Adverse Incidence Research Articles

P-2335. Comparison of Adverse Drug Effects and Incidence of CMV Infection Between Different Dosing Regimens for Valganciclovir in the Pediatric Solid Organ Transplant Population

Abstract Background Valganciclovir has become widely used for the prevention of (CMV) infection in solid organ transplant (SOT) patients in both adult and pediatric populations. However, there is no consensus about the optimum dosing regimen in pediatric patients. Our study aims to compare the frequency of side effects and rate of CMV between two commonly used dosing regimens. Methods In August 2020, as part of quality improvement initiative our internal SOT guideline for Valganciclovir dosing switched from weight-based (15-25 mg/kg/dose) to the manufacturer recommended dosing based on body surface area and estimated glomerular filtration rate (BSA/eGFR). We retrospectively reviewed medical records of pediatric patients (0-20 years) who underwent SOT (including liver, heart, and kidney) from 2/2015 to 2/2024. The collected data include age, transplanted organ, occurrence of abnormal liver functions (LFT) and neutropenia, and number of episodes of CMV infection during prophylaxis and 6 months post-prophylaxis. Moderate and severe neutropenia were defined as absolute neutrophil count (ANC) 500-1000 and ANC < 500, respectively. Results 116 pediatric SOT recipients were distributed almost equally between heart (32%), kidney (34%), and liver (34%) transplants. 28/116 (24%) received BSA/eGFR-based dosing. The median duration of prophylaxis was 3.9 months (IQR 2.9-6). The frequency of abnormal LFTs were similar in both dosing groups (64% in the BSA/eGFR group vs 65% in the weight-based group). Moderate neutropenia was more frequent in the BSA/eGFR group (36%) compared to the weight-based group (17%) and severe neutropenia occurred in 11% and 18%, respectively. However, these differences were not significantly different(P=0.11). CMV infection occurred in 27% of total population of patients with no significant difference in breakthrough infection on prophylaxis between the two groups (4% vs 10%, P=0.45). Conclusion In pediatric SOT recipients, valganciclovir prophylaxis dosed based on BSA/eGFR or weight had a similar side effect profile for liver toxicity and severe neutropenia. In addition, there was no significant difference in the occurrence of CMV infections between the dosing regimens. Disclosures All Authors: No reported disclosures

Efficacy of e-learning using video content in improving trainees' biliary cannulation skills and understanding (with video).

E-learning with video content was created to improve trainees' biliary cannulation techniques; this study aimed to evaluate its educational effect prospectively. E-learning program was conducted using videos demonstrating biliary cannulation for 24 papillae, targeting trainees with 2-6 years of experience in endoscopic retrograde cholangiopancreatography. Ten consecutive cases of biliary cannulation for native papillae performed by trainees were prospectively assessed before and after the e-learning, respectively. The primary outcome was the difficult biliary cannulation rate; the secondary outcomes included a comprehension score assigned by the trainer for each biliary cannulation (maximum of 6 points), trainee failure rate, and adverse events incidence. Eleven trainees participated in the e-learning program. The overall and per-trainee analyses showed no significant differences in the difficult biliary cannulation rate, trainee failure rate, and adverse event incidence before and after e-learning. However, the overall analysis showed a significant increase in comprehension scores after e-learning (median 4vs. 5, p<0.01) and the per-trainee analysis revealed that the rate of comprehension score ≥5 increased significantly after e-learning (p=0.02). Comprehension score<5 (odds ratio: 4.31, p<0.01) and endoscopic retrograde cholangiopancreatography experience<3 years (odds ratio: 2.15, p=0.01) were independent risk factors for difficult biliary cannulation. Additionally, the difficult biliary cannulation incidence showed a negative correlation with the comprehension score (p<0.01). E-learning using video content did not result in a reduction in the difficult biliary cannulation rate. However, it significantly enhanced procedural understanding, indicating its potential to support future acquisition of biliary cannulation skills.

Efficacy and safety of hydroxyurea therapy on patients with β-thalassemia: a systematic review and meta-analysis.

Our aim is to review the safety and efficacy of hydroxyurea (HU) on β-thalassemia patients. Studies that evaluated the safety and efficacy of HU on β-thalassemia patients were searched in Pub-Med, Cochrane Databases, Web of Science, China-Biology-Medicine, CNKI, Embase, VIP, and WanFang data. The proportions of response rate (RR) (50% fall in transfusion need in transfusion-dependent β-thalassemia patients, or 1 g/dL elevate in hemoglobin (Hb) levels in transfusion-independent β-thalassemia patients) and good RR (transfusion-free in transfusion-dependent β-thalassemia patients or 2 g/dL elevate in Hb levels in transfusion-independent β-thalassemia patients) were utilized to evaluate the effect size (ES). The secondary outcomes were the adverse events incidence rates of HU in β-thalassemia patients. Two randomized controlled trials (RCTs) and 25 single-armed observational studies with typically 1,748 individuals were involved in our analysis. All 27 clinical trials were reported with fair quality. HU, in transfusion-dependent β-thalassemia patients, was related to a significant decrease in transfusion requirements [a pooled RR of 0.37 and a pooled good RR of 0.65 (95% CI, 0.53-0.76)]; in transfusion-independent β-thalassemia patients, it was correlated to an excellent raise in Hb levels [a pooled RR of 0.20 (95% CI, 0.08-0.35) and a pooled good RR of 0.53 (95% CI, 0.41-0.65)]. Neutropenia and leucopenia were the most prevalent adverse events in β-thalassemia patients treated with HU, while the incidence rates of other side effects were relatively lower. Our findings demonstrated that β-thalassemia patients tolerated and responded well to HU. Due to the control arms absence in the involved studies, more double-masked RCTs are essential for proving the safety and efficacy of HU in β-thalassemia patients.

Efficacy and safety of creatine phosphate sodium in the treatment of viral myocarditis: A systematic review and meta-analysis.

To systematically evaluate the efficacy and safety of creatine phosphate sodium in the treatment of viral myocarditis, and to provide guidance for its clinical treatment. We conducted a search of The Cochrane Library, PubMed, EMbase, and Web of Science databases to retrieve randomized controlled trials (RCTs) on the use of creatine phosphate sodium (CPS) in the treatment of viral myocarditis. The search was conducted up to April 2024. After screening the literature, extracting data, and evaluating the risk of bias in the included studies, we performed a meta-analysis using RevMan 5.4 and Stata17.0 statistical software. A total of 104 articles were retrieved, and 9 articles with a combined total of 1,116 patients were ultimately included in the meta-analysis. The results of the meta-analysis indicated that the overall efficacy rate in the phosphocreatine sodium treatment group was higher than that in the control group [RR = 1.22, 95%CI (1.15, 1.28), P<0.00001]. Furthermore, post-treatment levels of cardiac troponin I [MD = 0.1, 95%CI (0.07, 0.13), P<0.00001] and creatine kinase isoenzyme [MD = 9.43, 95%CI (7.04,11 .82), P<0 .00001] in the phosphocreatine treatment group were lower compared to those in the control group; both differences between groups were statistically significant. Additionally, there was no significant difference observed in adverse reaction incidence between the phosphocreatine sodium treatment group and conventional treatment group [RR = 1 .07, 95% CI (0 .68, 1 .67), P = O .77]. Creatine phosphate sodium treatment can significantly improve the therapeutic effect of patients with viral myocarditis, and can reduce the levels of cTnI and CK-MB. Compared with conventional treatment, it has good safety.

The efficacy and safety of negative pressure wound therapy in paediatric burns: a systematic review and meta-analysis of randomized controlled trials

BackgroundAlthough the effective application of negative pressure wound therapy (NPWT) has been exemplified in diverse clinical studies, its potential and safety, specifically regarding paediatric burns, are yet to be fully confirmed. Our most recent systematic review and meta-analysis strive to investigate the impact of NPWT within the realm of paediatric burns.MethodsWe sourced relevant articles from databases including PubMed, Embase, the Cochrane Database, Web of Science, the International Clinical Trials Registry Platform, China National Knowledge Infrastructureris, the VIP Database for Chinese Technical Periodicals, and the Wanfang database. We defined the primary outcome measure as the healing time, while healing rate, numbers of dressing changes, detection rate of positive bacteria, incidence rate of adverse reactions, scar scale scores, and treatment costs were considered as secondary outcome measures. Pooling of data was conducted and the results were articulated as relative risk (RR), mean difference (MD), and standardized mean difference (SMD), all with a 95% confidence interval (CI).ResultsIn this systematic review and meta-analysis, a total of 12 studies involving 1033 individuals were examined, including 559 paediatric burn patients who underwent NPWT (referred to as the treatment group) and 543 patients who received treatments other than NPWT (referred to as the control group). The amalgamated data from these studies exhibited that the treatment group experienced significant reductions in healing time (SMD = -1.60; 95% CI: -2.26 - -0.95; p < 0.001, I2 = 92.8%), the number of required dressing changes (SMD = -4.6; 95% CI: -5.84 - -3.36; p < 0.001, I2 = 92.4%), positive bacteria detection rate (RR = 0.61; 95% CI: 0.26–1.46; p = 0.004, I2 = 81.8%), incidence of adverse reactions (RR = 0.61; 95% CI: 0.33–1.12; p = 0.005, I2 = 68%), scar scale scores (SMD = -1.66; 95% CI: -2.54 - -0.79; p < 0.001, I2 = 89.4%), as well as in treatment costs (SMD = 0.92; 95% CI: -1.66–3.49; p < 0.001, I2 = 98.4%). Additionally, these individuals showed an increased rate of healing (RR = 1.17; 95% CI: 0.99–1.39; p < 0.001, I2 = 78%). Subgroup analysis did not find that the degree of burn was one of the sources of high heterogeneity.ConclusionOur meta-analysis points to the effectiveness of NPWT in treating paediatric burns. Notably, it significantly mitigates healing duration, frequency of dressing alterations, positive bacterial detection rate, adverse reactions incidence, scar scale scores and treatment costs, all while propelling the acceleration of wound healing.

Validation of the rates of adverse event incidence in administrative healthcare data through patient chart review: A scoping review protocol

Background Patient safety is a key issue for health systems and a growing global public health challenge. Administrative healthcare data provide a coded summary of a patient and their encounter with the healthcare system. These aggregated datasets are often used to inform research and decisions relating to health service planning and therefore it is vital that they are accurate and reliable. Given the reported inaccuracy of these datasets for detecting and recording adverse events, there have been calls for validation studies to explore their reliability and investigate further their potential to inform research and health policy. Researchers have since carried out validation studies on the rates of adverse events in administrative data through chart reviews therefore, it seems appropriate to identify and chart the evidence and results of these studies within a scoping review. Methods The scoping review will be conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews. A search of databases such as PubMed, CINAHL, ScienceDirect and Scopus will be conducted in addition to a search of the reference lists of sourced publications and a search for grey literature. Following this, Covidence will be used to screen the sourced publications and subsequently extract data from the included sources. A numerical summary of the literature will be presented in addition to a charting based on the qualitative content analysis of the studies included. Conclusions This protocol provides the structure for the conduct of a review to identify and chart the evidence on validation studies on rates of adverse events in administrative healthcare data. This review will aim to identify research gaps, chart the evidence of and highlight any flaws within administrative datasets to improve extraction and coding practices and enable researchers and policy makers to use these data to their full potential.

Improving the efficacy of combinatorial pharmacogenetic testing in schizophrenia therapy in China: a meta-analysis

AimPharmacogenetics/pharmacogenomics (PGx) testing has appeared as a convincing approach to assisting clinicians in adjusting drug selection and dosage according to the patient’s genetic information. The purpose of this meta-analysis was to compare the clinical efficacy of PGx guided treatment (experimental group) and empirical treatment (control group) in schizophrenia patients.MethodsA thorough search and review of the literature referring to PGx testing guided therapy for schizophrenia was conducted in the PubMed, CNKI, VIP, and Wanfang databases. Data were collected from the eligible studies after quality assessment, and RevMan software was used to conduct a meta-analysis comparing the clinical outcomes between the experimental and control groups.ResultsSeven trials were included, encompassing 1557 Chinese patients (767 in the experimental group and 790 in the control group). The pooled results revealed that the experimental group demonstrated more improved symptom remission and functional recovery than the control group; the adverse drug reaction incidence was also lower in the experimental group.ConclusionThe meta-analysis findings confirm the significant beneficial clinical utility of pharmacogenetic testing guided therapy for schizophrenia. The conclusion should be viewed cautiously, considering several limitations in this study.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease: a multicentre, randomized, double-blind, phase 2 trial

BackgroundFailure of systemic corticosteroid therapy is common in patients with newly diagnosed acute graft-versus-host disease (aGVHD) above grade II. Mesenchymal stem cells (MSCs) have been used as a tolerable and potentially effective second-line therapy for steroid-refractory aGVHD (SR-aGVHD); however, well-designed, prospective, controlled studies are lacking.MethodsThis multicentre, randomized, double-blind, placebo-controlled, exploratory phase 2 study enrolled patients with SR-aGVHD above grade II from 7 centres. Patients were randomized 1:1 to receive umbilical cord-derived MSCs or placebo added to one centre’s choice of second-line agents (except for ruxolitinib). The agents were infused twice weekly. Patients with complete response (CR), no response (NR), or progression of disease (PD) at d28 received 8 infusions, and those with partial response (PR) received the above infusions for another 4 weeks. The per-protocol population consisted of patients who received ≥ 8 infusions. The primary endpoint was the overall response rate (ORR, CR + PR) at d28, analyzed in the per-protocol and intention-to-treat populations.ResultsSeventy-eight patients (median age 38, range 13–62) were enrolled: 40 in the MSC group and 38 in the control. Patients in the MSC group received a median of 8 doses, with a median response time of 14 days. In intention-to-treat analysis, ORR at d28 was 60% for MSC group and 50% for control group (p = 0.375). The 2-year cumulative incidence of moderate to severe cGVHD was marginally lower in the MSC group than in the control (13.8% vs. 39.8%, p = 0.067). The 2-year failure-free survival was similar between the MSC and control groups (52.5% vs. 44.4%, p = 0.43). In per-protocol analysis (n = 62), ORR at d28 was significantly greater in the MSC group than in the control group (71.9% vs. 46.7%, p = 0.043). Among patients with gut involvement, ORR at d28 was significantly greater in the MSC group than in the control (66.7% vs. 33.3%, p = 0.031). The adverse events incidences were similar between groups.ConclusionsIn this exploratory study, there was no superior ORR at d28 demonstrated in the MSC group compared with the control. However, MSCs showed a gradual treatment effect at a median of 2 weeks. Patients who completed 8 infusions may benefit from adding MSCs to one conventional second-line agent, especially those with gut involvement. MSCs was well tolerated in patients with SR-aGVHD.Trial registrationchictr.org.cn ChiCTR2000035740.

The risk of upper gastrointestinal bleeding associated with concomitant proton pump inhibitor administration during dual antiplatelet therapy with aspirin and prasugrel: a retrospective single-center study

ObjectiveDual‐antiplatelet therapy (DAPT) and proton pump inhibitor (PPI) are frequently prescribed after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) placement. However, studies that evaluate the optimal PPI when used as primary prevention in patients without a history of peptic ulcer disease or upper gastrointestinal bleeding (UGIB), particularly in the context of DAPT involving prasugrel, are lacking. This study aimed to assess the efficacy and safety of PPI use in preventing UGIB in this patient population.MethodsThis study included patients who underwent PCI with coronary stent placement for acute coronary syndrome or stable angina at our institution from January 2015 to December 2020. Eligible patients started DAPT with aspirin and prasugrel and concomitantly received PPI therapy (lansoprazole or esomeprazole), with a follow-up period of two years. The primary endpoint was UGIB incidence, diagnosed during follow-up, serving as an efficacy measure. Secondary endpoints included the assessment of major bleeding (as defined by the Thrombolysis in Myocardial Infarction major bleeding criteria) and clinically relevant non-major bleeding events. Safety outcomes focused on adverse event incidence attributable to PPI use.ResultsAmong the 165 patients analyzed, 109 and 56 were included in the lansoprazole and esomeprazole groups, respectively, with cumulative incidence of UGIB at 96 weeks of 0.9% (1/109) and 3.6% (2/56). No significant differences in terms of major bleeding events or other bleeding outcomes were observed between the two groups. Adverse events related to PPI use were reported as diarrhea/soft stools in 7 (6%) cases and thrombocytopenia in 1 (1%) case in the lansoprazole group, whereas no such events were observed in the esomeprazole group. No clinically significant hematologic or biochemical abnormalities were reported.ConclusionThis study evaluated the efficacy and safety of PPIs in combination with DAPT, including prasugrel, following PCI, and suggests that lansoprazole and esomeprazole may offer comparable efficacy in preventing UGIB.

Efficacy and safety of daprodustat in patients on peritoneal dialysis in the ASCEND-D trial.

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is approved for treatment of anemia in dialysis patients with CKD in some parts of the world. This subgroup analysis examined the efficacy and safety of daprodustat versus darbepoetin alfa in patients with anemia of CKD undergoing peritoneal dialysis (PD). ASCEND-D (NCT02879305) was an open-label, Phase 3 trial; patients with CKD were randomized to daprodustat daily and epoetin alfa (HD patients) or darbepoetin alfa (PD patients). In PD patients, prespecified analyses of the co-primary endpoints of mean change in hemoglobin from baseline to Weeks 28-52 using an ANOVA model and first occurrence of a major cardiovascular event (MACE) using a Cox proportional hazards model were conducted. The secondary endpoints were average monthly intravenous iron dose to Week 52 and treatment-emergent adverse events. Additional post hoc analyses were conducted. Overall, 340 PD patients (daprodustat n=171, darbepoetin alfa n=169) were randomized. Mean age was 53.6 years (±14 SD), 55% male, 56% White. For daprodustat and darbepoetin alfa groups respectively, mean change in hemoglobin was 0.38 and 0.23g/dL [adjusted mean difference 0.15, 95% confidence interval (CI), -0.04, 0.34], and first occurrence of adjudicated MACE occurred in 40 (23.4%) and 46 (27.2%) patients (HR 0.84; 95% CI, 0.55-1.28). No heterogeneity was observed between PD and HD patients for these endpoints in ASCEND-D. Serum hepcidin was lower with daprodustat; there was no difference in other iron parameters, intravenous iron usage, transfusion requirement, blood pressure, or quality of life. There were no differences in adverse events or incidence of peritonitis between the groups. This subgroup analysis of the ASCEND-D trial demonstrated comparable efficacy and safety of daprodustat versus darbepoetin alfa in PD patients, supporting its use in the treatment of anemia in these patients.

Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer

Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. ClinicalTrials.gov Identifier: NCT04012606.

Efficacy and safety of YOXINTINE for depression: A double-blinded, randomized, placebo-controlled, phase 2 clinical trial

BackgroundYOXINTINE contains >98 % of 20(S)-protopanaxadial (PPD), a metabolic product of ginsenosides with pre-clinical neuroprotective activity. Animal experiments and previous studies have shown that PPD has good antidepressant effect and safety. PurposeTo evaluate YOXINTINE in treating depression compared with a placebo in Chinese patients. Study DesignThis was a multicenter, double-blinded, randomized, placebo-controlled, phase 2 clinical trial. MethodsThe study included 178 randomized (1:1:1) Chinese patients with depression. Patients were randomly assigned to receive oral YOXINTINE at doses of 200 or 400 mg or a placebo administered twice daily for 8 weeks. The primary outcome was assessed by measuring changes in the Montgomery–Asberg Depression Rating Scale (MADRS) total score. All adverse reactions were recorded. All demographic and baseline characteristics were comparable. ResultsThe changes in MADRS total scores from baseline were −10.43 for the placebo group, −16.24 for the 200 mg YOXINTINE group, and −13.60 for the 400 mg YOXINTINE group. The differences in MADRS total score changes compared with the placebo were −5.81 (95 % CI: −7.69, −3.92; P < 0.0001) and −3.17 (95 % CI: −5.08, −1.25; P = 0.0013) for the 200 mg and 400 mg groups, respectively. The results indicated a significantly greater MADRS score reduction in the 200 mg group (P = 0.0058, 95 % CI: 0.78, 4.51). Adverse event incidence was comparable among all groups. ConclusionOral YOXINTINE is safe and significantly improves depressive symptoms. PPD may exhibit antidepressant properties through mechanisms distinct from monoamine reuptake inhibition. Registration numberChiCTR2300070568

The effectiveness and safety of posaconazole enteric-coated tablet versus oral suspension in invasive fungal infections

Posaconazole enteric-coated tablet and oral suspension are two oral drugs in the treatment of invasive fungal infections (IFIs). This study compared the effectiveness and safety between posaconazole enteric-coated tablet and oral suspension, and provided a real world basis for the clinical practice. A retrospective cohort study was performed on IFIs patients treated with posaconazole enteric–coated tablet or oral suspension. The primary endpoints were in-hospital mortality, treatment discontinuation rate and clinical effective rate. The secondary endpoints were adverse events incidence (liver dysfunction, renal dysfunction and hypokalemia). One hundred and forty-four patients were totally included and divided into enteric-coated tablet group (n = 46) and oral suspension group (n = 98). There was no significant difference in effectiveness and safety between two groups. The female (OR = 0.130, P = 0.018) and diabetes mellitus (OR = 4.242, P = 0.003) were independently associated with combined in-hospital mortality/treatment discontinuation rate. The renal replacement therapy (OR = 10.071, P = 0.006), hypoalbuminemia (OR = 6.646, P = 0.002) and posaconazole duration (OR = 1.119, P = 0.002) were risk factors for liver dysfunction. The posaconazole enteric-coated tablet has comparable effectiveness and safety with oral suspension in IFIs, which need large-scale cases studies to confirm in the future.

Mechanical Thrombectomy for Treatment of Acute Cerebral Infarction due to Distal Medium Vessel Occlusions: A Retrospective Cohort Study.

Mechanical thrombectomy (MT) is standard of care for acute cerebral infarction (ACI) due to large vessel occlusions. However, its clinical efficacy in patients with ACI due to distal medium vessel occlusions (DMVOs) remains unclear. This study evaluates the efficacy and safety of MT in patients with ACI due to DMVOs. Totally, 306 patients with ACI at a very early stage were assigned into DMVOs-MT, M1-MT, and DMVOs-intravenous thrombolysis (IVT) groups. These groups were compared regarding baseline data, recanalization rate, location of vessel occlusions, number of thrombectomy, first-pass recanalization, mRS scores, NIHSS scores, 90-day mRS scores, incidence of adverse events, and mortality. Risk factors for poor prognosis of patients with DMVOs following MT were analyzed. DMVOs-MT and M1-MT groups showed comparable first-pass recanalization rates, recanalization rates, and NIHSS score reduction ratios, with marked differences in location of vessel occlusions. Versus DMVOs-IVT, DMVOs-MT had increased differences between pre- and post-treatment NIHSS scores and between pre-treatment NIHSS scores and NIHSS scores at discharge and elevated NIHSS reduction ratios. The poor prognosis rate of DMVOs-MT group was insignificantly different from that of M1-MT group but lower than that of DMVOs-IVT group. Adverse events and mortality incidences were comparable among the three groups. Diabetes, first-pass recanalization, and pre-treatment NIHSS scores were independent risk factors for poor prognosis in DMVO patients after MT. MT is as effective and safe in patients with DMVOs as in patients with M1 occlusions. In patients with DMVOs, MT has higher efficacy and safety than IVT.

Darolutamide in Japanese patients with metastatic hormone-sensitive prostate cancer: Phase 3 ARASENS subgroup analysis.

In the global ARASENS study (NCT02799602), darolutamide plus androgen-deprivation therapy (ADT) and docetaxel significantly reduced risk of death by 32.5% versus placebo plus ADT and docetaxel (hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.57-0.80; p < 0.0001), with a favorable safety profile in patients with metastatic hormone-sensitive prostate cancer (mHSPC). We investigated outcomes in Japanese participants. Patients were randomized 1:1 to oral darolutamide 600 mg twice daily or placebo, plus ADT and docetaxel. The primary endpoint was overall survival. The Japanese subgroup comprised 148 patients (darolutamide 63, placebo 85). In the Japanese versus overall population, more patients were aged ≥75 years (darolutamide/placebo 35%/22% vs. 16%/17%) and had body mass index <25 kg/m2 (78%/79% vs. 46%/43%), The ECOG performance status 0 (92%/88% vs. 72%/71%), de novo mHSPC (95%/97% vs. 86%/87%), and Gleason score ≥8 (94%/92% vs. 78%/79%). Median treatment duration was 43.3/15.4 months for darolutamide/placebo. The overall survival HR for darolutamide versus placebo was 0.91 (95% CI 0.50-1.64), despite 85% of patients in the placebo group receiving subsequent life-prolonging therapy. Darolutamide prolonged time to castration-resistant prostate cancer (HR 0.31; 95% CI 0.17-0.55). Treatment-emergent adverse event incidences were generally similar between groups. Adverse events known to be associated with docetaxel (e.g., neutropenia) were more frequent in the Japanese versus overall population. In conclusion, efficacy outcomes showed positive trends for darolutamide plus ADT and docetaxel in Japanese patients with mHSPC, consistent with the overall population, despite higher risk factors. The combination was well tolerated, with no new safety signals in Japanese patients.

The correlation between the confusion assessment method for intensive care units 7-item, the intensive care delirium screening checklist and adverse outcomes after post-cardiac surgery delirium

Abstract Background Postoperative Delirium(POD) and Subsyndromal Delirium(SSD) remain prevalent, particularly among the cardiovascular surgical population due to the utilization of cardiopulmonary bypass. Adverse outcomes, such as prolonged ICU stay, extended length of stay, and increased incidence of adverse events, are associated with individuals diagnosed with Postoperative Delirium or those experiencing fluctuations between Postoperative Delirium and Subsyndromal Delirium during ICU stays. Therefore, early delirium screening is of utmost importance. The Intensive Care Delirium Screening Checklist(ICDSC) and the Confusion Assessment Method for the Intensive Care Unit 7-item(CAM-ICU-7) are validated delirium screening instruments for critical patients. Purpose This study aims to determine whether the ICDSC or the CAM-ICU-7 is the superior predictor for adverse outcomes following Postoperative Delirium among the cardiovascular population. Methods In this prospective cohort study, 84 patients who underwent elective cardiovascular surgery underwent a total of 833 paired assessments(ICDSC and CAM-ICU-7) twice daily by the researcher. The correlation between the results of ICDSC and CAM-ICU-7 was evaluated. Multiple linear regression was employed to explore associations between ICDSC and CAM-ICU-7 and length of ICU stay, length of overall stay, and the total number of adverse events. The best model was selected after testing with Pearson's correlation coefficient, Hotelling's t, and Steiger's Z tests. Logistic regression explored associations between ICDSC and CAM-ICU-7 and adverse events. Results Postoperative Delirium incidence evaluated by the ICDSC and CAM-ICU-7 was 47.61% and 45.23%, respectively. The incidence of fluctuations between Postoperative Delirium and Subsyndromal Delirium evaluated by the ICDSC and CAM-ICU-7 was 34.52% and 21.43%, respectively. The agreement between the ICDSC and CAM-ICU-7 is high(kappa = 0.835, p&amp;lt;0.001) in detecting Postoperative Delirium but fair in detecting Subsyndromal Delirium(kappa = 0.213, p&amp;lt;0.001). Our research revealed that the length of ICU stay can be predicted by POD(detected by ICDSC and CAM-ICU-7) and fluctuated POD and SSD(detected by ICDSC but not CAM-ICU-7). However, only fluctuated POD and SSD detected by ICDSC could predict hospital length of stay. The total number of adverse events and incidence could be predicted by POD either detected by ICDSC or CAM-ICU-7 but only fluctuated POD and SSD detected by ICDSC, not CAM-ICU-7, could predict the total number of adverse events. Conclusions Both ICDSC and CAM-ICU-7 can detect Postoperative Delirium with high agreement. However, ICDSC could identify more individuals with both Postoperative Delirium and Subsyndromal Delirium, thus predicting more adverse outcomes than CAM-ICU-7. Therefore, ICDSC emerges as the superior delirium screening instrument for the cardiovascular population.

Outdoor living environment and cardiovascular disease risk: results from a Swedish cohort

Abstract Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. While sociodemographic, dietary and lifestyle factors have been well documented in relation to CVD, environmental factors have been less studied. However, considering the ongoing biodiversity, climate, and health crises, it is imperative to better understand the interplay between the environment and health. This study aimed to examine the associations between green qualities of the residential environment and CVD. The Malmö Diet and Cancer study is a prospective cohort initiated in the 1990s in the city of Malmö (southern Sweden). At baseline, participants were invited to a health screening, including extensive questionnaires about socioeconomic conditions, lifestyle and diet, clinical examination and blood sampling. The residential coordinates of the participants at baseline were linked to the Scania Outdoor Environment Database comprising scores for a range of perceived qualities of the neighbourhood outdoor environment. Three greenness-related dimensions (serene, natural, diverse) were selected for this substudy. Information on incidence of CVD until 2019 was retrieved from Swedish registers. Adjusted Cox proportional hazards models were used to estimate associations between green-related qualities and cardiovascular diseases (major adverse coronary events). Approximately 27000 participants were included, of which 60% were women. The average age at baseline was 58 years old (±8). Mean follow-up was 20 years (±7) and 4318 cases of major adverse coronary events were identified. Preliminary results suggest that several sociodemographic and lifestyle factors, as well as some aspects of neighbourhood greenness, were associated to increased cardiovascular incidence. Neighbourhood greenness might play a role in major adverse coronary events incidence. Further investigation on underlying mechanisms is required. Key messages • Identifying environmental risk factors for cardiovascular disease is of importance for public health. • Neighbourhood greenness might play a role in cardiovascular disease incidence, and underlying mechanisms need to be investigated further.

Short vs Standard Duration Dual Antiplatelet Therapy after Percutaneous Coronary Intervention with New-Generation Drug-Eluting Stents: A Meta- Analysis

Objective: In patients with coronary artery disease, dual antiplatelet therapy (DAPT) is recommended after percutaneous coronaryintervention, but the duration is still debated. This meta-analysis compared short-duration (1 to 3 months) to standard-time (twelve months) double antiplatelet treatment in patients who received coronary intervention with new generation drug eluting Stent.Methodology: To conduct this examination, we methodically looked at PubMed, Cochrane CENTRAL, Embase, and Web of Sciencedatabases for randomized controlled trials, evaluating varying durations of double antiplatelet treatment following new generation stents implantation from July to September 2023. Seven randomized controlled trials were included with a total of 22,945 patients. The primary efficacy endpoint was the incidence of Major adverse cardiovascular events, such as cardiac mortality, heart attack, stent coagulation, and target vessel revascularization; while the safety endpoint was the incidence major bleeding. Secondary endpoints were major adverse cardiovascular and cerebro-vascular complications, any bleeding, and net adverse cardiovascular incidence for a year after stent implantation.Results: Short-time DAPT was linked to a significantly less incidence of major bleeding (0.8% vs 1.5%), any bleeding (2.5% vs 4.2%)and NACE (2.5% vs 4.2%) compared to standard duration of DAPT. No significant variation was noticed among the two groups regarding major adverse cardiovascular events (4.1% vs. 4.2%) and acute cardiovascular and cerebrovascular incidents (4.7% vs. 4.8%). Short-duration DAPT in patients with acute coronary syndrome was linked with decreased risk of bleeding and net adverse cardiovascular events.Conclusion: Short-duration DAPT significantly lowers bleeding risk and reduces net clinical adverse events without increasing ischemic risk, making it a reasonable choice for people with new-generation drug eluting stents, particularly those with highbleeding risk or recent surgery.

Effect of CYP3A5*3 genotype on exposure and efficacy of quetiapine: A retrospective, cohort study

BackgroundThe involvement of cytochrome P450 3A5 (CYP3A5) in the metabolism of quetiapine has been proposed, though conclusive evidence is lacking. This study aimed to quantitatively assess the impact of CYP3A5 genetic variability on quetiapine exposure in a Chinese patient population. MethodsPatient data were retrospectively collected from the database of the Mental Health Centre at the First Hospital of Hebei Medical University, covering the period from September 1, 2019, to July 1, 2023. The study included patients genotyped for CYP3A5 who were treated with quetiapine. Inclusion criteria for the analysis of pharmacokinetic parameters, such as serum concentrations of the drug and its metabolites, included oral administration of quetiapine, availability of information on the prescribed daily dose and concomitant medications, and the determination of steady-state blood levels at the time of sampling (after at least 3 days of continuous administration at the same dose). Exclusion criteria comprised polypharmacy with known CYP3A4 inducers or inhibitors, as well as patients with hepatic or renal insufficiency. The primary endpoint was the exposure to quetiapine and N-dealkylquetiapine, measured using dose-corrected concentrations (C/D). The secondary endpoint was the metabolism of quetiapine to N-dealkylquetiapine, assessed by the ratio of metabolite to parent drug concentrations. The third endpoint is the differences in adverse reactions, QTc intervals, and biochemical parameters among patients with different CYP3A5 genotypes. ResultBased on the inclusion and exclusion criteria, clinical data from 207 patients were ultimately included in the study. Of these, 20 patients had the CYP3A5*1/*1 genotype, 78 had the CYP3A5*1/*3 genotype, and 109 had the CYP3A5*3/*3 genotype. The CYP3A5*3 variant was found to significantly impact the metabolism of quetiapine. The C/D values for both quetiapine and N-dealkyl quetiapine were notably higher in individuals with the *3/*3 genotype compared to those with the *1/*1 and *1/*3 genotypes (P1 < 0.001 and P2 = 0.002, respectively). A comparison of the variability in metabolic ratios among different genotype groups revealed no significant difference (P = 0.067). However, a post hoc analysis indicated that the metabolic ratio in poor metabolizers was significantly lower than that in intermediate metabolizers (P = 0.021). The analysis of adverse reaction incidence and QTc intervals among different genotypes showed no statistically significant differences (P = 0.652, P = 0.486). However, comparison of biochemical parameters across different genotype groups revealed that alanine aminotransferase, uric acid, hemoglobin, and gamma-glutamyl transferase levels were significantly higher in patients with the CYP3A5*3/*3 genotype compared to those with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes. ConclusionThe results indicated that the genetic polymorphism of CYP3A5*3 significantly influences the metabolism of quetiapine. Specifically, carriers of the CYP3A5*3/*3 genotype exhibited higher blood levels of quetiapine, with a greater likelihood of these levels exceeding the therapeutic range. This finding underscores the need for clinicians to pay special attention to the efficacy and occurrence of adverse reactions when prescribing quetiapine to patients carrying the CYP3A5*3/*3 genotype.

A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer

BackgroundPatients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. MethodsPatients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH−, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. ResultsIntravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. ConclusionsP-AscH− infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).