Albumin therapy for hepatic encephalopathy: current evidence and controversies.

Hepatic encephalopathy (HE) is a common complication that occurs in 16-21% of end-stage cirrhosis patients. Emerging evidence suggests that systemic inflammation and oxidative stress may play a role in the development of HE. Recent understanding on the anti-inflammatory properties of human albumin has led to growing interest of using human albumin for the treatment and prevention of HE among decompensated patients. In this review, we aim to discuss the current evidence and controversies of using human albumin for the treatment and prevention of HE in advanced cirrhosis patients.

Effectiveness of Sensor-based Rehabilitation in Improving Outcomes in Patients Undergoing Total Knee Arthroplasty.

BACKGROUND: Physical rehabilitation after total knee arthroplasty (TKA) is important for long-term functional recovery. Recently, sensor-based home rehabilitation (SHR) has gained prominence as a promising method that allows monitoring and guidance that is both structured and accessible, compared to traditional methods of physical rehabilitation. Despite the advent of wearable sensor systems, there is a paucity of evidence regarding SHR in the current literature. Thus, this systematic review aimed to evaluate the effect of wearable SHR on post-TKA outcomes. METHODS: We performed a systematic search of three electronic databases from the beginning of record to March 12, 2021. Primary outcomes were patient-reported outcome measures (PROMs) after rehabilitation, including the Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) and Knee Society Score (KSS). Secondary outcomes were physical activity levels and functional performance including range of motion (ROM) and Timed Up and Go Test (TUG). RESULTS: A total of 16 studies involving 1321 subjects were included. All wearable sensors in our included studies involved a combination of accelerometers, gyroscopes and magnetometers as functional units. These studies reported favourable outcomes for all three PROMs, although the extent of improvement in specific domains varied among studies. Moreover, physical activity in terms of daily steps and time spent on physical activity increased post-rehabilitation. Similarly, there were improvements in ROM and TUG that reflected a favourable post-operative trajectory during rehabilitation. CONCLUSION: SHR is effective for improving subjective and objective outcomes post-TKA. The role of SHR should be evaluated by a dedicated cost-benefit analysis to facilitate its wider adoption in healthcare systems.

Effectiveness of sleeve gastrectomy plus fundoplication versus sleeve gastrectomy alone for treatment of patients with severe obesity: a systematic review and meta-analysis.

BACKGROUND: Laparoscopic sleeve gastrectomy (SG) is a widely performed bariatric surgery, but it is associated with an increased risk of gastroesophageal reflux (GERD) in the long term. The addition of fundoplication to laparoscopic SG may improve lower oesophageal sphincter function and reduce postoperative GERD. OBJECTIVES: This systematic review and meta-analysis aims to compare the efficacy and safety of SG plus fundoplication (SG + F) versus SG alone for the treatment of patients with severe obesity (≥35 kg/m2). SETTING: Meta-analysis. METHODS: Three electronic databases were searched from inception until January 2023. Studies were included if they compared outcomes of SG + F versus SG in patients with severe obesity (≥35 kg/m2). The primary outcome was remission of GERD postoperatively. Secondary outcomes were the percentage of excess weight loss, percentage of total weight loss, postoperative complication rate, operative time, and length of stay. RESULTS: A total of 5 studies with 539 subjects (212 SG + F and 327 SG alone) were included. The mean preoperative body mass index was 42.6 kg/m2. SG + F achieved higher remission of GERD compared with laparoscopic SG (odds ratio [OR] = 13.13; 95% CI, 3.54-48.73; I2 = 0%). However, the percentage of total weight loss was lower in the SG + F group (mean difference [MD] = -2.75, 95% CI, -4.28 to -1.23; I2 = 0%), whereas there was no difference in the percentage of excess weight loss (MD = -0.64; 95% CI, -20.62-19.34; I2 = 83%). There were higher postoperative complications in SG + F (OR = 2.56; 95% CI, 1.12-5.87; I2 = 0%) as well. There was no difference in operative time or length of stay between the 2 groups. CONCLUSION: SG + F achieved better GERD remission but is associated with lesser weight loss and increased postoperative complications compared with SG alone. Further studies are required to ascertain the overall clinical benefit of SG + F for patients with severe obesity.

Caveolin-1 in vascular health and glaucoma: A critical vascular regulator and potential therapeutic target.

Caveolin-1 (Cav-1) is an integral scaffolding membrane protein found in most cell types. Cav-1 has been found to contribute significantly to ocular function, with mutations of Cav-1 being associated with a genetic risk of glaucoma development. Raised intraocular pressure (IOP) is a major modifiable risk factor for glaucoma. Cav-1 may be involved in both IOP-dependent and independent mechanisms involving vascular dysregulation. Systemic vascular diseases including hypertension, diabetes and hyperlipidaemia, have been shown to be associated with glaucoma development. Cav-1 is closely interlinked with endothelial nitric oxide synthase pathways that mediate vascular function and prevent cardiovascular diseases. Endothelial nitric oxide synthase and endothelin-1 are key vasoactive molecules expressed in retinal blood vessels that function to autoregulate ocular blood flow (OBF). Disruptions in the homeostasis of OBF have led to a growing concept of impaired neurovascular coupling in glaucoma. The imbalance between perfusion and neuronal stimulation arising from Cav-1 depletion may result in relative ischemia of the optic nerve head and glaucomatous injury. OBF is also governed by circadian variation in IOP and systemic blood pressure (BP). Cav-1 has been shown to influence central BP variability and other circadian rhythms such as the diurnal phagolysosomal digestion of photoreceptor fragments and toxic substrates to maintain ocular health. Overall, the vast implications of Cav-1 on various ocular mechanisms leading to glaucoma suggest a potential for new therapeutics to enhance Cav-1 expression, which has seen success in other neurodegenerative diseases.

Outcomes of Intraoperative Pyloric Drainage on Delayed Gastric Emptying Following Esophagectomy: A Systematic Review and Meta-analysis.

BACKGROUND: Intraoperative pyloric drainage in esophagectomy may reduce delayed gastric emptying (DGE) but is associated with risk of biliary reflux and other complications. Existing evidence is heterogenous. Hence, this meta-analysis aims to compare outcomes of intraoperative pyloric drainage versus no intervention in patients undergoing esophagectomy. METHODS: PubMed/MEDLINE, Embase, Web of Science, and the Cochrane were searched from inception up to July 2022. Exclusion criteria were lack of objective evidence (e.g., symptoms of nausea or vomiting) of DGE. The primary outcome was incidence of DGE. Secondary outcomes were incidence of pulmonary complications, bile reflux, anastomotic leak, operative time, and mortality. RESULTS: There were nine studies including 1164 patients (pyloric drainage n = 656, no intervention n = 508). Intraoperative pyloric drainage included pyloroplasty (n = 166 (25.3%)), pyloromyotomy (n = 214 (32.6%)), botulinum toxin injection (n = 168 (25.6%)), and pyloric dilatation (n = 108 (16.5%)). Pyloric drainage is associated with reduced DGE (odds ratio (OR): 0.54, 95% confidence interval (CI): 0.39-0.74, I2 = 50%). There was no significant difference in incidence of pulmonary complications (OR: 0.74, 95% CI: 0.51-1.08; I2 = 0%), biliary reflux (OR: 1.43, 95% CI: 0.80-2.54, I2 = 0%), anastomotic leak (OR: 0.79, 95% CI: 0.48-1.29; I2 = 0%), operative time (MD: + 22.16 min, 95% CI: - 13.27-57.59 min; I2 = 76%), and mortality (OR: 1.13, 95% CI: 0.48-2.64, I2 = 0%) between the pyloric drainage and no intervention groups. CONCLUSIONS: Pyloric drainage in esophagectomy reduces DGE but has similar post-operative outcomes. Further prospective studies should be carried out to compare various pyloric drainage techniques and its use in esophagectomy, especially minimally-invasive esophagectomy.

Combination of Fibrosis-4, liver-stiffness measurement, and Fibroscan-AST score to predict liver-related outcomes in nonalcoholic fatty liver disease.

INTRODUCTION: Noninvasive tests, such as Fibrosis-4 (FIB-4), liver-stiffness measurement (LSM) by vibration-controlled transient elastography, and Fibroscan-AST (FAST), are frequently used for risk stratification in NAFLD. The comparative performance of FIB-4 and LSM and FAST to predict clinical outcomes of patients with NAFLD remained unclear. We aim to evaluate the performance of FIB-4, LSM, and FAST scores to predict clinical outcomes in patients with NAFLD. METHODS: We included consecutive adult patients with NAFLD with transient elastography performed between 2015 and 2022 from the United States and Singapore. Patients with NAFLD stratified based on baseline FIB-4, LSM, and FAST score were followed up until clinical outcomes notably liver-related events (LREs), LREs or death, death, and major adverse cardiac events. RESULTS: A total of 1262 patients with NAFLD (63% with obesity and 37% with diabetes) with vibration-controlled transient elastography were followed up for median 3.5 years. FIB-4 stratified patients with NAFLD into low-risk (<1.3), intermediate-risk (1.3-2.67), and high-risk (>2.67) in 59.4%, 31.5%, and 9.1%, respectively. No LRE occurred with baseline FIB-4 <1.3, regardless of LSM and FAST score. Higher FIB-4 was associated with a higher risk of LREs within each LSM category. FIB-4 had a higher area under the received operating characteristic curve than LSM or FAST score to predict LRE. CONCLUSIONS: In this multicenter international study, FIB-4 and LSM synergistically predicted the risk of LRE. In patients with FIB-4 <1.3, vibration-controlled transient elastography may incorrectly classify up to 10% of the patients as high risk. FIB-4 should be incorporated into risk stratification in NAFLD even among patients who underwent VCTE.

Acute Myocardial Infarction and Risk of Cognitive Impairment and Dementia: A Review.

Cognitive impairment (CI) shares common cardiovascular risk factors with acute myocardial infarction (AMI), and is increasingly prevalent in our ageing population. Whilst AMI is associated with increased rates of CI, CI remains underreported and infrequently identified in patients with AMI. In this review, we discuss the evidence surrounding AMI and its links to dementia and CI, including pathophysiology, risk factors, management and interventions. Vascular dysregulation plays a major role in CI, with atherosclerosis, platelet activation, microinfarcts and perivascular inflammation resulting in neurovascular unit dysfunction, disordered homeostasis and a dysfunctional neurohormonal response. This subsequently affects perfusion pressure, resulting in enlarged periventricular spaces and hippocampal sclerosis. The increased platelet activation seen in coronary artery disease (CAD) can also result in inflammation and amyloid-ß protein deposition which is associated with Alzheimer's Dementia. Post-AMI, reduced blood pressure and reduced left ventricular ejection fraction can cause chronic cerebral hypoperfusion, cerebral infarction and failure of normal circulatory autoregulatory mechanisms. Patients who undergo coronary revascularization (percutaneous coronary intervention or bypass surgery) are at increased risk for post-procedure cognitive impairment, though whether this is related to the intervention itself or underlying cardiovascular risk factors is debated. Mortality rates are higher in dementia patients with AMI, and post-AMI CI is more prevalent in the elderly and in patients with post-AMI heart failure. Medical management (antiplatelet, statin, renin-angiotensin system inhibitors, cardiac rehabilitation) can reduce the risk of post-AMI CI; however, beta-blockers may be associated with functional decline in patients with existing CI. The early identification of those with dementia or CI who present with AMI is important, as subsequent tailoring of management strategies can potentially improve outcomes as well as guide prognosis.

Impact of atrial fibrillation on the treatment effect of bridging thrombolysis in ischemic stroke patients undergoing endovascular thrombectomy: a multicenter international cohort study.

BACKGROUND: The role of bridging intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) in the treatment of acute ischemic stroke (AIS) remains debatable. Atrial fibrillation (AF) associated strokes may be associated with reduced treatment effect from IVT. This study compares the effect of bridging IVT in AF and non-AF patients. METHODS: This retrospective cohort study comprised anterior circulation large vessel occlusion (LVO) AIS patients receiving EVT alone or bridging IVT plus EVT within 6 hours of symptom onset. Primary outcome was good functional outcome defined as modified Rankin Scale (mRS) 0-2 at 90 days. Secondary outcomes were successful reperfusion defined as expanded Thrombolysis In Cerebral Infarction (eTICI) grading ≥2b flow, symptomatic intracerebral hemorrhage (sICH), and in-hospital mortality. RESULTS: We included 705 patients (314 AF and 391 non-AF patients). The mean age was 68.6 years and 53.9% were male. The odds of good functional outcomes with bridging IVT was higher in the non-AF (adjusted odds ratio (aOR) 2.28, 95% CI 1.06 to 4.91, P=0.035) compared with the AF subgroups (aOR 1.89, 95% CI 0.89 to 4.01, P=0.097). However, this did not constitute a significant effect modification by the presence of AF on bridging IVT (interaction aOR 0.12, 95% CI -1.94 to 2.18, P=0.455). The rate of successful reperfusion, sICH, and mortality were similar between bridging IVT and EVT for both AF and non-AF patients. CONCLUSION: The presence of AF did not modify the treatment effect of bridging IVT. Further individual patient data meta-analysis of randomized trials may shed light on the comparative efficacy of bridging IVT in AF versus non-AF LVO strokes.

Intragastric Balloon as Bridging Therapy Prior to Bariatric Surgery for Patients with Severe Obesity (BMI ≥ 50 kg/m2): a Systematic Review and Meta-analysis.

Bariatric surgery for patients with severe obesity (body mass index (BMI) ≥ 50kg/m2) is technically challenging. Intragastric balloon (IGB) has been proposed for weight loss before bariatric surgery to reduce surgical risks but its efficacy remains unclear. We conducted a systematic review and meta-analysis of the effectiveness of IGB as bridging therapy and assess potential complications. Amongst 2419 citations, 13 studies were included. IGB resulted in a BMI reduction of 6.60 kg/m2 (MD=6.60, 95% CI: 5.06-8.15; I2=72%). The total post-procedural complication rate was 8.13% (95% CI: 4.04-13.17%), with majority being balloon intolerance. Overall, IGB is effective as a bridging therapy with adequate procedural safety profile, but further study is needed to evaluate the risk reduction for bariatric surgery and long-term weight-loss outcomes.

Efficacy and safety of sofosbuvir/velpatasvir with or without ribavirin in hepatitis C genotype 3 compensated cirrhosis: A meta-analysis.

BACKGROUND: Hepatitis C virus (HCV) is a leading cause of liver cirrhosis and hepatocellular carcinoma globally. Sofosbuvir/velpatasvir (SOF/VEL) is an effective pan-genotypic direct-acting antiviral combination for treatment of chronic HCV infection. While the addition of ribavirin (RBV) to SOF/VEL improved sustained virological response (SVR12) in genotype 3 (GT3) decompensated cirrhosis patients, the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear. AIM: To evaluate the efficacy and safety of SOF/VEL, with or without RBV in GT3 compensated cirrhosis patients. METHODS: We searched four electronic databases (PubMed/Medline, Embase, Cochrane Library and Web of Science) from inception up to June 2021 using both free text and MeSH terms. There was no restriction on language, geography, publication dates and publication status (full text or abstracts). All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL, with or without RBV, were included, regardless of age, gender or prior treatment experience. The primary outcome was sustained virological response 12-wk post-treatment (SVR12). The secondary outcome was treatment-related adverse events, as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL. The pooled relative risk (RR), 95%CI and heterogeneity (I 2) were estimated using Review Manager version 5.3. RESULTS: From 1752 citations, a total of seven studies (2 randomized controlled trials, 5 cohort studies) with 1088 subjects were identified. The SVR12 was similar in GT3 compensated cirrhosis patients, regardless of the use of RBV, for both the intention-to-treat RR 1.03, 95%CI: 0.99-1.07; I 2 = 0%) and the per-protocol analysis (RR: 1.03, 95%CI: 0.99-1.07; I 2 = 48%). The overall pooled rate of treatment-related adverse events was 7.2%. Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL (RR: 4.20, 95%CI: 1.29-13.68; I 2 = 0%). Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions. However, addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients. CONCLUSION: Ribavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL. Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.

Efficacy and safety of albumin infusion for overt hepatic encephalopathy: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The efficacy and safety of albumin infusion for treatment and prevention of overt hepatic encephalopathy (OHE) among cirrhosis patients remained controversial. We performed a systematic review and meta-analysis to evaluate the benefit of albumin infusion for the treatment and prevention of OHE. METHODS: We performed a systematic search of 4 electronic databases up to 31st January 2021. The primary outcome was the resolution of OHE. Secondary outcomes were inpatient mortality and albumin-associated adverse events. We assessed the pooled odds' risk, pooled mean differences, 95% confidence interval and heterogeneity using Review Manager Version 5.3. RESULTS: A total of 12 studies (2,087 subjects) were identified. Among cirrhosis patients with OHE, albumin infusion was associated with a lower pooled risk of OHE (OR=0.43, 95%CI: 0.27, 0.68; I2=0%). Among patients without baseline OHE, albumin infusion was associated with a lower pooled risk of developing OHE (OR=0.53, 95%CI: 0.32, 0.86; I2=62%). Albumin infusion was associated with a lower pooled risk of inpatient mortality (OR=0.36, 95%CI: 0.21, 0.60; I2=0%). CONCLUSION: Well-powered randomized trials are required to confirm the benefits of albumin infusion for the prevention and treatment of overt hepatic encephalopathy among decompensated cirrhosis patients.

Loss of Caveolin-1 Impairs Light Flicker-Induced Neurovascular Coupling at the Optic Nerve Head.

Glaucoma is a neurodegenerative disease, which results in characteristic visual field defects. Intraocular pressure (IOP) remains the main risk factor for this leading cause of blindness. Recent studies suggest that disturbances in neurovascular coupling (NVC) may be associated with glaucoma. The resultant imbalance between vascular perfusion and neuronal stimulation in the eye may precede retinal ganglion cell (RGC) loss and increase the susceptibility of the eye to raised IOP and glaucomatous degeneration. Caveolin-1 (Cav-1) is an integral scaffolding membrane protein found abundantly in retinal glial and vascular tissues, with possible involvement in regulating the neurovascular coupling response. Mutations in Cav-1 have been identified as a major genetic risk factor for glaucoma. Therefore, we aim to evaluate the effects of Cav-1 depletion on neurovascular coupling, retinal vessel characteristics, RGC density and the positive scotopic threshold response (pSTR) in Cav-1 knockout (KO) versus wild type C57/Bl6 mice (WT). Following light flicker stimulation of the retina, Cav-1 KO mice showed a smaller increase in perfusion at the optic nerve head and peripapillary arteries, suggesting defective neurovascular coupling. Evaluation of the superficial capillary plexus in Cav-1 KO mice also revealed significant differences in vascular morphology with higher vessel density, junction density and decreased average vessel length. Cav-1 KO mice exhibited higher IOP and lower pSTR amplitude. However, there was no significant difference in RGC density between Cav-1 KO and wild type mice. These findings highlight the role of Cav-1 in regulating neurovascular coupling and IOP and suggest that the loss of Cav-1 may predispose to vascular dysfunction and decreased RGC signaling in the absence of structural loss. Current treatment for glaucoma relies heavily on IOP-lowering drugs, however, there is an immense potential for new therapeutic strategies that increase Cav-1 expression or augment its downstream signaling in order to avert vascular dysfunction and glaucomatous change.