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Additional file 1: Figure S1. Process of studies��� selection. Table S1. Summary of risk of bias assessment. Figure S2. Cochrane risk of bias (graph) for the 23 trials. Figure S3. Risk ratios (RR) for MACE estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Table S2. Ranking of treatments by P-score value for all outcomes. Table S3. Overall heterogeneity levels for each of the seven outcomes. Figure S4. Risk ratios (RR) for nonfatal myocardial infarction estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Figure S5. Risk ratios (RR) for nonfatal stroke estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Figure S6. Risk ratios (RR) for cardiovascular death estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Figure S7. Risk ratios (RR) for total death estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Figure S8. Risk ratios (RR) for hospitalization for heart failure estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Figure S9. Risk ratios (RR) for the renal outcome estimates according to direct (DPP-4 inhibitors, GLP-1RA and SGLT-2 inhibitors against placebo) and indirect (DPP-4 inhibitors vs GLP-1RA or SGLT-2 inhibitors, and GLP-1RA vs SGLT-2 inhibitors) comparisons. Table S4. Effects of novel antidiabetic drugs on cardiorenal endpoints established by network meta-analysis using a frequentist approach. PRISMA checklist.

Instituto de Salud Carlos III; Miguel Servet program (CPII20/00009) from the Institute of Health Carlos III (cofunded by the European Social Fund (ESF) – ESF investing in your future) (...), Llaha, F., Cayssials, V., Farràs, M., Agudo, A., Sandström, M., Eriksen, A.K., Tjønneland, A., Boutron-Ruault, M.-C., Laouali, N., Truong, T., Le Cornet, C., Katzke, V., Schulze, M., Palli, D., Krogh, V., Signoriello, S., Tumino, R., Ricceri, F., Skeie, G., Jensen, T.M.E., Chen, S.L.F., Lasheras, C., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Guevara, M., Almquist, M., Nilson, L.M., Hennings, J., Papier, K., Heath, A., Weiderpass, E., Rinaldi, S., Zamora-Ros, R.

Ambulatory blood pressure (BP) monitoring allows concurrent evaluation of BP control and nocturnal BP dipping status, both related to adverse outcomes. However, few studies have assessed the prognostic role of combining information on dipping status and achieved ambulatory BP in patients with chronic kidney disease (CKD).Prospective observational cohort study.906 patients with hypertension and CKD attending 1 of 3 Italian nephrology clinics.Four groups were defined by simultaneously classifying systolic ambulatory BP levels as being at goal (daytime SBP 135 and nighttime SBP 120 mm Hg) or above goal, and the presence or absence of nocturnal dipping (nighttime to daytime SBP ratio of 0.9 versus ≥0.9).The composite of time to initiation of maintenance dialysis or estimated glomerular filtration rate (eGFR) decline ≥50%, and the composite of fatal and nonfatal cardiovascular events.Multivariable Cox proportional hazards models were used to estimate risks of kidney disease progression and cardiovascular disease in the 4 exposure groups where nocturnal dipping with systolic ambulatory BP at goal was the reference group.The mean patient age was 63.8 years, 61% were male, and 26.4% had diabetes; eGFR was 41.1 ± 20.8 mL/min/1.73 mLack of a diverse cohort (all those enrolled were White). Residual uncontrolled confounding.Systolic ambulatory BP above goal or the absence of nocturnal dipping, regardless of ambulatory BP, is associated with higher risks of cardiovascular disease and kidney disease progression among patients with CKD.Among patients with chronic kidney disease (CKD), ambulatory blood pressure (BP) monitoring improves the identification of individuals at high risk of clinical disease outcomes. Those with uncontrolled ambulatory BP are known to have a higher risk of developing cardiovascular disease and kidney disease progression, particularly when their ambulatory BP does not decline by at least 10% at night. Whether this is also true for patients with presence of optimal ambulatory BP levels but a BP pattern of no nighttime decline is largely unknown. We measured ambulatory BP in 900 Italian patients with CKD and followed them for several years. We found that, independent of ambulatory BP level, the absence of nighttime reductions in BP was associated with worsening of CKD and more frequent cardiovascular events. The absence of nighttime declines in BP is an independent risk factor for adverse events among patients with CKD. Future studies are needed to examine whether treating the absence of nighttime declines in BP improves clinical outcomes.

To find prognostic factors for advanced ovarian cancer patients undergoing first-line therapy with carboplatin, paclitaxel and bevacizumab, we investigated the expression of a disintegrin and metalloprotease 17 (ADAM17) in cancer tissues. ADAM17 has been involved in ovarian cancer development, progression and cell resistance to cisplatin. Tissue microarrays from 309 ovarian cancer patients enrolled in the MITO16A/MANGO-OV2 clinical trial were analyzed by immunohistochemistry for ADAM17 protein expression. Intensity and extent of staining were combined into a semi-quantitative visual grading system (H score) which was related to clinicopathological characteristics of cases and the clinical outcome of patients by univariate and multivariate Cox regression models. ADAM17 immunostaining was detected in most samples, mainly localized in the tumor cells, with variable intensity across the cohort. Kaplan–Meier survival curves, generated according to the best cut-off value for the ADAM17 H score, showed that high ADAM17 expression was associated with worse prognosis for PFS and OS. However, after the application of a shrinkage procedure to adjust for overfitting hazard ratio estimates, the ADAM17 value as prognostic factor was lost. As subgroup analysis suggested that ADAM17 expression could be prognostically relevant in cases with no residual disease at baseline, further studies in this patient category may be worth planning.

Background Whether a very low-protein diet supplemented with ketoanalogues (sVLPD), compared with a standard low-protein diet (LPD), improves outcomes in patients with chronic kidney disease (CKD) under stable nephrology care is undefined. Objectives To compare the effectiveness of sVLPD compared with LPD in patients regularly seen in tertiary nephrology care. Methods Participants were patients with CKD stages 4-5, followed for at least 6 mo, randomly allocated to receive sVLPD or LPD [0.35 or 0.60 g/kg ideal body weight (IBW)/d, respectively], stratified by center and CKD stage. The primary outcome was time to renal death, defined as the first event between end-stage renal disease (ESRD) and all-cause mortality; secondary outcomes were the single components of the primary outcome, cardiovascular outcome, and nutritional status. Results We analyzed 223 patients (sVLPD, n = 107; LPD, n = 116). Mean age was 64 y, 61% were male, and 35% had diabetes. Median protein intake (PI), which was 0.8 g/kg IBW/d at baseline in both groups, was 0.83 and 0.60 g/kg IBW/d in LPD and sVLPD, respectively, during the trial with a large decrease only in sVLPD (P = 0.011). During a median of 74.2 mo, we recorded 180 renal deaths (141 dialysis and 39 deaths before dialysis). Risk of renal death did not differ in sVLPD compared with LPD (HR: 1.17; 95% CI: 0.88, 1.57; P = 0.28). No difference was observed for ESRD (HR: 1.12; 95% CI: 0.81, 1.56; P = 0.51), mortality (HR: 0.95; 95% CI: 0.62, 1.45; P = 0.82), or time to fatal/nonfatal cardiovascular events (P = 0.2, log-rank test). After 36 mo, still active patients were 45 in sVLPD and 56 in LPD. No change of nutritional status emerged during the study in any arm. Conclusions This long-term pragmatic trial found that in patients with CKD under stable nephrology care, adherence to protein restriction is low. Prescribing sVLPD compared with standard LPD is safe but does not provide additional advantage to the kidney or patient survival.