Urinary incontinence as a possible signal of neuromuscular toxicity during immune checkpoint inhibitor treatment: Case report and retrospective pharmacovigilance study.

Background: Immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), but there is limited evidence regarding the association between urinary incontinence and ICIs. Methods: We described the case of a patient experiencing urinary incontinence who later experienced a series of irAEs such as myocarditis, myositis, and neurologic diseases while on ICI treatment in our hospital. In addition, we queried the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from the third quarter of 2010 to the third quarter of 2020 to perform a retrospective study to characterize the clinical features of urinary incontinence associated with ICIs. Result: In the FAERS study, 59 cases of ICI-related urinary incontinence were retrieved, and approximately 32.2% of the cases were fatal. Combination therapy with nervous system drugs and age >80 years old were the significant risk factors for fatal outcomes. Among these cases of ICI-related urinary incontinence, 40.7% (n = 24) occurred concomitantly with other adverse events, especially, neurological (fifteen cases), cardiovascular (seven cases), musculoskeletal (six cases), and urological disorders (five cases). Five cases had an overlapping syndrome similar to our case report, including one case of myasthenia gravis with myocarditis and another of myasthenic syndrome with polymyositis. Conclusion: ICI-related urinary incontinence might be a signal of fatal neuromuscular irAEs, especially when it occurs concomitantly with ICI-associated neuromuscular-cardiovascular syndrome. Clinicians should be aware of the occurrence of urinary incontinence to identify potentially lethal irAEs in the early phase.

Endovascular thrombectomy with or without intravenous alteplase for acute ischemic stroke due to large vessel occlusion: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Among patients who had an ischaemic stroke presenting directly to a stroke centre where endovascular thrombectomy (EVT) is immediately available, there is uncertainty regarding the role of intravenous thrombolysis agents before or concurrently with EVT. To support a rapid guideline, we conducted a systematic review and meta-analysis to examine the impact of EVT alone versus EVT with intravenous alteplase in patients who had an acute ischaemic stroke due to large vessel occlusion. METHODS: In November 2021, we searched MEDLINE, Embase, PubMed, Cochrane, Web of Science, clincialtrials.gov and the ISRCTN registry for randomised controlled trials (RCTs) comparing EVT alone versus EVT with alteplase for acute ischaemic stroke. We conducted meta-analyses using fixed effects models and assessed the certainty of evidence using the GRADE approach. RESULTS: In total 6 RCTs including 2334 participants were eligible. Low certainty evidence suggests that, compared with EVT and alteplase, there is possibly a small decrease in the proportion of patients independent with EVT alone (risk ratio (RR) 0.97, 95% CI 0.89 to 1.05; risk difference (RD) -1.5%; 95% CI -5.4% to 2.5%), and possibly a small increase in mortality with EVT alone (RR 1.07, 95% CI 0.88 to 1.29; RD 1.2%, 95% CI -2.0% to 4.9%) . Moderate certainty evidence suggests that there is probably a small decrease in symptomatic intracranial haemorrhage (sICH) with EVT alone (RR 0.75, 95% CI 0.52 to 1.07; RD -1.0%; 95%CI -1.8% to 0.27%). CONCLUSIONS: Low certainty evidence suggests that there is possibly a small decrease in the proportion of patients that achieve functional independence and a small increase in mortality with EVT alone. Moderate certainty evidence suggests that there is probably a small decrease in sICH with EVT alone. The accompanying guideline provides contextualised guidance based on this body of evidence. PROSPERO REGISTRATION NUMBER: CRD42021249873.

Effect of bariatric surgery on long-term cardiovascular outcomes: a systematic review and meta-analysis of population-based cohort studies.

This meta-analysis aimed to compare the effects of bariatric surgery and nonsurgery on cardiovascular outcomes in patients with obesity. A systematic literature search of the Medline (via PubMed), Embase, and Cochrane Central Register of Controlled Trials databases was performed until August 18th, 2021. Population-based cohort studies comparing long-term cardiovascular outcomes for patients with obesity undergoing bariatric surgery or not were included. A meta-analysis of relative risks (RRs) was performed for all outcomes. We conducted subgroup analyses and meta-regression to explore sources of heterogeneity and the stability of the results. Twenty-one population-based cohort studies involving 2,857,016 participants were identified. The major adverse cardiovascular event (MACE) RR in the bariatric surgery group was .53 (95% confidence interval [CI] = .45-.62, P < .001) relative to the nonsurgical group. Relative to the nonsurgical group, the risk of myocardial infarction (MI) (RR = .40, 95% CI = .30-.52, P < .001), stroke (RR = .60, 95% CI = .46-.79, P < .001), cardiovascular death (RR = .43, 95% CI = .35-.54, P < .001), and all-cause death (RR = .44, 95% CI = .32-.59, P < .001) was significantly reduced for patients who underwent bariatric surgery. In subgroup analyses, as the proportion of patients with diabetes mellitus increased, lower RRs for MACE, MI, and stroke were observed in the surgery group relative to the nonsurgical group. The decreased risk of MACE was also observed in the subgroup with median follow-up duration ≥5 years.Bariatric surgery improves cardiovascular outcomes in patients with obesity, especially providing long-term benefits, and this effect is more pronounced in patients with comorbid diabetes.

Opioid exposure during pregnancy and the risk of congenital malformation: a meta-analysis of cohort studies.

BACKGROUND: Opioid exposure during pregnancy has increased alarmingly in recent decades. However, the association between prenatal opioid exposure and congenital malformation risk has still been controversial. We aim to assess the association between opioid exposure during pregnancy and the risk of congenital malformations. METHOD: PubMed, Embase, and Cochrane library of clinical trials were systematically searched to September 13th, 2021. Cohort studies reporting risk of congenital malformation after opioid exposure compared with non-exposure during pregnancy were included. Risk of studies was appraised with the ROBINS-I tool. Meta-analysis was conducted using the random-effects model. Subgroup analyses were conducted for the primary outcome based on indication, exposed period, whether adjusted data was used, and risk of bias assessment. Meta-regression was performed to evaluate the relation of publication year. MAIN RESULTS: Eighteen cohort studies with 7,077,709 patients were included. The results showed a significant increase in the risk of overall congenital malformation (RR = 1.30, 95%CI: 1.11-1.53), major malformation (RR = 1.57, 95%CI:1.11-2.22), central nervous system malformation (RR = 1.36, 95% CI:1.19-1.55), and limb malformation (RR = 2.27, 95%CI:1.29-4.02) with opioid exposure during pregnancy. However, the predictive interval conveyed a different result on overall congenital malformation (95%PI: 0.82-2.09) and major malformation (95%PI: 0.82-2.09). No association between opioid exposure and overall congenital malformation in the first trimester (RR = 1.12, 95%CI:0.97-1.31) and prescribed for analgesic or antitussive treatment (RR = 1.03, 95%CI:0.94-1.13) were observed. In subgroups that study provided data adjusted for confounders (RR = 1.06, 95%CI:0.93-1.20) or identified moderate or serious risk of bias (RR = 1.00, 95%Cl: 0.85-1.16; RR = 1.21, 95%Cl: 1.60-2.68), no association was found. CONCLUSION: Opioid exposed in the first trimester or prescribed for analgesic or antitussive treatment did not increase the risk of overall congenital malformation. The findings should be discussed in caution considering the situation of individual patients and weigh out its potential risk of congenital malformation. TRIAL REGISTRATION: Registration number: CRD42021279445 .

Efficacy and safety of genotype-guided warfarin dosing versus non-genotype-guided warfarin dosing strategies: A systematic review and meta-analysis of 27 randomized controlled trials.

OBJECTIVE: To evaluate the efficacy and safety of genotype-guided dosing (GD) strategies compared to non-genotype-guided dosing (non-GD) strategies for warfarin. METHODS: Databases were searched up to July 2021. Meta-analysis was conducted with the Review Manager software (version 5.4) and R (version 4.0.5). Risk ratio (RR), mean difference (MD), and 95% confidence intervals (CIs) were used. Subgroup analyses were conducted based on ethnicity and dosing regimen in non-GD group. Meta-regression was performed to evaluate the relation of covariates. This study is registered with PROSPERO (CRD42021245654). RESULTS: 27 randomized controlled trials with a total of 9906 patients were included. The GD group resulted in a significantly improved time in therapeutic range compared with non-GD group in follow-up duration within 30 days (MD: 5.95, 95%CI: 2.41-9.22, P = 0.001) and beyond 30 days (MD: 4.93, 1.40-8.47, P = 0.006), time to the first therapeutic international normalized ratio (MD: -1.80, -2.69 - -0.92, P < 0.0001), and time to reach stable dose (MD: -5.08, -7.09 - -3.07, P < 0.00001), incidence of major bleeding events (RR: 0.50, 0.33-0.75, P = 0.0008), total bleeding events (RR: 0.83, 0.73-0.95, P = 0.006), and thromboembolism (RR: 0.69, 0.49-0.96, P = 0.03). No differences were found in stable dose achievement, minor bleeding events, over anticoagulation, and all-cause mortality. Four improved efficacy outcomes were observed in GD group compared with fixed dosing group. Only time to the therapeutic INR was shortened in GD group compared with clinical adjusted dosing group. The result showed no difference of safety outcomes between GD group and fixed dosing group whereas a decreased incidence of major bleeding events was observed when comparing to clinical adjusted dosing group. CONCLUSION: GD strategy was superior to fixed dosing strategy in term of efficacy outcomes and comparable to fixed dosing strategy in safety outcomes. Clinical adjusted regimen could partly substitute the genotype-guided dosing strategy for efficacy in insufficient conditions, but the risk of major bleeding events should be monitored.

Genotype-Guided Antiplatelet Therapy Versus Standard Therapy for Patients with Coronary Artery Disease: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Previous studies on the efficacy and safety of genotype-guided antiplatelet therapy in patients with coronary artery disease (CAD) or undergoing percutaneous coronary intervention (PCI) have been inconclusive. AIM: We conducted a meta-analysis to evaluate if the genotype-guided antiplatelet strategy is superior to the standard therapy in patients with CAD or undergoing PCI. METHOD: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to October 1st, 2021. Studies reporting efficacy and safety outcomes in the genotype-guided treatment and standard treatment groups were included. The two groups were statistically compared. RESULT: Eleven randomized controlled trials (RCTs) involving 11740 patients were included in this meta-analysis. Compared with the standard treatment group, the genotype-guided group had significant lower risks of all efficacy outcomes, including major adverse cardiovascular events (MACEs) (RR 0.60, 95%, CI 0.44-0.82, P=0.001), all-cause death (RR 0.70, 95% CI 0.51-0.95, P=0.02), cardiovascular death (RR 0.71, 95% CI 0.53-0.95, P=0.02), myocardial infarction (RR 0.53, 95% CI 0.42-0.67, P<0.0001), stroke (RR 0.64, 95% CI 0.41-0.98, P=0.04), stent thrombosis (RR 0.63, 95% CI 0.43-0.91, P=0.01) and targeted vessel revascularization (RR 0.79, 95% CI 0.67-0.92, P=0.003). There was no significant difference in any bleeding events between the two groups. As a result of the subgroup analyses, the genotype-guided treatment was more likely to reduce the incidence of MACEs in the subgroup where the proportion of patients with ACS was ≥ 90%, and subgroup of the Chinese population. CONCLUSION: Genotype-guided antiplatelet treatment could reduce the risk of MACEs without increasing the risk of bleeding events as compared with the standard treatment in patients with CAD or those undergoing PCI. In addition, Genotype-guided antiplatelet treatment might benefit Chinese population or patients with ACS.

Clinical practice guidelines for management of dual antiplatelet therapy in patients with noncardiac surgery: A critical appraisal using the AGREE II instrument.

WHAT IS KNOWN AND OBJECTIVE: Despite the availability of clinical practice guidelines (CPGs), there are considerable differences in their recommendations in the perioperative management of stented patients who need elective noncardiac surgery. Our aim was to systematically review the quality of CPGs for perioperative management of dual antiplatelet therapy (DAPT) and summarize the recommendations. METHODS: A systematic search for perioperative DAPT guidelines was conducted on PubMed, Embase and websites of guideline organizations and professional societies until 4 February 2021. Independently, two assessors appraised the quality of CPGs using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument and extracted the data. Recommendations were summarized, and a comparative study was conducted to analyse the consistency among guidelines. RESULTS AND DISCUSSION: A total of 10 guidelines fulfilled our inclusion criteria. The domain of scope and purpose and clarity of presentation obtained the highest median scores, while the domain of stakeholder involvement and rigour of development obtained the lowest median scores. Three guidelines (ACCP, ESC/ESA and ACC/AHA) with a score of at least 60% in most AGREE II domains were recommended. Recommendations across perioperative management of DAPT guidelines were inconsistent. WHAT IS NEW AND CONCLUSION: The ACCP, ESC/ESA and ACC/AHA CPGs were recommended. There is a need for high-quality prospective studies assessing different management strategies on this issue. Given the lack of consensus, the results of this study will help to guide perioperative dual antiplatelet management strategies for patients with coronary stents who are undergoing noncardiac surgery.

DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation.

Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.

Effect of polymorphisms of MTHFR in controlled ovarian stimulation: a systematic review and meta-analysis.

OBJECTIVE: Although several studies have reported a potential impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on controlled ovarian stimulation (COS), the results remain controversial. The aim of the systematic review and meta-analysis was to evaluate the effect of MTHFR polymorphism on COS outcomes. METHODS: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to December 2, 2020. COS clinical outcomes based on gene polymorphisms were included. Two reviewers independently extracted the data. The primary outcome was the number of oocytes retrieved. The secondary outcomes were the number of metaphase II (MII) oocytes, stimulation duration, basal follicle-stimulating hormone (FSH) level, FSH dosage, positive pregnancy test, ongoing pregnancy rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Meta-analysis was performed using a fixed-effect model or random-effect model with Review Man 5.3.5. Mean difference (MD) with 95% confidence intervals (95%CIs) was calculated for continuous outcomes. The quality assessment of included studies was evaluated by using the Newcastle-Ottawa Scale. RESULTS: Eleven studies were included in the systematic review, and seven studies with 2015 participants were included in the meta-analysis. Basal FSH level was significantly lower in CC homozygotes than TT homozygotes (four studies, 867 participants, MD - 0.54, 95%CI - 0.85 to - 0.23, P = 0.0006; I2 = 0%) of MTHFR (rs1801133). FSH dose was significantly fewer in CC homozygotes compared with CT heterogeneous (three studies, 949 participants, MD - 75.78, 95%CI - 135.23 to - 16.33, P = 0.01; I2 = 32%) or CT/TT model (three studies, 1097 participants, MD - 80.18, 95%CI - 135.54 to - 24.81, P = 0.005; I2 = 42%). Differences in the oocytes retrieved and stimulation duration were insignificant. Gene variants on MTHFR (rs1801133) and MTHFR (rs1801131) were reported in ongoing pregnancy rate, clinical pregnancy rate, and live birth rate. CONCLUSION: Studies to date indicate that polymorphisms of MTHFR could influence basal FSH level and FSH dose. The results could be useful to promote clinical practice on COS protocols. Further studies are needed to evaluate the clinical relevance of the multigene combination on COS.