Incidence Of Adverse Events Research Articles

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Staged Bilateral MRI-Guided Focused Ultrasound Subthalamotomy for Parkinson Disease.

Unilateral magnetic resonance imaging (MRI)-guided focused ultrasound subthalamotomy (FUS-STN) improves cardinal motor features among patients with asymmetrical Parkinson disease (PD). The feasibility of bilateral FUS-STN is as yet unexplored. To assess the safety and effectiveness of staged bilateral FUS-STN to treat PD. This prospective, open-label, case series study was conducted between June 18, 2019, and November 7, 2023, at HM-CINAC, Puerta del Sur University Hospital, Madrid, Spain, and included 6 patients with PD who had been treated with unilateral FUS-STN contralateral to their most affected body side and whose parkinsonism on the untreated side had progressed and was not optimally controlled with medication. Staged bilateral FUS-STN. Primary outcomes were assessed 6 months after the second treatment and included safety (incidence and severity of adverse events after second treatment) and effectiveness in terms of motor change (measured with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III [MDS-UPDRS III]) in the off-medication state (ie, after at least 12 hours of antiparkinsonian drug withdrawal) compared with baseline (ie, prior to the first side ablation). Secondary outcomes included motor change in patients in the on-medication state (ie, after usual antiparkinsonian medication intake), motor complications (measured with the MDS-UPDRS IV), daily living activities (measured with the MDS-UPDRS I-II), quality of life (measured with the 39-item Parkinson's Disease Questionnaire), change in dopaminergic treatment, patient's global impression of change (measured with the Global Impression of Change [PGI-C] scale), and long-term (24-month) follow-up. Of 45 patients previously treated with unilateral FUS-STN, 7 were lost to follow-up, and 4 were excluded due to adverse events. Of the remaining 34 patients, 6 (median age at first FUS-STN, 52.6 years [IQR, 49.0-57.3 years]; 3 women [50%]) experienced progression of parkinsonism on the untreated body side and were included. At the time of the first FUS-STN, patients' median duration of disease was 5.7 years (IQR, 4.7-7.3 years). The median time between procedures was 3.2 years (IQR, 1.9-3.5 years). After the second FUS-STN, 4 patients presented with contralateral choreic dyskinesia, which resolved by 3 months. Four patients developed speech disturbances, which gradually improved but remained in a mild form for 2 patients at 6 months; 1 patient experienced mild imbalance and dysphagia during the first week after treatment, which subsided by 3 months. No behavioral or cognitive disturbances were found on neuropsychological testing. For patients in the off-medication state, MDS-UPDRS III scores improved by 52.6% between baseline and 6 months after the second FUS-STN (from 37.5 [IQR, 34.2-40.0] to 20.5 [IQR, 8.7-24.0]; median difference, 23.0 [95% CI, 7.0-33.7]; P = .03). The second treated side improved by 64.3% (MDS-UPDRS III score, 17.0 [IQR, 16.0-19.5] prior to the second treatment vs 5.5 [IQR, 3.0-10.2]; median difference, 9.5 [95% CI, 3.2-17.7]; P = .02). After the second procedure, all self-reported PGI-C scores were positive. Findings of this pilot study suggest that staged bilateral FUS-STN was safe and effective for the treatment of PD, although mild but persistent speech-related adverse events were observed among a small number of patients.

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm phase I trial.

This study compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. Healthy volunteers (N = 200) aged 18-55 years and with body mass index of 18.5-29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0-1344, AUC0-∞, and Cmax for both groups were entirely within the standard 80-125% bioequivalence acceptance range at 101.88% (93.31-111.23%), 105.38% (95.06-116.81%), and 91.29% (84.38-98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. NCT05203289.

Adverse events in endoscopic ultrasound-guided choledochoduodenostomy with lumen-apposing metal stents: A systematic review and meta-analysis.

Several meta-analyses have analyzed the technical and clinical success of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) by using lumen-apposing metal stents (LAMS) in malignant biliary obstruction, but those concerning adverse events (AEs) are scarce. The current systematic review and meta-analysis was conducted to evaluate the AEs after EUS-CDS with LAMS. A comprehensive literature search of PubMed, Embase, Scopus, Web of Science, and the Cochrane Library was conducted for studies reporting the outcomes of EUS-CDS with LAMS. The main endpoints were the incidence of overall and specific AEs. Moreover, the stent dysfunction, and reintervention rates were evaluated independently. A total of 21 studies (n=1438) were included in the final meta-analysis. The pooled rate of technical and clinical success was 93.5% (95% confidence interval [CI]: 91.3-95.1) and 88.0% (95% CI: 83.9-91.1), respectively. After EUS-CDS with LAMS, the pooled incidence of overall AEs was 20.1% (95% CI: 16.0-24.9). The estimated rate of early AEs was 10.6% (95% CI: 7.9-14.2), and late AEs was 11.2% (95% CI: 8.2-15.2). Infection/cholangitis was the commonest AE, with a pooled incidence of 6.1% (95% CI: 3.7-10.1). The estimated incidence of stent dysfunction and reintervention was 10.5% (95% CI: 7.5-14.4), and 12.1% (95% CI: 9.3-15.7), respectively. Despite with a high technical and clinical success rate, EUS-CDS with LAMS may be associated with overall AEs and stent dysfunction in one-fifth and one-tenth of cases, respectively. Further efforts are required to optimize its safety and long-term stent patency.

Safety of immune checkpoint inhibitors in patients aged over 80 years: a retrospective cohort study

BackgroundImmuno-oncology (IO) drugs are essential for treating various cancer types; however, safety concerns persist in older patients. Although the incidence of immune-related adverse events (irAEs) is similar among age groups, higher rates of hospitalization or discontinuation of IO therapy have been reported in older patients. Limited research exists on IO drug safety and risk factors in older adults. Our investigation aimed to assess the incidence of irAEs and identify the potential risk factors associated with their development.MethodsThis retrospective analysis reviewed the clinical data extracted from the medical records of patients aged > 80 years who underwent IO treatment at our institution. Univariate and multivariate analyses were performed to assess the incidence of irAEs.ResultsOur study included 181 patients (median age: 82 years, range: 80–94), mostly men (73%), with a performance status of 0–1 in 87% of the cases; 64% received IO monotherapy. irAEs occurred in 35% of patients, contributing to IO therapy discontinuation in 19%. Our analysis highlighted increased body mass index, eosinophil counts, and albumin levels in patients with irAEs. Eosinophil count emerged as a significant risk factor for any grade irAEs, particularly Grade 3 or higher, with a cutoff of 118 (/μL). The group with eosinophil counts > 118 had a higher frequency of irAEs, and Grade 3 or higher events than the group with counts ≤ 118.ConclusionIO therapy is a safe treatment option for patients > 80 years old. Furthermore, patients with elevated eosinophil counts at treatment initiation should be cautiously managed.

Safety and efficacy of neoadjuvant chemotherapy with paclitaxel, carboplatin, and cetuximab for locally advanced head and neck squamous cell carcinoma.

As a substantial waiting time is usually required for radical surgery, safe and effective preoperative neoadjuvant chemotherapy (NAC) is desired for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC). However, the significance of NAC in advanced HNSCC is still unclear. This study aimed to assess the safety and efficacy of NAC using the paclitaxel, carboplatin, and cetuximab (PCE) regimen. We retrospectively evaluated the background characteristics, incidence of adverse events, overall response rate (ORR), pathological response, recurrence-free survival (RFS), and overall survival (OS) in 26 patients. Patients receiving the PCE regimen were further divided into two groups based on the number of chemotherapy cycles (one cycle or more) and eligibility for cisplatin. Patients aged ≥ 75years and those with an estimated glomerular filtration rate (eGFR) < 60mL/min were classified as ineligible for cisplatin. The median age was 70 (27-81) years. The median eGFR at treatment initiation was 63.2 (41.1-89.7)mL/min. Fourteen (53.8%) patients were ineligible for cisplatin. Grade 3 or higher neutropenia was observed in 11 of 25 (42.3%) patients. No delay in or withdrawal from surgery was observed. The ORR was 65.4%. The 2-year RFS and OS were 61.5% and 76.7%, respectively. No significant differences in safety and efficacy between the number of chemotherapy cycles and cisplatin eligibility were observed. NAC using the PCE regimen for patients with locally advanced HNSCC, including cisplatin-ineligible patients, has acceptable toxicity and favorable efficacy.

Perampanel as monotherapy or first adjunctive therapy in pediatric and adult patients with epilepsy: the first United States-based phase IV open-label ELEVATE study.

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4years with focal-onset seizures or generalized tonic-clonic seizures in the United States. The study included Screening, Titration (≤ 13weeks), Maintenance (39weeks), and Follow-up (4weeks) Periods. During Titration, perampanel was initiated at 2mg/day and up-titrated to 4mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8weeks and 32 (59.3%) patients completed the study. Retention rate at 12months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy.

The Efficacy and Safety of Hyperthermic Intravesical Chemotherapy Compared with Other Instillation Methods in Treating Intermediate- and High-Risk Non-Muscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Background. In order to prevent the recurrence and progression of intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), various bladder instillation therapies have been developed in recent years. Among these, device-assisted Hyperthermic Intravesical Chemotherapy (HIVEC) has received a great deal of attention. Objective. To identify the efficacy and safety of HIVEC, we conducted this meta-analysis. Methods. We identified relevant articles from PubMed, Embase, and Cochrane Library databases. All published randomized controlled trials (RCTs) describing the role of bladder instillation for the treatment of intermediate- and high-risk NMIBC were involved. Outcomes included 1–3 years Recurrence-Free Survival (RFS), 1–3 years Progression-Free Survival (PFS), 5 years Overall Survival (OS), Adverse Events (AEs), and relevant subgroup analyses. Result. Our study involved a total of 10 RCTs and 1360 patients. In subgroup analysis, we found that compared to MMC instillation, HIVEC decreased the 1–3 years RFS (OR = 0.51; p=0.009) while not increasing the incidence of AEs (OR = 0.86; p=0.30). Compared with BCG instillation, HIVEC reduced the incidence of serious AEs (OR = 0.21; p=0.04) while bringing the same efficacy (OR = 0.78; p=0.63). Conclusion. HIVEC combined the advantages of efficacy and safety compared with the two recommended instillation modalities. As a potential alternative therapy, its widespread clinical effect remains to be further evaluated.

Risk of adverse events in patients with bullous pemphigoid treated with oral corticosteroids in the United States

AbstractBackgroundThe potential association of long‐term oral corticosteroid (OCS) use with adverse events (AEs) in patients with bullous pemphigoid (BP) is not well characterized in a real‐world setting.ObjectiveTo evaluate the effect of OCS use and treatment duration on the incident AEs in patients with BP.MethodsThis retrospective cohort study used medical and pharmacy claims and patient enrollment data from IQVIA PharMetrics® Plus from 2006−2021. Eligible patients had a diagnosis of BP between 1 January 2006 and 30 June 2020 (≥2 claims for BP ≥ 30 days apart). Patients in the OCS cohort also had a claim for OCS use, ≥7.5 mg daily dose of prednisone or equivalent, and no claims for a nonoral systemic corticosteroid (CS) at any time during the study period. A control cohort of patients with BP not using OCS was also selected. Relative risk ratios were estimated between the incidence of AEs in OCS users with different exposure durations (short‐term, &lt;30 days; medium‐term, 30−90 days; long‐term, &gt;90 days) and nonusers by Poisson regression, after adjusting for age, sex, prior drug use, and baseline Charlson Comorbidity Index score within the follow‐up period.ResultsAt the 1‐year follow‐up, long‐term OCS users had a higher incidence of infections, cataract, osteoporosis, heart failure, depression or anxiety, and diabetes compared with OCS nonusers (p &lt; 0.05). Furthermore, compared with nonusers, long‐term users had increased 1‐year risks (risk ratio; 95% confidence interval) for heart failure (2.27; 1.50−3.44), diabetes (2.05; 1.30−3.24), osteoporosis (1.72; 1.23−2.41), and infection (1.50; 1.13−1.99). Long‐term OCS users also had increased 1‐year risks for heart failure (2.00; 1.21−3.28) and osteoporosis (1.70; 1.16−2.50) compared with short‐term OCS users.ConclusionLong‐term OCS use (≥7.5 mg) in patients with BP was associated with an increased risk of AEs. Study findings demonstrate a need for steroid‐sparing options with an improved safety profile.

Intra-articular dexmedetomidine improves outcomes of postoperative analgesia after arthroscopic meniscus surgery

ABSTRACT Objectives The evaluation of the outcomes of patients undergoing arthroscopic unilateral meniscus repair on receiving intra-articular injection (IAI) of dexmedetomidine (DXM) alone in dose of 2 µg/kg or in dose of 1 µg/kg with other analgesics. Patients & Methods 150 patients were randomly distributed between 5-groups: C-Group received saline, Study Group I (SI-Group) received DXM 2 µg/kg, SII, SIII and SIV groups received DXM 1 µg/kg with ketamine 0.5 mg/kg, dexamethasone (DXA) 8-mg or ketorolac 30-mg, respectively, with bupivacaine. Bupivacaine spinal anesthesia was provided, and IAI was injected through an arthroscopic port as a single shot. The study outcome is the efficacy of IAI of DXM as judged by pain scores, duration till requesting morphine, times of requesting, and total dose of morphine used during 12-h after IAI. Results Pain scores and the cumulative scores were significantly lower in the study groups with lower frequency of requests and the total dose of morphine compared to the C-Group with insignificant difference between study groups. The incidence of adverse events was significantly lower in SIII-Group than in other groups. Patients’ and surgeons’ satisfaction was higher in the study groups than C-Group. Conclusion The IAI of DXM alone or in combination with any other analgesic is an effective and safe analgesic modality for post-arthroscopic surgeries. All additives were effective in terms of reduction of pain score and opioid consumption, but the side effects of ketamine and duration of analgesia of ketorolac are questionable. However, DXA is an efficient analgesic with minimal side effects.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results

Immunosuppressant Agents as Add-On Therapy Failed to Improve the Outcome of Immunoglobulin A Nephropathy with Crescent Score C1.

Background The renoprotective benefits of adding immunosuppressant therapy to corticosteroid (CS) treatment for immunoglobulin A nephropathy (IgAN) patients with less than 25% crescent formation (C1) remains uncertain, warranting further research. Methods A retrospective study was conducted on IgAN patients with crescent C1 lesions confirmed by renal biopsy at Xinqiao Hospital between May 1, 2017, and May 1, 2020. Patients were stratified into either the CS treatment group or the CS combined with an additional immunosuppressant therapy group. Follow-up assessments were conducted within 24 months. Propensity score analysis was used to match patients receiving CS and CS+immunosuppressant drug treatment in a 1:1 ratio. Primary outcomes included changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Subgroup analyses were performed to evaluate the benefits of different populations. Composite endpoint outcomes comprised a 30% eGFR decrease, end-stage kidney disease (ESKD) necessitating dialysis or transplant, or kidney disease-related mortality. Adverse events were also compared between the two groups. Results: 296 IgAN patients with C1 lesions were included in the analysis. Baseline characteristics indicated that IgAN patients in the CS+immunosuppressant group exhibited poorer renal function and higher UACR levels. Propensity score analysis effectively minimized the influence of baseline clinical characteristics, including age, serum creatinine, initial eGFR, UACR, and 24-hour proteinuria. Both treatment groups demonstrated continuous eGFR improvement and significant UACR reduction during follow-up, especially at 6 months. However, no significant differences in eGFR and UACR reduction rates were observed between the two groups throughout the entire follow-up period, both before and after matching. Subgroup analysis revealed improved eGFR in both treatment groups, notably among patients with an initial eGFR below 90 ml/min/1.73 m2. Conversely, IgAN patients with C1 lesions and a cellular crescent ratio exceeding 50% treated with CS and immunosuppressant therapy experienced a significant improvement in renal function and a decline in urinary protein creatinine ratio. Composite endpoint outcomes did not significantly differ between the two groups, while the incidence of adverse events was comparable. Conclusion Our findings suggest that the addition of immunosuppressant therapy to corticosteroid monotherapy did not confer significant therapeutic advantages in patients with C1 lesions compared to CS monotherapy, although some specific patient populations appeared to derive modest benefits from this combined approach.

Efficacy and safety of traditional Chinese medicine decoction as an adjuvant treatment for diabetic nephropathy: a systematic review and meta-analysis of randomized controlled trials

Objective: This study aimed to assess the efficacy and safety of traditional Chinese medicine decoction as an adjunctive treatment for diabetic nephropathy in systematic evaluations.Methods: A comprehensive search was conducted in PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases, covering the period from January 2013 to July 2023. The search was restricted to randomized controlled trials (RCTs) conducted within the past decade that investigated the use of TCM decoction as an adjunctive treatment for diabetic nephropathy. The control group received western medicine treatment, while the intervention group received TCM decoction in addition to the conventional treatment. Endnote and Excel were employed for literature management and data organization, and Revman 5.3 and Stata 16 software were used for the analyses.Results: 66 RCTs involving 6,951 participants were included in this study. The clinical efficacy of TCM decoction as an adjunctive treatment for diabetic nephropathy was found to be significantly higher than that of the control group (OR = 3.12, 95% CI [2.70, 3.60], I2 = 0%, p &amp;lt; 0.00001). The incidence of adverse events did not differ significantly between the intervention group and the control group (OR = 0.94, 95% CI [0.60, 1.48], I2 = 0%, p = 0.94). According to the secondary outcomes of renal function and blood glucose indicators, the intervention group showed better therapeutic efficacy compared to the control group. The most frequently used TCM categories were tonifying medicine, blood-activating medicine, astringent medicine, diuretic medicine, heat-clearing medicine, and laxative medicine. Among them, the top five frequently used Chinese medicine were Astragalus mongholicus Bunge [Fabaceae; Astragali mongholici radix](58 times), Salvia miltiorrhiza Bunge [Lamiaceae; Radix et rhizoma salviae miltiorrhizae] (42 times), Dioscorea oppositifolia L. [Dioscoreaceae; Dioscoreae rhizoma] (38 times), Poria cocos (Schw.) Wolf [Polyporaceae; Poria] (38 times), and Cornus officinalis Siebold &amp;amp; Zucc. [Cornaceae; Corni fructus] (35 times).Conclusion: The combined use of TCM decoction with western medicine in the treatment of diabetic nephropathy can enhance clinical effectiveness and 2 This is a provisional file, not the final typeset article achieve superior therapeutic effects in comparison to western medicine alone, without significant risks.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier [CRD42022529144].

Assessing the safety of bedaquiline: insight from adverse event reporting system analysis

BackgroundThe development and marketing of Bedaquiline (BDQ) represent significant advancements in treating tuberculosis, particularly multidrug-resistant forms. However, comprehensive research into BDQ’s real-world safety remains limited.PurposeWe obtained BDQ related adverse event (AE) information from the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) to assess its safety and inform drug usage.MethodsThe AE data for BDQ from 2012 Q4 to 2023 Q3 was collected and standardized. Disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Multi-item Gamma Poisson Shrinker (MGPS), and Bayesian Confidence Propagation Neural Network (BCPNN) was used to quantify signals of BDQ-related AEs. Logistic regression was used to analyze the individual data of hepatotoxicity and drug-induced liver injury, and multiple linear regression models were established. Additionally, network pharmacology was employed to identify the potential biological mechanisms of BDQ-induced liver injury.ResultsWe identified 2017 case reports directly related to BDQ. Our analysis identified 341 Preferred Terms (PTs) characterizing these AEs across 27 System Organ Classes (SOC). An important discovery was the identification of AEs associated with ear and labyrinth disorders, which had not been documented in the drug’s official leaflet before. Subgroup analysis revealed a negative correlation between BDQ-related liver injury and females (OR: 0.4, 95%CI: 0.3–0.6). In addition, via network pharmacology approach, a total of 76 potential targets for BDQ related liver injury were predicted, and 11 core target genes were selected based on the characterization of protein-protein interactions. The pathway linked to BDQ-induced liver injury was identified, and it was determined that the PI3K-Akt signaling pathway contained the highest number of associated genes.ConclusionThe analysis of the FAERS database revealed adverse events linked to BDQ, prompting the use of a network pharmacology approach to study the potential molecular mechanism of BDQ-induced liver injury. These findings emphasized the significance of drug safety and offered understanding into the mechanisms behind BDQ-induced liver injury. BDQ demonstrated distinct advantages, including reduced incidence of certain adverse events compared to traditional treatments such as injectable agents and second-line drugs. However, it is important to acknowledge the limitations of this analysis, including potential underreporting and confounding factors. This study provides valuable insights into the safety of BDQ and its role in the management of MDR-TB, emphasizing the need for continued surveillance and monitoring to ensure its safe and effective use.

Systematic review and network meta-analysis on the efficacy and safety of parmacotherapy for hand osteoarthritis.

Hand osteoarthritis poses a significant health challenge globally due to its increasing prevalence and the substantial burden on individuals and the society. In current clinical practice, treatment options for hand osteoarthritis encompass a range of approaches, including biological agents, antimetabolic drugs, neuromuscular blockers, anti-inflammatory drugs, hormone medications, pain relievers, new synergistic drugs, and other medications. Despite the diverse array of treatments, determining the optimal regimen remains elusive. This study seeks to conduct a network meta-analysis to assess the effectiveness and safety of various drug intervention measures in the treatment of hand osteoarthritis. The findings aim to provide evidence-based support for the clinical management of hand osteoarthritis. We performed a comprehensive search across PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials was conducted until September 15th, 2022, to identify relevant randomized controlled trials. After meticulous screening and data extraction, the Cochrane Handbook's risk of bias assessment tool was applied to evaluate study quality. Data synthesis was carried out using Stata 15.1 software. 21 studies with data for 3965 patients were meta-analyzed, involving 20 distinct Western medicine agents. GCSB-5, a specific herbal complex that mainly regulate pain in hand osteoarthritis, showed the greatest reduction in pain [WMD = -13.00, 95% CI (-26.69, 0.69)]. CRx-102, s specific medication characterized by its significant effect for relieving joint stiffness symptoms, remarkably mitigated stiffness [WMD = -7.50, 95% CI (-8.90, -6.10)]. Chondroitin sulfate displayed the highest incidence of adverse events [RR = 0.26, 95% CI (0.06, 1.22)]. No substantial variation in functional index for hand osteoarthritis score improvement was identified between distinct agents and placebo. In summary, GCSB-5 and CRx-102 exhibit efficacy in alleviating pain and stiffness in HOA, respectively. However, cautious interpretation of the results is advised. Tailored treatment decisions based on individual contexts are imperative.

The effect of intraoperative low-dose ketamine versus dexmedetomidine infusion on postoperative bowel recovery in patients undergoing gastrointestinal malignancy surgeries: Placebo-controlled, randomized trial

Abstract Background and Aims: No studies have compared the effects of ketamine and dexmedetomidine on bowel recovery. We evaluated the effects of intraoperative low-dose ketamine or dexmedetomidine infusion on postoperative bowel recovery in patients undergoing gastrointestinal (GI) malignancy surgeries. Material and Methods: This placebo-controlled, randomized study was carried out in 84 American Society of Anesthesiologists II patients, aged 18–70 years, of either gender, undergoing elective open GI malignancy surgeries. Patients received intraoperative infusion of ketamine @ 0.1 mg kg-1 h-1 (KET), dexmedetomidine @ 0.25 μg kg-1 h-1 (DEX), or normal saline (placebo). Primary outcome was the time to first flatus and/or stool. Secondary outcomes included time to extubation, total analgesic requirement, postoperative pain scores, time to feeds, duration of intensive care unit (ICU) and hospital stay, and the incidence of adverse events. Continuous data were analyzed by the one-way analysis of variance (ANOVA) or the Kruskal–Wallis test. Categorical data were analyzed by the Chi-square test or the Fisher’s exact test. Results: Median time to passage of flatus and/or stool was 3 [interquartile range (IQR) 2–3] days in the KET group, 2 [IQR 2–3] days in the DEX group, and 2 [IQR 2–3] days in the placebo group (P = 0.53 for placebo vs. KET, 0.81 for placebo vs. DEX, and 0.99 for KET vs. DEX). Pain scores and analgesic consumption were significantly less in the intervention groups versus placebo (P &lt; 0.001). No difference was seen in other secondary outcomes. Conclusion: Low-dose ketamine or dexmedetomidine did not result in early bowel recovery despite lower pain scores and opioid consumption in patients undergoing open GI malignancy surgeries. Key Message: What is known: Ketamine and dexmedetomidine may promote bowel recovery by improving analgesia and decreasing opioid usage.Main findings: This randomized controlled trial found no evidence of earlier bowel recovery with ketamine or dexmedetomidine versus placebo despite lower pain scores and analgesic consumption in the ketamine and dexmedetomidine groups.

Comparison of neoadjuvant chemotherapy or chemoradiotherapy plus immunotherapy for locally resectable esophageal squamous cell carcinoma

BackgroundNeoadjuvant chemotherapy plus immunotherapy (nCT + ICIs) and neoadjuvant chemoradiotherapy plus immunotherapy (nCRT + ICIs) both induced favorable pathological response and tolerant toxicities for locally resectable esophageal squamous cell carcinoma (ESCC). However, few studies compared safety and efficacy between the two treatment strategies.MethodsThis retrospective study collected clinical data of locally resectable ESCC patients who underwent nCT + ICIs or nCRT + ICIs followed by esophagectomy from November 2019 to December 2022. The incidence of adverse events, surgical outcomes, short and long-term efficacy, and treatment costs were compared.ResultsA total of 206 patients were included, with a ratio of 158:48 between nCT + ICIs group and nCRT + ICIs group. The two groups exhibited well-balanced baseline characteristics. Most adverse events were grade 1-2 in both groups. The nCT + ICIs group had a longer operative time (334.00 ± 170.2 min vs 279.60 ± 88.31 min, P=0.020) than nCRT + ICIs group, but there were no differences in surgical complications. Although nCT + ICIs group had a lower pCR rate (32.3% vs 52.1%, P=0.004), the 2-year overall survival (84.42% vs 81.70%, P=0.860), 2-year disease-free survival (83.21% vs 80.47%, P=0.839), and recurrence patterns were similar to nCRT + ICIs group. In addition, nCT + ICIs group had significantly lower expenses (188796.00 ± 107704.00 RMB vs 231808.00 ± 48067.00 RMB, P=0.045).ConclusionOverall, nCT + ICIs have comparable safety and efficacy compared to nCRT + ICIs for locally resectable ESCC, but with lower hospitalization costs.

Efficiency of succinylated gelatin and amino acid infusions for kidney uptake reduction of radiolabeled αvβ6-integrin targeting peptides: considerations on clinical safety profiles.

68Ga-Trivehexin is an investigational PET radiopharmaceutical (NCT05799274) targeting αvβ6-integrin for PET imaging of carcinomas. 177Lu-D0301 is a structurally related therapeutic peptide tetramer. However, it showed considerable kidney uptake in rodents, impeding clinical applicability. We therefore evaluated the impact of different kidney protection strategies on the biodistribution of both agents in normal and tumor-bearing mice. Ex-vivo biodistribution of 68Ga-Trivehexin (90min p.i.) and 177Lu-D0301 (90min and 24h p.i.) was determined in healthy C57BL/6N and H2009 (human lung adenocarcinoma) xenografted CB17-SCID mice without and with co-infusion of 100µL of solutions containing 2.5% arginine + 2.5% lysine (Arg/Lys), 4% succinylated gelatin (gelofusine, gelo), or combinations thereof. Arg/Lys was injected either i.p. 30min before and after the radiopharmaceutical, or i.v. 2min before the radiopharmaceutical. Gelo was administered either i.v. 2min prior activity, or pre-mixed and injected together with the radiopharmaceutical (n = 5 per group). C57BL/6N mice were furthermore imaged by PET (90min p.i.) and SPECT (24h p.i.). Kidney uptake of 68Ga-Trivehexin in C57BL/6N mice was reduced by 15% (Arg/Lys i.p.), 25% (Arg/Lys i.v.), and 70% (gelo i.v.), 90min p.i., relative to control. 177Lu-D0301 kidney uptake was reduced by 2% (Arg/Lys i.p.), 41% (Arg/Lys i.v.), 61% (gelo i.v.) and 66% (gelo + Arg/Lys i.v.) 24h p.i., compared to control. Combination of Arg/Lys and gelo provided no substantial benefit. Gelo furthermore reduced kidney uptake of 177Lu-D0301 by 76% (90min p.i.) and 85% (24h p.i.) in H2009 bearing SCID mice. Since tumor uptake was not (90min p.i.) or only slightly reduced (15%, 24h p.i.), the tumor/kidney ratio was improved by factors of 3.3 (90min p.i.) and 2.6 (24h p.i.). Reduction of kidney uptake was demonstrated by SPECT, which also showed that the remaining activity was located in the cortex. The kidney uptake of both investigated radiopharmaceuticals was more efficiently reduced by gelofusine (61-85%) than Arg/Lys (25-41%). Gelofusine appears particularly suitable for reducing renal uptake of αvβ6-integrin targeted 177Lu-labeled peptide multimers because its application led to approximately three times higher tumor-to-kidney ratios. Since the incidence of severe adverse events (anaphylaxis) with succinylated gelatin products (reportedly 0.0062-0.038%) is comparable to that of gadolinium-based MRI or iodinated CT contrast agents (0.008% and 0.04%, respectively), clinical use of gelofusine during radioligand therapy appears feasible if similar risk management strategies as for contrast agents are applied.

The potential of triglyceride-glucose index in improving the prediction of post-percutaneous coronary intervention clinical outcomes: a systematic review and meta-analysis

Introduction Despite percutaneous coronary intervention is the current preferred reperfusion modality, the incidence of major adverse cardiovascular events (MACE) is still high. Currently, GRACE score is used for predicting PCI outcomes. The TyG (triglyceride-glucose) index, a potential predictor based on insulin resistance of cardiovascular disease, has not been considered in the GRACE score. Objective To assess the potential of the TyG index in predicting cardiovascular adverse clinical outcomes in patients undergoing PCI. Method Following PRISMA guidelines, the authors reviewed literature from five databases. We included studies investigating post-PCI outcomes based on the TyG index level. Effect size was estimated using RevMan to calculate pooled odds ratio and mean difference, and R software to perform diagnostic test accuracy. Results Overall, 31,671 post-PCI patients with acute coronary syndrome were included in this study. A significant difference in TyG index was found between patients who experienced MACE and those who did not [MD: 0.3 (0.2–0.4), p < .05]. Higher TyG index was strongly correlated with higher MACE [OR: 2.01 (1.45–2.77), p < .05], especially revascularization [OR: 2.40 (1.72–3.36), p < .05], followed by myocardial infarction [OR: 1.80 (2.41–2.86), p < .05], death [OR: 1.36 (0.86–2.15), p = .19], and stroke [OR: 1.09 (0.79–1.50), p = .59]. Tyg Index showed 55% sensitivity, 60% specificity, and 0.612 accuracy. The addition of the TyG index to the GRACE scoring improved the predictive model’s AUC (0.746 vs. 0.809). Conclusion This systematic review and meta-analysis comprises evidence-based results for the correlation of TyG index and post-PCI outcomes, demonstrating modest sensitivity, specificity, accuracy, and enhanced predictive value of GRACE score.

Association of Safety-Net Hospital Status With Outcomes Following Head and Neck Cancer Operations.

To assess perioperative and readmission outcomes of patients undergoing head and neck cancer (HNCA) surgery at safety-net hospitals (SNHs) in a modern cohort. Retrospective cohort study. Nationwide Readmissions Database (NRD), 2010 to 2019. All elective adult (≥18 years) admissions involving HNCA resection were identified from the NRD. To calculate safety-net burden, the proportion of Medicaid or uninsured patients admitted to each hospital for any indication was tabulated annually, with centers in the highest quartile defined as SNHs. To perform risk adjustment in assessing perioperative and readmission outcomes, multivariable regression models were developed. Of an estimated 133,018 head and neck surgical patients, 26.5% (n = 35,268) received treatment at a SNH. Utilization of SNHs increased over the decade-long study period, with 29.8% of individuals treated at these sites in 2019. After multivariable adjustment, several patient factors were noted to be associated with SNHs, including younger age, lower comorbidity burden, and income within the lowest quartile. Although incidence of adverse events decreased at both SNHs and non-SNHs during the study period, treatment at SNHs remained associated with these events after risk adjustment (adjusted odds ratio: 1.17, 95% confidence interval: 1.08-1.28, P < .001). SNHs continue to provide valuable specialty care to underserved populations, often with limited financial resources. Despite promising results from prior decades demonstrating comparable perioperative outcomes, the present study noted increased adverse events following HNCA surgery at these sites. Such findings underscore the need for continued advocacy to secure necessary funding for these centers.