Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.

OBJECTIVE: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum. METHODS: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls. RESULTS: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity. INTERPRETATION: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

Brain Iron Dysregulation in Iron Deficiency Anemia-Related Restless Leg Syndrome Revealed by Neuron-Derived Extracellular Vesicles: A Case-Control Study.

Brain iron deficiency (ID) and, to a degree, systemic ID have been implicated in restless leg syndrome (RLS) pathogenesis. Previously, we found increased ferritin in neuron-derived extracellular vesicles (NDEVs) in RLS, suggesting a mechanism for depleting intracellular iron by secreting ferritin-loaded NDEVs. In this study, we hypothesized that increased NDEV ferritin occurs even in RLS accompanied by systemic ID and that neuronal intracellular iron depletion in RLS also manifests as NDEV abnormalities in other iron regulatory proteins, specifically, decreased transferrin receptor (TfR) and increased ferroportin. To address these hypotheses, we studied 71 women with ID anemia, 36 with RLS, and 35 without RLS. Subjects with RLS again showed higher NDEV ferritin and also decreased TfR, suggesting diminished neuronal capacity for iron uptake. Findings inform a more complete understanding of the pathogenic role of neuronal iron homeostasis and dissociate it from peripheral ID. ANN NEUROL 2024.

Imaging-based non-invasive liver disease assessment for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Transient elastography (TE), shear-wave elastography (SWE), and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). APPROACH AND RESULTS: A comprehensive search for studies assessing LSM by TE, SWE, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), utilizing histopathology as standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV co-infection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. CONCLUSION: LSM from TE, SWE, and MRE show acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Blood-based biomarkers have been proposed as an alternative to liver biopsy for non-invasive liver disease assessment (NILDA) in chronic liver disease (CLD). Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4) and cirrhosis (F4), as compared to biopsy in CLD. APPROACH AND RESULTS: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aminotransferase-to-platelet ratio index (APRI) and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in hepatitis B virus (HBV) and C virus (HCV), HIV-HCV/HBV co-infection, and nonalcoholic fatty liver disease (NAFLD). Positive (LR+) and negative (LR) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86 respectively; LR+ and LR for NAFLD F2-4, F3-4 and F4 were 2-65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15 respectively. Overall, proportional odds ratio indicated FIB-4 <1.45 was better than APRI <0.5 for F2-4. FIB-4 >3.25 was also better than APRI >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS: Blood-based biomarkers are associated with small-to-moderate change in pre-test probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV co-infection, and NAFLD, with limited comparative or combination studies for other CLD.

Open-Label Sulforaphane Trial in FMR1 Premutation Carriers with Fragile-X-Associated Tremor and Ataxia Syndrome (FXTAS).

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

Comparative assessment of Alzheimer's disease-related biomarkers in plasma and neuron-derived extracellular vesicles: a nested case-control study.

Introduction: Alzheimer's disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aß deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers. Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aß42, Aß40, total Tau, P181-Tau) alongside several other exploratory markers. Results: The Aß42/Aß40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aß42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aß42/Aß40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker. Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Effectiveness and safety of intracranial events associated with the use of direct oral anticoagulants for atrial fibrillation: A systematic review and meta-analysis of 92 studies.

AIMS: Observational studies have investigated the effectiveness and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) used in nonvalvular atrial fibrillation. We performed a systematic review and meta-analysis assessing the risk of ischaemic stroke, thromboembolism (TE) and intracranial haemorrhage (ICH) associated with the use of DOACs and VKAs. METHODS: Medline and Embase were systematically searched until April 2021. Observational studies were gathered and hazard ratios (HRs) with 95% confidence intervals (CI) were extracted. Subgroup analyses based on DOAC doses, history of chronic kidney disease, stroke, exposure to VKA, age and sex were performed. A random-effects model was used. RESULTS: We included 92 studies and performed 107 comparisons. Apixaban was associated with lower risk of stroke (HR: 0.82, 95% CI: 0.68-0.99) compared to dabigatran. Rivaroxaban was associated with lower risk of stroke (HR: 0.90, 95% CI: 0.83-0.98) compared to VKA. Dabigatran (HR: 0.85, 95% CI: 0.80-0.91), rivaroxaban (HR: 0.83, 95% CI: 0.77-0.89) and apixaban (HR: 0.75, 95% CI: 0.65-0.86) were associated with lower risk for TE/stroke compared to VKA. Apixaban (HR: 1.32, 95% CI: 1.03-1.68) and rivaroxaban (HR: 1.58, 95% CI: 1.31-1.89) were associated with higher risk of ICH compared to dabigatran. Dabigatran (HR: 0.48, 95% CI: 0.44-0.52), apixaban (HR: 0.60, 95% CI: 0.49-0.73) and rivaroxaban (HR: 0.73, 95% CI: 0.65-0.81) were associated with lower risk of ICH compared to VKA. CONCLUSION: Our study demonstrated significant differences in the risk of ischaemic stroke, TE/stroke and ICH associated with individual DOACs compared to both other DOACs and VKA.

Isolated Abducens Nerve Palsy in a Patient With COVID-19: A Case Report and Literature Review.

INTRODUCTION: The pandemic of coronavirus disease 2019 (COVID-19) stands as a major global health and social burden. As cases are growing, several other symptoms, besides the typical respiratory ones, are emerging. The involvement of the nervous system is increasingly recognized with manifestations ranging from hyposmia to meningoencephalitis and cranial neuropathies. CASE REPORT: We report the case of a 41-year-old female patient who presented to the emergency department complaining of diplopia and headache over the last 2 days. She denied any medical history, as well as any other neurological or respiratory symptom. A detailed neurological and ophthalmological examination revealed a limitation to the abduction of the right eye due to palsy of the right lateral rectus muscle causing painless, horizontal diplopia in the right gaze. The computed tomography of the brain was normal. Based on the detected lymphopenia, she was tested for COVID-19 and was positive. The cerebrospinal fluid analysis showed no abnormalities, while also a repeated head computed tomography was similarly normal. The patient received no specialized medical treatment, and after 6 days, she was discharged home having a minimal degree of persistent diplopia. Two weeks later, brain magnetic resonance imaging was performed that was similarly unrevealing. CONCLUSIONS: Isolated abducens nerve palsy can be the only presenting symptom in COVID-19. Although several pathophysiological mechanisms have been proposed, the exact nature of this manifestation has not been clarified yet. Vigilance is required by neurologists to detect and manage patients with such subtle clinical presentations.

Dabigatran, rivaroxaban, and apixaban are superior to warfarin in Asian patients with non-valvular atrial fibrillation: An updated meta-analysis.

BACKGROUND: Most of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation (AF) originated from western countries. AIM: To systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran, rivaroxaban, and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF. METHODS: Medline, Cochrane, and ClinicalTrial.gov databases were reviewed. A random-effect model meta-analysis was used and I-square was utilized to assess the heterogeneity. The primary outcome was ischemic stroke. The secondary outcomes were all-cause mortality, major bleeding, intracranial hemorrhage, and gastrointestinal bleeding. RESULTS: Twelve studies from East Asia or Southeast Asia and 441450 patients were included. Dabigatran, rivaroxaban, and apixaban were associated with a significant reduction in the incidence of ischemic stroke [hazard ratio (HR) = 0.78, 95% confidence interval (CI): 0.65-0.94; HR = 0.79, 95%CI: 0.74-0.85, HR = 0.70, 95%CI: 0.62-0.78; respectively], all-cause mortality (HR = 0.68, 95%CI: 0.56-0.83; HR = 0.66, 95%CI: 0.52-0.84; HR = 0.66, 95%CI: 0.49-0.90; respectively), and major bleeding (HR = 0.61, 95%CI: 0.54-0.69; HR = 0.70, 95%CI: 0.54-0.90; HR = 0.58, 95%CI: 0.43-0.78; respectively) compared to warfarin. CONCLUSION: Dabigatran, rivaroxaban, and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.

Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: A systematic review and network meta-analysis.

AIM: To compare the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. METHODS: We searched Medline, Embase, the Cochrane Library, and grey literature sources until 29 September 2020 for randomized controlled trials of at least 24 weeks' duration assessing the effects of glucose-lowering drugs on body weight and blood pressure in adults with type 2 diabetes. We performed frequentist network meta-analyses and calculated weighted mean differences and 95% confidence intervals combining trial arms of different approved doses of a given intervention into a single group. We evaluated the confidence in pooled estimates using the CINeMA (Confidence In Network Meta-Analysis) framework. RESULTS: In total, 424 trials (276 336 patients) assessing 21 antidiabetic medications from nine drug classes were included. Subcutaneous semaglutide was the most efficacious in reducing body weight followed by oral semaglutide, exenatide twice-daily, liraglutide, and the sodium-glucose co-transporter-2 (SGLT-2) inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. The same agents also conferred the greatest reductions in systolic blood pressure. Metformin had a modest effect in reducing body weight and systolic blood pressure. Diastolic blood pressure was reduced with the SGLT-2 inhibitors pioglitazone, exenatide twice-daily and semaglutide. In subgroup analyses of trials with over 52 weeks' duration, semaglutide and SGLT-2 inhibitors reduced both body weight and systolic blood pressure. CONCLUSIONS: Semaglutide and SGLT-2 inhibitors conferred reductions both in body weight and blood pressure that were sustainable for over 1 year of treatment. These agents may be preferable treatment options for patients with type 2 diabetes who are overweight/obese and/or hypertensive.

Comparative efficacy and safety of glucose-lowering drugs as adjunctive therapy for adults with type 1 diabetes: A systematic review and network meta-analysis.

AIM: To assess the efficacy and safety of glucose-lowering drugs used as an adjunct to insulin therapy in adults with type 1 diabetes. METHODS: We searched Medline, Embase and the Cochrane Central Register of Controlled Trials up to 24 January 2020 for randomized controlled trials. Our primary outcome was change in HbA1c. We additionally assessed eight efficacy and six safety secondary endpoints. We performed random effects frequentist network meta-analysis to estimate mean differences (MDs) and odds ratios (ORs), alongside 95% confidence intervals (CIs). We assessed risk of bias and evaluated confidence in the evidence for the primary outcome. RESULTS: We included 58 trials comprising 13 216 participants. Overall, sodium-glucose co-transporter (SGLT) inhibitors, liraglutide, glibenclamide, acarbose and metformin reduced HbA1c compared with placebo (MDs ranging from -0.46% [95% CI -0.64% to -0.29%] for empagliflozin to -0.20% [-0.35% to -0.06%] for metformin). SGLT inhibitors, exenatide daily, liraglutide and metformin reduced body weight and total daily insulin dose, while liraglutide and SGLT inhibitors reduced blood pressure. Diabetic ketoacidosis and genital infections were more frequent with SGLT inhibitors, while exenatide, liraglutide, pramlintide and metformin increased the incidence of nausea. No drug increased the incidence of severe hypoglycaemia. Confidence in evidence was mainly moderate to very low. CONCLUSIONS: Specific drugs may improve glycaemic control and reduce body weight, blood pressure and total daily insulin dose in patients with type 1 diabetes. However, low quality of evidence and an increased risk of diabetic ketoacidosis, genital infections or gastrointestinal adverse events should be taken into consideration by healthcare providers and patients. Future long-term trials are needed to clarify their benefit-to-risk profile and elucidate their role in clinical practice.

Prospective Surveillance and Risk Reduction of Cancer Treatment-Related Lymphedema: Systematic Review and Meta-Analysis.

PROBLEM IDENTIFICATION: Secondary lymphedema is a chronic condition that may result from cancer-related treatments. Evidence is emerging on prospective surveillance and risk reduction. LITERATURE SEARCH: Databases were systematically searched through April 1, 2019, for comparative studies evaluating interventions aiming to prevent lymphedema in patients with cancer. DATA EVALUATION: A random-effects model was used to perform meta-analysis, when appropriate. SYNTHESIS: A total of 26 studies (4,095 patients) were included, with 23 providing data sufficient for meta-analysis. Surveillance programs increased the likelihood of detecting lymphedema. Physiotherapy, exercise programs, and delayed exercise reduced the incidence of lymphedema. IMPLICATIONS FOR RESEARCH: Future research should standardize (a) evidence-based interventions to reduce the development of lymphedema and increase the likelihood of early detection and (b) outcome measures to build a body of evidence that leads to practice change. SUPPLEMENTAL MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //onf.ons.org/supplementary-material-systematic-review-cancer-treatment-related-lymphedema.

Targeted Therapy- and Chemotherapy-Associated Skin Toxicities: Systematic Review and Meta-Analysis.

PROBLEM IDENTIFICATION: Preventing and managing skin toxicities can minimize treatment disruptions and improve well-being. This systematic review aimed to evaluate the effectiveness of interventions for the prevention and management of cancer treatment-related skin toxicities. LITERATURE SEARCH: The authors systematically searched for comparative studies published before April 1, 2019. Study selection and appraisal were conducted by pairs of independent reviewers. DATA EVALUATION: The random-effects model was used to conduct meta-analysis when appropriate. SYNTHESIS: 39 studies (6,006 patients) were included; 16 of those provided data for meta-analysis. Prophylactic minocycline reduced the development of all-grade and grade 1 acneform rash in patients who received erlotinib. Prophylaxis with pyridoxine 400 mg in capecitabine-treated patients lowered the risk of grade 2 or 3 hand-foot syndrome. Several treatments for hand-foot skin reaction suggested benefit in heterogeneous studies. Scalp cooling significantly reduced the risk for severe hair loss or total alopecia associated with chemotherapy. IMPLICATIONS FOR RESEARCH: Certainty in the available evidence was limited for several interventions, suggesting the need for future research. SUPPLEMENTAL MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //onf.ons.org/supplementary-material-targeted-therapy-and-chemotherapy-associated-skin-toxicity-systematic-review.

Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

BACKGROUND: Several pharmacologic options for type 2 diabetes are available. PURPOSE: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes. DATA SOURCES: Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020. STUDY SELECTION: English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. DATA EXTRACTION: Pairs of reviewers extracted data and appraised risk of bias. DATA SYNTHESIS: 453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively. LIMITATION: Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk. CONCLUSION: In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes. PRIMARY FUNDING SOURCE: European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).

Carvedilol for prevention of variceal bleeding: a systematic review and meta-analysis.

BACKGROUND: Beta-blockers are used for prophylaxis of variceal bleeding. Our aim was to assess the efficacy and safety of carvedilol for primary or secondary prevention of variceal bleeding in patients with cirrhosis. METHODS: We searched Medline, Embase, CENTRAL and gray literature sources for randomized controlled trials (RCTs) comparing carvedilol with placebo or any active intervention. We synthesized data using random effects models. We summarized the strength of evidence using GRADE criteria. RESULTS: We included 13 trials with 1598 patients. Carvedilol was as efficacious as endoscopic variceal ligation (EVL) (4 RCTs, risk ratio [RR] 0.74, 95% confidence interval [CI] 0.37-1.49) or propranolol (3 RCTs, RR 0.76, 95%CI 0.27-2.14) for primary prevention of variceal bleeding. Likewise, carvedilol was as efficacious as EVL (3 RCTs, RR 1.10, 95%CI 0.75-1.61), non-selective beta-blockers (NSBBs) plus isosorbide-5-mononitrate (2 RCTs, RR 1.02, 95%CI 0.70-1.51) or propranolol (2 RCTs, RR 0.39, 95%CI 0.15-1.03) for secondary prevention of variceal bleeding. Carvedilol was associated with lower all-cause mortality compared to EVL (3 RCTs, RR 0.51, 95%CI 0.33-0.79). There was no difference in any other efficacy outcome. Finally, there were no significant differences in the safety profiles compared with EVL and NSBBs. Our confidence in the effect estimates for all outcomes was very low. CONCLUSION: Carvedilol is as efficacious and safe as standard-of-care interventions for the primary and secondary prevention of variceal bleeding.

Intravenous Immunoglobulin for Patients With Alzheimer's Disease: A Systematic Review and Meta-Analysis.

AIM: To assess the efficacy and safety of intravenous immunoglobulin (IVIg) for patients with Alzheimer's disease (AD). MATERIALS AND METHODS: We searched electronic databases and other sources for randomized controlled trials comparing IVIg with placebo or other treatment for adults with AD. Primary outcome was change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). RESULTS: Five placebo-controlled trials were included in the meta-analysis. Compared to placebo, IVIg 0.2 and 0.4 g/kg once every two weeks did not change ADAS-Cog score (weighted mean difference: 0.37, 95% confidence interval: -1.46 to 2.20 and 0.77, -1.34 to 2.88, respectively). Furthermore, except for an increase in the incidence of rash, IVIg did not affect the incidence of other adverse events. CONCLUSION: IVIg, albeit safe, is inefficacious for treatment of patients with AD. Future trials targeting earlier stages of disease or applying different dosing regimens may be warranted to clarify its therapeutic potential.

Semaglutide for type 2 diabetes mellitus: A systematic review and meta-analysis.

AIMS: To assess the efficacy and safety of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes. MATERIALS AND METHODS: We searched major electronic databases and grey literature sources for randomized controlled trials comparing semaglutide with placebo or other antidiabetic agents. Primary outcome was change from baseline in HbA1c. Secondary endpoints included change from baseline in body weight, blood pressure, heart rate and incidence of hypoglycaemia, gastrointestinal adverse effects, pancreatitis and diabetic retinopathy. RESULTS: A total of 6 placebo-controlled and 7 active-controlled studies with subcutaneous semaglutide were included. We identified only 1 trial with oral semaglutide. Compared with placebo, subcutaneous semaglutide 0.5 and 1 mg reduced HbA1c by 1.01% (95% CI, 0.56-1.47) and 1.38% (1.05-1.70), respectively. Both doses demonstrated superior glycaemic efficacy compared to other antidiabetic agents, including sitagliptin, exenatide, liraglutide, dulaglutide and insulin glargine. Semaglutide also had a beneficial effect on body weight (mean difference vs placebo -4.11 kg, 95% CI -4.85 to -3.37 for semaglutide 1 mg) and systolic blood pressure. We did not observe increased hypoglycaemia rates with semaglutide; nevertheless, we noted an increased incidence of nausea, vomiting and diarrhoea. Cases of pancreatitis were infrequent and the odds ratio for diabetic retinopathy compared with placebo was 1.32 (95% CI, 0.98-1.77). CONCLUSIONS: Semaglutide is a potent once-weekly GLP-1 RA, significantly reducing HbA1c, body weight and systolic blood pressure. However, it is associated with increased incidence of gastrointestinal adverse events. Results for pancreatitis and retinopathy require further assessment in post-approval pharmacovigilance studies.