Abstract Background & Aims Childhood obesity is increasing and is associated with adult obesity. Antibiotics have been used to promote weight gain in livestock for several decades. Antibiotics are ...commonly prescribed for children, but it is not clear how exposure to antibiotics early in life affects risk for obesity. We performed a population-based cohort study to assess the association between antibiotic exposure before age 2 years and obesity at age 4 years. Methods We performed a retrospective cohort study of 21,714 children in The Health Improvement Network —a population-representative dataset of more than 10 million individuals derived from electronic medical records from 1995 through 2013 in the United Kingdom. Eligible subjects were registered within 3 months of birth with complete follow-up and height and weight were recorded within 12 months of their 4th birthday. Antibiotic exposure was assessed before age 2 years, and classified based on anti-anaerobic activity. The primary outcome was obesity at age 4 years. We performed logistic regression analyses, adjusting for maternal and sibling obesity, maternal diabetes, mode of delivery, socioeconomic status, year and country of birth, and urban dwelling. Results In the cohort, 1306 of the children (6.4%) were obese at 4 years of age. Antibiotic exposure was associated with an increased risk of obesity at 4 years (odds ratio OR=1.21; 95% confidence interval CI, 1.07–1.38). Odds ratios increased with repeated exposures: for 1–2 prescriptions, OR=1.07 (95% CI, 0.91-1.23); for 3–5 prescriptions, OR=1.41 (95% CI, 1.20–1.65); for 6 or more prescriptions, OR=1.47 (95% CI, 1.19–1.82). Antifungal agents were not associated with obesity (OR=0.81; 95% CI, 0.59–1.11). Conclusions Administration of 3 or more courses of antibiotics before children reach an age of 2 years is associated with an increased risk of early childhood obesity.
Abstract Background Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated ...incidence rates of acute liver injury associated with oral azole antifungals. Methods We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. Results Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years 95% confidence intervals (CIs)) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 11.4-14.6), ketoconazole (19.3 13.8-26.3), and itraconazole (24.5 10.6-48.2). Rates were higher with voriconazole (181.9 112.6-278.0) and posaconazole (191.1 23.1-690.4), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 1.4-2.7), ketoconazole (2.9 1.1-6.3), and itraconazole (0.0 0.0-11.2), but more frequent with voriconazole (16.7 2.0-60.2) and posaconazole (93.4 2.4-520.6). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 95% CI, 3.68-5.94) and severe acute liver injury (hazard ratio 5.62 95% CI, 2.56-12.35). Conclusions Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole-induced liver injury.
Importance Bleeding esophageal varices has been studied extensively, but bleeding gastric varices (BGV) has received much less investigation. However, BGV has been reported in ≤30% of patients with ...acute variceal bleeding. In our studies of 1,836 bleeding cirrhotics, 12.7% were bleeding from gastric varices. BGV mortality rate of 45–55% has been reported. The BGV literature has mainly involved retrospective case reports, often with short-term follow-up. Objective We sought to describe the results of a prospective, randomized, controlled trial (RCT) in unselected, consecutive patients with BGV comparing endoscopic therapy (ET) with portacaval shunt (PCS; n = 518), and later comparing emergency transjugular intrahepatic portosystemic shunt (TIPS) with emergency portacaval shunt (EPCS; n = 70). Design, setting, and participants Initially, our RCT involved 518 patients with BGV comparing ET with direct PCS regarding control of bleeding, mortality rate, and disability. When entry of patients ended, the RCT was expanded to compare emergency TIPS with EPCS ( n = 70). This RCT of BGV was separate from our other RCTs of bleeding esophageal varices. Interventions Initially, ET was compared with PCS. In the second part of our RCT, emergency TIPS was compared with emergency PCS (EPCS). Main outcome measures Outcomes were survival, control of bleeding, portal-systemic encephalopathy (PSE), quality of life, and direct costs of care. In the RCT of ET versus PCS, 28 and 30%, respectively, were in Child class C. In the expanded RCT of TIPS versus EPCS, 40 and 41%, respectively, were in Child class C. Permanent control of BGV was achieved in 97–100% of patients treated by emergency or elective PCS, compared with 27–29% by ET. TIPS was even less effective, achieving long-term control of BGV in only 6%. Survival rates after PCS were greater at all time intervals and in all Child classes ( P < .001). Repeated episodes of PSE occurred in 50% of TIPS patients, 16-17% treated by ET, and 8-11% treated by PCS. Shunt stenosis or occlusion occurred in 67% of TIPS patients, in contrast with 0–2% of PCS patients. Conclusion These results support the conclusion that PCS is uniformly effective, whereas ET and TIPS are not very effective.
Background The mortality rate of bleeding esophageal varices in cirrhosis is highest during the period of acute bleeding. This is a report of a randomized trial that compared endoscopic sclerotherapy ...(EST) with emergency portacaval shunt (EPCS) in cirrhotic patients with acute variceal hemorrhage. Study Design A total of 211 unselected consecutive patients with cirrhosis and acutely bleeding esophageal varices who required at least 2 U of blood transfusion were randomized to EST (n = 106) or EPCS (n = 105). Diagnostic workup was completed within 6 hours and EST or EPCS was initiated within 8 hours of initial contact. Longterm EST was performed according to a deliberate schedule. Ninety-six percent of patients underwent more than 10 years of followup, or until death. Results The percent of patients in Child's risk classes were A, 27.5; B, 45.0; and C, 27.5. EST achieved permanent control of bleeding in only 20% of patients; EPCS permanently controlled bleeding in every patient (p ≤0.001). Requirement for blood transfusions was greater in the EST group than in the EPCS patients. Compared with EST, survival after EPCS was significantly higher at all time intervals and in all Child's classes (p ≤0.001). Recurrent episodes of portal-systemic encephalopathy developed in 35% of EST patients and 15% of EPCS patients (p ≤0.01). Conclusions EPCS permanently stopped variceal bleeding, rarely became occluded, was accomplished with a low incidence of portal-systemic encephalopathy, and compared with EST, produced greater longterm survival. The widespread practice of using surgical procedures mainly as salvage for failure of endoscopic therapy is not supported by the results of this trial ( clinicaltrials.gov # NCT00690027 ).
Abstract Background and Aims Bleeding esophageal varices is responsible for much of the high mortality rate in cirrhosis. An important objective of management of bleeding varices is to develop ...reliable tools for predicting survival, controlling bleeding and encephalopathy, and improve quality of life. This study compared two widely used prognostic tools, the model for end-stage liver disease (MELD) and the Child-Turcotte (C-T) score, in a randomized controlled trial of emergency treatment of bleeding varices. Methods We randomized 211 unselected consecutive patients with cirrhosis and bleeding varices to endoscopic sclerotherapy (n = 106) or emergency portacaval shunt (n = 105). Diagnosis and treatment were accomplished within 20 hours. Follow-up was 100% for 10 y. We compared the prognostic powers of MELD and C-T upon entry, and then monthly for the first year and every 3 months thereafter. Statistical analysis included computation of receiver operating curves, the area under the curve, and the proportion of variability. Results In baseline determinations of MELD versus C-T, there were no significant differences in predicting survival, recurrent encephalopathy, and rebleeding. The Child-Turcotte score was a stronger predictor than MELD of hospital readmissions and readmission days. In serial determinations over years, the prognostic power of both MELD and C-T was substantial, but C-T was significantly more effective in predicting survival and time to recurrent encephalopathy. Conclusions In this first long-term comparison of MELD versus C-T in cirrhosis with bleeding varices, C-T was consistently as effective as MELD in predicting survival, encephalopathy, rebleeding, hospital readmissions, and readmission days. In some measures, C-T was a more effective prognostic tool than MELD.
Background Patients who require dialysis are at high risk for cardiovascular mortality, which may be improved by mineralocorticoid receptor antagonists (MRAs). Study Design Systematic review and ...meta-analysis of randomized controlled trials. Setting & Population Adults undergoing long-term hemodialysis or peritoneal dialysis with or without heart failure. Selection Criteria for Studies Randomized controlled trials evaluating an MRA in dialysis and reported at least one outcome of interest. Intervention Spironolactone (8 trials) or eplerenone (1 trial) compared to placebo (7 trials) or standard of care (2 trials). Outcomes Cardiovascular and all-cause mortality, hyperkalemia, serum potassium level, hypotension, change in blood pressure, and gynecomastia. Results We identified 9 trials including 829 patients. The overall quality of evidence was low due to methodologic limitations in most of the included trials. The relative risk (RR) for cardiovascular mortality was 0.34 (95% CI, 0.15-0.75) for MRA-treated compared with control patients. The RR for all-cause mortality was 0.40 (95% CI, 0.23-0.69). The RR for hyperkalemia for MRA treatment was 3.05 (95% CI, 1.21-7.70). Sensitivity analyses demonstrated wide variability in RRs for cardiovascular mortality, all-cause mortality, and hyperkalemia, suggesting further uncertainty in the confidence of the primary results. Limitations Trial quality and size insufficient to robustly and precisely identify a treatment effect. Conclusions Given the uncertainty of both the benefits and harms of MRAs in dialysis, large high-quality trials are required.
Background The incidence of malignancy in patients with chronic pruritus and nondiseased skin is unknown. Objective We sought to assess the hazard ratio (HR) of incident overall malignancy and ...incident malignancy by subtype in patients with chronic pruritus during the 5 years after diagnosis. Methods A population-based cohort study was performed in the Health Improvement Network. In all, 8744 patients with chronic pruritus were matched with 31,580 patients without chronic pruritus based on sex, age, and practice. Primary outcomes were HR of incident malignancy and HR of malignancy subtypes. Results The fully adjusted HR for incident malignancy in patients with chronic pruritus was 1.14 (95% confidence interval 0.98-1.33). The fully adjusted HR for incident hematologic malignancy and incident bile duct malignancy in patients with chronic pruritus was 2.02 (95% confidence interval 1.48-2.75) and 3.73 (95% confidence interval 1.55-8.97), respectively. The incidence of hematologic malignancy and cholangiocarcinoma in patients with chronic pruritus was 0.0016 and 0.0003 per person-year, respectively. Limitations Potential for misclassification and detection biases is a limitation. Conclusions Chronic pruritus without concomitant skin changes is a risk factor for having undiagnosed hematologic and bile duct malignancies, but not other malignancies. The overall incidence of these malignancies in patients with chronic pruritus is very low.
To investigate whether endometrial ablation is associated with increased risk or delayed diagnosis of endometrial cancer compared with medical management of abnormal uterine bleeding.
Multi-centered ...retrospective cohort study (Canadian Task Force classification II-2).
The study was performed using data from The Health Improvement Network, a representative population-based cohort of patients in 495 outpatient general practitioner practices in the United Kingdom.
Women aged >25 years with abnormal uterine bleeding diagnosed between June 1994 and September 2010.
Endometrial ablation, medical management, or both.
A total of 234 721 women met study inclusion and exclusion criteria, 4776 of whom underwent endometrial ablation and the remaining 229 945 received medical management. Cox models compared endometrial cancer rates between ablation and medical management groups using hazard ratios. To investigate a possible diagnostic delay, the median time from bleeding diagnosis to endometrial cancer diagnosis in women in whom endometrial cancer developed was compared using the Mann-Whitney U test. All statistical tests were 2-tailed, with α = .05. During a median observation period of 4.07 years (interquartile range IQR, 1.88-7.17), endometrial cancer developed in 3 women in the ablation group and 601 women in the medical management group (ablation hazard ratio, 0.45; 95% confidence interval, 0.15-1.40; p = .17). Median time to diagnosis was 237 in the ablation group, and 299 days in the medical management group (ablation IQR, 155-1350; medical management IQR, 144-1133.5; p = .99). Adjusted and sensitivity analyses did not change the results.
No difference was observed in endometrial cancer rates, and there was no delay in diagnosis when comparing endometrial ablation vs medical management. Further studies are needed to investigate the effect of previous ablation exposure on histology or cancer stage at manifestation of endometrial cancer.
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