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Introduction Regular physical activity is associated with longevity in adults receiving hemodialysis, but it is uncertain whether this association varies by causal pathways (cardiovascular and noncardiovascular). Methods DIET-HD was a prospective, multinational study of adults undergoing hemodialysis across Europe and Argentina. We classified participants as physically inactive, occasionally active (irregularly to once a week), or frequently active (twice a week or more), using a self-reported questionnaire. Potential confounders were balanced across exposure groups using propensity scores. Weighted Cox proportional hazards models with double robust estimators evaluated the association between physical activity and all-cause, cardiovascular, and noncardiovascular mortality. Results Of 8043 participants in DIET-HD, 6147 (76%) had information on physical activity. A total of 2940 (48%) were physically inactive, 1981 (32%) occasionally active, and 1226 (20%) frequently active. In a median follow-up of 3.8 years (19,677 person-years), 2337 (38%) deaths occurred, including 1050 (45%) from cardiovascular causes. After propensity score weighting, occasional physical activity was associated with lower all-cause (adjusted hazard ratio [aHR] = 0.80, 95% CI = 0.72–0.89), cardiovascular (aHR = 0.82, 95% CI = 0.70–0.96), and noncardiovascular (aHR = 0.81, 95% CI = 0.69–0.94) mortality compared with inactivity. Frequent physical activity was associated with lower all-cause (aHR = 0.82, 95% CI = 0.71–0.95) and cardiovascular (aHR = 0.77, 95% CI = 0.62–0.94) mortality, but not noncardiovascular mortality (aHR = 0.88, 95% CI = 0.72–1.08). A dose-dependent association of physical activity with cardiovascular death was observed (P trend = 0.01). Conclusion Compared with self-reported physical inactivity, occasional and frequent physical activities were associated, dose dependently, with lower cardiovascular mortality in adults receiving hemodialysis., Graphical abstract

PURPOSE There is a substantial gap between people having a mental disorder and those treated for this disorder. Studies that assessed the influence of age on healthcare use for major depressive disorder (MDD) have provided inconsistent results. We aimed to assess healthcare use in terms of treatment-seeking and psychotropic medication use in four age groups of 45- to 85-year-old community dwellers meeting criteria for MDD. METHODS Data stemmed from CoLaus|PsyCoLaus, a population-based prospective cohort study. Diagnostic information on mental disorders, utilization of professional healthcare and psychotropic drugs was elicited using a semi-structured interview. Associations between age groups and healthcare use were established using logistic regression models with serial adjustments for socio-demographic and depression characteristics as well as comorbid mental disorders and cardio-metabolic features. RESULTS Compared to participants of the youngest age group (ages 45 to 54 years), (1) those older than 75 years were less likely to use healthcare from psychiatrists or psychologists (OR: 0.4 [95% CI 0.17-0.96]), although the frequency of using any professional health care did not vary across age groups; (2) those older than 55 years used any psychotropic medication more frequently; and (3) those aged 55-64 years used antidepressants more frequently (OR: 1.61 [95% CI 1.07-2.44]), whereas those aged 65-74 years used anxiolytics more frequently (OR: 2.30 [95% CI 1.15-4.58]). CONCLUSION Age is a complex biological and social factor that influences healthcare use.

Aim: To help to remove misperception of an appropriate position of trifluridine/tipiracil (FTD/TPI) in the treatment of metastatic colorectal cancer. Materials & methods: The RAND Corporation/UCLA Appropriateness Method was used by a panel of Italian experts to develop recommendations concerning daily practice with FTD/TPI. Forty-three clinical scenarios were discussed in two rounds and the resulting statements were rated as appropriate, uncertain or inappropriate, according to the median score. Results: Several topics were dealt with, covering the profile of eligible patients, therapeutic options beyond the second line, the practice of treatment with FTD/TPI, evaluation and efficacy and toxicity, as well as costs and compliance. Conclusion: FTD/TPI is an important therapeutic resource in refractory metastatic colorectal cancer that combines manageability and safety.

The combination of perioperative chemotherapy plus complete surgical resection is currently accounted as the first-choice strategy in patients with locally advanced Gastric Cancer (LAGC). Nevertheless, the partial response rate makes it necessary to search biological parameters useful to select patients who would benefit most from neoadjuvant chemotherapy (NAD-CT). We performed a retrospective analysis on a cohort of 65 LAGC cases, EBV negative and without MMR defect, submitted to perioperative chemotherapy plus surgical resection. We evaluated the neutrophil-lymphocytes ratio (NLR) in peripheral blood, the TILs density (reported as CD4/CD8 tissue ratio) and PD-L1 expression by immunohistochemistry on bioptic tissues before the treatment. Results were correlated with the biological features, histological response (TRG) and clinical outcome (PFS and OS). We found that NLR, TILs and PD-L1 expression showed a significant correlation with TNM stage, lymphovascular invasion and response to NAD-CT (TRG). Correlating the NLR, TILs and PD-L1 expression with PFS and OS, we found that patients with lower NLR levels (

Background Clinical practice guidelines of dietary management are designed to promote a balanced diet and maintain health in patients undergoing haemodialysis but they may not reflect patients’ preferences. We aimed to investigate the consistency between the dietary intake of patients on maintenance haemodialysis and guideline recommendations. Methods Cross-sectional analysis of the DIET-HD study, which included 6,906 adults undergoing haemodialysis in 10 European countries. Dietary intake was determined using the Global Allergy and Asthma European Network (GA2LEN) Food Frequency Questionnaire (FFQ), and compared with the European Best Practice Guidelines. Consistency with guidelines was defined as achieving the minimum daily recommended intake for energy (≥ 30 kcal/kg) and protein (≥ 1.1 g/kg), and not exceeding the maximum recommended daily intake for phosphate (≤ 1000 mg), potassium (≤ 2730 mg), sodium (≤ 2300 mg) and calcium (≤ 800 mg). Results Overall, patients’ dietary intakes of phosphate and potassium were infrequently consistent with guidelines (consistent in 25% and 25% of patients, respectively). Almost half of the patients reported that energy (45%) and calcium intake (53%) was consistent with the guidelines, while the recommended intake of sodium and protein was consistent in 85% and 67% of patients, respectively. Results were similar across all participating countries. Intake was consistent with all six guideline recommendations in only 1% of patients. Conclusion Patients on maintenance haemodialysis usually have a dietary intake which is inconsistent with current recommendations, especially for phosphate and potassium.

Supplemental Digital Content is available in the text., OBJECTIVES: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019. DESIGN: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery. SETTING: International. PATIENTS: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed. CONCLUSIONS: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.

Background Cardiac rehabilitation is a medically supervised program after coronary events that involves exercise and dietary modification. We evaluated the comparative benefits and harms of cardiac rehabilitation strategies via a network meta-analysis. Methods We followed a pre-specified protocol (PROSPERO: CRD42018094998). We searched Embase, MEDLINE, and Cochrane Central Register of Randomized Trials databases for randomized controlled trials that evaluated cardiac rehabilitation vs a second form of rehabilitation or standard/usual care in adults after myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, or angiography. Risk of bias and evidence quality was evaluated using the Cochrane tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. Pairwise and Bayesian network meta-analyses were performed for 11 clinical outcomes. Results We included 134 randomized controlled trials involving 62,322 participants. Compared with standard care, exercise-only cardiac rehabilitation reduced the odds of cardiovascular mortality (odds ratio [OR], 0.70; 95% credibility interval [CrI], 0.51-0.96; moderate-quality evidence), major adverse cardiovascular events (OR, 0.57; 95% CrI, 0.40-0.78; low-quality evidence), nonfatal myocardial infarction (OR, 0.71; 95% CrI, 0.54-0.93; moderate-quality evidence), all-cause hospitalization (OR, 0.74; 95% CrI, 0.54-0.98; moderate-quality evidence), and cardiovascular hospitalization (OR, 0.69; 95% CrI, 0.51-0.88; moderate-quality evidence). Exercise-only cardiac rehabilitation was associated with lower cardiovascular hospitalization risk relative to cardiac rehabilitation without exercise (OR, 0.68; 95% CrI, 0.48-0.97; moderate-quality evidence). Conclusions Cardiac rehabilitation programs containing exercise might provide broader cardiovascular benefits compared with those without exercise.

BackgroundThe diagnosis of check-point inhibitor-related pneumonitis (CIP) relies on radiological and clinical patterns which are not specific and can mimic other conditions (cancer progression, infectious diseases or interstitial pneumonitis). Cell pattern analysis of bronchoalveolar lavage (BAL) is well-known to support the diagnosis of interstitial lung disease; nevertheless, this analysis is somewhat performed and not required by immune-toxicity management guidelines for CIP.MethodsWe performed BAL analysis in 5 metastatic melanoma (MM) patients who developed CIP among 112 patients treated with checkpoint inhibitors. We also correlated the BAL features with the computed tomography (CT) scan patterns and with various peripheral blood parameters to better define the profile of this patient population.ResultsBAL flow cytometer and cytopathology analyses showed typical and homogeneous features with increased lymphoid population, prevalent CD8 + T cells and inversion of the CD4/CD8 ratio. Moreover, the extent of activated CD3 + HLA-DR + T cells was related to the grading of adverse events. Blood leucocytosis, hypoxemia, normal values for procalcitonin and lactate dehydrogenase were also found together with a cryptogenic organizing pneumonia-like radiologic pattern. In all our patients, CIP was associated with partial or complete response.ConclusionsIdentification of a specific BAL cellular pattern allows clinicians to place this investigation in the appropriate position of CIP diagnosis and management to avoid misdiagnosis or considering this condition as progressive disease and delaying proper treatment.

Rationale & Objective Comparative benefits and harms of calcimimetic agents used for the treatment of secondary hyperparathyroidism have not been well characterized. We sought to compare the effectiveness of 3 calcimimetic agents using published data. Study Design Systematic review of randomized controlled trials and network meta-analysis. Setting & Study Population Adults with chronic kidney disease enrolled in a clinical trial of a calcimetic agent. Search Strategy & Sources MEDLINE, EMBASE, CENTRAL (from February 7, 2013, to November 21, 2019), and a published meta-analysis. Data Extraction Two reviewers independently extracted the study data, assessed risk of bias, and rated evidence certainty using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Analytical Approach Frequentist network meta-analysis was conducted. The primary review outcomes were achievement of a target reduction in serum parathyroid hormone (PTH) levels and hypocalcemia. Additional outcomes were nausea, vomiting, serious adverse events, all-cause mortality, cardiovascular mortality, heart failure, and fracture. Results 36 trials (11,247 participants) were included. All except 4 trials involved dialysis patients. Median follow-up was 26 weeks (range, 1 week to 21.2 months). Compared with placebo, calcimimetic agents had higher odds of achieving target PTH levels with high or moderate certainty. Etelcalcetide had the highest odds of achieving a PTH target compared with evocalcet (OR, 4.93; 95% CI, 1.33-18.2) and cinacalcet (OR, 2.78; 95% CI, 1.19-6.67). Etelcalcetide appeared to cause more hypocalcemia than cinacalcet and evocalcet. Cinacalcet and to a lesser extent etelcalcetide appeared to cause more nausea than placebo. Differences in risk for mortality, cardiovascular end points, or fractures across calcimimetic agents could not be discerned with sufficient certainty. Limitations Lack of longer-term data; heterogeneous end point definitions. Conclusions Evidence of the benefits of calcimimetic therapy is limited to short-term assessment of a putative surrogate outcome (serum PTH). Although etelcalcetide was associated with the largest reduction in PTH levels, side-effect profiles differed across the 3 calcimimetic agents, making it not possible to identify 1 preferred agent.

Background There is still limited evidence from prospective high-risk research on the evolution of specific disorders that may emerge early in the development of mood disorders. Moreover, few studies have examined the specificity of mood disorder subtypes among offspring of parents with both major subtypes of mood disorders and controls based on prospective tracking across the transition from childhood to adulthood. Our specific objectives were to (a) identify differences in patterns of psychopathological precursors among youth with (hypo)mania compared to MDD and (b) examine whether these patterns differ by subtypes of parental mood disorders. Methods Our data stem from a prospective cohort study of 449 directly interviewed offspring (51% female, mean age 10.1 years at study intake) of 88 patients with BPD, 71 with MDD, 30 with substance use disorders and 60 medical controls. The mean duration of follow-up was 13.2 years with evaluations conducted every three years. Results Within the whole cohort of offspring, MDE (Hazard Ratio = 4.44; 95%CI: 2.19-9.02), CD (HR = 3.31;1.55-7.07) and DUD (HR = 2.54; 1.15-5.59) predicted the onset of (hypo)manic episodes, whereas MDD in offspring was predicted by SAD (HR = 1.53; 1.09-2.15), generalized anxiety (HR = 2.56; 1.05-6.24), and panic disorder (HR = 3.13; 1.06-9.23). The early predictors of (hypo)mania in the whole cohort were also significantly associated with the onset of (hypo)mania among the offspring of parents with BPD. Conclusions The onset of mood disorders is frequently preceded by identifiable depressive episodes and nonmood disorders. These precursors differed by mood subtype in offspring. High-risk offspring with these precursors should be closely monitored to prevent the further development of MDD or conversion to BPD.

Hepatic resection is the gold standard treatment for patients affected by liver-limited colorectal metastases. Reports addressing the impact of multidisciplinary team (MDT) evaluation on survival are controversial. The aim of this study was to evaluate the benefit of MDT management in these patients in our Institution experience. The objective of the analysis was to compare survivals of patients managed within our MDT (MDT cohort) to those of patients referred to surgery from other hospitals without MDT discussion (non-MDT cohort). Of the 523 patients, 229 were included in the MDT cohort and 294 in the non-MDT cohort. No difference between the two groups was found in terms of median overall survival (52.5 vs 53.6 months; HR 1.13; 95% CI, 0.88–1.45; p = 0.344). In the MDT cohort there was a higher number of metastases (4.5 vs 2.7; p p p

Background Anxiety disorders have been related to cardiovascular diseases via low-grade inflammation, but longitudinal studies on the association between generalized anxiety disorder (GAD) and inflammatory biomarkers are sparse. Furthermore, no studies have examined the association between GAD and the “cardio-protective” adipocytokine adiponectin in this context so far. Methods In a Swiss population-based sample of 2,415 adults participating in baseline and follow-up exams (mean follow-up duration=5.5 years), we diagnosed a total of 55 persons (2.3%) with GAD using a validated semi-structured psychiatric interview. We prospectively examined the relation between GAD and circulating levels of inflammatory biomarkers (i.e., C-reactive protein, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and adiponectin), in linear regression models, statistically controlled for the baseline inflammatory marker, socioeconomic status, cardiovascular risk factors, health behaviors, and psychiatric disorders. Results Compared to those without GAD, individuals with GAD had lower IL-6 (β=-0.249, 95%-CI -0.493-(-0.004), p=0.046), and adiponectin (β=-0.264, 95%-CI -0.482-(-0.045), p=0.018) levels at follow-up after adjustment for all covariates. Moreover, GAD was unrelated to several other inflammatory measures. Conclusion Individuals with GAD do not seem to exhibit chronic low-grade inflammation, suggesting different underlying biobehavioral mechanisms to those from other anxiety disorders. Low adiponectin levels may be linked to symptoms of GAD through brain areas directly involved in the processing of fear and anxiety.

Advanced age is associated with comorbidities and immune system impairment, which may influence the efficacy and tolerability of immune checkpoint inhibitors. There is evidence that anti-PD1 antibodies in advanced melanoma are equally effective in patients65 years. However, data on patients75 years are lacking as co-morbidities and logistics often exclude them from clinical trials.We retrospectively reviewed the clinical records of older patients with advanced melanoma undergoing any-line treatment with an anti-PD1 (nivolumab/pembrolizumab) to investigate its clinical effectiveness and toxicity in a real-life setting. Clinical response was assessed using RECIST criteria and toxicity was evaluated according to CTCAE 4.0. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the Cox model was used to assess potential prognostic factors.174 patients were considered; 59.2% males, median age 79 years (range 75-93). The majority had a performance status of 0 and normal lactate dehydrogenase (LDH) levels (55.2% and 52.4%, respectively). 69.1% had multiple co-morbidities. 56.9% received nivolumab. 36.7% of cases showed an objective response and the disease control rate was 56.3%. Median OS was 17.2 months [95% CI: 8.87-not reached] and a better prognosis was observed for patients with normal LDH (p .001) and lower performance status (p .001). Treatment was well tolerated, only 11 patients experiencing severe (grade 3/4) toxicity. There were no treatment-related deaths. Adverse events were managed with corticosteroids and additional immunosuppressive agents were unnecessary.Anti-PD1 antibodies appear effective and well tolerated in older patients with advanced melanoma.

Background Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but remains infrequently and inconsistently measured in clinical trials and poorly managed in clinical settings. A recently completed systematic review of pain in ADPKD identified 26 different outcome measures. None of these measures were considered appropriate as a core outcome measure due to the lack of patient-important dimensions, inadequate content, relatively long duration of completion time and limited evidence to support psychometric robustness. Methods We convened an international Standardized Outcomes in Nephrology–Polycystic Kidney Disease consensus workshop involving 21 patients/caregivers and 40 health professionals (clinicians, nurses, researchers, policy makers and industry representatives) from 18 countries to discuss the identification or development of a core outcome measure for pain. Results Four themes were identified highlighting fundamental issues for the measurement of pain in ADPKD: distressing and disrupting life participation; variability and ambiguity in defining pain; stigma, frustration and adaptation to pain; and ensuring validity and feasibility of pain measures. Conclusions Existing measures were found to be insufficient in capturing pain as a core outcome and there was consensus on the need for a new validated measure that is simple, succinct and addresses the impact of pain on life participation. This measure will facilitate the appropriate prioritization of pain in all trials and guide clinical decision making in people with ADPKD.

BACKGROUND: Steroids have been used widely since the early 1970s for the treatment of adult‐onset minimal change disease (MCD). Recently, newer agents have been used in adult MCD aiming to reduce the risk of adverse effects. The response rates to immunosuppressive agents in adult MCD are more variable than in children. The optimal agent, dose, and duration of treatment for the first episode of nephrotic syndrome, or for disease relapse(s) have not been determined. This is an update of a review first published in 2008. OBJECTIVES: We aimed to 1) evaluate the benefits and harms of different agents, including both immunosuppressive and non‐immunosuppressive agents, in adults with MCD causing the nephrotic syndrome; and 2) evaluate the efficacy of interventions on 'time‐to‐remission' of nephrotic syndrome, in adults with MCD causing the nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 21 July 2021 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 (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi‐RCTs of any intervention for MCD with nephrotic syndrome in adults over 18 years were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non‐immunosuppressive agents were assessed. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random‐effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Fifteen RCTs (769 randomised participants) were identified; four studies evaluated different prednisolone regimens, eight studies evaluated the calcineurin inhibitors (CNIs) (tacrolimus or cyclosporin), two studies evaluated enteric‐coated mycophenolate sodium (EC‐MPS) and one study evaluated levamisole. In all but two studies of non‐corticosteroid agents, reduced‐dose prednisolone was given with the treatment agent and the comparator was high‐dose prednisolone. In the risk of bias assessment, 11 and seven studies were at low risk of bias for sequence generation and allocation concealment, respectively. No studies were at low risk of performance bias and eight studies were at low risk of detection bias. Thirteen, 10 and six studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with no specific treatment, it is uncertain whether prednisolone increases the number with complete remission (1 study, 28 participants: RR 1.44, 95% CI 0.95 to 2.19), complete or partial remission (1 study, 28 participants: RR 1.38, 95% CI 0.98 to 1.95), subsequent relapse (1 study, 28 participants: RR 0.75, 95% CI 0.48 to 1.17), or reduces the adverse effects because the certainty of the evidence is very low. Compared with oral prednisolone alone, it is uncertain whether intravenous methylprednisolone and prednisolone increase the number with complete remission (2 studies, 35 participants: RR 1.76, 95% CI 0.17 to 18.32; I² = 90%), relapse (two studies, 19 participants. RR 1.18, 95% CI 0.65 to 2.15; I² = 0%) or adverse events because the certainty of the evidence is very low. Compared with prednisolone alone, CNIs with reduced‐dose prednisolone or without prednisolone probably make little or no difference to the number achieving complete remission (8 studies; 492 participants: RR 0.99, 95% CI 0.93 to 1.05; I² = 0%), complete or partial remission (4 studies, 269 participants: RR 1.01, 95% CI 0.96 to 1.05; I² = 0%), or relapse (7 studies; 422 participants: RR 0.73, 95% CI 0.51 to 1.03; I² = 0%) (moderate certainty evidence), may reduce the risk of obesity or Cushing's Syndrome (5 studies; 388 participants: RR 0.11, 95% CI 0.02 to 0.59; I² = 45%) and the risk of acne (4 studies; 270 participants: RR 0.15, 95% CI 0.03 to 0.67; I² = 0%) (low certainty evidence); and had uncertain effects on diabetes or hyperglycaemia, hypertension, and acute kidney injury (AKI) (low certainty evidence). Compared with prednisolone alone, EC‐MPS with reduced‐dose prednisolone probably make little or no difference to the number undergoing complete remission at 4 weeks (1 study, 114 participants: RR 1.12, 95% CI 0.84 to 1.50), and at 24 weeks probably make little or no difference to the number undergoing complete remission (2 studies, 134 participants: RR 1.12, 95% CI 0.84 to 1.38; I² = 0%) (moderate certainty evidence), complete or partial remission (2 studies 134 participants: RR 0.92, 95% CI 0.75 to 1.12; I² = 0%), relapse (2 studies, 83 participants: RR 0.50, 95% CI 0.07 to 3.74; I² = 56%) (low certainty evidence); or to the adverse events of new‐onset glucose intolerance, death, or AKI (low certainty evidence). One study (24 participants) compared levamisole and prednisolone with prednisolone in patients with relapsing disease. The authors identified no differences in mean relapse rate or adverse effects but no standard deviations were provided. AUTHORS' CONCLUSIONS: This updated review has identified evidence for the efficacy and adverse effects of CNIs and EC‐MPS with or without reduced‐dose prednisolone compared with prednisolone alone for the induction of remission in adults with MCD and nephrotic syndrome with some reductions in steroid‐associated adverse events. RCT data on the efficacy and adverse effects of rituximab in adults with MCD are awaited. Further, adequately powered RCTs are required to determine the relative efficacies of CNIs and EC‐MPS and to evaluate these medications in patients with relapsing or steroid‐resistant disease.

Background Only a few studies with conflicting results have examined the effects of sex on the prospective association between depression and subsequent obesity. Objective (1) To simultaneously assess the associations of the subtypes (atypical, melancholic, unspecified) of major depressive disorder (MDD) measured at baseline and subtypes of major depressive episodes (MDE) that emerged during a 5.5-year follow-up with changes in obesity markers (body mass index, waist circumference, fat mass) during this follow-up, and (2) to test the effect of sex on these associations. Methods Data from CoLaus|PsyCoLaus, a population-based cohort study including 2702 participants (50.1% women, mean age 49.6 years). Criteria for mental disorders were elicited using semi-structured interviews. Results History of atypical MDD at baseline was associated with a steeper increase in BMI and waist circumference, whereas atypical MDE during follow-up was associated with a steeper increase in the three studied obesity markers. Melancholic MDD at baseline was associated with a steeper increase in BMI. Several significant interactions with sex were found indicating higher increase in fat mass in men than in women following melancholic MDD reported at baseline, higher decrease in BMI and fat mass in women than in men related to melancholic MDE emerging during follow-up and higher increase in waist circumference in men than in women following unspecified MDD reported at baseline. Limitations Urban sample which may not be representative for the whole population. Conclusions Our results further advocate for the specific need of a thorough monitoring of obesity markers in patients with atypical MDD and suggest less favorable obesity marker changes mainly related to melancholic MDE in men.

This work investigates the role of metabolite levels in the intellectual impairment of subjects with Down syndrome (DS). Homocysteine, folate, vitamin B12, uric acid (UA), creatinine levels and MTHFR C677T genotype were analyzed in 147 subjects with DS. For 77 subjects, metabolite levels were correlated with cognitive tests. Griffiths-III test was administered to 28 subjects (3.08–6.16 years) and WPPSI-III test was administered to 49 subjects (7.08–16.08 years). Significant correlations were found among some metabolite levels and between homocysteine levels and MTHFR C677T genotype. Moreover, homocysteine, UA and creatinine levels resulted increased with age. We did not find any correlation between metabolites and cognitive test score in the younger group. Homocysteine showed statistically significant correlation with WPPSI-III subtest scores when its level is ≥ 7.35 µmol/L, remaining correlated in higher thresholds only for non-verbal area scores. Vitamin B12 showed correlations with all WPPSI-III subtest scores when its level is

Simple Summary The status of microsatellite instability (MSI-H) in gastric or gastroesophageal junction cancer (GC/GEJC) patients eligible for radical surgery proved to be prognostic for an improved survival outcome and predictive for poor/no benefit from the combination of adjuvant/peri-operative chemotherapy. MSI-H tumors display a high sensitivity to immunotherapy and exploratory studies showed that a pre-operative treatment with immune-checkpoint inhibitors may achieve elevated rates of pathological complete responses. The ongoing proof-of-concept INFINITY study is aimed at investigating the role of the combo-immunotherapy durvalumab plus tremelimumab as a neoadjuvant or potentially definitive treatment (avoiding surgery in case of complete clinical response) for MSI-H resectable GC/GEJC patients. Abstract In resectable gastric or gastroesophageal junction cancer (GC/GEJC), the powerful positive prognostic effect and the potential predictive value for a lack of benefit from the combination of adjuvant/peri-operative chemotherapy for the MSI-high status was demonstrated. Given the high sensitivity of MSI-high tumors for immunotherapy, exploratory trials showed that combination immunotherapy induces a high rate of complete pathological response (pCR), potentially achieving cancer cure without surgery. INFINITY is an ongoing phase II, multicentre, single-arm, multi-cohort trial investigating the activity and safety of tremelimumab and durvalumab as neoadjuvant (Cohort 1) or potentially definitive (Cohort 2) treatment for MSI-high/dMMR/EBV-negative, resectable GC/GEJC. About 310 patients will be pre-screened, to enroll a total of 31 patients, 18 and 13 in Cohort 1 and 2, at 25 Italian Centres. The primary endpoint of Cohort 1 is rate of pCR (ypT0N0) and negative ctDNA after neoadjuvant immunotherapy, of Cohort 2 is 2-year complete response rate, defined as absence of macroscopic or microscopic residual disease (locally/regionally/distantly) at radiological examinations, tissue and liquid biopsy, during non-operative management without salvage gastrectomy. The ongoing INFINITY proof-of-concept study may provide evidence on immunotherapy and the potential omission of surgery in localized/locally advanced GC/GEJC patients selected for dMMR/MSI-high status eligible for radical resection.

Background Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. Methods RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. Results Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3–4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. Conclusions These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.

Few epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics.All residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design.The risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00-3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76-3.21).These results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

BackgroundCutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer whose incidence is growing parallel to the lengthening of the average lifespan. Cemiplimab, an antiPD-1 monoclonal antibody, is the first approved immunotherapy for patients with locally advanced CSCC (laCSCC) or metastatic CSCC (mCSCC) thanks to phase I and II studies showing high antitumor activity and good tolerability. Nevertheless, at present, very few data are available regarding cemiplimab in real-life experience and in frail, elderly, and immunosuppressed patients as well as regarding biomarkers able to predict response so as to guide therapeutic choices.Patients and MethodsWe built a retroprospective cohort study including 30 non-selected patients with laCSCC (25) and mCSCC (five) treated with cemiplimab from August 2019 to November 2020. Clinical outcomes, toxicity profile, and correlations with disease, patients, and peripheral blood parameters are explored.ResultsThe median age was 81 years (range, 36–95), with 24 males and five patients having an immunosuppressive condition, while the frailty prevalence was 83% based on index derived from age, Eastern Cooperative Oncology Group performance status, and Charlson Comorbidity Index. We reported 23 responses (76.7%) with nine complete responses (30%). A statistically significant higher response rate was observed in head and neck primary tumors and in patients with hemoglobin level >12 g/dl. No difference was observed with respect to frailty, median age, sex, and body mass index. The baseline low neuthophil/lymphocyte ratio and low platelet/lymphocyte ratio resulted to be also correlated with a better response. Moreover, lymphocyte, neutrophil, and monocyte behaviors had an opposite trend in responders and non-responders. An overall response was reported in four of five immunosuppressed patients. Seventeen patients (57.6%) have an ongoing response and are still alive. Six responders had interrupted treatment (two for toxicity and four for personal choice) but maintained their response. The treatment was well tolerated by the majority of patients. The most common adverse events were fatigue in seven patients (23.3%) and skin toxicity in 10 patients (33.3%), including pruritus in six patients, rash in three patients, and bullous erythema in one patient.ConclusionsIn our real-life experience, cemiplimab showed a high antitumor activity with acceptable safety profile similar to those in trials with selected patients. Moreover, its antitumor activity resulted to be not impaired in very elderly patients and in those with immunocompromised status.

BackgroundImmunotherapy with immune checkpoint inhibitors is one of the main therapies for advanced melanoma. Nevertheless, albeit remarkable, immunotherapy results are still unsatisfactory as more than half of patients progress, and resistance to treatment still has a dramatic impact on clinical outcomes. Local treatments such as radiotherapy or electrochemotherapy (ECT), in addition to local control with palliative intent, have been shown to release tumoral neoantigens that can stimulate a robust systemic antitumor immune response.Case PresentationWe report the case of a patient with multiple nodular melanoma lesions of the scalp initially treated with local ECT. Soon after the procedure, multiple new lesions appeared close to the treated ones, therefore the patient started a systemic treatment with the anti-PD-1 nivolumab. The lesions of the scalp did not respond to immunotherapy, presenting a loco-regional spreading. To control the bleeding and painful lesions, we performed a second ECT, while continuing systemic immunotherapy. The treated lesions responded to the second procedure, while the other lesions continued progressing in number and dimension. Unexpectedly, after 2 months from the second ECT, the patient presented a progressive shrinkage of both treated and untreated lesions until complete remission. Concomitantly, he developed immune-related adverse events including grade 4 thyroid toxicity, grade 2 vitiligo-like depigmentation and grade 2 pemphigoid. At present, after 18 months from the first ECT and 14 months from the starting of anti-PD-1 immunotherapy, the patient is in good clinical condition and complete remission of disease still persists.ConclusionThis case highlights the potential role of ECT in increasing tumor immunogenicity and consequently in inducing a powerful immune response overcoming primary resistance to checkpoint inhibitor immunotherapy.

Peritoneal carcinomatosis frequently occurs in advanced gastrointestinal and gynecological cancers. As factors such as poor drug uptake and distribution cause chemotherapy to be less effective, alternative therapies have been explored. Introduced in 2013, PIPAC (pressurized intraperitoneal aerosol chemotherapy) uses aerosolized chemotherapeutics sprayed into the patient’s peritoneal cavity using a laparoscopic approach. Despite the literature showing encouraging data regarding the tolerability and efficacy of PIPAC, there is a lack of articles on the role that imaging plays in selecting patients suitable for PIPAC. The aim of this study is to combine literature-based evidence and clinical experience to provide information able to support training radiologists, as well as experienced radiologists interested in innovative therapies.

Background & aims: Dietary and supplemental long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) have shown vascular benefits for the general population, but effects among people with chronic kidney disease (CKD) are largely uncertain. We aimed to evaluate the effects of n-3 PUFA intake among patients with CKD. Methods: We searched MEDLINE, Embase, and CENTRAL through January 12, 2018. Eligible studies were randomized controlled trials evaluating n-3 PUFA intake (supplementation or dietary) compared with placebo, standard care, or other treatment, on cardiovascular and all-cause mortality, end stage kidney disease (ESKD), acute transplant rejection, and allograft loss. Risks of bias and evidence certainty were assessed using Cochrane and Grading of Recommendations Assessment, Development and Evaluation processes. Results: Sixty trials (4129 participants) were eligible, all of supplementation, with a median follow-up of 6 months. Low to very low certainty evidence suggested that n-3 PUFA supplementation reduced cardiovascular death for participants on hemodialysis (39 events; relative risk (RR) 0.45, 95% confidence interval (CI) 0.23–0.89), prevented ESKD (29 events; RR 0.30, CI 0.09–0.98) in participants with CKD not receiving renal replacement therapy, and made little or no difference in all-cause mortality (215 events; RR 1.05, CI 0.84–1.33), acute transplant rejection (188 events; RR 0.98, CI 0.80–1.21) or allograft loss (39 events; RR 0.98, CI 0.54–1.81]). Risk of bleeding (44 events; RR 1.40, CI 0.78–2.49) and gastrointestinal side-effects (103 events; RR 1.14, CI 0.79–1.67) were uncertain. Conclusions: n-3 PUFA supplementation may reduce cardiovascular mortality in patients on hemodialysis but it is uncertain whether supplementation prevents mortality or ESKD in patients with CKD.

PsyCoLaus: A Prospective Study of the Links between Mental Health and Cardiovascular Diseases Abstract. PsyCoLaus, which includes an investigation of mental disorders and cognitive functioning, aims to determine the prevalence and the course of mental disorders in the general population and to study the mechanisms underlying the association between these disorders and cardiovascular diseases. This investigation revealed a very high lifetime prevalence rate of 43.6 % for major depressive disorder in Lausanne. We have also observed that the association between major depression and cardio-metabolic risk factors is essentially attributable to the atypical subtype, characterized by an increased appetite, heaviness in limbs, hypersomnia and conserved affective reactivity. Patients who suffer from this type of depression have an increased risk to develop overweight, diabetes and the metabolic syndrome and deserve particular clinical attention on the metabolic level.

Rationale & Objective In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. Study Design Prospective cohort study. Setting & Participants Adult hemodialysis patients treated in 20 Italian dialysis clinics. Exposures Patients’ cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients’ self-reported years of education. Outcome All-cause mortality. Analytical Approach Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. Results 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P = 0.7). Limitations Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. Conclusions Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

Background and objectives Whether a healthy dietary pattern may prevent the incidence of developing CKD is unknown. This study evaluated the associations between dietary patterns and the incidence of CKD in adults and children. Design, setting, participants, & measurements This systematic review and meta-analysis identified potential studies through a systematic search of MEDLINE, Embase and references from eligible studies from database inception to February 2019. Eligible studies were prospective and retrospective cohort studies including adults and children without CKD, where the primary exposure was dietary patterns. To be eligible, studies had to report on the primary outcome, incidence of CKD (eGFR Results Eighteen prospective cohort studies involving 630,108 adults (no children) with a mean follow-up of 10.4±7.4 years were eligible for analysis. Included studies had an overall low risk of bias. The evidence certainty was moderate for CKD incidence and low for eGFR decline (percentage drop from baseline or reduced by at least 3 ml/min per 1.73 m2 per year) and incident albuminuria. Healthy dietary patterns typically encouraged higher intakes of vegetables, fruit, legumes, nuts, whole grains, fish and low-fat dairy, and lower intakes of red and processed meats, sodium, and sugar-sweetened beverages. A healthy dietary pattern was associated with a lower incidence of CKD (odds ratio [OR] 0.70 (95% confidence interval [95% CI], 0.60 to 0.82); I2=51%; eight studies), and incidence of albuminuria (OR 0.77, [95% CI, 0.59 to 0.99]; I2=37%); four studies). There appeared to be no significant association between healthy dietary patterns and eGFR decline (OR 0.70 [95% CI, 0.49 to 1.01], I2=49%; four studies). Conclusions A healthy dietary pattern may prevent CKD and albuminuria.

Background International guidelines recommend dysplasia surveillance in IBD. Aim To compare endoscopic techniques for dysplasia surveillance METHODS: We searched MEDLINE, Embase, CENTRAL for randomised trials through May 2019. We estimated odds ratios (ORs) for binary and mean differences (MDs) for continuous outcomes, using frequentist random-effects network meta-analysis. We assessed study risk of bias and appraised evidence certainty using GRADE. Results Eighteen trials (2638 participants) were included. Standard definition white-light endoscopy (OR 0.44, 95% CI 0.26-0.73; high certainty) and i-SCAN (OR 0.47, 95% CI 0.25-0.90; moderate certainty) had lower odds of detecting neoplasia than chromoendoscopy. Fujinon intelligent colour enhancement (FICE), standard definition white-light endoscopy and i-SCAN had lower odds for this outcome than full spectrum high definition white-light endoscopy (ORs 0.02 to 0.15; low certainty). Standard definition white-light endoscopy had lower odds of detecting nonpolypoid neoplasia than full spectrum high definition white-light endoscopy, narrow band imaging, chromoendoscopy and high definition white-light endoscopy (ORs 0.01-0.14; moderate certainty). Full spectrum high definition white-light endoscopy ranked as the best technique for both outcomes (moderate certainty). Standard definition white-light endoscopy had lower odds of detecting neoplasia by target biopsy (OR 0.27, 95% CI 0.08-0.91) and had shorter procedure time (MD -14.81 minutes, 95% CI -25.03, -4.06) than chromoendoscopy (moderate certainty). Conclusions Chromoendoscopy, high definition white-light endoscopy, narrow band imaging, autofluorescence, FICE and full spectrum high definition white-light endoscopy may be comparable for dysplasia surveillance. Standard definition white-light endoscopy and i-SCAN probably provide lower yields for neoplasia identification. Full spectrum high definition white-light endoscopy may represent the first-line approach.

BackgroundPemphigus vulgaris (PV) is a rare and severe autoimmune blistering disorder affecting the skin and mucous membranes, characterized by the production of autoantibodies against two desmosomal adhesion proteins, desmoglein 1 and 3. In patients with advanced squamous cell carcinoma of the skin unfit for surgery and radiotherapy, immune check-point inhibitors, including the anti-Programmed Death-1 (PD-1) agent cemiplimab have been successfully employed proving relevant clinical outcomes. Cemiplimab is a monoclonal antibody capable of inhibiting PD-1 signalling that has recently been approved for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma. Although the peculiar setting of advanced CSCC involving elderly patients, rare and unusual skin immune-related adverse events such as PV could be observed in cemiplimab treated patients.Case ReportA 95-year-old man without a history of autoimmune disease was treated with cemiplimab for multiple and advanced squamous cell carcinomas of the head obtaining a complete response to therapy. After seven cycles of cemiplimab administered every 21 days, the patient developed a mucocutaneous blistering eruption. Clinical diagnosis of PV was suspected on the basis of the diffuse involvement of trunk and extremities with large blisters and necrotic eschar. It was carried out an ELISA test, that showed high level of circulating antibodies against desmoglein 1, thus confirming the diagnosis of PV. For this reason, cemiplimab infusion was discontinued and complete resolution of skin lesions was obtained using oral prednisone 0,8 mg/kg/daily for four weeks. Once remission was achieved, a maintenance dose of 10 mg/day was administered, observing a good control of bullous disease and low value of desmoglein 1. Response to CSCC persisted also during cemiplimab discontinuation, until obtaining a complete remission still persisting at 9 months after the last cycle of therapy.ConclusionThe case we observed is the first description of PV revealed from cemiplimab therapy, thus suggesting that cemiplimab could allow the arise of underlying autoimmune PV, through a mechanism both T and B-cell-mediated.

Background and objectives Dietary potassium restriction in people receiving maintenance hemodialysis is standard practice and is recommended in guidelines, despite a lack of evidence. We aimed to assess the association between dietary potassium intake and mortality and whether hyperkalemia mediates this association. Design, setting, participants, & measurements A total of 8043 adults undergoing maintenance hemodialysis in Europe and South America were included in the DIETary intake, death and hospitalization in adults with end-stage kidney disease treated with HemoDialysis (DIET-HD) study. We measured baseline potassium intake from the Global Allergy and Asthma European Network food frequency questionnaire and performed time-to-event and mediation analyses. Results The median potassium intake at baseline was 3.5 (interquartile range, 2.5–5.0) g/d. During a median follow-up of 4.0 years (25,890 person-years), we observed 2921 (36%) deaths. After adjusting for baseline characteristics, including cardiac disease and food groups, dietary potassium intake was not associated with all-cause mortality (per 1 g/d higher dietary potassium intake: hazard ratio, 1.00; 95% confidence interval [95% CI], 0.95 to 1.05). A mediation analysis showed no association of potassium intake with mortality, either through or independent of serum potassium (hazard ratio, 1.00; 95% CI, 1.00 to 1.00 and hazard ratio, 1.01; 95% CI, 0.96 to 1.06, respectively). Potassium intake was not significantly associated with serum levels (0.03; 95% CI, −0.01 to 0.07 mEq/L per 1 g/d higher dietary potassium intake) or the prevalence of hyperkalemia (≥6.0 mEq/L) at baseline (odds ratio, 1.11; 95% CI, 0.89 to 1.37 per 1 g/d higher dietary potassium intake). Hyperkalemia was associated with cardiovascular death (hazard ratio, 1.23; 95% CI, 1.03 to 1.48). Conclusions Higher dietary intake of potassium is not associated with hyperkalemia or death in patients treated with hemodialysis.

Background Traumatic experiences tend to be preserved in altered biomarker profiles. These profiles can be traced back from cross-sectional data regarding the age of exposure. Consequently, the change across developmental stages, e.g. from childhood to adulthood, can also be reconstructed. This study introduces a backtrace procedure that is illustrated using white blood cell (WBC) counts in full / partial post-traumatic stress disorder (PTSD). The procedure was applied separately on men's and women's data to provide a replication of the analysis based on different subsamples. Methods The analysis was carried out with data from the CoLaus|PsyCoLaus study (N = 5111, 2370 men and 2741 women, age range 35-88 years). It was restricted to traumatic experiences that occurred until the age of 35, i.e., the lower age limit of the sample. The WBC counts from up to two assessments were standardized, pooled and assigned to the reported age of trauma exposure. This resulted in age series for each marker, whereas the reference values were based on subjects who did not experience any trauma exposure. The backtrace procedure ascertained the peaks and troughs of the age series and determined the best-fitting critical age range surrounding each peak or trough based on the best p-value from simple t-tests. Results In CoLaus|PsyCoLaus, 750 participants reported trauma exposure until the age of 35, and 86 (out of 329 ) men and 187 (out of 421) women thereof were coded with a full or partial PTSD. Full / partial PTSD after trauma exposure in childhood was characterized by increased WBC counts (lymphocytes, eosinophils – in women also neutrophils). This pattern was partly retained during adolescence, in men due to eosinophils counts and in women due to lymphocyte counts. For exposure in young adulthood, the deviations were in the negative direction – in men with decreased basophils, in women with decreased lymphocytes and monocytes. Conclusions Summarizing, the backtrace approach revealed WBC profiles in PTSD that were specific to particular developmental age stages. The strongest persistent upregulation of the immune system related to trauma exposure was traceable to childhood / early adolescence both in men and in women. Further research will show which biomarkers are similarly suitable for backtracing as WBC counts. As in PTSD, the backtrace approach could also be applied to identifying persistent biomarker profiles in other mental disorders, as well as autoimmune and other chronic diseases.

Background and Aims Although high-dose haemodiafiltration (HDF) has shown some promising survival advantage compared with high-flux haemodialysis (HD), the evidence remains controversial. In view of these discrepant results, a definitive trial is required to determine whether high-dose HDF is superior to high-flux HD. The comparison of high-dose HDF with high-flux HD (CONVINCE) study will assess the benefits and harms of high-dose HDF versus conventional high-flux HD in adults with end-stage kidney disease (ESKD). Here we provide information on the baseline characteristics of the included patients and evaluate whether the patients randomised to HDF were able to reach a high-dose convection volume. Method This international, prospective, open label, randomised, controlled trial is aiming to recruit 1800 ESKD adults treated with high-flux HD in 9 European countries. Patients will be randomised 1:1 to high-dose HDF versus continuation of conventional high-flux HD. High-dose HDF is defined as a convection volume per session of ≥23 L (range ±1 L). The trial is designed with a follow-up time for each patient of at least 24 months and will assess all-cause mortality, cause-specific mortality, cardiovascular events, hospitalisation, patient-reported outcomes, and cost-effectiveness. For this study we tabulated the baseline characteristics for all randomised participants by treatment groups. For the patients randomised to HDF, we calculated the proportion of the patients reaching a convection volume of ≥ 23L. session on the first visit after baseline (i.e. 3 months) and compared baseline and treatment characteristics with the patients with a convection volume of Results CONVINCE has recruited, until the start of January 2021, 1139 patients in eight European countries. The mean age was 62.4 (SD: 13.2) years and 62% (n=709) patients were men. The mean dialysis vintage was 5.0 (6.1) years. The mean systolic blood pressure (BP) was 141 (22) mmHg, the diastolic BP was 73 (14) mmHg, and the body mass index (BMI) was 27.6 (5.7) kg/m2. Approximately one-third the patients had diabetes mellitus and 21% had a history of coronary heart disease at baseline. Of the patients randomised to HDF, over 85% achieved a convection volume of ≥23L/session. There were no apparent differences in baseline and treatment characteristics between the patients who reached a convective volume of ≥23L/session versus those who did not: the vascular access was, respectively, a fistula (82% vs 81%), catheter (13% vs 14%), and graft (5% vs 5%) access. Conclusion The CONVINCE study will run up to 2023 and addresses the question of benefits and harms, regarding survival, hospitalisation, patient-reported outcomes, and cost-effectiveness of high-dose HDF compared with high-flux HD in patients with ESKD. This first analysis shows that achievement of high-dose HDF is feasible for most patients and, most importantly, could be maintained during the present trial period.

Background and Aims A healthy lifestyle promotes cardiovascular health and reduces cardiac-related mortality in the general population, but its benefits in patients treated with hemodialysis are uncertain. The aim of this study was to evaluate the association of a modified American Heart Association (AHA) healthy lifestyle score, and its individual components, with all-cause and cardiovascular mortality in a large multinational cohort of patients treated with long-term hemodialysis. Method Based on the AHA’s recommendations for cardiovascular prevention, a modified healthy lifestyle score was derived from non-smoking, being physically active, higher body mass index (BMI, obesity paradox of higher BMI being protective of death in dialysis patients), healthy diet, and well-controlled systolic blood pressure for participants in the DIET-HD study, a multinational cohort study of adults on hemodialysis. Hazard ratios (aHR) were estimated to evaluate the association between the healthy lifestyle score [low (0 -3 points) as the referent, medium (4-6), and high (7-10)] and cardiovascular and all-cause mortality by using cox model. Results 5483 out of 9757 (56%) patients with complete lifestyle data were followed for a median of 3.8 years (17450.9 person-years). There were 2,163 deaths, of which 826 cardiovascular-related. Compared with patients with a low lifestyle score (963, 18%), the aHRs (95%CI) for all-cause mortality among those with medium (3,621, 66%) and high (899, 16%) were 0.70 (0.63-0.78) and 0.57 (0.49-0.66), respectively. Cardiovascular death was 17% [aHR, 0.83 (0.68-0.99] and 30% (0.70, 0.55-0.90) lower in patients with medium and high lifestyle score, respectively. Results were consistent in stratified or complete-case analyses, and after excluding early deaths. Risk reductions were largely driven by being a non-smoker, physically active and having a higher BMI. 20% of deaths were attributed to a medium/low lifestyle score (population attributable fraction; 95% CI 12-28%). Conclusion A healthier lifestyle, especially non-smoking, regular physical activity, and a higher BMI, is dose-dependently associated with lower all-cause and cardiovascular mortality in hemodialysis patients.

Peritoneal fibrosis is characterized by abnormal production of extracellular matrix proteins leading to progressive thickening of the submesothelial compact zone of the peritoneal membrane. This process may be caused by a number of insults including pathological conditions linked to clinical practice, such as peritoneal dialysis, abdominal surgery, hemoperitoneum, and infectious peritonitis. All these events may cause acute/chronic inflammation and injury to the peritoneal membrane, which undergoes progressive fibrosis, angiogenesis, and vasculopathy. Among the cellular processes implicated in these peritoneal alterations is the generation of myofibroblasts from mesothelial cells and other cellular sources that are central in the induction of fibrosis and in the subsequent functional deterioration of the peritoneal membrane. Myofibroblast generation and activity is actually integrated in a complex network of extracellular signals generated by the various cellular types, including leukocytes, stably residing or recirculating along the peritoneal membrane. Here, the main extracellular factors and the cellular players are described with emphasis on the cross-talk between immune system and cells of the peritoneal stroma. The understanding of cellular and molecular mechanisms underlying fibrosis of the peritoneal membrane has both a basic and a translational relevance, since it may be useful for setup of therapies aimed at counteracting the deterioration as well as restoring the homeostasis of the peritoneal membrane., European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant and Spanish Ministry of Science and Innovation/Fondo Europeo de Desarrollo Regional (PID2019-110132RB-I00/AEI/10.13039/501100011033)

Trisomy 21 (Down syndrome, DS) is the main human genetic cause of intellectual disability (ID). Lejeune hypothesized that DS could be considered a metabolic disease, and we found that subjects with DS have a specific plasma and urinary metabolomic profile. In this work we confirmed the alteration of mitochondrial metabolism in DS and also investigated if metabolite levels are related to cognitive aspects of DS. We analyzed the metabolomic profiles of plasma samples from 129 subjects with DS and 46 healthy control (CTRL) subjects by 1H Nuclear Magnetic Resonance (NMR). Multivariate analysis of the NMR metabolomic profiles showed a clear discrimination (up to 94% accuracy) between the two groups. The univariate analysis revealed a significant alteration in 7 metabolites out of 28 assigned unambiguously. Correlations among the metabolite levels in DS and CTRL groups were separately investigated and statistically significant relationships appeared. On the contrary, statistically significant correlations among the NMR-detectable part of DS plasma metabolome and the different intelligence quotient ranges obtained by Griffiths-III or WPPSI-III tests were not found. Even if metabolic imbalance provides a clear discrimination between DS and CTRL groups, it appears that the investigated metabolomic profiles cannot be associated with the degree of ID.

Background Few patients affected by gastric cancer peritoneal metastasis (GCPM) are offered locoregional treatment, despite several proof-of-efficacy trials. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has emerged in recent years as a promising tool to control peritoneal carcinomatosis. The combination of PIPAC with systemic chemotherapy may offer a greater clinical benefit than standard treatment alone. Methods A single-center cohort of 28 consecutive patients affected by GCPM was scheduled for bidirectional treatment, comprising PIPAC and systemic chemotherapy, from September 2017 to September 2019. Data recorded included safety, efficacy and survival outcomes. Ascite volumes, the Peritoneal Cancer Index (PCI) and pathological response through the Peritoneal Regression Grading Score (PRGS) were compared in those patients who underwent more than one PIPAC procedure. Results Forty-six PIPAC procedures were administered, with a mean of 1.7 PIPAC procedures per patient. The median time to resume systemic chemotherapy after PIPAC was 6 days (range 4–7). Concerning safety, two grade 3–4 CTCAE (Common Terminology Criteria for Adverse Events v4.0) toxicity events and one intraoperative complication were recorded. Thirteen patients repeated PIPAC. A pathological response was recorded in 61.5% of patients (one with complete and seven with partial regression). The median overall survival was 12.3 months in the overall population and 15.0 months in patients undergoing more than one PIPAC procedure. Conclusions A bidirectional approach for GCPM was feasible and safe, as the PIPAC procedure integrates well with several systemic chemotherapy regimens. The pathological response demonstrated the antitumoral efficacy of PIPAC. The proposed bidirectional approach may be further investigated in the first-line treatment of metastatic gastric cancer.

This article contains further data and information from our published manuscript [1]. We aim to identify significant transcriptome alterations of total normal human thyroid vs. histologically normal thyroid adjacent to papillary thyroid carcinoma. We performed a systematic meta-analysis of all the available gene expression profiles for the whole organ also collecting gene expression data for the normal thyroid adjacent to papillary thyroid carcinoma. A differential quantitative transcriptome reference map was generated by using TRAM (Transcriptome Mapper) software able to combine, normalize and integrate a total of 35 datasets from total normal thyroid and 40 datasets from histologically normal thyroid adjacent to papillary thyroid carcinoma from different sources. This analysis identified genes and genome segments that significantly discriminated the two groups of samples. Differentially expressed genes were grouped and enrichment function analyses were performed identifying the main features of the differentially expressed genes between total normal thyroid and histologically normal thyroid adjacent to papillary thyroid carcinoma. The search for housekeeping genes retrieved 414 loci.

Background: The impact of the new chemotherapy, fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) on body composition in gastric cancer (GC) patients remains unknown. We assessed body composition changes of GC patients receiving the FLOT regimen and their impact on treatment outcomes. Methods: Preoperative pre- and post-FLOT computed tomography (CT) scans of advanced GC patients were studied. Lumbar skeletal muscle index (SMI) and adipose indices were calculated before and after FLOT. Results: A total of 26 patients were identified between April 2019 and January 2020. Nineteen patients were sarcopenic at diagnosis. The mean BMI decreased (from 24.4 ± 3.7 to 22.6 ± 3.1; p < 0.0001) as well as the SMI (from 48.74 ± 9.76 to 46.52 ± 9.98; p = 0.009) and visceral adipose index (VAI) (from 49.04 ± 31.06 to 41.99 ± 23.91; p = 0.004) during preoperative FLOT therapy. BMI, SMI, and VAI variations were not associated with toxicity, Response Evaluation Criteria in Solid Tumors (RECIST), response, delay and completion of perioperative FLOT chemotherapy, and the execution of gastrectomy; a decrease of SMI ≥ 5% was associated with a higher Mandard tumor regression grade (p = 0.01). Conclusions: Almost three-quarters (73.1%) of GC patients were sarcopenic at diagnosis. Preoperative FLOT was associated with a further reduction in SMI, BMI, and VAI. These changes were not associated with short-term outcomes.

IntroductionFew epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics.MethodsAll residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design.ResultsThe risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00–3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76–3.21).ConclusionsThese results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, &lt, 3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM.

Objective To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design Network meta-analysis. Data sources Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool ( https://magicevidence.org/match-it/200820dist/#!/ ) for all outcomes. Conclusions In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. Systematic review registration PROSPERO CRD42019153180.

Rationale & Objective Coronavirus disease 2019 (COVID-19) disproportionately affects people with chronic diseases such as chronic kidney disease (CKD). We assessed the incidence and outcomes of COVID-19 in people with CKD. Study Design Systematic review and meta-analysis by searching MEDLINE, EMBASE, and PubMed through February 2021. Setting & Study Populations People with CKD with or without COVID-19. Selection Criteria for Studies Cohort and case-control studies. Data Extraction Incidences of COVID-19, death, respiratory failure, dyspnea, recovery, intensive care admission, hospital admission, need for supplemental oxygen, hospital discharge, sepsis, short-term dialysis, acute kidney injury, and fatigue. Analytical Approach Random-effects meta-analysis and evidence certainty adjudicated using an adapted version of GRADE (Grading of Recommendations Assessment, Development and Evaluation). Results 348 studies (382,407 participants with COVID-19 and CKD; 1,139,979 total participants with CKD) were included. Based on low-certainty evidence, the incidence of COVID-19 was higher in people with CKD treated with dialysis (105 per 10,000 person-weeks; 95% CI, 91-120; 95% prediction interval [PrI], 25-235; 59 studies; 468,233 participants) than in those with CKD not requiring kidney replacement therapy (16 per 10,000 person-weeks; 95% CI, 4-33; 95% PrI, 0-92; 5 studies; 70,683 participants) or in kidney or pancreas/kidney transplant recipients (23 per 10,000 person-weeks; 95% CI, 18-30; 95% PrI, 2-67; 29 studies; 120,281 participants). Based on low-certainty evidence, the incidence of death in people with CKD and COVID-19 was 32 per 1,000 person-weeks (95% CI, 30-35; 95% PrI, 4-81; 229 studies; 70,922 participants), which may be higher than in people with CKD without COVID-19 (incidence rate ratio, 10.26; 95% CI, 6.78-15.53; 95% PrI, 2.62-40.15; 4 studies; 18,347 participants). Limitations Analyses were generally based on low-certainty evidence. Few studies reported outcomes in people with CKD without COVID-19 to calculate the excess risk attributable to COVID-19, and potential confounders were not adjusted for in most studies. Conclusions The incidence of COVID-19 may be higher in people receiving maintenance dialysis than in those with CKD not requiring kidney replacement therapy or those who are kidney or pancreas/kidney transplant recipients. People with CKD and COVID-19 may have a higher incidence of death than people with CKD without COVID-19.

Vitamin D deficiency is associated with increased risks of mortality in people with chronic kidney disease. The benefits and harm of vitamin D supplementation on cardiovascular outcomes and mortality are unknown. We aimed to assess the effectiveness of calcifediol in reducing mortality in patients with vitamin D insufficiency on hemodialysis compared to no additional therapy. A phase III, multicenter, randomized, open-label trial was conducted including 284 adults with vitamin D insufficiency undergoing hemodialysis who were randomly assigned to receive oral calcifediol or standard care for 24 months. Two hundred eighty-four participants were enrolled (143 assigned to the calcifediol group and 141 to the no additional therapy group). The primary outcome (mortality) occurred in 34 and 31 participants in the calcifediol and control group, respectively [hazard ratio (HR) 1.03; 95% confidence interval (CI) 0.63–1.67]. Calcifediol had no detectable effects on cardiovascular death (HR 1.06; 95% CI 0.41–2.74), non-cardiovascular death (HR 1.13; 95% CI 0.62–2.04), nonfatal myocardial infarction (HR 0.20; 95% CI 0.02–1.67) or nonfatal stroke (HR could not be estimated). The incidence of hypercalcemia and hyperphosphatemia was similar between groups. None of the participants underwent parathyroidectomy. In adults treated with hemodialysis and who had vitamin D insufficiency, calcifediol supplementation for 24 months had inconclusive effects on mortality and cardiovascular outcomes. NCT01457001

Background Global migration toward Europe is increasing. Providing health assistance to migrants is challenging because numerous barriers limit their accessibility to health services. Migrants may be at a greater risk of developing asthma and receiving lower quality healthcare assistance than non-migrants. We aim to investigate whether immigrants as children and adolescents have higher rates of potentially avoidable hospitalization (PAH) for asthma compared to Italians. Methods We performed a retrospective longitudinal study using six cohorts of 2–17-year-old residents in North and Central Italy from 01/01/2001 to 31/12/2014 (N = 1,256,826). We linked asthma hospital discharges to individuals using anonymized keys. We estimated cohort-specific age and calendar-year-adjusted asthma PAH rate ratios (HRRs) and 95% confidence intervals (95%CIs) among immigrants compared to Italians. We applied a two-stage random effect model to estimate asthma PAH meta-analytic rate ratios (MHRRs). We analyzed data by gender and geographical area of origin countries. Results Three thousand three hundred four and 471 discharges for asthma PAH occurred among Italians and immigrants, respectively. Compared to Italians, the asthma PAH cohort-specific rate was higher for immigrant males in Bologna (HRR:2.42; 95%CI:1.53–3.81) and Roma (1.22; 1.02–1.45), and for females in Torino (1.56; 1.10–2.20) and Roma (1.82; 1.50–2.20). Asthma PAH MHRRs were higher only among immigrant females (MHRRs:1.48; 95%CI:1.18–1.87). MHRRs by area of origin were 63 to 113% higher among immigrants, except for Central-Eastern Europeans (0.80; 0.65–0.98). Conclusion The asthma PAH meta-analytic rate was higher among female children and adolescent immigrants compared to Italians, with heterogeneity among cohorts showing higher cohort-specific PAH also among males, with some differences by origin country. Access to primary care for children and adolescent immigrants should be improved and immigrants should be considered at risk of severe asthma outcomes and consequently targeted by clinicians.

Background Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. Objectives To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 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 (ICTRP) Search Portal, and ClinicalTrials.gov. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. Data collection and analysis Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. Main results Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. Authors' conclusions The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.

Background and objectives Fatigue is a very common and debilitating symptom and identified by patients as a critically important core outcome to be included in all trials involving patients receiving hemodialysis. A valid, standardized measure for fatigue is needed to yield meaningful and relevant evidence about this outcome. This study validated a core patient-reported outcome measure for fatigue in hemodialysis. Design, setting, participants, & measurements A longitudinal cohort study was conducted to assess the validity and reliability of a new fatigue measure (Standardized Outcomes in Nephrology-Hemodialysis Fatigue [SONG-HD Fatigue]). Eligible and consenting patients completed the measure at three time points: baseline, a week later, and 12 days following the second time point. Cronbach α and intraclass correlation coefficient were calculated to assess internal consistency, and Spearman rho was used to assess convergent validity. Confirmatory factor analysis was also conducted. Hemodialysis units in the United Kingdom, Australia, and Romania participated in this study. Adult patients aged 18 years and over who were English speaking and receiving maintenance hemodialysis were eligible to participate. Standardized Outcomes in Nephrology-Hemodialysis, the Visual Analog Scale for fatigue, the 12-Item Short Form Survey, and Functional Assessment of Chronic Illness Therapy–Fatigue were used. Results In total, 485 participants completed the study across the United Kingdom, Australia, and Romania. Psychometric assessment demonstrated that Standardized Outcomes in Nephrology-Hemodialysis is internally consistent (Cronbach α =0.81–0.86) and stable over a 1-week period (intraclass correlation coefficient =0.68–0.74). The measure demonstrated convergence with Functional Assessment of Chronic Illness Therapy–Fatigue and had moderate correlations with other measures that assessed related but not the same concept (the 12-Item Short Form Survey and the Visual Analog Scale). Confirmatory factor analysis supported the one-factor model. Conclusions SONG-HD Fatigue seems to be a reliable and valid measure to be used in trials involving patients receiving hemodialysis.

BACKGROUND: Calcium channel blockers (CCBs) are used to manage hypertension which is highly prevalent among people with chronic kidney disease (CKD). The treatment for hypertension is particularly challenging in people undergoing dialysis. OBJECTIVES: To assess the benefits and harms of calcium channel blockers in patients with chronic kidney disease requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies to 27 April 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi‐RCTs that compared any type of CCB with other CCB, different doses of the same CCB, other antihypertensives, control or placebo were included. The minimum study duration was 12 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random‐effects model and results expressed as risk ratio (RR), risk difference (RD) or mean difference (MD) with 95% confidence intervals (CI). MAIN RESULTS: This review included 13 studies (24 reports) randomising 1459 participants treated with long‐term haemodialysis. Nine studies were included in the meta‐analysis (622 participants). No studies were performed in children or in those undergoing peritoneal dialysis. Overall, risk of bias was assessed as unclear to high across most domains. Random sequence generation and allocation concealment were at low risk of bias in eight and one studies, respectively. Two studies reported low risk methods for blinding of participants and investigators, and outcome assessment was blinded in 10 studies. Three studies were at low risk of attrition bias, eight studies were at low risk of selective reporting bias, and five studies were at low risk of other potential sources of bias. Overall, the certainty of the evidence was low to very low for all outcomes. No events were reported for cardiovascular death in any of the comparisons. Other side effects were rarely reported and studies were not designed to measure costs. Five studies (451 randomised adults) compared dihydropyridine CCBs to placebo or no treatment. Dihydropyridine CCBs may decrease predialysis systolic (1 study, 39 participants: MD ‐27.00 mmHg, 95% CI ‐43.33 to ‐10.67; low certainty evidence) and diastolic blood pressure level (2 studies, 76 participants; MD ‐13.56 mmHg, 95% CI ‐19.65 to ‐7.48; I(2) = 0%, low certainty evidence) compared to placebo or no treatment. Dihydropyridine CCBs may make little or no difference to occurrence of intradialytic hypotension (2 studies, 287 participants; RR 0.54, 95% CI 0.25 to 1.15; I(2) = 0%, low certainty evidence) compared to placebo or no treatment. Other side effects were not reported. Eight studies (1037 randomised adults) compared dihydropyridine CCBs to other antihypertensives. Dihydropyridine CCBs may make little or no difference to predialysis systolic (4 studies, 180 participants: MD 2.44 mmHg, 95% CI ‐3.74 to 8.62; I(2) = 0%, low certainty evidence) and diastolic blood pressure (4 studies, 180 participants: MD 1.49 mmHg, 95% CI ‐2.23 to 5.21; I(2) = 0%, low certainty evidence) compared to other antihypertensives. There was no evidence of a difference in the occurrence of intradialytic hypotension (1 study, 92 participants: RR 2.88, 95% CI 0.12 to 68.79; very low certainty evidence) between dihydropyridine CCBs to other antihypertensives. Other side effects were not reported. Dihydropyridine CCB may make little or no difference to predialysis systolic (1 study, 40 participants: MD ‐4 mmHg, 95% CI ‐11.99 to 3.99; low certainty evidence) and diastolic blood pressure (1 study, 40 participants: MD ‐3.00 mmHg, 95% CI ‐7.06 to 1.06; low certainty evidence) compared to non‐dihydropyridine CCB. There was no evidence of a difference in other side effects (1 study, 40 participants: RR 0.13, 95% CI 0.01 to 2.36; very low certainty evidence) between dihydropyridine CCB and non‐dihydropyridine CCB. Intradialytic hypotension was not reported. AUTHORS' CONCLUSIONS: The benefits of CCBs over other antihypertensives on predialysis blood pressure levels and intradialytic hypotension among people with CKD who required haemodialysis were uncertain. Effects of CCBs on other side effects and cardiovascular death also remain uncertain. Dihydropyridine CCBs may decrease predialysis systolic and diastolic blood pressure level compared to placebo or no treatment. No studies were identified in children or peritoneal dialysis. Available studies have not been designed to measure the effects on costs. The shortcomings of the studies were that they recruited very few participants, had few events, had very short follow‐up periods, some outcomes were not reported, and the reporting of outcomes such as changes in blood pressure was not done uniformly across studies. Well‐designed RCTs, conducted in both adults and children with CKD requiring both haemodialysis and peritoneal dialysis, evaluating both dihydropyridine and non‐dihydropyridine CCBs against other antihypertensives are required. Future research should be focused on outcomes relevant to patients (including death and cardiovascular disease), blood pressure changes, risk of side effects and healthcare costs to assist decision‐making in clinical practice.

Mental health disorders figure among the many comorbidities of chronic obstructive pulmonary diseases.The purpose of this study is to evaluate the association of airway obstruction with mental disorders in the Swiss general population. PneumoLaus is based on the CoLaus|PsyCoLaus cohort inluding spirometry and a semi-structured interview on mental health in a random sample of the Lausanne general population(Switzerland).We defined reversible obstruction(RO) as FEV1/FVC LLN or FVC>LLN after bronchodilation(BD). Chronic obstruction(CO) was defined as FEV1/FVC In total, 2774 subjects performed spirometry and were assessed through the PsyCoLaus interview. We found evidence for associations of self-reported doctor-diagnosed asthma (OR 1.60, 95%CI 1.06–2.39) and COPD, emphysema or chronic bronchitis(OR 2.61, 95%CI 1.19–5.71) with recent remitted or current major depression(RCD). These associations were not found when spirometric criteria(CO, RO, FEV1, FVC in % predicted) were used instead of the self-reported diagnoses. There was some suggestion for associations between RO and RCD(OR 1.62, 95%CI 0.87-3.01) and RO and recent remitted/current anxiety disorder(OR 1.95, 95%CI 0.99–3.87). Subjects with known diagnosis of obstructive respiratory disease more frequently suffer from depression and anxiety. However, this association was not confirmed when using objective spirometric values instead of self-reported diagnoses.

Low muscle mass has been associated with worse clinical outcomes in various cancers. This work investigated whether, during tyrosine kinases inhibitors (TKIs) therapy, low muscle mass was associated with treatment toxicity and survival outcomes. A systematic literature search was performed in Pubmed, Web of Science, and Scopus databases from inception to June 2020, based on fixed inclusion and exclusion criteria. Effect sizes were estimated with hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI) and heterogeneity was assessed by measuring inconsistency (I2) based on the Chi squared test. A total of 24 retrospective studies were identified, enrolling patients treated with sorafenib (n = 12), sunitinib (n = 6), lenvatinib (n = 3), regorafenib (n = 2), gefitinib (n = 1), imatinib (n = 1), and pazopanib (n = 1). Thirteen studies were deemed eligible for pooled analyses. Meta-analyses found a significant effect of low muscle mass on dose-limiting toxicity (DLT) (OR 2.40, 95% CI 1.26–4.58, p = 0.008, I2 = 51%) in patients treated with TKI therapy. A subgroup analysis by treatment showed an association between DLT and low muscle during sorafenib or sunitinib, although not significant. A significant association between low skeletal muscle index and poorer overall survival was observed in HCC patients treated with sorafenib (HR 1.45, 95% CI 1.07–1.96, p = 0.02). For other TKIs, although some results showed an association between low muscle mass and worse outcomes, the number of studies for each TKI therapy was too small to reach conclusions. Skeletal muscle mass could influence the prognosis of some TKI-treated patients. This effect is demonstrated in sorafenib-treated HCC patients but remains almost unexplored in other cancer patients undergoing TKI therapy. Further prospective studies with large sample size and sufficient follow-up are needed to clarify the role of muscle mass in the metabolism of TKI-based cancer treatment, and its association with toxicity and survival.

Supplemental Digital Content is available in the text., Objectives: There are over 4,000 trials conducted in people with coronavirus disease 2019. However, the variability of outcomes and the omission of patient-centered outcomes may diminish the impact of these trials on decision-making. The aim of this study was to generate a consensus-based, prioritized list of outcomes for coronavirus disease 2019 trials. Design: In an online survey conducted in English, Chinese, Italian, Portuguese, and Spanish languages, adults with coronavirus disease 2019, their family members, health professionals, and the general public rated the importance of outcomes using a 9-point Likert scale (7–9, critical importance) and completed a Best-Worst Scale to estimate relative importance. Participant comments were analyzed thematically. Setting: International. Subjects: Adults 18 years old and over with confirmed or suspected coronavirus disease 2019, their family members, members of the general public, and health professionals (including clinicians, policy makers, regulators, funders, and researchers). Interventions: None. Measurements: None. Main Results: In total, 9,289 participants from 111 countries (776 people with coronavirus disease 2019 or family members, 4,882 health professionals, and 3,631 members of the public) completed the survey. The four outcomes of highest priority for all three groups were: mortality, respiratory failure, pneumonia, and organ failure. Lung function, lung scarring, sepsis, shortness of breath, and oxygen level in the blood were common to the top 10 outcomes across all three groups (mean > 7.5, median ≥ 8, and > 70% of respondents rated the outcome as critically important). Patients/family members rated fatigue, anxiety, chest pain, muscle pain, gastrointestinal problems, and cardiovascular disease higher than health professionals. Four themes underpinned prioritization: fear of life-threatening, debilitating, and permanent consequences; addressing knowledge gaps; enabling preparedness and planning; and tolerable or infrequent outcomes. Conclusions: Life-threatening respiratory and other organ outcomes were consistently highly prioritized by all stakeholder groups. Patients/family members gave higher priority to many patient-reported outcomes compared with health professionals.