Discontinuation of alpha-blocker therapy in men with lower urinary tract symptoms:a systematic review and meta-analysis

OBJECTIVES: We aimed to synthesise the available data for the effect of stopping alpha-blocker therapy among men with lower urinary tract symptoms. The focus was on symptom, uroflowmetry and quality of life outcomes, but we also reviewed the adverse events (AEs) and the number of patients who restarted therapy.DATA SOURCES: We searched MEDLINE/PubMed, EMBASE/Ovid and The Cochrane Central Register of Controlled Trials from inception to May 2018.ELIGIBILITY CRITERIA: We selected studies regardless of study design in which men were treated with an alpha-blocker for at least 3 months and in which the effects of alpha-blocker discontinuation were subsequently studied. Only controlled trials were used for the primary objective.DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed the risk of bias for the controlled studies only using the Cochrane Collaboration's tool for assessing risk of bias. Data were pooled using random-effects meta-analyses.RESULTS: We identified 10 studies (1081 participants) assessing the primary objective. Six studies (733 participants) assessed differences in AEs between continuation and discontinuation, and six studies (501 participants) reported the numbers of subjects that restarted treatment after discontinuation. No studies in primary care were identified. After discontinuing monotherapy, symptom scores increased and peak flow rates decreased at 3 and 6 months, but not at 12 months; however, neither parameter changed when alpha-blockers were stopped during combination therapy. Small differences in post-void residual volumes and quality of life scores were considered clinically irrelevant. We also found that 0%-49% of patients restarted after stopping alpha-blocker therapy and that AEs did not increase with discontinuation.CONCLUSIONS: Discontinuing alpha-blocker monotherapy leads to a worsening compared with continuing therapy. Discontinuing the alpha-blocker after combination therapy had no significant effects on outcomes in either the short or long term. Discontinuation may be appropriate for the frail, elderly or those with concomitant illness or polypharmacy. However, studies in primary care are lacking.PROSPERO REGISTRATION NUMBER: CRD42016032648.</p

Physiotherapy for Children with Functional Constipation:A Pragmatic Randomized Controlled Trial in Primary Care

Objective: To determine the effectiveness of physiotherapy plus conventional treatment compared with conventional treatment alone for the treatment of functional constipation in children age 4-17 years in primary care. Study design: Pragmatic randomized controlled trial with 8 months follow-up. Primary care physicians recruited children diagnosed with functional constipation (n = 234), and pediatricians recruited newly referred children with a diagnosis of functional constipation (n = 11). Conventional treatment comprised toilet training, nutritional advice, and laxative prescribing, whereas physiotherapy focused on resolving dyssynergic defecation. The primary outcome was treatment success over 8 months, defined as the absence of functional constipation (Rome III criteria) without laxative use. Secondary outcomes included the absence of functional constipation irrespective of continuation of laxative use and global perceived treatment effect. Results: Children were allocated to conventional treatment plus physiotherapy or conventional treatment alone (67 per group), mean (SD) age was 7.6 (3.5) years. Results of longitudinal analyses in the intention-to-treat population showed that the treatment success percentage was not statistically improved by adding physiotherapy to conventional treatment (adjusted relative risk [aRR] 0.80, 95% CI 0.44-1.30). At 4 months, fewer children receiving physiotherapy had treatment success (17%) than children receiving conventional treatment alone (28%), but this had equalized by 8 months (42% and 41%, respectively). The percentage of children without functional constipation, irrespective of continuation of laxative use, was not statistically different between groups over 8 months (aRR 1.12, 95% CI 0.82-1.34). Notably, parents reported significantly more global symptom improvement after physiotherapy than after conventional treatment (aRR 1.40; 95% CI 1.00-1.73). Conclusions: We find no evidence to recommend physiotherapy for all children with functional constipation in primary care. Trial registration: Netherlands Trial Registry: NTR4797

Diagnostic test strategies in children at increased risk of inflammatory bowel disease in primary care

Background: In children with symptoms suggestive of inflammatory bowel disease (IBD) who present in primary care, the optimal test strategy for identifying those who require specialist care is unclear. We evaluated the following three test strategies to determine which was optimal for referring children with suspected IBD to specialist care: 1) alarm symptoms alone, 2) alarm symptoms plus c-reactive protein, and 3) alarm symptoms plus fecal calprotectin. Methods: A prospective cohort study was conducted, including children with chronic gastrointestinal symptoms referred to pediatric gastroenterology. Outcome was defined as IBD confirmed by endoscopy, or IBD ruled out by either endoscopy or unremarkable clinical 12 month follow-up with no indication for endoscopy. Test strategy probabilities were generated by logistic regression analyses and compared by area under the receiver operating characteristic curves (AUC) and decision curves. Results: We included 90 children, of whom 17 (19%) had IBD (n = 65 from primary care physicians, n = 25 from general pediatricians). Adding fecal calprotectin to alarm symptoms increased the AUC significantly from 0.80 (0.67-0.92) to 0.97 (0.93-1.00), but adding c-reactive protein to alarm symptoms did not increase the AUC significantly (p > 0.05). Decision curves confirmed these patterns, showing that alarm symptoms combined with fecal calprotectin produced the diagnostic test strategy with the highest net benefit at reasonable threshold probabilities. Conclusion: In primary care, when children are identified as being at high risk for IBD, adding fecal calprotectin testing to alarm symptoms was the optimal strategy for improving risk stratification

Extended hypothermic oxygenated machine perfusion enables ex situ preservation of porcine livers for up to 24 hours

Background & Aims: End-ischemic hypothermic oxygenated machine perfusion (HOPE) of the donor liver for 1-2 h mitigates ischemia-reperfusion injury during subsequent liver transplantation. Extended preservation time may be preferred to facilitate difficult recipient hepatectomy or to optimize logistics. We therefore investigated whether end-ischemic dual HOPE (DHOPE) could extend preservation time for up to 24 h using a porcine liver reperfusion model. Methods: Following 30 min warm ischemia, porcine livers were subjected to 2 h static cold storage (SCS), followed by 2 h, 6 h, or 24 h DHOPE (n = 6 per group). Subsequent normothermic reperfusion was performed for 4 h using autologous blood. Two livers preserved by 24 h SCS served as additional controls. A proof of principle confirmation was carried out in 2 discarded human livers subjected to extended DHOPE. Hepatocellular and cholangiocyte injury and function were assessed. Oxidative stress levels and histology were compared between groups. Results: Perfusion flows remained stable during DHOPE, regardless of duration. After normothermic reperfusion, livers perfused for 24 h by DHOPE had similar lactate clearance, blood pH, glucose, and alanine aminotransferase levels, and biliary pH, bicarbonate, and LDH levels, as livers perfused for 2 h and 6 h. Levels of malondialdehyde and high-mobility group box 1 in serum and liver parenchyma were similar for all groups. Histological analysis of bile ducts and liver parenchyma revealed no differences between the groups. Extended DHOPE in discarded human livers preserved hepatocellular and cholangiocyte function and histology after reperfusion. In contrast, livers preserved by 24 h SCS were non-functioning. Conclusion: Extended end-ischemic DHOPE enabled successful preservation of porcine and discarded human donor livers for up to 24 h. Extended DHOPE enables safe extension of preservation time, which may facilitate allocation and transplantation from a logistical perspective, and further expand the donor pool. Lay summary: It has been suggested that preserving liver grafts with a technique called (dual) hypothermic oxygenated machine perfusion ([D]HOPE) leads to better outcomes after transplantation than if livers are stored on ice, especially if an organ is of lesser quality. In this study, we showed that DHOPE could be used to preserve liver grafts for up to 24 h. This extended procedure could be used globally to facilitate transplantation and expand the donor pool

Use of Laboratory Markers in Addition to Symptoms for Diagnosis of Inflammatory Bowel Disease in Children:A Meta-analysis of Individual Patient Data

IMPORTANCE: Blood markers and fecal calprotectin are used in the diagnostic workup for inflammatory bowel disease (IBD) in pediatric patients. Any added diagnostic value of these laboratory markers remains unclear.OBJECTIVE: To determine whether adding laboratory markers to evaluation of signs and symptoms improves accuracy when diagnosing pediatric IBD.DATA SOURCES: A literature search of MEDLINE and EMBASE from inception through September 26, 2016. Studies were identified using indexing terms and free-text words related to child, target condition IBD, and diagnostic accuracy.STUDY SELECTION: Two reviewers independently selected studies evaluating the diagnostic accuracy of more than 1 blood marker or fecal calprotectin for IBD, confirmed by endoscopy and histopathology or clinical follow-up, in pediatric patients with chronic gastrointestinal symptoms. Studies that included healthy controls and/or patients with known IBD were excluded.DATA EXTRACTION AND SYNTHESIS: Individual patient data from each eligible study were requested from the authors. In addition, 2 reviewers independently assessed quality with Quality Assessment of Diagnostic Accuracy Studies-2.MEAN OUTCOMES AND MEASURES: Laboratory markers were added as a single test to a basic prediction model based on symptoms. Outcome measures were improvement of discrimination by adding markers as a single test and improvement of risk classification of pediatric patients by adding the best marker.RESULTS: Of the 16 eligible studies, authors of 8 studies (n = 1120 patients) provided their data sets. All blood markers and fecal calprotectin individually significantly improved the discrimination between pediatric patients with and those without IBD, when added to evaluation of symptoms. The best marker-fecal calprotectin-improved the area under the curve of symptoms by 0.26 (95% CI, 0.21-0.31). The second best marker-erythrocyte sedimentation rate-improved the area under the curve of symptoms by 0.16 (95% CI, 0.11-0.21). When fecal calprotectin was added to the model, the proportion of patients without IBD correctly classified as low risk of IBD increased from 33% to 91%. The proportion of patients with IBD incorrectly classified as low risk of IBD decreased from 16% to 9%. The proportion of the total number of patients assigned to the intermediate-risk category decreased from 55% to 6%.CONCLUSIONS AND RELEVANCE: In a hospital setting, fecal calprotectin added the most diagnostic value to symptoms compared with blood markers. Adding fecal calprotectin to the diagnostic workup of pediatric patients with symptoms suggestive of IBD considerably decreased the number of patients in the group in whom challenges in clinical decision making are most prevalent.</p

Dual Versus Single Oxygenated Hypothermic Machine Perfusion of Porcine Livers:Impact on Hepatobiliary and Endothelial Cell Injury

Background: Hypothermic oxygenated machine perfusion (HOPE) reduces ischemia-reperfusion injury of donor livers and is increasingly used in clinical transplantation. However, it remains unclear whether perfusion via the portal vein alone (HOPE) or via both the portal vein and hepatic artery (dual HOPE or DHOPE) is superior. Methods: Twelve porcine livers donated after circulatory death were randomized for 2 h of HOPE (n = 6) or DHOPE (n = 6), followed by 4 h of warm reperfusion with whole blood, to mimic transplantation. Hepatobiliary and endothelial cell function and injury markers were determined in perfusate and bile samples. Biopsies of bile ducts, hepatic arteries, and liver parenchyma were collected to assess histological damage and the expression of endothelial protective genes (KLF-2, eNOS, ET-1, CD31, VWF, VEGF-A). Results: There were no differences in hepatobiliary function and injury after warm reperfusion between the groups, apart from a 2-fold lower concentration of alanine aminotransferase in the perfusate (P = 0.045) and a lower peak lactate dehydrogenase in bile (P = 0.04) of livers preserved by DHOPE. Endothelial cell function and injury, as assessed by perfusate nitric oxide and von Willebrand factor antigen levels, as well as endothelial protective gene expressions, were similar between the groups. The hepatic arteries of both groups showed no microscopic evidence of injury. Conclusions: This study did not reveal major differences in hepatobiliary or endothelial function and injury after preservation by single or dual HOPE of porcine livers donated after circulatory death

The course of mental health problems in children presenting with abdominal pain in general practice

Objective. To investigate the course of mental health problems in children presenting to general practice with abdominal pain and to evaluate the extent to which abdominal pain characteristics during follow-up predict the presence of mental health problems at 12 months' follow-up. Design. A prospective cohort study with one-year follow-up. Setting. 53 general practices in the Netherlands, between May 2004 and March 2006. Subjects. 281 children aged 4-17 years. Main outcome measures. The presence of a depressive problem, an anxiety problem, and multiple non-specific somatic symptoms at follow-up and odds ratios of duration, frequency, and severity of abdominal pain with these mental health problems at follow-up. Results. A depressive problem persisted in 24/74 children (32.9%; 95% CI 22.3-44.9%), an anxiety problem in 13/43 (30.2%; 95% CI 17.2-46.1%) and the presence of multiple non-specific somatic symptoms in 75/170 children (44.1%; 95% CI 36.7-51.6%). None of the abdominal pain characteristics predicted a depressive or an anxiety problem at 12 months' follow-up. More moments of moderate to severe abdominal pain predicted the presence of multiple nonspecific somatic symptoms at follow-up. Conclusions. In one-third of the children presenting to general practice for abdominal pain, anxiety and depressive problems persist during one year of follow-up. Characteristics of the abdominal pain during the follow-up period do not predict anxiety or depressive problems after one-year follow-up. We recommend following over time children seen in primary care with abdominal pain