Pregnancy Outcomes After Liver Transplantation: A Systematic Review and Meta-Analysis.

INTRODUCTION: Liver transplantation (LT) remains the gold standard for treatment of end-stage liver disease. Given the increasing number of liver transplantation in females of reproductive age, our aim was to conduct a systematic review and meta-analysis evaluating pregnancy outcomes after LT. METHODS: MEDLINE, Embase, and Scopus databases were searched for relevant studies. Study selection, quality assessment, and data extraction were conducted independently by 2 reviewers. Estimates of pregnancy-related outcomes in LT recipients were generated and pooled across studies using the random-effects model. RESULTS: A comprehensive search identified 1,430 potential studies. Thirty-eight studies with 1,131 pregnancies among 838 LT recipients were included in the analysis. Mean maternal age at pregnancy was 27.8 years, with a mean interval from LT to pregnancy of 59.7 months. The live birth rate was 80.4%, with a mean gestational age of 36.5 weeks. The rate of miscarriages (16.7%) was similar to the general population (10%-20%). The rates of preterm birth, preeclampsia, and cesarean delivery (32.1%, 12.5%, and 42.2%, respectively) among LT recipients were all higher than the rates for the general US population (9.9%, 4%, and 32%, respectively). Most analyses were associated with substantial heterogeneity. DISCUSSION: Pregnancy outcomes after LT are favorable, but the risk of maternal and fetal complications is increased. Large studies along with consistent reporting to national registries are necessary for appropriate patient counseling and to guide clinical management of LT recipients during pregnancy.

Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis.

OBJECTIVES: We aimed to investigate the efficacy and safety of different antithrombotic strategies in patients undergoing transcatheter aortic valve implantation (TAVI) using network meta-analyses. BACKGROUND: Meta-analyses comparing single antiplatelet therapy (SAPT) vs. dual antiplatelet therapy (DAPT), ± oral anticoagulant (OAC) was conducted to determine the appropriate post TAVI antithrombotic regimen. However, there was limited direct comparisons across the different therapeutic strategies. METHODS: MEDLINE and EMBASE were searched through December 2018 to investigate the efficacy and safety of different antithrombotic strategies (SAPT, DAPT, OAC, OAC + SAPT, and OAC + DAPT) in patients undergoing TAVI. The main outcome were all-cause mortality, major or life-threatening bleeding events, and stroke. RESULTS: Our search identified 3 randomized controlled trials and 10 nonrandomized studies, a total of 20,548 patients who underwent TAVI. All OACs were vitamin K antagonists. There was no significant difference on mortality except that OAC + DAPT had significantly higher rates of mortality compared with others (p < .05, I2 = 0%). SAPT had significantly lower rates of bleeding compared with DAPT, OAC+SAPT, and OAC+DAPT (hazard ratio [HR]: 0.59 [0.46-0.77], p < .001, HR: 0.58 [0.34-0.99], p = .045, HR: 0.41 [0.18-0.93], p = .033, respectively, I2 = 0%). There was no significant difference on stroke among all antithrombotic strategies. CONCLUSION: Patients who underwent TAVI had similar all-cause mortality rates among different antithrombotic strategies except OAC+DAPT. Patients on SAPT had significantly lower bleeding risk than those on DAPT, OAC + SAPT, and OAC + DAPT. Our results suggest SAPT is the preferred regimen when there is no indication for DAPT or OAC. When DAPT or OAC is indicated, DAPT + OAC should be avoided.

Does Pelvic Rotation Alter Radiologic Measurement of Anterior and Lateral Acetabular Coverage?

PURPOSE: The purpose of this study was to determine the radiologic tolerance of the lateral center edge angle (LCEA) and anterior center edge angle (ACEA) to pelvic rotation. METHODS: Eleven dry cadaveric pelvises from an osteological collection were reconstructed and placed in anatomic position with corresponding bilateral proximal femurs. Conventional anteroposterior (AP) and false-profile (FP) pelvic radiographs were taken at 5° increments with fluoroscopy from 0° to 25° of rotation. LCEA and ACEA were measured for conventional and rotated AP and FP fluoroscopic views, respectively. Statistical analysis was conducted to determine the error in ACEA and LCEA with pelvic rotation. RESULTS: The mean LCEA was 29.1° (95% confidence interval [CI], 25.5°-32.7°). Mean ACEA was 38.9° (95% CI, 34.1°-43.8°). There was significant change in the LCEA past 10° of rotation (P = .041). There was significant change in the ACEA with 5o or more of rotation (P < .001). The FP view rotated 40° from an AP view produced 6.8° (95% CI, 4.7-8.9) of error, whereas one rotated 90° from an AP view produced 13.2° (95% CI, 11.2°-15.3°) of error in the ACEA. An AP view rotated 25° toward the x-ray beam produced 2.3° (95% CI, 1.1°-3.4°) error, whereas one rotated 25° away from the beam produced 2.6° (95% CI, 1.5°-3.8°) of error. CONCLUSIONS: Rotation of AP and FP radiographs significantly affects the measured values of the LCEA and ACEA, respectively. The ACEA experiences more dramatic changes with rotation of the FP view compared with the LCEA with the same amount of rotation of an AP view. This study illustrates the importance of verifying the quality of the FP radiograph when using ACEA to guide therapy for hip pathology. CLINICAL RELEVANCE: This study emphasizes the importance of evaluating pelvic rotation when using the center edge angle to assess femoral head coverage.

Comparison of efficacy of pharmacological treatments for chronic idiopathic constipation: a systematic review and network meta-analysis.

OBJECTIVE: To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. DATA SOURCES: We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. STUDY SELECTION: Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. DATA EXTRACTION AND SYNTHESIS: Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. OUTCOMES: Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δb) in the number of SBM/week and Δb CSBM/week. RESULTS: Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δb in number of SBM/week. CONCLUSIONS: Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δb in the number of SBM/week in CIC.

Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis.

There is no universally available laboratory test to diagnose bile acid diarrhoea (BAD). OBJECTIVE: To conduct a systematic review and meta-analysis to identify a biomarker for idiopathic BAD in patients with functional bowel disorder (FBD) with diarrhoea. DESIGN: We searched multiple databases through 15 May 2015. Data were only available to estimate the diagnostic yield of each test (the prevalence of a positive test). Estimates were pooled across studies using the random effects model. RESULTS: We included 36 studies, enrolling 5028 patients (24 using 75selenium homotaurocholic acid test (75SeHCAT) retention of <10%, 6 using fasting serum C4, 3 using fasting serum fibroblast growth factor 19 (FGF19) and 2 based on total faecal bile acid (BA) excretion over 48 h). The diagnostic yields (and 95% CI) of abnormal tests were: 0.308 (0.247 to 0.377) for 75SeHCAT retention (<10%), 0.171 (0.134 to 0.217) for serum C4, 0.248 (0.147 to 0.385) for serum FGF19 and 0.255 (0.071 to 0.606) for total faecal BA excretion over 48 h. The majority of the analyses were associated with substantial heterogeneity. Performance characteristics relative to a gold standard test could not be estimated. CONCLUSIONS: Overall, the test with the highest diagnostic yield conducted in the largest number of studies was 75SeHCAT retention, which is not widely available in many countries outside Europe and Canada. Using different diagnostic tests, 25% (average) of patients with lower FBD with diarrhoea has evidence of idiopathic BAD. These tests serve to identify idiopathic BAD among patients with FBD with diarrhoea. Further studies are required to appraise the performance characteristics of tests for idiopathic BAD.

Pilot study of small bowel mucosal gene expression in patients with irritable bowel syndrome with diarrhea.

Prior studies in with irritable bowel syndrome with diarrhea (IBS-D) patients showed immune activation, secretion, and barrier dysfunction in jejunal or colorectal mucosa. We measured mRNA expression by RT-PCR of 91 genes reflecting tight junction proteins, chemokines, innate immunity, ion channels, transmitters, housekeeping genes, and controls for DNA contamination and PCR efficiency in small intestinal mucosa from 15 IBS-D and 7 controls (biopsies negative for celiac disease). Fold change was calculated using 2((-ΔΔCT)) formula. Nominal P values (P < 0.05) were interpreted with false detection rate (FDR) correction (q value). Cluster analysis with Lens for Enrichment and Network Studies (LENS) explored connectivity of mechanisms. Upregulated genes (uncorrected P < 0.05) were related to ion transport (INADL, MAGI1, and SONS1), barrier (TJP1, 2, and 3 and CLDN) or immune functions (TLR3, IL15, and MAPKAPK5), or histamine metabolism (HNMT); downregulated genes were related to immune function (IL-1ß, TGF-ß1, and CCL20) or antigen detection (TLR1 and 8). The following genes were significantly upregulated (q < 0.05) in IBS-D: INADL, MAGI1, PPP2R5C, MAPKAPK5, TLR3, and IL-15. Among the 14 nominally upregulated genes, there was clustering of barrier and PDZ domains (TJP1, TJP2, TJP3, CLDN4, INADL, and MAGI1) and clustering of downregulated genes (CCL20, TLR1, IL1B, and TLR8). Protein expression of PPP2R5C in nuclear lysates was greater in patients with IBS-D and controls. There was increase in INADL protein (median 9.4 ng/ml) in patients with IBS-D relative to controls (median 5.8 ng/ml, P > 0.05). In conclusion, altered transcriptome (and to lesser extent protein) expression of ion transport, barrier, immune, and mast cell mechanisms in small bowel may reflect different alterations in function and deserves further study in IBS-D.

Nonselective ß-Blockers and Survival in Patients With Cirrhosis and Ascites: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Nonselective ß-blockers (NSBBs), given to reduce the risk of variceal bleeding, have been associated with increased mortality in patients with cirrhosis and refractory ascites in some, but not all, studies. We performed a systematic review and meta-analysis to evaluate the effect of NSBBs on all-cause mortality in patients with cirrhosis and refractory ascites. METHODS: We performed a comprehensive search of MEDLINE, Embase, Web of Science, and Scopus databases through January 2015, supplemented with a manual search. Trial-specific risk ratios (RRs) were pooled using the random-effects model. RESULTS: Our analysis included 3 randomized control trials and 8 observational studies of propranolol, carvedilol, nadolol, and metoprolol, reporting 1206 deaths among 3145 patients with ascites. The control groups received other interventions to prevent variceal bleeding. NSBB use was not associated with increased all-cause mortality in all patients with ascites (RR, 0.95; 95% confidence interval [CI], 0.67-1.35); nonrefractory ascites alone (RR, 0.96; 95% CI, 0.50-1.82), or refractory ascites alone (RR, 0.95; 95% CI, 0.57-1.61). Results were similar in randomized controlled trials and observational studies. Use of NSBBs was not associated with increased mortality at 6, 12, 18, and 24 months. Overall, the included studies had a medium to high risk of bias, except for 3 clinical trials in which the risk of biased was determined to be low. CONCLUSIONS: The use of NSBBs was not associated with a significant increase in all-cause mortality in patients with cirrhosis and ascites or refractory ascites. Certainty in the available estimates is low; a randomized trial of only patients with ascites is needed to answer this question. This meta-analysis does not support the position that NSBBs routinely be withheld from patients with ascites.

The association of impaired lung function and nonalcoholic fatty liver disease: a systematic review.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and impaired lung function share similar risk factors and phenotypes, such as obesity and type 2 diabetes. The study is an updated meta-analysis to evaluate the association between NAFLD and impaired lung function. METHODS: A total of 696 articles were identified with mention of NAFLD and lung function (or pulmonary function testing) in MEDLINE, EMBASE, and Scopus. After de-duplication, 455 articles were screened, 18 underwent full-text review. Five studies met our review and inclusion criteria with an interrater reliability kappa score of 1. RESULTS: Five studies with a total of 118 118 subjects (28.4% with NAFLD) were included. The cross-sectional studies supported a statistically significant relationship between decreased pulmonary function tests and NAFLD. There was no association observed with obstructive lung pattern. One of the longitudinal studies revealed an association with increased rate of decline in forced vital capacity in patients with NAFLD and FIB4 score ≥1.30 (-21.7 vs. -27.4 mL/year, P = 0.001 in males, -22.4 vs. -27.9 mL/year, P = 0.016 in females). The second longitudinal study revealed that patients with impaired pulmonary function had an increased hazard ratio of developing NAFLD dependent on the severity of pulmonary impairment. CONCLUSIONS: This is the first systematic review that supports an association of NAFLD with decreased (restrictive) lung function. The estimated severity of liver fibrosis correlates with the rate of progression of restrictive lung function. There are also data showing that patients with impaired lung function have a higher risk of developing NAFLD.

Risk of amputation associated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of five randomized controlled trials.

Amputation has been known to be a rare adverse event of sodium glucose co-transporter-2 (SGLT2) inhibitors. It remains unclear whether the SGLT2 inhibitor as a class or specific categories of the SGLT2 inhibitors are linked with an increased risk of amputation. The objective of this meta-analysis was to investigate the association between the amputation risk and the use of SGLT2 inhibitors. The main outcome measure was the risk of amputation. Multiple databases were searched up to February 2020 and data extraction was performed. Inclusion criteria were randomized controlled trials (RCTs) which reported risk of amputation with SGLT2 inhibitors over non-SGLT2 inhibitors or placebo. The risk of bias was assessed by Cochrane bias tool. The initial search yielded 1,873 citations and a total of five RCTs were included in the meta-analysis. The five included studies evaluated a total of 39,067 patients with diabetes mellitus, including 21,395 patients on SGLT2 inhibitors. The incidence rate of amputation ranged from 0.36 to 3.18% in the SGLT2 inhibitor group and from 0% to 2.87% in the control group. Follow up duration ranged from 24 weeks to 4.2 years. Use of SGLT2 inhibitors was not associated with significant increase in the risk of amputation as compared with controls (OR: 1.31, 95% CI: 0.92-1.87, I2 = 75%). Subgroup analysis showed that neither canagliflozin, empagliflozin, nor dapagliflozin was associated with increased risk of amputation. In conclusion, our meta-analysis showed that neither canagliflozin nor other SGLT2 inhibitors increase the risk of amputation.

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

BACKGROUND: Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown. OBJECTIVES: This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis. METHODS: MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding. RESULTS: This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant. CONCLUSIONS: This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

The role of transjugular intrahepatic portosystemic shunt in the management of portal vein thrombosis: a systematic review and meta-analysis.

BACKGROUND: The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal vein thrombosis (PVT) remains controversial. This study aimed to conduct a systematic review and meta-analysis to evaluate the role of TIPS for the management of PVT in adult patients with liver disease. PATIENTS AND METHODS: Multiple databases were searched through April 2017. Data were gathered to estimate the rates of technical success, portal vein recanalization, portal patency, hepatic encephalopathy, and mean change in portal pressure gradient in patients with PVT who underwent TIPS. Estimates were pooled across studies using the random effects model. RESULTS: Eighteen studies were included in the analysis. The pooled technical success rate was 86.7% [95% confidence interval (CI)=78.6-92.1%]. Rate of portal vein recanalization was 84.4% (95% CI=78.4-89.0%). The rate of complete recanalization was 73.7% (95% CI=64.3-81.3%). Portal patency was 86.9% (95% CI=79.7-91.8%). Mean change in portal pressure gradient was 14.5 mmHg (95% CI=11.3-17.7 mmHg). Hepatic encephalopathy was 25.3% (95% CI=19.2-32.6%). The number of major adverse events reported across studies was low. The majority of the analyses were not associated with substantial heterogeneity. CONCLUSION: The use of TIPS in the management of PVT is feasible and effective in achieving a significant and sustainable reduction in clot burden with a low risk of major complications. TIPS should be considered as a viable treatment option in patients with PVT. Given the limited amount of randomized comparative studies reported, additional trials are warranted to assess the safety and efficacy of TIPS as a treatment modality in PVT, in comparison to other treatment options, such as anticoagulation.

Potential mechanisms of effects of serum-derived bovine immunoglobulin/protein isolate therapy in patients with diarrhea-predominant irritable bowel syndrome.

Serum-derived bovine immunoglobulin/protein isolate (SBI), an oral nutritional therapy, is efficacious in diverse diarrheal diseases. In an open-label study in 15 patients with irritable bowel syndrome-diarrhea (IBS-D), we evaluated effects of SBI (5.0 g, twice a day) for 8 weeks on safety, on bowel function and abdominal pain, tryptophan metabolism (K:T ratio), intestinal permeability (13C-mannitol and lactulose excretion), bile acid synthesis (fasting serum FGF-19 and C4), duodenal and stool microbiome, and the expression of 90 genes related to inflammation, immune function, and tight junctions in duodenal mucosa. Statistical analysis (paired tests, baseline vs. treatment) was based on intention to treat (ITT) principles. One of 15 Caucasian patients (13F, 2M, age 40.3 ± 2.3y, BMI 34.3 ± 3.0 kg/m2) withdrew without completing studies. There were improvements in stools/day (decrease, P < 0.001), ease of passage (P = 0.035), and evacuation (P = 0.004) with SBI therapy. Worst pain severity was numerically reduced in last 2 weeks' treatment (P = 0.078). Duodenal mucosal mRNA expression; serum C4, FGF-19, and KT ratio; small bowel or colon permeability; and stool microbiome were not significantly different after SBI therapy, compared to baseline. In duodenal brushings, there was considerable microbiota structure difference (ß diversity analysis P = 0.072, UniFrac) and, on taxonomic analysis, increased abundance of Proteobacteria Burkholderiales, Firmicutes Catonella, and unclassified genus organisms with SBI therapy. Thus, SBI therapy for 8 weeks in IBS-D patients is associated with improved bowel function; the mechanism of benefit is unclear, though there were microbiota structure differences in duodenal brushings. Further studies in patients with low-grade inflammation and intestinal barrier dysfunction at baseline are indicated.

Early investigational therapeutics for gastrointestinal motility disorders: from animal studies to Phase II trials.

INTRODUCTION: The most common gastrointestinal disorders that include evidence of dysmotility include: gastroparesis, the lower functional gastrointestinal disorders associated with altered bowel function (such as chronic [functional] diarrhea, chronic idiopathic constipation) and opioid-induced constipation. These conditions, which are grouped as gastrointestinal motility and functional disorders, are characterized by abnormal motor, sensory or secretory functions that alter bowel function and result in a significant disease burden, since currently available treatments do not completely alleviate symptoms. New drugs are being developed for these disorders, targeting mechanisms involved in the pathophysiology of these diseases, specifically, motor function, intestinal secretion and bile acid modulation. AREAS COVERED: The article provides a brief overview of motility disorders and the drugs approved and currently available for these indications. It also provides an evaluation of the efficacy, safety and possible mechanisms of the drugs currently under investigation for the treatment of gastroparesis, chronic diarrhea, chronic idiopathic constipation and opioid-induced constipation, based on animal to Phase II studies. Medications with complete Phase III trials are excluded from this discussion. EXPERT OPINION: Treatment of gastrointestinal motility disorders requires the understanding of the pathophysiological mechanisms, biomarkers to identify subgroups of these disorders and robust pharmacological studies from animal to Phase II studies. These are prerequisites for the development of efficacious medications and individualizing therapy in order to enhance the treatment of these patients.