Cranberries for preventing urinary tract infections.

BACKGROUND: Cranberries contain proanthocyanidins (PACs), which inhibit the adherence of p-fimbriated Escherichia coli to the urothelial cells lining the bladder. Cranberry products have been used widely for several decades to prevent urinary tract infections (UTIs). This is the fifth update of a review first published in 1998 and updated in 2003, 2004, 2008, and 2012. OBJECTIVES: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 13 March 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal (ICTRP) and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products compared with placebo, no specific treatment or other intervention (antibiotics, probiotics) for the prevention of UTIs were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) with 95% confidence intervals (CI) were calculated where appropriate. Study quality was assessed using the Cochrane risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: For this update 26 new studies were added, bringing the total number of included studies to 50 (8857 randomised participants). The risk of bias for sequence generation and allocation concealment was low for 29 and 28 studies, respectively. Thirty-six studies were at low risk of performance bias, and 23 studies were at low risk of detection bias. Twenty-seven, 41, and 17 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Forty-five studies compared cranberry products with placebo or no specific treatment in six different groups of participants. Twenty-six of these 45 studies could be meta-analysed for the outcome of symptomatic, culture-verified UTIs. In moderate certainty evidence, cranberry products reduced the risk of UTIs (6211 participants: RR 0.70, 95% CI 0.58 to 0.84; I² = 69%). When studies were divided into groups according to the treatment indication, cranberry products probably reduced the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs (8 studies, 1555 participants: RR 0.74, 95% CI 0.55 to 0.99; I² = 54%), in children (5 studies, 504 participants: RR 0.46, 95% CI 0.32 to 0.68; I² = 21%) and in people with a susceptibility to UTIs due to an intervention (6 studies, 1434 participants: RR 0.47, 95% CI 0.37 to 0.61; I² = 0%). However, in low certainty evidence, there may be little or no benefit in elderly institutionalised men and women (3 studies, 1489 participants: RR 0.93, 95% CI 0.67 to 1.30; I² = 9%), pregnant women (3 studies, 765 participants: RR 1.06, 95% CI 0.75 to 1.50; I² = 3%), or adults with neuromuscular bladder dysfunction with incomplete bladder emptying (3 studies, 464 participants: RR 0.97, 95% CI 0.78 to 1.19; I² = 0%). Other comparisons were cranberry products with probiotics (three studies) or antibiotics (six studies), cranberry tablets with cranberry liquid (one study), and different doses of PACs (two studies). Compared to antibiotics, cranberry products may make little or no difference to the risk of symptomatic, culture-verified UTIs (2 studies, 385 participants: RR 1.03, 95% CI 0.80 to 1.33; I² = 0%) or the risk of clinical symptoms without culture (2 studies, 336 participants: RR 1.30, 95% CI 0.79 to 2.14; I² = 68%). Compared to probiotics, cranberry products may reduce the risk of symptomatic, culture-verified UTIs (3 studies, 215 participants: RR 0.39, 95% CI 0.27 to 0.56; I = 0%). It is unclear whether efficacy differs between cranberry juice and tablets or between different doses of PACs as the certainty of the evidence was very low. The number of participants with gastrointestinal side effects probably does not differ between those taking cranberry products and those receiving placebo or no specific treatment (10 studies, 2166 participants: RR 1.33, 95% CI 1.00 to 1.77; I² = 0%; moderate certainty evidence). There was no clear relationship between compliance with therapy and the risk for repeat UTIs. No difference in the risk for UTIs could be demonstrated between low, moderate and high doses of PACs. AUTHORS' CONCLUSIONS: This update adds a further 26 studies taking the total number of studies to 50 with 8857 participants. These data support the use of cranberry products to reduce the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs, in children, and in people susceptible to UTIs following interventions. The evidence currently available does not support its use in the elderly, patients with bladder emptying problems, or pregnant women.

Cranberries for preventing urinary tract infections.

BACKGROUND: Cranberries contain proanthocyanidins (PACs), which inhibit the adherence of p-fimbriated Escherichia coli to the urothelial cells lining the bladder. Cranberry products have been used widely for several decades to prevent urinary tract infections (UTIs). This is the fifth update of a review first published in 1998 and updated in 2003, 2004, 2008, and 2012. OBJECTIVES: To assess the effectiveness of cranberry products in preventing UTIs in susceptible populations. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 13 March 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) or quasi-RCTs of cranberry products compared with placebo, no specific treatment or other intervention (antibiotics, probiotics) for the prevention of UTIs were included. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed and extracted data. Information was collected on methods, participants, interventions and outcomes (incidence of symptomatic UTIs, positive culture results, side effects, adherence to therapy). Risk ratios (RR) with 95% confidence intervals (CI) were calculated where appropriate. Study quality was assessed using the Cochrane risk of bias assessment tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: For this update, 26 new studies were added, bringing the total number of included studies to 50 (8857 randomised participants). The risk of bias for sequence generation and allocation concealment was low for 29 and 28 studies, respectively. Thirty-six studies were at low risk of performance bias, and 23 studies were at low risk of detection bias. Twenty-seven, 41, and 17 studies were at low risk of attrition bias, reporting bias and other bias, respectively. Forty-five studies compared cranberry products with placebo, water or no specific treatment in six different groups of participants. Twenty-six of these 45 studies could be meta-analysed for the outcome of symptomatic, culture-verified UTIs. In moderate certainty evidence, cranberry products reduced the risk of UTIs (6211 participants: RR 0.70, 95% CI 0.58 to 0.84; I² = 69%). When studies were divided into groups according to the treatment indication, cranberry products probably reduced the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs (8 studies, 1555 participants: RR 0.74, 95% CI 0.55 to 0.99; I² = 54%), in children (5 studies, 504 participants: RR 0.46, 95% CI 0.32 to 0.68; I² = 21%) and in people with a susceptibility to UTIs due to an intervention (6 studies, 1434 participants: RR 0.47, 95% CI 0.37 to 0.61; I² = 0%). However, there may be little or no benefit in elderly institutionalised men and women (3 studies, 1489 participants: RR 0.93, 95% CI 0.67 to 1.30; I² = 9%; moderate certainty evidence), pregnant women (3 studies, 765 participants: RR 1.06, 95% CI 0.75 to 1.50; I² = 3%; moderate certainty evidence), or adults with neuromuscular bladder dysfunction with incomplete bladder emptying (3 studies, 464 participants: RR 0.97, 95% CI 0.78 to 1.19; I² = 0%; low certainty evidence). Other comparisons were cranberry products with probiotics (three studies) or antibiotics (six studies), cranberry tablets with cranberry liquid (one study), and different doses of PACs (two studies). Compared to antibiotics, cranberry products may make little or no difference to the risk of symptomatic, culture-verified UTIs (2 studies, 385 participants: RR 1.03, 95% CI 0.80 to 1.33; I² = 0%) or the risk of clinical symptoms without culture (2 studies, 336 participants: RR 1.30, 95% CI 0.79 to 2.14; I² = 68%). Compared to probiotics, cranberry products may reduce the risk of symptomatic, culture-verified UTIs (3 studies, 215 participants: RR 0.39, 95% CI 0.27 to 0.56; I = 0%). It is unclear whether efficacy differs between cranberry juice and tablets or between different doses of PACs, as the certainty of the evidence was very low. The number of participants with gastrointestinal side effects probably does not differ between those taking cranberry products and those receiving a placebo or no specific treatment (10 studies, 2166 participants: RR 1.33, 95% CI 1.00 to 1.77; I² = 0%; moderate certainty evidence). There was no clear relationship between compliance with therapy and the risk for repeat UTIs. No difference in the risk for UTIs could be demonstrated between low, moderate and high doses of PACs. AUTHORS' CONCLUSIONS: This update adds a further 26 studies, taking the total number of studies to 50 with 8857 participants. These data support the use of cranberry products to reduce the risk of symptomatic, culture-verified UTIs in women with recurrent UTIs, in children, and in people susceptible to UTIs following interventions. The evidence currently available does not support its use in the elderly, patients with bladder emptying problems, or pregnant women.

Clinical management of melanocytic tumours of uncertain malignant potential (MelTUMPs), including melanocytomas: A systematic review and meta-analysis.

Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta-analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB-positivity. Meta-analysis was performed on the SNB-positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow-up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta-analysis was 32% (95% CI: 23-44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma-related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).

Exercise training for adults undergoing maintenance dialysis.

BACKGROUND: Dialysis treatments weigh heavily on patients' physical and psychosocial health. Multiple studies have assessed the potential for exercise training to improve outcomes in adults undergoing dialysis. However, uncertainties exist in its relevance and sustainable benefits for patient-important outcomes. This is an update of a review first published in 2011. OBJECTIVES: To assess the benefits and safety of regular structured exercise training in adults undergoing dialysis on patient-important outcomes including death, cardiovascular events, fatigue, functional capacity, pain, and depression. We also aimed to define the optimal prescription of exercise in adults undergoing dialysis. SEARCH METHODS: In this update, we conducted a systematic search of the Cochrane Kidney and Transplant Register of Studies up to 23 December 2020. The Register includes studies identified from CENTRAL, MEDLINE, EMBASE, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov as well as kidney-related journals and the proceedings of major kidney conferences. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of any structured exercise programs of eight weeks or more in adults undergoing maintenance dialysis compared to no exercise or sham exercise. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the search results for eligibility, extracted the data and assessed the risk of bias using the Cochrane risk of bias tool. Whenever appropriate, we performed random-effects meta-analyses of the mean difference in outcomes. The primary outcomes were death (any cause), cardiovascular events and fatigue. Secondary outcomes were health-related quality of life (HRQoL), depression, pain, functional capacity, blood pressure, adherence to the exercise program, and intervention-related adverse events. MAIN RESULTS: We identified 89 studies involving 4291 randomised participants, of which 77 studies (3846 participants) contributed to the meta-analyses. Seven studies included adults undergoing peritoneal dialysis. Fifty-six studies reported aerobic exercise interventions, 21 resistance exercise interventions and 19 combined aerobic and resistance training within the same study arm. The interventions lasted from eight weeks to two years and most often took place thrice weekly during dialysis treatments. A single study reported death and no study reported long-term cardiovascular events. Five studies directly assessed fatigue, 46 reported HRQoL and 16 reported fatigue or pain through their assessment of HRQoL. Thirty-five studies assessed functional capacity, and 21 reported resting peripheral blood pressure. Twelve studies reported adherence to exercise sessions, and nine reported exercise-related adverse events. Overall, the quality of the included studies was low and blinding of the participants was generally not feasible due to the nature of the intervention. Exercise had uncertain effects on death, cardiovascular events, and the mental component of HRQoL due to the very low certainty of evidence. Compared with sham or no exercise, exercise training for two to 12 months may improve fatigue in adults undergoing dialysis, however, a meta-analysis could not be conducted. Any exercise training for two to 12 months may improve the physical component of HRQoL (17 studies, 656 participants: MD 4.12, 95% CI 1.88 to 6.37 points on 100 points-scale; I² = 49%; low certainty evidence). Any exercise training for two to 12 months probably improves depressive symptoms (10 studies, 441 participants: SMD -0.65, 95% CI -1.07 to -0.22; I² = 77%; moderate certainty evidence) and the magnitude of the effect may be greater when maintaining the exercise beyond four months (6 studies, 311 participants: SMD -0.30, 95% CI 0.14 to -0.74; I² = 71%). Any exercise training for three to 12 months may improve pain (15 studies, 872 participants: MD 5.28 95% CI -0.12 to 10.69 points on 100 points-scale; I² = 63%: low certainty evidence) however, the 95% CI indicates that exercise training may make little or no difference in the level of pain. Any exercise training for two to six months probably improves functional capacity as it increased the distance reached during six minutes of walking (19 studies, 827 participants: MD 49.91 metres, 95% CI 37.22 to 62.59; I² = 34%; moderate certainty evidence) and the number of sit-to-stand cycles performed in 30 seconds (MD 2.33 cycles, 95% CI 1.71 to 2.96; moderate certainty evidence). There was insufficient evidence to assess the safety of exercise training for adults undergoing maintenance dialysis. The results were similar for aerobic exercise, resistance exercise, and a combination of both aerobic and resistance exercise. AUTHORS' CONCLUSIONS: It is uncertain whether exercise training improves death, cardiovascular events, or the mental component of HRQoL in adults undergoing maintenance dialysis. Exercise training probably improves depressive symptoms, particularly when the intervention is maintained beyond four months. Exercise training is also likely to improve functional capacity. Low certainty evidence suggested that exercise training may improve fatigue, the physical component of quality of life, and pain. The safety of exercise training for adults undergoing dialysis remains uncertain.

Organ transplantation and outcomes in patients with a past history of melanoma: A systematic review and meta-analysis.

BACKGROUND: The incidence of melanoma is steadily rising around the world. There is uncertainty about the safety of solid organ transplantation in patients with a prior history of melanoma. AIM: To review studies reporting patients with a history of melanoma before solid organ transplantation. METHODS: Electronic searches of Medline, Embase, and the Cochrane library up to March 2020. All study designs, in any language and without sample size restriction, were eligible for inclusion. Risk of bias was assessed using established tools, and meta-analysis was performed using a random-effects model. RESULTS: We identified 41 studies reporting 703 100 transplant recipients and 1692 had pre-transplantation melanomas. Risk of death, expressed as a hazard ratio, in patients with pre-transplantation melanoma relative to those without prior melanoma, was 1.32 (95% CI: 1.09-1.59). After transplantation, 13.1% of patients with pre-transplantation melanoma developed new or recurrent melanoma (IQR: 4.8%-18.2%). CONCLUSIONS: Around 1-in-400 transplant recipients had a prior history of melanoma. This was associated with a greater than 1-in-10 risk of new or recurrent melanoma after transplantation and an increased risk of death. A 5-year waiting time between a melanoma diagnosis and transplantation has been recommended based on historic registry data, but very little additional information is available to justify or revise this.

Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome.

BACKGROUND: Primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome in adults. Without treatment, approximately 30% of patients will experience spontaneous remission and one third will have persistent proteinuria. Approximately one-third of patients progress toward end-stage kidney disease (ESKD) within 10 years. Immunosuppressive treatment aims to protect kidney function and is recommended for patients who do not show improvement of proteinuria by supportive therapy, and for patients with severe nephrotic syndrome at presentation due to the high risk of developing ESKD. The efficacy and safety of different immunosuppressive regimens are unclear. This is an update of a Cochrane review, first published in 2004 and updated in 2013. OBJECTIVES: The aim was to evaluate the safety and efficacy of different immunosuppressive treatments for adult patients with PMN and nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 1 April 2021 with support from the Cochrane Kidney and Transplant Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating effects of immunosuppression in adults with PMN and nephrotic syndrome were included. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, quality assessment, and data synthesis were performed using Cochrane-recommended methods. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Sixty-five studies (3807 patients) were included. Most studies exhibited a high risk of bias for the domains, blinding of study personnel, participants and outcome assessors, and most studies were judged unclear for randomisation sequence generation and allocation concealment. Immunosuppressive treatment versus placebo/no treatment/non-immunosuppressive treatment In moderate certainty evidence, immunosuppressive treatment probably makes little or no difference to death, probably reduces the overall risk of ESKD (16 studies, 944 participants: RR 0.59, 95% CI 0.35 to 0.99; I² = 22%), probably increases total remission (complete and partial) (6 studies, 879 participants: RR 1.44, 95% CI 1.05 to 1.97; I² = 73%) and complete remission (16 studies, 879 participants: RR 1.70, 95% CI 1.05 to 2.75; I² = 43%), and probably decreases the number with doubling of serum creatinine (SCr) (9 studies, 447 participants: RR 0.46, 95% CI 0.26 to 0.80; I² = 21%). However, immunosuppressive treatment may increase the number of patients relapsing after complete or partial remission (3 studies, 148 participants): RR 1.73, 95% CI 1.05 to 2.86; I² = 0%) and may lead to a greater number experiencing temporary or permanent discontinuation/hospitalisation due to adverse events (18 studies, 927 participants: RR 5.33, 95% CI 2.19 to 12.98; I² = 0%). Immunosuppressive treatment has uncertain effects on infection and malignancy. Oral alkylating agents with or without steroids versus placebo/no treatment/steroids Oral alkylating agents with or without steroids had uncertain effects on death but may reduce the overall risk of ESKD (9 studies, 537 participants: RR 0.42, 95% CI 0.24 to 0.74; I² = 0%; low certainty evidence). Total (9 studies, 468 participants: RR 1.37, 95% CI 1.04 to 1.82; I² = 70%) and complete remission (8 studies, 432 participants: RR 2.12, 95% CI 1.33 to 3.38; I² = 37%) may increase, but had uncertain effects on the number of patients relapsing, and decreasing the number with doubling of SCr. Alkylating agents may be associated with a higher rate of adverse events leading to discontinuation or hospitalisation (8 studies 439 participants: RR 6.82, 95% CI 2.24 to 20.71; I² = 0%). Oral alkylating agents with or without steroids had uncertain effects on infection and malignancy. Calcineurin inhibitors (CNI) with or without steroids versus placebo/no treatment/supportive therapy/steroids We are uncertain whether CNI with or without steroids increased or decreased the risk of death or ESKD, increased or decreased total or complete remission, or reduced relapse after complete or partial remission (low to very low certainty evidence). CNI also had uncertain effects on decreasing the number with a doubling of SCr, temporary or permanent discontinuation or hospitalisation due to adverse events, infection, or malignancy. Calcineurin inhibitors (CNI) with or without steroids versus alkylating agents with or without steroids We are uncertain whether CNI with or without steroids increases or decreases the risk of death or ESKD. CNI with or without steroids may make little or no difference to total remission (10 studies, 538 participants: RR 1.01, 95% CI 0.89 to 1.15; I² = 53%; moderate certainty evidence) or complete remission (10 studies, 538 participants: RR 1.15, 95% CI 0.84 to 1.56; I² = 56%; low certainty evidence). CNI with or without steroids may increase relapse after complete or partial remission. CNI with or without steroids had uncertain effects on SCr increase, adverse events, infection, and malignancy. Other immunosuppressive treatments Other interventions included azathioprine, mizoribine, adrenocorticotropic hormone, traditional Chinese medicines, and monoclonal antibodies such as rituximab. There were insufficient data to draw conclusions on these treatments. AUTHORS' CONCLUSIONS: This updated review strengthened the evidence that immunosuppressive therapy is probably superior to non-immunosuppressive therapy in inducing remission and reducing the number of patients that progress to ESKD. However, these benefits need to be balanced against the side effects of immunosuppressive drugs. The number of included studies with high-quality design was relatively small and most studies did not have adequate follow-up. Clinicians should inform their patients of the lack of high-quality evidence. An alkylating agent (cyclophosphamide or chlorambucil) combined with a corticosteroid regimen had short- and long-term benefits, but this was associated with a higher rate of adverse events. CNI (tacrolimus and cyclosporin) showed equivalency with alkylating agents however, the certainty of this evidence remains low. Novel immunosuppressive treatments with the biologic rituximab or use of adrenocorticotropic hormone require further investigation and validation in large and high-quality RCTs.

One-Time Fecal Immunochemical Screening for Advanced Colorectal Neoplasia in Patients with CKD (DETECT Study).

BACKGROUND: In patients with CKD, the risk of developing colorectal cancer is high and outcomes are poor. Screening using fecal immunochemical testing (FIT) is effective in reducing mortality from colorectal cancer, but performance characteristics of FIT in CKD are unknown. METHODS: To determine the detection rates and performance characteristics of FIT for advanced colorectal neoplasia (ACN) in patients with CKD, we used FIT to prospectively screen patients aged 35-74 years with CKD (stages 3-5 CKD, dialysis, and renal transplant) from 11 sites in Australia, New Zealand, Canada, and Spain. All participants received clinical follow-up at 2 years. We used a two-step reference standard approach to estimate disease status. RESULTS: Overall, 369 out of 1706 patients who completed FIT (21.6%) tested positive; 323 (87.5%) underwent colonoscopies. A total of 1553 (91.0%) completed follow-up; 82 (4.8%) had died and 71 (4.2%) were lost. The detection rate of ACN using FIT was 6.0% (5.6%, 7.4%, and 5.6% for stages 3-5 CKD, dialysis, and transplant). Sensitivity, specificity, and positive and negative predictive values of FIT for ACN were 0.90, 0.83, 0.30, and 0.99, respectively. Of participants who underwent colonoscopy, five (1.5%) experienced major colonoscopy-related complications, including bowel perforation and major bleeding. CONCLUSIONS: FIT appears to be an accurate screening test for patients with CKD, such that a negative test may rule out the diagnosis of colorectal cancer within 2 years. However, the risk of major complications from work-up colonoscopy are at least ten-fold higher than in the general population.

Long-term antibiotics for preventing recurrent urinary tract infection in children.

BACKGROUND: Urinary tract infection (UTI) is common in children. Symptoms include fever, lethargy, anorexia, and vomiting. UTI is caused by Escherichia coli in over 80% of cases and treatment is a course of antibiotics. Due to acute illness caused by UTI and the risk of pyelonephritis-induced permanent kidney damage, many children are given long-term (several months to 2 years) antibiotics aimed at preventing recurrence. This is the third update of a review first published in 2001 and updated in 2006, and 2011. OBJECTIVES: To assess whether long-term antibiotic prophylaxis was more effective than placebo/no treatment in preventing recurrence of UTI in children, and if so which antibiotic in clinical use was the most effective. We also assessed the harms of long-term antibiotic treatment. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 30 July 2018 through contact with the Cochrane Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised comparisons of antibiotics with other antibiotics, placebo or no treatment to prevent recurrent UTI in children. DATA COLLECTION AND ANALYSIS: Two authors independently assessed and extracted information for the initial and previous updates. A random-effects model was used to estimate risk ratio (RR) and risk difference (RD) for recurrent UTI with 95% confidence intervals (CI). MAIN RESULTS: In this update sixteen studies (2036 children randomised, 1977 analysed) were included. Seven studies (612 children) compared two or more types of antibiotics, six (1088 children) compared antibiotics with placebo or no treatment, one four-armed study compared circumcision with and without antibiotic treatment, one study compared dose of antibiotic, and one three-armed study compared two different antibiotics as well as no treatment. Of the sixteen included studies only one study was judged to be at low risk of bias for all domains, with the majority judged to be at unclear risk of bias due to very poorly reported methodology. The number of studies judged to be a low risk of bias was: selection bias (7); performance bias (4); detection bias (1); attrition bias (6); reporting bias (7); and other bias (2). The number of studies judged to be at high risk of bias was: selection bias (0); performance bias (5); detection bias (1); attrition bias (4); reporting bias (6); and other bias (1).Compared to placebo/no treatment, antibiotics lead to a modest decrease in the number of repeat symptomatic UTI in children; however the estimate from combining all studies was not certain and the confidence interval indicates low precision indicating that antibiotics may make little or no difference to risk of repeat infection (RR 0.75, 95% CI 0.28 to 1.98). When we combined only the data from studies with concealed treatment allocation, there was a similar reduction in risk of repeat symptomatic UTI in children taking antibiotics (RR 0.68) and we have greater certainty in this estimate because of the more robust study designs, the confidence interval is smaller and it does not include the point of no effect (95% CI 0.48 to 0.95). The estimated reduction in risk of repeat symptomatic UTI for children taking antibiotics was similar in children with vesicoureteric reflux (VUR) (RR 0.65, 95% CI 0.39 to 1.07) compared to those without VUR (RR 0.56, 95% CI 0.15 to 2.12) however there was considerable uncertainty due to imprecision from fewer events in the smaller group of children with VUR. There was no consistency in occurrence of adverse events, with one study having more events in the placebo group and a second study having more events in the antibiotics group. Three studies reported data for antibiotic resistance with the analysis estimating the risk of a UTI caused by a bacteria resistant to the prophylactic antibiotic being almost 2.5 times greater in children on antibiotics than for children on placebo or no treatment (RR 2.40, 95% CI 0.62 to 9.26). However the confidence interval is wide, showing imprecision and there may be little or no difference between the two groups.Eight studies involving 659 children compared one antibiotic with another but few studies compared the same combination for the same outcome so little data could be pooled. Two studies reported microbial resistance data and analysis showed that treatment with nitrofurantoin may lead to a lower risk of a UTI caused by a bacteria resistant to the treatment drug compared to children given trimethoprim-sulphamethoxazole as their prophylactic treatment (RR 0.54, 95% CI 0.31 to 0.92). AUTHORS' CONCLUSIONS: Long-term antibiotics may reduce the risk of repeat symptomatic UTI in children who have had one or more previous UTIs but the benefit may be small and must be considered together with the increased risk of microbial resistance.

Interventions for primary vesicoureteric reflux.

BACKGROUND: Vesicoureteric reflux (VUR) results in urine passing retrograde up the ureter. Urinary tract infections (UTI) associated with VUR have been considered a cause of permanent renal parenchymal damage in children with VUR. Management has been directed at preventing UTI by antibiotic prophylaxis and/or surgical correction of VUR. This is an update of a review first published in 2004 and updated in 2007 and 2011. OBJECTIVES: The aim of this review was to evaluate the available evidence for both benefits and harms of the currently available treatment options for primary VUR: operative, non-operative or no intervention. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 3 May 2018 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings, and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: RCTs in any language comparing any treatment of VUR and any combination of therapies. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed quality and extracted data. Dichotomous outcomes were expressed as risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean differences (MD) with 95% CI. Data were pooled using the random effects model. MAIN RESULTS: Thirty four studies involving 4001 children were included. Interventions included; long-term low-dose antibiotics, surgical reimplantation of ureters, endoscopic injection treatment, probiotics, cranberry products, circumcision, and oxybutynin. Interventions were used alone and in combinations. The quality of conduct and reporting of these studies was variable, with many studies omitting crucial methodological information used to assess the risk of bias. Only four of the 34 studies were considered at low risk of bias across all fields of study quality. The majority of studies had many areas of uncertainty in the risk of bias fields, reflecting missing detail rather than stated poor design.Low-dose antibiotic prophylaxis compared to no treatment/placebo may make little or no difference to the risk of repeat symptomatic UTI (9 studies, 1667 children: RR 0.77, 95% CI 0.54 to 1.09; low certainty evidence) and febrile UTI (RR 0.83, 95% CI 0.56 to 1.21; low certainty evidence) at one to two years. At one to three years, antibiotic prophylaxis made little or no difference to the risk of new or progressive renal damage on DMSA scan (8 studies, 1503 children: RR 0.73, 95% CI 0.33 to 1.61; low certainty evidence). Adverse events were reported in four studies with little or no difference between treatment groups (1056 children: RR 0.94, 95% CI 0.81 to 1.08; ), but antibiotics increased the likelihood of bacterial drug resistance threefold (187 UTIs: RR 2.97, 95% CI 1.54 to 5.74; moderate certainty evidence).Seven studies compared long-term antibiotic prophylaxis alone with surgical reimplantation of ureters plus antibiotics, but only two reported the outcome febrile UTI (429 children). Surgery plus antibiotic treatment may reduce the risk of repeat febrile UTI by 57% (RR 0.43, 95% CI 0.27 to 0.70; moderate certainty evidence). There was little or no difference in the risk of new kidney defects detected using intravenous pyelogram at 4 to 5 years (4 studies, 572 children, RR 1.09, 95% CI 0.79 to 1.49; moderate certainty evidence)Four studies compared endoscopic injection with antibiotics alone and three reported the outcome febrile UTI. This analysis showed little or no difference in the risk of febrile UTI with endoscopic injection compared to antibiotics (RR 0.74, 95% CI 0.31 to 1.78; low certainty evidence). Four studies involving 425 children compared two different materials for endoscopic injection under the ureters (polydimethylsiloxane (Macroplastique) versus dextranomer/hyaluronic acid polymer (Deflux), glutaraldehyde cross-linked (GAX) collagen (GAX) 35 versus GAX 65 and Deflux versus polyacrylate polyalcohol copolymer (VANTRIS)) but only one study (255 children, low certainty evidence) had the outcome of febrile UTI and it reported no difference between the materials. All four studies reported rates of resolution of VUR, and the two studies comparing Macroplastique with Deflux showed that Macroplastique was probably superior to dextranomer/hyaluronic acid polymer (3 months: RR 0.50, 95% CI 0.33 to 0.78; 12 months: RR 0.54 95% CI 0.35 to 0.83; low certainty evidence)Two studies compared probiotic treatment with antibiotics and showed little or no difference in risk of repeat symptomatic UTI (RR 0.82 95% CI 0.56 to 1.21; low certainty evidence)Single studies compared circumcision with antibiotics, cranberry products with no treatment, oxybutynin with placebo, two different surgical techniques and endoscopic injection with no treatment. AUTHORS' CONCLUSIONS: Compared with no treatment, the use of long-term, low-dose antibiotics may make little or no difference to the number of repeat symptomatic and febrile UTIs in children with VUR (low certainty evidence). Considerable variation in the study designs and subsequent findings prevented drawing firm conclusions on efficacy of antibiotic treatment.The added benefit of surgical or endoscopic correction of VUR over antibiotic treatment alone remains unclear since few studies comparing the same treatment and with relevant clinical outcomes were available for analysis.

Urinary tract infections in febrile children: Changing spectra of pathogenic bacteria and antibiotic susceptibilities?

AIM: To compare the spectra of pathogens causing febrile urinary tract infections (UTI) in children, treatment and antimicrobial susceptibility between 2004-2006 and 2007-2009. METHODS: UTI were identified from a cohort study of febrile children younger than 5 years presenting to a large tertiary children's hospital's emergency department with febrile illnesses. We compared pathogenic profiles, antibiotic choices and susceptibilities between 2004-2006 and 2007-2009 and tested for differences using χ2 and Fisher's exact tests. Antibiotic choice was compared with national therapeutic guideline recommendations for UTI in children (oral cotrimoxazole, cephalexin or amoxycillin-clavulanate or intravenous gentamicin plus ampicillin). RESULTS: There were 539 (2.71%) confirmed UTI from 19 889 febrile illnesses in 2004-2006 and 654 (2.99%) confirmed UTI from 21 846 febrile illnesses in 2007-2009. There was no difference in the frequency of the isolated pathogens by period: Escherichia coli (69.2 vs. 69.7%, P = 0.85), Proteus mirabilis (7.9 vs. 7.2%, P = 0.66) and Klebsiella species (6.2 vs. 4.7%, P = 0.25). National therapeutic guideline recommendations were followed in 277 of 539 (51.4%) versus 318 of 654 (48.6%) (P = 0.34). Oral antibiotics were given in 20.6 versus 18.9%. There was no difference in extended spectrum beta lactamase (1.5 vs. 1.7%, P = 0.82) or other antibiotic susceptibilities (e.g. E. coli: cotrimoxazole = 75.9 vs. 75.2%, P = 0.8). CONCLUSIONS: Overall, approximately 3% of febrile illnesses were due to UTI, but we found no change in the spectrum of pathogens or antibiotic susceptibility patterns, including extended-spectrum beta-lactamase, with time. In both time periods, treatment followed therapeutic guidelines approximately half the time, and most pathogens were susceptible to oral antibiotics, but they were infrequently used.

Scope and Consistency of Outcomes Reported in Randomized Trials Conducted in Adults Receiving Hemodialysis: A Systematic Review.

BACKGROUND: Clinical trials are most informative for evidence-based decision making when they consistently measure and report outcomes of relevance to stakeholders. We aimed to assess the scope and consistency of outcomes reported in trials for hemodialysis. STUDY DESIGN: Systematic review. SETTING & POPULATION: Adults requiring maintenance hemodialysis enrolled in clinical trials. SELECTION CRITERIA: All Cochrane systematic reviews of interventions published by August 29, 2016, and the trials published and registered in ClinicalTrials.gov since January 2011. INTERVENTIONS: Any hemodialysis-related interventions. OUTCOMES: Frequency and characteristics of the reported outcome domains and measures. RESULTS: From the 362 trials, we extracted and classified 10,713 outcome measures (a median of 21 [IQR, 10-39] per trial) into 81 different outcome domains, of which 42 (52%) were surrogate; 25 (31%), clinical; and 14 (17%), patient reported. The number of outcome measures reported significantly changed over time. The 5 most commonly reported domains were all surrogates: phosphate (125 [35%] trials), dialysis adequacy (120 [33%]), anemia (115 [32%]), inflammatory markers (114 [31%]), and calcium (109 [30%]). Mortality, cardiovascular diseases, and quality of life were reported very infrequently (73 [20%], 44 [12%], and 32 [9%], respectively). LIMITATIONS: For feasibility, we included a sampling frame that included only trials identified in Cochrane systematic reviews or ClinicalTrials.gov. CONCLUSIONS: Outcomes reported in clinical trials involving adults receiving hemodialysis are focused on surrogate outcomes, rather than clinical and patient-centered outcomes. There is also extreme multiplicity and heterogeneity at every level: domain, measure, metric, and time point. Estimates of the comparative effectiveness of available interventions are unreliable and improvements over time have been inconsistent.

Public preferences for communicating personal genomic risk information: a focus group study.

BACKGROUND: Personalized genomic risk information has the potential to motivate behaviour change and promote population health, but the success of this will depend upon effective risk communication strategies. OBJECTIVE: To determine preferences for different graphical and written risk communication formats, and the delivery of genomic risk information including the mode of communication and the role of health professionals. DESIGN: Focus groups, transcribed and analysed thematically. PARTICIPANTS: Thirty-four participants from the public. METHODS: Participants were provided with, and invited to discuss, a hypothetical scenario giving an individual's personalized genomic risk of melanoma displayed in several graphical formats. RESULTS: Participants preferred risk formats that were familiar and easy to understand, such as a 'double pie chart' and '100 person diagram' (pictograph). The 100 person diagram was considered persuasive because it humanized and personalized the risk information. People described the pie chart format as resembling bank data and food (such as cake and pizza). Participants thought that email, web-based platforms and postal mail were viable options for communicating genomic risk information. However, they felt that it was important that a health professional (either a genetic counsellor or 'informed' general practitioner) be available for discussion at the time of receiving the risk information, to minimize potential negative emotional responses and misunderstanding. Face-to-face or telephone delivery was preferred for delivery of high-risk results. CONCLUSIONS: These public preferences for communication strategies for genomic risk information will help to guide translation of genome-based knowledge into improved population health.

Republished: value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.

OBJECTIVE: The leukocyte count is frequently used to evaluate suspected bacterial infections but estimates of its test performance vary considerably. We evaluated its accuracy for the detection of serious bacterial infections in febrile children. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department. PATIENTS: Febrile 0-5-year-olds who had a leukocyte count on presentation. OUTCOME MEASURES: Accuracy of total white blood cell and absolute neutrophil counts for the detection of urinary tract infection, bacteraemia, pneumonia and a combined ('any serious bacterial infection') category. Logistic regression models were fitted for each outcome. Reference standards were microbiological/radiological tests and clinical follow-up. RESULTS: Serious bacterial infections were present in 714 (18.3%) of 3893 illness episodes. The area under the receiver operating characteristic curve for 'any serious bacterial infection' was 0.653 (95% CI 0.630 to 0.676) for the total white blood cell count and 0.638 (95% CI 0.615 to 0.662) for absolute neutrophil count. A white blood cell count threshold >15×10(9)/L had a sensitivity of 47% (95% CI 43% to 50%), specificity 76% (95% CI 74% to 77%), positive likelihood ratio 1.93 (95% CI 1.75 to 2.13) and negative likelihood ratio 0.70 (95% CI 0.65 to 0.75). An absolute neutrophil count threshold >10×10(9)/L had a sensitivity of 41% (95% CI 38% to 45%), specificity 78% (95% CI 76% to 79%), positive likelihood ratio 1.87 (95% CI 1.68 to 2.09) and negative likelihood ratio 0.75 (95% CI 0.71 to 0.80). CONCLUSIONS: The total white blood cell count and absolute neutrophil count are not sufficiently accurate triage tests for febrile children with suspected serious bacterial infection.

When does a melanoma metastasize? Implications for management.

Selecting which patients with clinically-localized melanoma require treatment other than wide excision of the primary tumor is based on the risk or presence of metastatic disease. This in turn is linked to survival. Knowing if and when a melanoma is likely to metastasize is therefore of great importance. Several studies employing a range of different methodologies have suggested that many melanomas metastasize long before the primary lesion is diagnosed. Therefore, waiting for dissemination of metastatic disease to become evident before making systemic therapy available to these patients may be less effective than giving them post-operative adjuvant therapy initially if the metastatic risk is high. The identification of these high-risk patients will assist in selecting those to whom adjuvant systemic therapy can most appropriately be offered. Further studies are required to better identify high-risk patients whose primary melanoma is likely to have already metastasized.

Effect of smoking on melanoma incidence: a systematic review with meta-analysis.

BACKGROUND: There is a strong correlation between cigarette smoking and the development of many cancer types. It is therefore paradoxical that multiple reports have suggested a reduced incidence of melanoma in smokers. This study aimed to analyze all existing studies of melanoma incidence in smokers relative to non-smokers. METHODS: Searches of MEDLINE and Embase were conducted for studies reporting data on melanoma in smokers and never-smokers. No study design limitations or language restrictions were applied. The outcome examined was the association between smoking status and melanoma. Analyses focussed on risk of melanoma in smokers and never-smokers generated from multivariable analyses and these were pooled using a fixed effects model. Risk of bias was assessed using the Newcastle-Ottawa tool. FINDINGS: Forty-nine studies that included 59,429 melanoma patients were identified. Pooled analyses showed that current-smokers had a significantly-reduced risk of melanoma both in males (risk ratio (RR) 0.60, 95%CI_0.56 to0.65, p < .001) and females (RR 0.79- 95%-CI-0.73-to-0.86, p < .001). Male former-smokers had a 16% reduction in melanoma risk compared to never-smokers (RR-0.84,-95%CI-0.77-to-0.93, p < .001), but no risk reduction was observed in female former-smokers (RR-1.0-95%CI-0.92-to-1.08). INTERPRETATION: Current-smokers have a significantly-reduced risk of developing melanoma compared to never-smokers, with a reduction in melanoma risk of 40% in men and 21% in women.

High-resolution epitope mapping of commercial antibodies to ANCA antigens by yeast surface display.

Epitope mapping provides critical insight into antibody-antigen interactions. Epitope mapping of autoantibodies from patients with autoimmune diseases can help elucidate disease immunogenesis and guide the development of antigen-specific therapies. Similarly, epitope mapping of commercial antibodies targeting known autoantigens enables the use of those antibodies to test specific hypotheses. Anti-Neutrophil Cytoplasmic Autoantibody (ANCA) vasculitis results from the formation of autoantibodies to multiple autoantigens, including myeloperoxidase (MPO), proteinase-3 (PR3), plasminogen (PLG), and peroxidasin (PXDN). To perform high-resolution epitope mapping of commercial antibodies to these autoantigens, we developed a novel yeast surface display library based on a series of >5000 overlapping peptides derived from their protein sequences. Using both FACS and magnetic bead isolation of reactive yeast, we screened 19 commercially available antibodies to the ANCA autoantigens. This approach to epitope mapping resulted in highly specific, fine epitope mapping, down to single amino acid resolution in many cases. Our study also identified cross-reactivity between some commercial antibodies to MPO and PXDN, which suggests that patients with apparent autoantibodies to both proteins may be the result of cross-reactivity. Together, our data validate yeast surface display using maximally overlapping peptides as an excellent approach to linear epitope mapping.

Preventing urinary tract infections in early childhood.

Urinary tract infection (UTI) is common in children, causes them considerable discomfort, as well as distress to parents and has a tendency to recur. Approximately 20% of those children who experience one infection will have a repeat episode. Since 1975, 11 trials of long-term antibiotics compared with placebo or no treatment in 1,550 children have been published. Results have been heterogeneous, but the largest trial demonstrated a small reduction (6% absolute risk reduction, risk ratio 0.65) in the risk of repeat symptomatic UTI over 12 months of treatment. This effect was consistent across sub groups of children based upon age, gender, vesicoureteric reflux status and number of prior infections. Trials involving re-implantation surgery (and antibiotics compared with antibiotics alone) for the sub-group of children with vesicoureteric reflux have not shown a reduction in repeat UTI, with the possible exception of a very small benefit for febrile UTI. Systematic reviews have shown that circumcision reduces the risk of repeat infection but 111 circumcisions would need to be performed to prevent one UTI in unpredisposed boys. Given the need for anaesthesia and the risk of surgical complication, net clinical benefit is probably restricted to those who are predisposed (such as those with recurrent infection). Many small trials in complementary therapies have been published and many suggest some benefit, however inclusion of children is limited. Only three trials involving 394 children for cranberry products, two trials with a total of 252 children for probiotics and one trial with 24 children for vitamin A are published. Estimates of efficacy vary widely and imprecision is evident. Multiple interventions to prevent UTI in children exist. Of those, long-term low dose antibiotics has the strongest evidence base, but the benefit is small. Circumcision in boys reduces the risk substantially, but should be restricted to those at risk. There is little evidence of benefit of re-implantation alone, and the benefit of this procedure over antibiotics alone is very small. Cranberry concentrate is probably effective.

Cranberry products and prevention of urinary tract infections.

CLINICAL QUESTION: Are cranberry products (juice, tablets, capsules, and syrup) associated with prevention of urinary tract infections (UTIs) compared with placebo or other treatments? BOTTOM LINE: Cranberry products are not associated with prevention of UTIs. However, lack of association of cranberry products with a reduced incidence of UTIs in clinical trials may be due to lack of participant adherence, lack of sufficient active ingredient in the cranberry product, or lack of sufficient statistical power.

Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus.

Multiple genome-wide scans for hereditary prostate cancer (HPC) have identified susceptibility loci on nearly every chromosome. However, few results have been replicated with statistical significance. One exception is chromosome 22q, for which five independent linkage studies yielded strong evidence for a susceptibility locus in HPC families. Previously, we refined this region to a 2.53 Mb interval, using recombination mapping in 42 linked pedigrees. We now refine this locus to a 15 kb interval, spanning Apolipoprotein L3 (APOL3), using family-based association analyses of 150 total prostate cancer (PC) cases from two independent family collections with 506 unrelated population controls. Analysis of the two independent sets of PC cases highlighted single nucleotide polymorphisms (SNPs) within the APOL3 locus showing the strongest associations with HPC risk, with the most robust results observed when all 150 cases were combined. Analysis of 15 tagSNPs across the 5' end of the locus identified six SNPs with P-values < or =2 × 10(-4). The two independent sets of HPC cases highlight the same 15 kb interval at the 5' end of the APOL3 gene and provide strong evidence that SNPs within this 15 kb interval, or in strong linkage disequilibrium with it, contribute to HPC risk. Further analyses of this locus in an independent population-based, case-control study revealed an association between an SNP within the APOL3 locus and PC risk, which was not confirmed in the Cancer Genetic Markers of Susceptibility data set. This study further characterizes the 22q locus in HPC risk and suggests that the role of this region in sporadic PC warrants additional studies.