years) and adult patients (mean age 51.5 ± 11.6 years) received similar bemiparin doses 8470 ± 2362 International units (IU)/d versus 8754 ± 1593 IU/d, during a similar median [Interquartile range] period of 28 [9–118] versus 30 [10–90] days, respectively. At 30‐day follow up a total of 24 elderly patients (15.7%), reached at least one of the end points, as compared with six adult patients (8.6%) (absolute difference 7.1%; 95% confidence interval [95% CI], −1.6 to 15.8). Recurrence of venous thromboembolic disease occurred in five elderly patients (3.3%) and in five adult patients (7.1%) (absolute difference −3.9%; 95% CI, −10.5 to 2.8). There were two episodes of major bleeding each in elderly (1.3%) and adult (2.9%) patients (absolute difference −1.6%; 95% CI, −5.8 to 2.7). Conclusion: Bemiparin showed a similar efficacy and safety profile in the treatment of venous thromboembolic disease in elderly and adult patients. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Conventional injection technique with adrenaline during removal of impacted third molar of mandible had proportionally increased pain during administration with slow onset of action and shorter duration of anesthesia. Purpose: The purpose of this study was to compare the effective nature of 8.4% and 7.5% buffered lidocaine hydrochloride during surgical removal of mandibular impacted third molar. Materials and Method: This prospective crossover study included 50 patients requiring bilateral removal of impacted mandibular third molars. Group I included 50 impacted mandibular third molars that were administered with 8.4% buffered lidocaine hydrochloride and group II included 50 impacted mandibular third molars were administered with 7.5% buffered lidocaine hydrochloride. The outcome variables were pain on injection, time of onset of anesthesia, and duration of action of anesthesia. The above parameters were recorded by the investigator and statistically analyzed through Chi-square test using SPSS software. Results: Patients in group I had mild pain (1.02) and patients in group II (5.74) had moderate pain with a statistical significance of p< 0.05 for group I respectively. The mean onset of action of anesthesia in group I was 0.08 seconds and 0.59 seconds in group II (p< 0.05). The duration of anesthesia was 342.51 minutes from group I and 122.06 minutes in group II (p< 0.05) respectively. Conclusion: Lidocaine hydrochloride buffered with 8.4 % sodium bicarbonate was found to be more effective in reduction of pain during injection, also had a faster onset of action and longer duration of the action of anesthesia when compared to 7.5% buffered lidocaine hydrochloride. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Chemotherapy-induced mucositis is the most common complication during cancer treatment. This complication can lead to pain, increased risk of infection and malnutrition. Therefore, it is important to find a solution to reduce the severity and duration of side effects. Purpose: This study aimed to assess the efficacy of Mucosamin spray as an adjunct for prevention of oral mucositis in children under chemotherapy. Materials and Method: This parallel-design clinical trial evaluated 48 patients aged 5 to 15 years with leukemia and lymphoma presenting to the Hematology Department of Mofid and Mahak Hospitals. The patients were randomly divided into two groups (n=24). Before starting chemotherapy, all patients received oral hygiene instructions (toothbrushing without flossing). Patients in both groups were requested to use a mouthwash composed of nystatin, aluminum-magnesium hydroxide suspension (aluminum MgS), and diphenhydramine for 1 min every morning on a daily basis starting the day before treatment. Patients in the intervention group were also requested to spray their entire oral mucosa with Mucosamin spray 3 times a day in addition to using the mouthwash. Patients were requested to refrain from eating and drinking for 1h after spraying. The patients were clinically examined by a senior dental student once every other day for 20 days regarding the occurrence, severity, and duration of oral mucositis. Data were analyzed using the Chi-square and Mann-Whitney tests, Kaplan-Meier survival analysis, and log rank test. Results: No significant difference was noted between the two groups in the incidence, severity, or time of development of mucositis (p> 0.05). The 7-day non-recovery percentage was 72.7% (SE= 13.4) and 25.0% (SE= 15.3) in the control and test groups, respectively, indicating shorter duration (faster healing) of mucositis in the intervention group (p= 0.01). Conclusion: Within the limitations of this study, it seems that prophylactic application of Mucosamin spray can shorten the course of oral mucositis, in case of its occurrence. [ABSTRACT FROM AUTHOR]

Statement of the Problem: Dental caries and periodontal disease are the most common oral problems. Chemical antibacterial agents often have side effects; thus, researchers have long been in search for organic and herbal products to prevent dental caries and periodontal disease. Purpose: The present study has aimed to assess the effects of Dracocephalum moldavica essential oil on Streptococcus mutans, Streptococcus salivarius, Streptococcus sobrinus, and Lactobacillus acidophilus compared to Chlorhexidine (CHX). Materials and Method: In this in vitro study, the plants were collected from Zanjan Province, Iran. Analysis of the essential oil was carried out by gas chromatography/mass chromatography. Micro-broth dilution and disc diffusion methods were used for assessment of the antimicrobial activity, and minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were evaluated. Results: The mean diameter of the growth inhibition zones in the well plate method for Dracocephalum moldavica showed that it had greater antimicrobial activity against Lactobacillus acidophilus than others (p Value= 0.01). Furthermore, Dracocephalum moldavica had higher antimicrobial activity than CHX. The results of MIC and MBC showed that Dracocephalum moldavica had lower antibacterial activity than CHX. Conclusion: Dracocephalum moldavica essential oil demonstrated antibacterial properties against cariogenic bacteria. Given that other favorable properties of these essential oils are confirmed, they may be suitable for use as antibacterial agents in the formulation of oral healthcare products. [ABSTRACT FROM AUTHOR]

The purpose of this investigation is to compare Cutibacterium acnes diagnosis using culturing vs. genomic DNA sequencing (NextGen) at various timepoints and locations during primary total shoulder arthroplasty. Additionally, we intend to compare the effects of hydrogen peroxide on standard culture technique results with genomic DNA sequencing. A prospective diagnostic study of 40 patients undergoing primary total shoulder arthroplasty was performed. Intraoperatively, 4 tissue samples were collected per patient: subdermal skin edge following initial skin incision, subdermal skin edge following hydrogen peroxide soak for 5 minutes, glenohumeral joint capsule, and subdermal skin edge prior to wound closure. Each tissue specimen was collected twice (one for culture analysis and the other for genomic (NextGen) DNA sequencing analysis) for a total of 8 specimens per patient and 320 tissue specimens in total. All anaerobic cultures were held for 14 days. Each culture plate was divided into quadrants and the amount of growth was quantified. Tissue samples were collected for genomic sequencing DNA analysis. Genomic sequencing results provided relative percentage of bacteria for each specimen detected. There were 18/40 males (45%) and no postoperative complications. Average age was 72.2 ± 11.8. Overall, 18% (29/160) of standard anaerobic cultures were positive for C. Acnes and 26% (942/160) were positive with genomic (Nextgen) DNA sequencing. When comparing the NextGen results with anaerobic standard cultures, there was a calculated negative predictive value of 85.6% and positive predictive value of 28.6%. Sensitivity of the NextGen was 41.4% and specificity was 77.1%. Bacterial culture rates did not significantly change from the beginning to the end of surgery as demonstrated on standard culturing and the NextGen analysis (P >.05). After treatment with hydrogen peroxide, the standard culturing technique showed no significant difference between the samples; however, there was a significant increase in bacterial burden (12.4%) noted with NextGen analysis (P =.0147). NextGen culturing is a novel technique to help identify shoulder prosthetic joint infections. These results show that, NextGen is better at identifying the absence of infection, but has a high false positive rate indicative of its ability to identify contaminants as compared to standard anaerobic culturing methods. The increase in bacterial burden after peroxide treatment noted with NextGen could also be secondary to the test's increased ability to identify both living and dead bacterial pathogens. [ABSTRACT FROM AUTHOR]

The article examines the safety of using mineralocorticoid receptor antagonists (MRAs) in heart failure patients with renal dysfunction, based on a post hoc analysis of the RALES and EMPHASIS HF trials. Topics discussed include the potential for MRAs to worsen renal function, the overall benefits of continuing MRA therapy despite renal impairment, and the increased risk of hyperkalemia associated with MRAs in patients with reduced glomerular filtration rate (GFR).

Background: Today, there are many treatment options available for the management of ulcerative colitis, creating challenges in selecting the most efficacious and cost-effective treatment sequences. Treatments in the anti-tumor necrosis factor alpha (TNFα) therapeutic class, as well as vedolizumab, are widely used and endorsed as first-line options according to treatment guidelines. The aim of this study was to compare treatment sequences involving vedolizumab and the anti-TNFα treatment adalimumab in terms of cost-effectiveness in the treatment of moderately to severely active ulcerative colitis in Italy. Methods: A cost-effectiveness model comparing treatment sequences within the Italian National Health Service in terms of costs and quality-adjusted life years (QALYs) with a lifetime horizon was developed. The analysis focused on the relative positioning of vedolizumab and adalimumab, leveraging the results of the landmark head-to-head VARSITY clinical trial as key inputs. The robustness of the results was investigated through a range of sensitivity and scenario analyses. Results: The strategy of vedolizumab as a first-line advanced therapy followed by adalimumab was associated with higher costs and health benefits compared with first-line adalimumab followed by vedolizumab. The incremental cost-effectiveness ratio was €16,146/QALY, which was found to be robust to changes to inputs associated with areas of high uncertainty. Conclusion: This economic evaluation estimated a 94% probability that vedolizumab as a first-line advanced therapy is cost-effective at a threshold of €33,004/QALY when compared with first-line adalimumab sequences. Using clinical trial evidence to inform the efficacy of second-line treatments estimated that the effectiveness of anti-TNFα treatments is not substantially reduced by vedolizumab exposure. [ABSTRACT FROM AUTHOR]

Background: Obsessive-compulsive disorder (OCD) is a prevalent and burdensome mental health condition, often resistant to conventional treatments. Agomelatine (Valdoxan), a compound acting on serotonin and melatonin systems, has shown promise in treating those with treatment-resistant OCD based on anecdotal reports and case studies. Methods: A randomized, double-blind controlled trial was conducted with 60 patients diagnosed with treatment-resistant OCD. Participants were randomized into an intervention group (receiving agomelatine 50 mg/day) and a control group (receiving placebo). OCD symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) over a 12-week period. Results: There were no significant differences in age, gender, or baseline Y-BOCS scores between intervention and control groups. Agomelatine did not demonstrate a significant improvement in OCD symptoms compared to placebo. Adverse events were comparable between groups, and liver enzyme levels remained within the normal range. Conclusion: This study, while not confirming superior efficacy compared to placebo, underscores the need for continued investigation into agomelatine's potential for treating specific subgroups of OCD patients, underscoring the need for more comprehensive and well-controlled trials in the future. [ABSTRACT FROM AUTHOR]

Background: Comorbid major depressive disorder (MDD) and opium use disorder (OUD) are known to increase the risk of suicide. The purpose of this study was to compare the efficacy and safety of adjunctive therapy with either ketamine or buprenorphine in patients with comorbid MDD and OUD. Methods: This was a randomized double-blind controlled trial in adults admitted to a hospital in Iran. Sixty-six participants were enrolled and received either ketamine or buprenorphine, along with current antidepressant therapy. The primary outcome was change in depressive symptoms assessed using the Beck Depression Inventory (BDI) after 2 hours, 24 hours, and 7 days following initiation of treatment. Secondary outcomes included changes in suicidal ideation, evaluated by the Beck Scale for Suicidal Ideation (BSSI). Results: Both groups experienced a significant decrease in the severity of depression following the interventions (p <.05). However, there was no significant difference in the between-group comparison (p >.05). Both groups also exhibited a significant reduction in suicidal ideation compared to before the study, with the decrease in severity being over 85% in both groups (p <.05). Conclusion: Both ketamine and buprenorphine appear to be equally effective in reducing symptoms of depression and suicidal ideation among individuals with MDD and OUD. [ABSTRACT FROM AUTHOR]

Objective: There is growing evidence that adding non-steroidal anti-inflammatory drugs to some psychopharmacological treatments may help to improve symptoms in patients suffering from major depressive disorder. The present study examined the therapeutic efficacy of adding celecoxib to escitalopram and the safety of doing so. Method: In this double-blind randomized controlled trial, 60 patients with major depressive disorder were randomly assigned to either treatment with escitalopram plus celecoxib (intervention group) or escitalopram and placebo. All patients were evaluated blind to treatment group with the Hamilton Depression Rating Scale (HDRS) before the intervention as well at 4 and 8 weeks after initiating treatment. Chi-square and paired t-test were used to examine between-group differences at those assessment times. Results: There was no significant difference in depressive symptoms between intervention and placebo groups at baseline. However, at 4 and 8 weeks after the beginning of treatment, there were significant between-group differences in HDRS scores, favoring the intervention group. No between-group differences were found in treatment-related side effects. Conclusions: Adding celecoxib to escitalopram may improve symptoms of depression in patients with major depressive disorder without increasing the risk of drug-related side effects. [ABSTRACT FROM AUTHOR]

Objective: We aim to compare drug effectiveness and persistence between the reference etanercept (ETN) and ETN biosimilar SB4 in patients with psoriatic arthritis (PsA) naive to ETN and to investigate drug effectiveness and persistence in those undergoing a mandatory nonmedical switch from ETN to SB4. Methods: We used a retrospective comparative database study including 1,138 patients with PsA treated with ETN or SB4 (years 1999–2021) in Norway. Disease activity score in 28 joints (DAS28) and drug persistence were compared between unmatched ETN (n = 644) and SB4 (n = 252) cohorts and in matched analyses (n = 144, both cohorts) at baseline using a propensity score (PS) to adjust for confounders. Drug persistence was analyzed with the Kaplan‐Meier method. Results: In unmatched analyses, difference in change from baseline between ETN (n = 140) and SB4 (n = 132) for DAS28 at one year was mean 0.67 (95% confidence interval [CI] 0.38–0.96) in favor of ETN. In PS‐matched analyses, the difference in change from baseline between ETN (n = 54) and SB4 (n = 54) was mean 0.09 (95% CI −0.33 to 0.50), and the mean difference assessed with an analysis of covariance model was 0.01 (95% CI −0.38 to 0.40), both within predefined equivalence margin (±0.6). Drug persistence at one year was mean 0.75 (95% CI 0.71–0.78) for ETN, mean 0.58 (95% CI 0.51–0.63) for SB4, hazard ratio (HR) 2.45 (95% CI 2.02–2.97) in unmatched analysis, and mean 0.55 (95% CI 0.46–0.63) for ETN, mean 0.60 (95% CI 0.51–0.67) for SB4, HR 1.29 (95%CI 0.94–1.76) in PS‐matched cohorts. Conclusion: At one year, outcomes for PsA disease activity and drug persistence were comparable for patients treated with either ETN or SB4. In patients undergoing a mandatory nonmedical switch from ETN to SB4, drug effectiveness was maintained during a two‐year period. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and safety of Sanjie Analgesic Capsule (SAC) in Chinese patients with endometriosis-associated pain. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 15 centers between November 2013 and July 2017 in China. Eligible 323 patients with endometriosis were randomized at a 3:1 ratio to the SAC group (241 cases) and placebo group (82 cases) by stratified block randomization. Patients in the SAC or placebo groups were given SAC or placebo 1.6 g 3 times per day, orally, respectively since the first day of menstruation for 3 consecutive menstrual cycles. The primary endpoint was clinical response to dysmenorrhea evaluated using a 10-point Visual Analogue Scale at 3 and 6 months. The secondary endpoint was the pain score evaluated by VAS (chronic pelvic pain, defecation pain, and dyspareunia) at 3 and 6 months, and the pain recurrence rate at 6 months. Adverse events (AEs) were recorded during the study. Results: A total of 241 women were included in the SAC group, and 82 were in the placebo group. Among these women, 217 (90.0%) and 71 (86.6%) completed the intervention, respectively. At 3 months, overall response rate (ORR) was significantly higher in women administered SAC (80.1%) compared with those who received a placebo (30.5%, P<0.01). Six months after treatment, the ORR for dysmenorrhea was 62.7% in the SAC group and 31.7% in the placebo group (P<0.01). Chronic pelvic pain and defecation pain were significantly improved by SAC compared with placebo (both P<0.05). The incidence rates of total AEs events in the SAC and placebo groups were 6.6% and 9.8%, respectively, and no significant difference was shown between the two groups (P=0.339). Conclusion: SAC is well-tolerated and may improve dysmenorrhea in women with endometriosis-associated pain. (Trial registration: ClinicalTrials.gov, No. NCT02031523) [ABSTRACT FROM AUTHOR]

Objective: To confirm the efficacy and safety of Ganyushu Granule (GYSG) in treating premenstrual syndrome (PMS) in patients with Gan (Liver) depression and qi stagnation syndrome (GDQSS) and determine its effective dosage. Methods: From June 2018 to March 2021, a total of 240 PMS women with GDQSS were included and randomly divided into 3 groups in a 1:1:1 ratio using central block randomization: high-dose GYSG group (n=78, GYSG 2 packs/time), low-dose GYSG group (n=82, GYSG and its simulant 1 pack/time), and placebo group (n=80, GYSG simulant 2 packs/time). Treatment with GYSG or placebo was given thrice daily and for up to 3 menstrual cycles. Primary outcomes were PMS diary (PMSD) score and premenstrual tension syndrome self-rating scale (PMTS). Secondary outcomes were Chinese medicine (CM) syndrome efficacy. PMSD, PMTS, and efficacy of CM were evaluated with menstrual cycles during the treatment period. Outcome indicators were analyzed after each menstrual cycle. All analyses were performed using an intention-to-treat method, and clinical safety was assessed. Results: Of the 216 patients included in the effectiveness analysis, 70, 75, and 71 patients were in the high-, low-dose GYSG, and placebo groups, respectively. From the 2nd treatment cycle, the change in PMSD scores in the high- and low-dose groups was lower than that in the placebo group (P<0.05). PMTS scores in the high-dose GYSG group after the 1st treatment cycle was lower than that in the placebo group (P<0.05), while after the 3rd treatment cycle, that in the low-dose group was lower than that in the placebo group (P<0.05). After the 2nd treatment cycle, the high-dose GYSG group had the best CM syndrome efficacy (P<0.05). No serious adverse reactions were reported. Conclusions: GYSG was safe and well-tolerated at both doses for treating PMS patients with GDQSS. High-dose GYSG might be the optimal dose for a phase III trial. (Registration No. ChiCTR1800016595) [ABSTRACT FROM AUTHOR]

The electrospun nanofiber system is correlated with high efficacy of drug delivery. This study aims to investigate the effect of nanofiber-based delivery of evodiamine, an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth, on intrahepatic cholangiocarcinoma (ICC), as well as to explore the molecular mechanisms. An electrospun nanofiber system carrying evodiamine was generated. Compared to evodiamine treatment alone, the nano-evodiamine exhibited more pronounced effects on suppressing proliferation, colony formation, invasiveness, migration, apoptosis resistance, cell cycle progression, and in vivo tumorigenesis of two ICC cell lines (HUCC-T1 and RBE). ICC cells exhibited increased expression of histone deacetylase 4 (HDAC4) while decreased tropomyosin 1 (TPM1). HDAC4 suppressed TPM1 expression by removing H3K9ac modifications from its promoter. Nano-evodiamine reduced HDAC4 protein levels in ICC cells, thus promoting transcription and expression of TPM1. Either overexpression of HDAC4 or downregulation of TPM1 negated the tumor-suppressive effects of nano-evodiamine. Collectively, this study demonstrates that the electrospun nanofiber system enhances the efficiency of evodiamine. Additionally, evodiamine suppresses the malignant properties of ICC cells. The findings may provide fresh insights into the application of electrospun nanofiber system for drug delivery and the effects of evodiamine on tumor suppression. [ABSTRACT FROM AUTHOR]

Introduction: Limited awareness exists regarding real-world data (RWD) for palbociclib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced/metastatic breast cancer in populations from certain countries outside of Western regions. Methods: A systematic scoping review was conducted using PubMed and Embase to evaluate RWD for palbociclib from countries outside of Western regions that are underrepresented in clinical trials. Search criteria were aligned with our research question for relevant English-language publications, without restrictions on publication date, followed by Phase 1 (title and abstract) and Phase 2 (full-text) screening of retrieved citations as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analyses of eligible studies were done separately for abstracts and full-text publications to enhance the precision and reliability of the results. Results: Database search yielded 1485 non-duplicate records, 46 qualified for inclusion, of which 47.8% were published as full text. The analysis of outcomes, based exclusively on full-text publications that collectively included 2048 patients treated with palbociclib, revealed the median progression-free survival (PFS) of 20.2–36.7 months, overall survival (OS) of 39.9 months (reported in one publication) and objective response rate (ORR) of 45.3–80.0% with first-line treatment. In ≥ second line, the median PFS, OS and ORR ranged from 7.0 to 24.2 months, 11 to 19.6 months, and 13.9% to 47.9%, respectively. The safety profile of palbociclib was similar to that reported in pivotal clinical studies, and no new safety concerns were identified. Conclusions: A comprehensive volume of evidence demonstrates that palbociclib's effectiveness and safety profile in real-world settings align with those observed in clinical trials, offering valuable insights for clinical decision-making in countries outside of Western regions underrepresented in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. Methods: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15–180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. Results: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). Conclusions: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy. [ABSTRACT FROM AUTHOR]

Background: Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer poses a challenge due to limited targeted therapies. Current neoadjuvant treatment primarily utilizes chemotherapy, with conflicting results regarding efficacy in patients with HER2-low breast cancer. Trastuzumab deruxtecan (T-DXd) shows promise in HER2-low metastatic disease, and preliminary evidence suggests synergy with endocrine therapy. Objective: This editorial explores the hypothesis that neoadjuvant T-DXd with or without endocrine therapy offers efficacy in the clinical management of HR+/HER2-low breast cancer. Methods: We propose a phase II study with two treatment arms: T-DXd + letrozole and T-DXd alone. The primary endpoint is the radiological complete response rate. Secondary endpoints include pathological complete response rate, safety, event-free survival, and overall survival. Exploratory analyses will compare the arms to identify potential for optimizing treatment efficacy and minimizing side effects. Conclusions: This study design allows for initial assessment of T-DXd with or without endocrine therapy in the treatment of HER2-low breast cancer. The findings may pave the way for personalized treatment strategies and inform future research, potentially leading to a chemotherapy-sparing approach. [ABSTRACT FROM AUTHOR]