Needle tract seeding and abdominal recurrence following pre-treatment biopsy of gastrointestinal stromal tumors (GIST): results of a systematic review.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare abdominal tumors. Pretreatment biopsies may be used to diagnose a GIST and enable tailored treatment. Some experts are skeptical about biopsies because they fear tumor cell seeding. The objective of this study was to determine if pretreatment biopsy is associated with increased tumor recurrence. METHODS: We performed a systematic literature search and included studies assessing the oncological outcome of GIST patients who underwent a pre-treatment core needle biopsy or fine needle aspiration. We assessed methodological quality with the Newcastle-Ottawa-Scale for non-randomized studies. This review was registered in the PROSPERO database (CRD42021170290). RESULTS: Three non-randomized studies and eight case reports comprising 350 patients were eligible for inclusion. No prospective study designed to answer the review question was found. One case of needle tract seeding after percutaneous core needle biopsy of GIST was reported. None of the studies reported an increased rate of abdominal recurrence in patients with pretreatment biopsy. CONCLUSIONS: The existing evidence does not indicate a relevant risk of needle tract seeding or abdominal recurrence after pre-treatment biopsy of GIST. Biopsy can safely be done to differentiate GIST from other tumors and to select the most appropriate treatment.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

Decline of COPD exacerbations in clinical trials over two decades - a systematic review and meta-regression.

BACKGROUND: An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials. METHODS: We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (pB). RESULTS: Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); pB <  0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available study and baseline characteristics such as forced expiratory volume in 1 s (FEV1) did not alter the observed trend considerably. Two subsets of studies, one using a true placebo group and the other allowing inhaled corticosteroids in the "placebo" group, also yielded consistent results. CONCLUSIONS: In conclusion, this meta-regression indicates that the rate of COPD exacerbations decreased over the past two decades to a clinically relevant extent independent of important prognostic factors. This suggests that care is needed in the design of new trials or when comparing results from older trials with more recent ones. Also a considerable effect of adjunct therapy on COPD exacerbations can be assumed. REGISTRATION: PROSPERO 2018 CRD4218118823.

Relationship between menopausal hormone therapy and mortality after breast cancer The MARIEplus study, a prospective case cohort.

Cohort studies of breast cancer (BC) patients, but not of disease-free women at inclusion, have found menopausal hormone therapy (MHT) to be associated with decreased BC specific mortality (BCM). Here, the German population-based MARIEplus BC cohort was analyzed to further elucidate associations of prediagnostic MHT with BCM (and modification by tumor characteristics), recurrence, and secondarily with other cause and overall mortality. Enrolled 2002-2005, incident invasive BC cases (N = 3,321) were followed up for a median of 6.1 years. Cox proportional hazards models adjusted for tumor characteristics, mammography and lifestyle were applied. Compared with never users of MHT, current users at date of diagnosis had significantly lower BCM (Hazard ratio (HR) 0.72, 95% CI 0.53-0.97) and risk of recurrence (HR 0.61, 95% CI 0.46-0.82). The MHT related reduced BCM was confined to patients with low grade tumors (HR 0.44, 95% CI 0.28-0.70; phet = 0.01) and not modified by estrogen receptor or nodal status. BCM decreased with MHT duration in current and increased in past users (phet = 0.015). Mortality due to causes other than BC and overall mortality were also reduced in current MHT users (HR 0.51, 95% CI 0.32-0.81, HR 0.66, 95% CI 0.52-0.86, respectively). Favorable tumor characteristics and mammographic surveillance could not fully explain associations of current MHT use with BCM and recurrence risk. Thus, the study contributes to the evidence that prediagnostic MHT does not have a negative impact on prognosis after BC. The restriction of a reduced BCM to low grade tumors should be confirmed in independent studies.

A Comprehensive Multistate Model Analyzing Associations of Various Risk Factors With the Course of Breast Cancer in a Population-Based Cohort of Breast Cancer Cases.

We employed a semi-Markov multistate model for the simultaneous analysis of various endpoints describing the course of breast cancer. Results were compared with those from standard analyses using a Cox proportional hazards model. We included 3,012 patients with invasive breast cancer newly diagnosed between 2001 and 2005 who were recruited in Germany for a population-based study, the Mamma Carcinoma Risk Factor Investigation (MARIE Study), and prospectively followed up until the end of 2009. Locoregional recurrence and distant metastasis were included as intermediate states, and deaths from breast cancer, secondary cancer, and other causes were included as competing absorbing states. Tumor characteristics were significantly associated with all breast cancer-related endpoints. Nodal involvement was significantly related to local recurrence but more strongly related to distant metastases. Smoking was significantly associated with mortality from second cancers and other causes, whereas menopausal hormone use was significantly associated with reduced distant metastasis and death from causes other than cancer. The presence of cardiovascular disease at diagnosis was solely associated with mortality from other causes. Compared with separate Cox models, multistate models allow for dissection of prognostic factors and intermediate events in the analysis of cause-specific mortality and can yield new insights into disease progression and associated pathways.

Determinants of long-term fatigue in breast cancer survivors: results of a prospective patient cohort study.

OBJECTIVE: Fatigue is among the most distressing symptoms across the breast cancer continuum. However, little is known about the factors contributing to long-term persisting fatigue. Therefore, we explored determinants of long-term physical, affective, and cognitive fatigue in a prospective cohort of breast cancer patients. METHODS: Breast cancer patients recruited in a population-based case-control study (MARIE study) provided comprehensive data on sociodemographics, lifestyle, and preexisting medical conditions. At follow-up (median 6.3 years post-diagnosis, MARIEplus), disease-free cancer survivors (N = 1928) reported current fatigue using a validated multidimensional questionnaire. Additionally, survivors retrospectively rated their fatigue levels before diagnosis, during the treatment phase, and 1 year post-surgery. Linear regression analyses were performed. RESULTS: As major determinants of long-term physical, affective, and cognitive fatigue, multiple regression analyses revealed preexisting psychological or depressive disorders, migraine, analgesic use, peripheral arterial obstructive disease (PAOD), and arthritis. A physically inactive lifestyle and obesity were associated with persisting physical fatigue. Aromatase inhibitors were also associated with long-term fatigue, especially cognitive fatigue. Chemotherapy and, to a lower extent, radiotherapy were major contributors to the development of fatigue during the treatment phase, yet were not associated with long-term fatigue. CONCLUSIONS: Although the development of fatigue in breast cancer patients seems largely impacted by cancer therapy, for the long-term persistence of fatigue, preexisting medical or psychological conditions related to depression or pain and lifestyle factors appear to be more relevant. Physicians, psycho-oncologists, and researchers may need to distinguish between acute fatigue during therapy and long-term persisting fatigue with regard to its pathophysiology and treatment.

Circulating 25-hydroxyvitamin D and postmenopausal breast cancer survival: Influence of tumor characteristics and lifestyle factors?

We previously reported that lower post-diagnostic circulating 25-hydroxyvitamin D [25(OH)D] concentrations were associated with higher risk of overall mortality and distant disease in stage I-IV postmenopausal breast cancer survivors. This association was now re-examined in an extended dataset to investigate potential effect modification by tumor characteristics and lifestyle factors. A prospective cohort study was conducted in Germany including 2,177 incident stage I-IV postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2001 and 2005 and median follow-up time was 5.3 years. Cox proportional hazards models were stratified by age at diagnosis, study center and season of blood collection and adjusted for other prognostic factors. A meta-analysis of studies on circulating 25(OH)D and mortality in breast cancer patients was performed to summarize evidence. Lower concentrations of 25(OH)D were significantly associated with higher risk of overall mortality [hazard ratio (HR) lowest vs. highest tertile = 1.86; 95% confidence interval (CI): 1.22, 2.82; p-trend = 0.002] and distant disease (HR = 1.76; 95% CI: 1.24, 2.49; p-trend = 0.003) in stage I-IIIa but not in stage IIIb-IV breast cancer patients. No significant interaction by lifestyle factors was observed (all p-interaction > 0.05). The meta-analysis yielded significant associations with overall and breast cancer-specific mortality (lowest vs. highest quantile: HR = 1.52; 95% CI: 1.22, 1.88 and HR = 1.74; 95% CI: 1.23, 2.40, respectively). In conclusion, post-diagnostic circulating 25(OH)D concentrations were associated with overall mortality and distant disease in stage I-IIIa postmenopausal breast cancer patients. This association was not strongly modified by lifestyle factors.

Enterolactone concentrations and prognosis after postmenopausal breast cancer: assessment of effect modification and meta-analysis.

We previously reported that high concentrations of enterolactone, a lignan metabolite, are associated with lower mortality in 1,140 breast cancer patients from Germany. Using an extended set of 2,182 patients aged 50-74 years at diagnosis (2001-2005) and prospectively followed up until 2009, we investigated whether the association with mortality differs by lifestyle factors and tumor characteristics. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression. Potential differential effects by tumor characteristics and lifestyle factors were assessed and a meta-analysis of five studies addressing lignan exposure and breast cancer prognosis was performed to summarize evidence. Median enterolactone concentrations were 17.4 (± 30.5 standard deviation) and 22.9 nmol L(-1) (± 44.8), respectively, for 269 deceased and 1,913 patients still alive. High enterolactone concentrations were significantly associated with lower all-cause mortality (per 10 nmol L(-1) : HR 0.94, 95% CI 0.90-0.98), breast cancer-specific mortality (HR 0.94, 0.89-0.99), and distant disease-free survival (HR 0.94, 0.90-0.98). Associations were found for stage 0-IIIA but not for stage IIIB-IV disease (p(het) = 0.01) and were stronger in patients with BMI <25 kg m(-2) than those with BMI ≥ 25 (p(het) = 0.04). In patients with healthy lifestyle (BMI <25, nonsmoker, physically active), the inverse association with all-cause mortality was still apparent (HR 0.92, 0.85-0.99). The meta-analysis yielded significant associations both for all-cause (HR 0.57, 0.42-0.78) and breast cancer-specific mortality (HR 0.54, 0.39-0.75). Our findings show that high lignan exposure is associated with reduced mortality in breast cancer patients. The inverse association observed in this study cannot be entirely explained by a healthy lifestyle.

Methods for non-proportional hazards in clinical trials: A systematic review.

For the analysis of time-to-event data, frequently used methods such as the log-rank test or the Cox proportional hazards model are based on the proportional hazards assumption, which is often debatable. Although a wide range of parametric and non-parametric methods for non-proportional hazards has been proposed, there is no consensus on the best approaches. To close this gap, we conducted a systematic literature search to identify statistical methods and software appropriate under non-proportional hazard. Our literature search identified 907 abstracts, out of which we included 211 articles, mostly methodological ones. Review articles and applications were less frequently identified. The articles discuss effect measures, effect estimation and regression approaches, hypothesis tests, and sample size calculation approaches, which are often tailored to specific non-proportional hazard situations. Using a unified notation, we provide an overview of methods available. Furthermore, we derive some guidance from the identified articles.

Association of pre-diagnosis physical activity with recurrence and mortality among women with breast cancer.

Evidence is emerging that physical activity (PA) may improve overall survival after breast cancer diagnosis. However, the effect of PA on breast cancer recurrence and on cause-specific mortality is less investigated. We assessed the association of pre-diagnosis PA with recurrence, overall and cause-specific survival in a prospective cohort study in Germany including 3,393 non-metastatic breast cancer patients aged 50-74 years. Cox proportional hazards models were calculated adjusted for relevant prognostic factors. During a median follow-up of 5.6 years, 367 patients deceased. Overall mortality was significantly inversely associated with pre-diagnosis recreational PA. However, this effect was mainly attributed to deaths due to causes other than breast cancer. Multiple fractional polynomial analyses yielded a nonlinear association with markedly increased non-breast cancer mortality for women who did not engage in any sports or cycling in the years before the breast cancer diagnosis with a hazard ratio (HR, none vs. any) of 1.71, 95% confidence interval (1.16, 2.52). There were no further risk reductions with increasing activity levels. The association with breast cancer-specific mortality showed a similar dose-response but was far less pronounced with HR (none vs. any) = 1.22 (0.91, 1.64). In contrast, regarding cancer recurrence the dose-response was linear. However, this association was restricted to estrogen/progesterone receptor-negative (ER-/PR-) cases (p interaction = 0.033) with HR (highest vs. no recreational PA) = 0.53 (0.24, 1.16), p trend = 0.0045. Thus, breast cancer patients with a physically inactive lifestyle pre-diagnosis may decease prematurely irrespective of their cancer prognosis. Higher levels of exercise may reduce the risk of recurrence of ER-/PR- breast tumors.

Pre-diagnostic alcohol consumption and postmenopausal breast cancer survival: a prospective patient cohort study.

Study results on the association of alcohol consumption with breast cancer survival are inconsistent, partly due to the use of different survival outcomes. We assessed the association of pre-diagnostic alcohol consumption with survival and recurrence in a prospective cohort study in Germany including 2,522 postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2001 and 2005 and vital status, causes of death, and recurrences were verified through the end of 2009. Cox proportional hazards models were stratified by age at diagnosis and study center and adjusted for relevant prognostic factors. Alcohol consumption was non-linearly associated with increased breast cancer-specific mortality [e.g., ≥12 vs. <0.5 g/day: hazard ratio (HR) = 1.74, 95 % confidence interval (CI): 1.13, 2.67]. Results were independent of estrogen receptor status. A non-significantly decreased risk of mortality due to other causes was found (≥12 vs. <0.5 g/day: HR = 0.67, 95 % CI: 0.35, 1.29). Alcohol consumption was not associated with overall mortality (≥12 vs. <0.5 g/day: HR = 1.28, 95 % CI: 0.90, 1.81) and breast cancer recurrence (≥12 vs. <0.5 g/day: HR = 1.08, 95 % CI: 0.73, 1.58). In conclusion, our findings show that consumption of alcohol before diagnosis is non-linearly associated with increased breast cancer-specific mortality but may be associated with decreased risk of mortality due to other causes.

The association between dietary lignans, phytoestrogen-rich foods, and fiber intake and postmenopausal breast cancer risk: a German case-control study.

Phytoestrogens are structurally similar to estrogens and may affect breast cancer risk by mimicking estrogenic/antiestrogenic properties. In Western societies, whole grains and possibly soy foods are rich sources of phytoestrogens. A population-based case-control study in German postmenopausal women was used to evaluate the association of phytoestrogen-rich foods and dietary lignans with breast cancer risk. Dietary data were collected from 2,884 cases and 5,509 controls using a validated food-frequency questionnaire, which included additional questions phytoestrogen-rich foods. Associations were assessed using conditional logistic regression. All analyses were adjusted for relevant risk and confounding factors. Polytomous logistic regression analysis was performed to evaluate the associations by estrogen receptor (ER) status. High and low consumption of soybeans as well as of sunflower and pumpkin seeds were associated with significantly reduced breast cancer risk compared to no consumption (OR = 0.83, 95% CI = 0.70-0.97; and OR = 0.66, 95% CI = 0.77-0.97, respectively). The observed associations were not differential by ER status. No statistically significant associations were found for dietary intake of plant lignans, fiber, or the calculated enterolignans. Our results provide evidence for a reduced postmenopausal breast cancer risk associated with increased consumption of sunflower and pumpkin seeds and soybeans.

COPD mortality and exacerbations in the placebo group of clinical trials over two decades: a systematic review and meta-regression.

A decreasing trend in exacerbation rates has been observed in COPD. Because mortality is linked to exacerbations, it is of interest to investigate whether a similar time trend is also present in mortality rates. We performed a systematic review of placebo groups in published randomised controlled trials. Mortality rate was modelled based on a Poisson distribution for the event counts. Adding information on mortality as well as on newly published studies on a previous database, we performed a meta-regression. Among the 56 included studies representing 14 166 patients, an annual decrease in mortality rates of 6.1% (-0.6%, 12.6%) (p=0.073) was observed. Consistent results were obtained in subgroups as well as when adjusting for potential confounders. The correlation between exacerbation rate and mortality rate was positive but weak as well as insignificant. In summary, analysis of randomised controlled trials in COPD patients showed a decrease in mortality in the placebo arms over the last two decades. This effect is comparable to the previously observed decrease in annual exacerbation rate. Albeit insignificant, our results suggest that care is needed in the design of new trials or when comparing results from trials published many years apart.

Reducing antibiotic use in uncomplicated urinary tract infections in adult women: a systematic review and individual participant data meta-analysis.

BACKGROUND: Randomised controlled trials (RCTs) investigated analgesics, herbal formulations, delayed prescription of antibiotics, and placebo to prevent overprescription of antibiotics in women with uncomplicated urinary tract infections (uUTI). OBJECTIVES: To estimate the effect of these strategies and to identify symptoms, signs, or other factors that indicate a benefit from these strategies. DATA SOURCES: MEDLINE, EMBASE, Web of Science, LILACS, Cochrane Database of Systematic Reviews and of Controlled Trials, and ClinicalTrials. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: RCTs investigating any strategies to reduce antibiotics vs. immediate antibiotics in adult women with uUTI in primary care. METHODS: We extracted individual participant data (IPD) if available, otherwise aggregate data (AD). Bayesian random-effects meta-analysis of the AD was used for pairwise comparisons. Candidate moderators and prognostic indicators of treatment effects were investigated using generalised linear mixed models based on IPD. RESULTS: We analysed IPD of 3524 patients from eight RCTs and AD of 78 patients. Non-antibiotic strategies increased the rates of incomplete recovery (OR 3.0; 95% credible interval (CrI), 1.7-5.5; Bayesian p-value (pB) = 0.0017; τ = 0.6), subsequent antibiotic treatment (OR 3.5; 95% CrI, 2.1-5.8; pB = 0.0003) and pyelonephritis (OR 5.6; 95% CrI, 2.3-13.9; pB = 0.0003). Conversely, they decreased overall antibiotic use by 63%. Patients positive for urinary erythrocytes and urine culture were at increased risk for incomplete recovery (OR 4.7; 95% CrI, 2.1-10.8; pB = 0.0010), but no difference was apparent where both were negative (OR 0.8; 95% CrI, 0.3-2.0; pB = 0.667). In patients treated using non-antibiotic strategies, urinary erythrocytes and positive urine culture were independent prognostic indicators for subsequent antibiotic treatment and pyelonephritis. CONCLUSIONS: Compared to immediate antibiotics, non-antibiotic strategies reduce overall antibiotic use but result in poorer clinical outcomes. The presence of erythrocytes and tests to confirm bacteria in urine could be used to target antibiotic prescribing.

B vitamins and the risk of total mortality and cardiovascular disease in end-stage renal disease: results of a randomized controlled trial.

BACKGROUND: In observational studies, hyperhomocysteinemia has been found to be a risk factor for total mortality and cardiovascular events in patients with end-stage renal disease. These patients have grossly elevated homocysteine levels that can be lowered by supplementation with folic acid and vitamin B(12). We conducted a randomized clinical trial with B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality. METHODS AND RESULTS: This randomized, double-blind multicenter study was conducted in 33 dialysis centers in north and east Germany between July 2002 and July 2008. We randomly assigned 650 patients with end-stage renal disease who were undergoing hemodialysis to 2 postdialysis treatments: 5 mg folic acid, 50 microg vitamin B(12), and 20 mg vitamin B(6) (active treatment) or 0.2 mg folic acid, 4 microg vitamin B(12), and 1.0 mg vitamin B(6) (placebo) given 3 times per week for an average of 2 years. The primary outcome was total mortality; the secondary outcome was fatal and nonfatal cardiovascular events. The primary outcome occurred in 102 patients (31%) receiving the active treatment and in 92 (28%) receiving placebo (hazard ratio, 1.13; 95% confidence interval, 0.85 to 1.50; P=0.51). The secondary outcome occurred in 83 patients (25%) receiving the active treatment and in 98 (30%) receiving placebo (hazard ratio, 0.80; 95% confidence interval, 0.60 to 1.07; P=0.13). CONCLUSIONS: Increased intake of folic acid, vitamin B(12), and vitamin B(6) did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease. Clinical Trial Registration- URL: www.anzctr.org.au. Unique identifier: ACTRN12609000911291. URL: www.cochrane-renal.org. Unique identifier: CRG010600027.

Applications of artificial intelligence/machine learning approaches in cardiovascular medicine: a systematic review with recommendations.

Aims: Artificial intelligence (AI) and machine learning (ML) promise vast advances in medicine. The current state of AI/ML applications in cardiovascular medicine is largely unknown. This systematic review aims to close this gap and provides recommendations for future applications. Methods and results: Pubmed and EMBASE were searched for applied publications using AI/ML approaches in cardiovascular medicine without limitations regarding study design or study population. The PRISMA statement was followed in this review. A total of 215 studies were identified and included in the final analysis. The majority (87%) of methods applied belong to the context of supervised learning. Within this group, tree-based methods were most commonly used, followed by network and regression analyses as well as boosting approaches. Concerning the areas of application, the most common disease context was coronary artery disease followed by heart failure and heart rhythm disorders. Often, different input types such as electronic health records and images were combined in one AI/ML application. Only a minority of publications investigated reproducibility and generalizability or provided a clinical trial registration. Conclusions: A major finding is that methodology may overlap even with similar data. Since we observed marked variation in quality, reporting of the evaluation and transparency of data and methods urgently need to be improved.

Strategies to reduce antibiotic use in women with uncomplicated urinary tract infection in primary care: protocol of a systematic review and meta-analysis including individual patient data.

INTRODUCTION: Uncomplicated urinary tract infection (UTI) in women is a common reason to present in general practice and is usually treated with antibiotics to reduce symptom severity and duration. Results of recent clinical trials indicate that non-antibiotic treatment approaches can also be effective. However, it remains unclear which patients would benefit from antibiotic treatment and which can effectively and safely be treated without antibiotics. This systematic review and meta-analysis aims to estimate the effect of treatment strategies to reduce antibiotic use in comparison with immediate antibiotic treatment and to identify prognostic factors and moderators of treatment effects. A further aim is to identify subgroups of patients benefiting from a specific therapy. METHODS AND ANALYSIS: A systematic literature search will be performed to identify randomised controlled trials which investigated the effect of treatment strategies to reduce antibiotic use in female adults with uncomplicated UTI compared with immediate antibiotic treatment. Therefore, the primary outcome of the meta-analysis is incomplete recovery. Anonymised individual patient data (IPD) will be collected. Aggregate data will be used for pairwise comparisons of treatment strategies using meta-analysis models with random effects accounting for potential between-study heterogeneity. Potential effect moderators will be explored in meta-regressions. For IPD, generalised linear mixed models will be used, which may be adjusted for baseline characteristics. Interactions of baseline variables with treatment effects will be explored. These models will be used to assess direct comparisons of treatment, but might be extended to networks. ETHICS AND DISSEMINATION: The local institutional review and ethics board judged the project a secondary analysis of existing anonymous data which meet the criteria for waiver of ethics review. Dissemination of the results will be via published scientific papers and presentations. Key messages will be promoted for example, via social media or press releases. PROSPERO REGISTRATION NUMBER: CRD42019125804.

Homocysteine as a risk factor for cardiovascular disease in patients treated by dialysis: a meta-analysis.

BACKGROUND: In the general population, increased homocysteine concentrations are a risk factor for cardiovascular disease and mortality. However, it is not known whether this also applies to patients with end-stage renal disease. STUDY DESIGN: Meta-analysis of retrospective (11 studies including 1,506 individuals), prospective observational studies (12 studies including 1,975 individuals), and intervention trials (5 studies including 1,642 dialysis patients). Analyses were carried out separately, according to the study design. SETTING & POPULATION: Studies of patients with end-stage renal disease treated by means of hemodialysis or peritoneal dialysis. SELECTION CRITERIA FOR STUDIES: Studies investigating the association between total homocysteine level and cardiovascular disease or total mortality or the influence of vitamin supplementation on cardiovascular or mortality risk. INTERVENTION: In intervention studies, vitamin preparations with folic acid alone or in combination with other vitamins, such as vitamin B(12) and B(6), were used. OUTCOMES: In retrospective studies, cases are patients with cardiovascular diseases. Outcomes for prospective observational and intervention studies are cardiovascular events and total mortality. RESULTS: In retrospective studies, there was no significant overall difference in homocysteine concentrations between cases and controls (weighted mean difference in homocysteine, 2.82 micromol/L; 95% confidence interval [CI], -2.22 to 7.86; P = 0.3). The pooled overall risk estimate for prospective observational studies suggests no association between homocysteine level (5-micromol/L increase) and total mortality (hazard ratio [HR], 1.02; 95% CI, 0.93 to 1.12; P = 0.7), but there was an association with cardiovascular events (HR, 1.09; 95% CI, 1.03 to 1.14; P = 0.001). In subgroup analysis of patients not receiving vitamins, an increase in homocysteine level was associated with increased mortality (HR, 1.07; 95% CI, 1.02 to 1.13; P = 0.01). For intervention trials with B vitamins, there was a significant risk reduction for cardiovascular disease (relative risk, 0.73; 95% CI, 0.56 to 0.94; P = 0.02), but no risk reduction for total mortality or the composite end point including total mortality (relative risk, 1.01; 95% CI, 0.88 to 1.15; P = 0.9). LIMITATIONS: Many studies are small, which may lead to the observed heterogeneity. Some intervention trials are neither placebo controlled nor randomized. Separate analyses for specific end points and patients treated by means of hemodialysis or peritoneal dialysis were not possible. CONCLUSION: Total homocysteine level may be a risk factor for cardiovascular events and total mortality in patients with end-stage renal disease not receiving vitamin supplementation or folic acid food fortification. There may be a potential for reducing cardiovascular disease in this population by folic acid supplementation.

Sarcopenia as Prognostic Factor in Lung Cancer Patients: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: Sarcopenia describes the loss of skeletal muscle mass. While this condition is associated with a high mortality in cancer patients, its influence on survival is still underestimated. PATIENTS AND METHODS: A systematic review for articles was performed using the PubMed database, Cochrane Library, Biomed Central, Science Direct and by manual search. We used data of overall survival in sarcopenic patients for assessing the death risk. We extracted hazard ratio estimates from univariate and multivariate Cox proportional hazards models for meta-analysis. RESULTS: A total of 15 studies were eligible for meta-analysis including a total of 2,521 lung cancer patients. Univariate meta-analysis revealed a two-fold increased death risk in sarcopenic patients; multivariate meta-analysis yielded a significant, three-fold elevated risk of death. This higher mortality is independent of tumour stage. CONCLUSION: Muscle loss is an independent risk factor for increased death risk in lung cancer patients independent of cancer stage. This argues for implementing screening for sarcopenia into cancer care.

Washout of water-soluble vitamins and of homocysteine during haemodialysis: effect of high-flux and low-flux dialyser membranes.

AIM: Vitamin deficiencies are common in patients with end-stage renal disease (ESRD) owing to dietary restrictions, drug-nutrient interactions, changes in metabolism, and vitamin losses during dialysis. The present study investigated the levels of serum and red blood cell (RBC) folate, plasma pyridoxal-5'-phosphate (PLP), serum cobalamin, blood thiamine, blood riboflavin, and plasma homocysteine (tHcy) before and after haemodialysis treatment. METHODS: Vitamin and tHcy blood concentrations were measured in 30 patients with ESRD before and after dialysis session either with low-flux (n = 15) or high-flux (n = 15) dialysers. RESULTS: After the dialysis procedure, significantly lower concentrations of serum folate (37%), plasma PLP (35%), blood thiamine (6%) and blood riboflavin (7%) were observed. No significant changes were found for serum cobalamin or for RBC folate. There were no differences in the washout of water-soluble vitamins between treatments with low-flux and high-flux membranes. Furthermore, a 41% lower concentration in tHcy was observed. The percentage decrease in tHcy was significantly greater in the patients treated with high-flux dialysers (48% vs 37%; P < 0.01). The percentage change during dialysis was significantly inversely related to the molecular weight of the vitamins measured (r =-0.867, P < 0.01). CONCLUSION: This study showed significantly lower blood or serum levels of various water-soluble vitamins after dialysis, independently of the dialyser membrane. The monitoring of the vitamin status is essential in patients treated with high-flux dialysers as well as in patients treated with low-flux dialysers.