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Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17,Ptrend = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31;Ptrend = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer. What's new? Drinking alcohol can make the skin more sensitive to sunlight and vulnerable to skin cancer. Here, the authors conducted a large prospective cohort study to evaluate whether alcohol consumption correlates with skin cancer risk. Among the 450 112 participants, there were 2457 cases of melanoma, 8711 of basal cell carcinoma, and 1928 of squamous cell carcinoma. There was a positive association between alcohol and all three cancer types, stronger in men than in women. The association varied somewhat by beverage type.

Data regarding early predictors of clinical deterioration in patients with infection of severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) is still scarce. The aim of the study is to identify early symptoms or signs that may be associated with severe coronavirus disease 2019(COVID-19).We conducted a multicentre prospective cohort study on a cohort of patients with COVID-19 in home isolation from March 2020 to April 2021. We assessed longitudinal clinical data (fever, dyspnea, need for hospitalization) through video calls at three specific time points: the beginning of symptoms or the day of the first positivity of the nasopharyngeal swab for SARS-CoV-2-RNA (t0 ), and 3 (t3 ) and 7 (t7 ) days after the onset of symptoms. We included 329 patients with COVID-19: 182 (55.3%) males, mean age 53.4 ± 17.4 years, median Charlson comorbidity index(CCI) of 1 (0-3). Of the 329 patients enrolled, 171 (51.98%) had a mild, 81 (24.6%) a moderate, and 77 (23.4%) a severe illness; 151 (45.9%) were hospitalized. Compared to patients with mild COVID-19, moderate and severe patients were older (p

BackgroundPoly (ADP-ribose) polymerase inhibitors have transformed the management landscape for patients with ovarian cancer, demonstrating remarkable improvements in progression-free survival and overall survival. Unfortunately, most relapses are due to an acquired mechanism of resistance to these agents. We hypothesize that secondary cytoreductive surgery, removing resistant clones, might help to overcome the development of resistance to poly (ADP-ribose) polymerase inhibitors, prolonging their therapeutic effect.Primary ObjectiveTo determine the efficacy of olaparib beyond progression compared with standard platinum-based chemotherapy in patients with recurrent ovarian cancer progressed during or after poly (ADP-ribose) polymerase inhibitor maintenance therapy after secondary cytoreductive surgery.Study HypothesisOlaparib administered beyond progression is more effective in increasing progression-free survival and progression-free survival 2 compared with second-line platinum-based chemotherapy in patients after secondary cytoreductive surgery.Trial DesignPhase III, randomized, open-label, multicenter trial. Eligible patients will be randomized in a 1:1 ratio to receive olaparib or platinum-based chemotherapy of the investigator’s choice.Major Eligibility CriteriaEligible patients must have high-grade serous or endometrioid ovarian cancer progressed during or after first-line poly (ADP-ribose) polymerase inhibitor maintenance therapy and must have undergone secondary cytoreductive surgery.Primary EndpointThe dual primary endpoints will include progression-free survival and progression-free survival 2. Progression-free survival is defined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as the time between randomization and progression or death from any cause. Progression-free survival 2 is defined by the investigator using RECIST version 1.1 as the time frame from randomization to the second progression or death from any cause after subsequent treatment.Sample SizeApproximately 200 patients will be enrolled in this study.Estimated Dates for Completing Accrual and Presenting ResultsEnrollment will be completed in 2024. Results will be presented in 2026.Trial RegistrationEudraCT 2021-000245-41NCT05255471

Aim: Early-stage epithelial ovarian cancer (eEOC) patients have a generally favorable prognosis but unpredictable recurrence. Accurate prediction of risk of relapse is still a major concern, essentially to avoid overtreatment. Our robust tissue-based miRNA signature named MiROvaR, predicting early EOC recurrence in mostly advanced-stage EOC patients, is here challenged in an independent cohort to extend its classifying ability in the early-stage EOC setting. Methods: We retrospectively selected patients who underwent comprehensive surgical staging at our institution including stages from IA to IIB. miRNA expression profile was analysed in 89 cases and MiROvaR algorithm was applied using the previously validated cut-off for patients' classification. The primary endpoint was progression-free survival (PFS) at 5 years. Complete follow-up time (median = 112 months) was also considered as secondary analysis. Results: MiROvaR was assessable on 87 cases (19 events of disease progression) and classified 68 (78%) low-risk and 19 (22%) high-risk patients. Recurrence rate at primary end-point was 39% for high-risk patients as compared to 9.5% for low-risk ones. Accordingly, their Kaplan–Meier PFS curves were significantly different at both primary and secondary analysis (p = 0.0006 and p = 0.03, respectively). While none of the prominent clinical variables had prognostic relevance, MiROvaR significantly predicted disease recurrence at the 5-year assessment (primary endpoint analysis; HR:5.43, 95%CI:1.82–16.1, p = 0.0024; AUC = 0.78, 95%CI:0.53–0.82) and at complete follow-up time (HR:2.67, 95%CI:1.04–6.8, p = 0.041; AUC:0.68, 95%CI:0.52–0.82). Conclusions: We validated MiROvaR performance in identifying at diagnosis eEOC patients' at higher risk of early relapse thus enabling selection of the most effective therapeutic approach.

Background: Left ventricular (LV) diastolic dysfunction is common in non-dialysis chronic kidney disease (ND-CKD) patients; however, the prevalence estimated according to the new diagnostic criteria as well as the prognostic role of diastolic dysfunction on CKD progression remain unknown. Method: We longitudinally evaluated consecutive ND-CKD patients and preserved systolic function (LV ejection fraction > 50%). According to the recently updated guidelines, LV diastolic dysfunction was assessed by four echocardiographic variables (annular e' velocity, average mitral valve E-wave/e' ratio, left atrial volume index and tricuspid regurgitation). Patients were classified as diastolic dysfunction, indeterminate and normal. Time-dependent estimated glomerular filtration rate (eGFR) change was assessed by mixed-effects regression model. Cumulative incidence of composite renal outcome (eGFR decline > 50% or chronic dialysis) was also estimated. Results: Among 140 patients (age 66.2 ± 14.5 years; 61% males; eGFR 39.8 ± 21.8 ml/min per 1.73m2; 43.6% diabetics), diastolic dysfunction occurred in 22.9%, indeterminate in 45.7% and normal in 31.4%. Prevalence of diastolic dysfunction was much lower than that estimated with older criteria (62.7%). Logistic regression (odds ratio, 95% confidence interval [CI]) showed that diastolic dysfunction was associated with lower eGFR (0.97, 0.94-0.99), older age (1.08, 1.01-1.06) and night-time systolic blood pressure (1.04, 1.00-1.07). Across 1702 eGFR measurements collected during a median follow-up of 4.6 years, eGFR decline (ml/min per 1.73m2; per year) was faster in patients with diastolic dysfunction (-2.12, 95% CI from -2.68 to -1.56) and in the indeterminate (11.2/100 pts per year) as compared to normal (-1.14, 95% CI from -1.64 to -0.63). Incidence of composite renal outcome was significantly higher in diastolic dysfunction (13.8/100 pts/year) than in normal group (3.5/100 pts per year)'. Conclusion: In ND-CKD population, LV diastolic dysfunction is less frequent than previously described and acts as independent predictor of CKD progression.

Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P 2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = − 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = − 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. Conclusions The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

Objective To determine the accuracy of interpretation of a non-contrast MRI protocol in characterizing adnexal masses. Methods and materials Two hundred ninety-one patients (350 adnexal masses) who underwent gynecological MRI at our institution between the 1st of January 2008 and the 31st of December 2018 were reviewed. A random subset (102 patients with 121 masses) was chosen to evaluate the reproducibility and repeatability of readers’ assessments. Readers evaluated non-contrast MRI scans retrospectively, assigned a 5-point score for the risk of malignancy and gave a specific diagnosis. The reference standard for the diagnosis was histopathology or at least one-year imaging follow-up. Diagnostic accuracy of the non-contrast MRI score was calculated. Inter- and intra-reader agreement was analyzed with Cohen’s kappa statistics. Results There were 53/350 (15.1%) malignant lesions in the whole cohort and 20/121 (16.5%) malignant lesions in the random subset. Good agreement between readers was found for the non-contrast MRI score (к = 0.73, 95% confidence interval [CI] 0.58–0.86) whilst the intra-reader agreement was excellent (к = 0.81, 95% CI 0.70–0.88). The non-contrast MRI score value of ≥ 4 was associated with malignancy with a sensitivity of 84.9%, a specificity of 95.9%, an accuracy of 94.2% and a positive likelihood ratio of 21 (area under the receiver operating curve 0.93, 95% CI 0.90–0.96). Conclusion Adnexal mass characterization on MRI without the administration of contrast medium has a high accuracy and excellent inter- and intra-reader agreement. Our results suggest that non-contrast studies may offer a reasonable diagnostic alternative when the administration of intravenous contrast medium is not possible. Key Points • A non-contrast pelvic MRI protocol may allow the characterization of adnexal masses with high accuracy. • The non-contrast MRI score may be used in clinical practice for differentiating benign from malignant adnexal lesions when the lack of intravenous contrast medium precludes analysis with the O–RADS MRI score.

Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P Conclusions GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

BackgroundSince COVID-19 was declared a pandemic, attempts have been made to monitor trends over time and to compare countries and regions. Insufficient testing for COVID-19 underestimates the incidence and inflates the case-fatality proportion. Given the age- and sex- distribution of morbidity and mortality from COVID-19, the underlying sex- and age-distribution of a population needs to be accounted for. The aim of this paper is to present a method for monitoring trends of COVID-19 using adjusted mortality trend ratios (AMTR).MethodsAge- and sex-mortality distribution of a reference population composed of the first 14,086 fatalities which occurred before the end of March and were reported in Europe by some countries were used to calculate age- and sex-specific mortality rates per 1,000,000 population. These were applied to each country population to calculate the expected deaths. Adjusted Mortality Trend Ratios (AMTRs) with 95% confidence intervals (C.I.) were calculated for selected European countries from 17/03/2020 to 22/06/2020 by dividing observed cumulative mortality, by expected mortality times the crude mortality of the reference population. These estimated the sex- and age-adjusted mortality for COVID-19 per million population in each country.ResultsThe cumulative mortality from COVID-19, the crude mortality rates, and the AMTRs were calculated for each country and compared. United Kingdom, Italy, France and Spain registered the highest mortality in Europe. On 22/06/2020 in Europe the total mortality rate from COVID-19 was 352 per 1,000,000 inhabitants; and it was highest in Belgium (850 per 1,000,000 inhabitants) followed by Spain, UK, Italy, Sweden and France. When accounting for the underlying age and sex structure of each country, Belgium remained the single country experiencing the highest AMTR of 929 per million inhabitants on 22/06/2020; however Ireland – which had a CMR in line with the total European population – emerged as having experienced a much more important impact of COVID-19 mortality with an AMTR of 550/million on 22/06/2020, higher than Sweden and Italy.ConclusionsIn understanding and managing the pandemic of COVID-19, comparable international data is a priority. Our methods allow a fair comparison of mortality in space and over time. The authors urge the WHO, given the absence of age and sex-specific mortality data for direct standardisation, to adopt this method to estimate the comparative mortality from COVID-19 pandemic worldwide.Key messageComparing trends of the COVID-19 pandemic over time and in space is essential to monitor the disease and compare different local policiesUsing the concept of indirect standardisation we propose a method to effectively compare age- and sex-adjusted mortality rates trends interpretable as deaths for COVID-19 per million inhabitantsApplying this methods, interesting features of the infection in Europe emerged; e.g. by 22/06/2020 Belgium is the most severely affected country with an AMTR of 929 per million inhabitants, followed by the UK; Ireland and Sweden rank fourth and fifth most affected country in EuropeThe WHO should consider using this method for monitoring the spread of COVID-19, which only requires recording the total number of death from COVID-19 from each country/region

Extended right or left hemicolectomy are the most common surgical treatments for splenic flexure colon cancer. Extended resection (including distal pancreasectomy and/or splenectomy), has been often indicated for the treatment for the splenic flexure cancer, because the lymphatic drainage at this site is poorly defined and assumed as heterogeneous. Between January 2006 and May 2016, 103 patients with splenic flexure colon cancer were enrolled in the study. We evaluated the clinicopathological findings and outcomes of all patients and associated them to the different surgical treatment. Out of 103 selected cases an extended right hemicolectomy was performed in 22 (21.4%) patients, an extended left hemicolectomy in 24 (23.3%) patients, a segmental resection of the splenic flexure in 57 (55.3%) patients; the combined resection of adjacent organs showing tumor adherence was carried out in 11 (10.7%) patients. The tumor infiltrated near organs (T4) in 5 patients. No significant differences in complications were found among the three groups. In all groups no differences were found in the total number of harvested lymphnodes. After a median follow-up of 42 months, 30 recurrences and 19 deaths occurred (12 for tumor progression). There was no difference in overall and progression free survival among the three different surgical treatments. According to our results, the partial resection of splenic flexure was not associated with a worse prognosis and it was leading for a satisfactory oncological outcome. It is our opinion that the extended surgery is seldomly indicated to cure splenic flexure cancer.

To evaluate whether pre-emptive skin analgesia using a lidocaine patch 5% would improve the effects of systemic morphine analgesia for controlling acute post-thoracotomy pain. Background: To evaluate whether pre-emptive skin analgesia using a lidocaine patch 5% would improve the effects of systemic morphine analgesia for controlling acute post-thoracotomy pain. Methods: This was a double-blind, placebo controlled, prospective study. Patients were randomly assigned to receive lidocaine 5% patch (lidocaine group) or a placebo (placebo group) three days before thoracotomy. Postoperative analgesia was induced in all cases with intravenous morphine analgesia. The intergroup differences were assessed in order to evaluate whether the lidocaine patch 5% would have effects on pain intensity when at rest and after coughing (primary end-point) on morphine consumption, on the recovery of respiratory function, and on peripheral painful pathways measured with N2 and P2 laser-evoked potential (secondary end-points). Results: A total of 90 patients were randomized, of whom 45 were allocated to the lidocaine group and 45 to the placebo group. Lidocaine compared with the placebo group showed a significant reduction in pain intensity both at rest (P = 0.013) and after coughing (P = 0.015), and in total morphine consumption (P = 0.001); and also showed a better recovery of flow expiratory volume in one second (P = 0.025) and of forced vital capacity (P = 0.037). The placebo group compared with the lidocaine group presented a reduction in amplitude of N2 (P = 0.001) and P2 (P = 0.03), and an increase in the latency of N2 (P = 0.023) and P2 (P = 0.025) laser-evoked potential. Conclusions: The preventive skin analgesia with lidocaine patch 5% seems to be a valid adjunct to intravenous morphine analgesia for controlling post-thoracotomy pain. However, our initial results should be corroborated/confirmed by larger studies.

Background: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. Methods: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). Results: We studied 562 patients (age 66.2 ± 14.5 y, 61% males, eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was “absent” in 50.7%, “resolving” in 15.6%, “new onset” in 16.6%, and “persistent” in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p &lt, 0.0001), K-binders (from 2.0 to 7.7%, p &lt, 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p &lt, 0.001), these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR &lt, 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). Conclusions: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

Breast Implant Associated-Anaplastic Large Cell Lymphoma (BIA-ALCL) is a distinctive type of T-cell lymphoma arising around breast implants. We performed a review of the existing literature with the aim of providing an evidence-based overview of the available data on BIA-ALCL with a standardized evaluation of the quality of the studies and investigating the potential association between textured breast implants and BIA-ALCL.We analyzed the literature reporting estimates of relative or absolute risks of BIA-ALCL in case-control, cohort studies and case series studies. The total number of BIA-ALCL cases reported in literature is very low. Furthermore, most of the reported cases have been reported in case-control studies or case series. This means that our knowledge is based on a low level of evidence. Moreover, low-medium quality scores were observed in the included case series studies. In relation to the rarity of the event, better information could only derived by international cooperation to pool together data deriving from all over the world, with the clear need of better reporting patients and implant characteristics in case series and when adding data to public registries. Level of Evidence IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

We thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution to, and ongoing support of, the EPIC Study. We thank Aude De Bruycker for her graphical support., (1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through foodfrequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association., Research Foundation Flanders (FWO, 189019N), Research Foundation Flanders (FWO, V427019N), International Agency for Research on Cancer (IARC), Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, NIHR Imperial Biomedical Research Center (BRC), Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford), (United Kingdom)

Purpose Endometriosis is a chronic debilitating inflammatory pathology which interests females in their reproductive age. Its pathogenesis has not yet been clearly defined. Recent evidence linked chemical agents as endocrine-disrupting chemicals to endometriosis. Phthalates are a widely used class of such compounds. This study aimed to summarize the current literature evaluating the link between exposure to phthalates and occurrence of endometriosis. Methods A systematic review of literature and meta-analysis has been carried out following PRISMA guidelines to assess such link. Fourteen studies have been included in the review. Risk of bias has been assessed through the Newcastle Ottawa Scale. Results We observed association between endometriosis and increased urinary levels of MBP/MnBP, MEOHP, and MEHHP, but not for others. Blood-derived analysis showed statistically significant link between endometriosis and BBP, DEHP, DnBP, and MEHP. Conclusion Given the wide heterogeneity of included studies, results should be taken with caution. Further studies with more rigorous methodology are encouraged to unravel the true link between this class of toxic compounds and manifestation of endometriosis.

Background It is unknown whether faster progression of chronic kidney disease (CKD) in men than in women relates to differences in ambulatory blood pressure (ABP) levels. Methods We prospectively evaluated 906 hypertensive CKD patients (553 men) regularly followed in renal clinics to compare men versus women in terms of ABP control [daytime Results Age, estimated glomerular filtration rate and use of renin–angiotensin system inhibitors were similar in men and women, while proteinuria was lower in women [0.30 g/24 h interquartile range (IQR) 0.10–1.00 versus 0.42 g/24 h, IQR 0.10–1.28, P = 0.025]. No sex-difference was detected in office BP levels; conversely, daytime and nighttime BP were higher in men (134 ± 17/78 ± 11 and 127 ± 19/70 ± 11 mmHg) than in women (131 ± 16/75 ± 11, P = 0.005/P Conclusions Our study highlights that higher ABP significantly contributes to higher risks of ESKD and mortality in men.

Background Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a “cytokine storm”. IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor. Methods This multicentre study project includes a single-arm phase 2 study and a further parallel cohort, enrolling hospitalized patients with COVID-19 pneumonia and oxygen saturation at rest in ambient air ≤93% or requiring respiratory support. Patients receive tocilizumab 8 mg/kg (up to 800 mg) as one intravenous administration. A second administration (same dose) after 12 h is optional. Two-week and one-month lethality rates are the co-primary endpoints. Sample size planned for the phase 2 study is 330 patients. The parallel cohort will include patients who cannot enter the phase 2 study because being intubated from more than 24 h, or having already received tocilizumab, or the phase 2 study has reached sample size. Primary analysis will include patients enrolled in the phase 2 study. Results of the primary analysis will be validated in the prospective cohort of patients consecutively registered after phase 2 closure from March 20 to March 24, who were potentially eligible for the phase 2 study. Conclusion This trial aims to verify the safety and efficacy of tocilizumab in the Italian population with COVID-19 pneumonia and respiratory impairment. EudraCT Number: 2020–001110-38; Clinicaltrials.gov ID NCT04317092

Background Italy has been the first Western country to be heavily affected by the spread of SARS-COV-2 infection and among the pioneers of the clinical management of pandemic. To improve the outcome, identification of patients at the highest risk seems mandatory. Objectives Aim of this study is to identify comorbidities and clinical conditions upon admission associated with in-hospital mortality in several COVID Centers in Campania Region (Italy). Methods COVOCA is a multicentre retrospective observational cohort study, which involved 18 COVID Centers throughout Campania Region, Italy. Data were collected from patients who completed their hospitalization between March-June 2020. The endpoint was in-hospital mortality, assessed either from data at discharge or death certificate, whilst all exposure variables were collected at hospital admission. Results Among 618 COVID-19 hospitalized patients included in the study, 143 in-hospital mortality events were recorded, with a cumulative incidence of about 23%. At multivariable logistic analysis, male sex (OR 2.63, 95%CI 1.42–4.90; p = 0.001), Chronic Liver Disease (OR 5.88, 95%CI 2.39–14.46; p Conclusion Mortality of patients hospitalized for COVID-19 appears strongly affected by both clinical conditions on admission and comorbidities. Originally, we observed a very poor outcome in subjects with a chronic liver disease, alongside with an increase of hepatic damage.

Background: Area deprivation index (ADI) associates with prognosis in non-dialysis CKD. However, no study has evaluated this association in CKD patients under unrestricted nephrology care. Methods: We performed a long-term prospective study to assess the role of deprivation in CKD progression and mortality in stage 1–4 CKD patients under regular nephrology care, living in Naples (Italy). We used ADI calculated at census block levels, standardized to mean values of whole population in Naples, and linked to patients by georeference method. After 12 months of “goal-oriented” nephrology treatment, we compared the risk of death or composite renal outcomes (end-stage kidney disease or doubling of serum creatinine) in the tertiles of standardized ADI. Estimated glomerular filtration rate (eGFR) decline was evaluated by mixed effects model for repeated eGFR measurements. Results: We enrolled 715 consecutive patients (age: 64 ± 15 years; 59.1% males; eGFR: 49 ± 22 mL/min/1.73 m2). Most (75.2%) were at the lowest national ADI quintile. At referral, demographic, clinical, and therapeutic features were similar across ADI tertiles; after 12 months, treatment intensification allowed better control of hypertension, proteinuria, hypercholesterolaemia, and anaemia with no difference across ADI tertiles. During the subsequent long-term follow-up (10.5 years [interquartile range 8.2–12.6]), 166 renal events and 249 deaths were registered. ADI independently associated with all-cause death (p for trend = 0.020) and non-cardiovascular (CV) mortality (p for trend = 0.045), while CV mortality did not differ (p for trend = 0.252). Risk of composite renal outcomes was similar across ADI tertiles (p for trend = 0.467). The same held true for eGFR decline (p for trend = 0.675). Conclusions: In CKD patients under regular nephrology care, ADI is not associated with CKD progression, while it is associated with all-cause death due to an excess of non-CV mortality.

BACKGROUND: the Covid-19 pandemic has provoked a huge of clinical and epidemiological research initiatives, especially in the most involved countries. However, this very large effort was characterized by several methodological weaknesses, both in the field of discovering effective treatments (with too many small and uncontrolled trials) and in the field of identifying preventable risks and prognostic factors (with too few large, representative and well-designed cohorts orcase-control studies). OBJECTIVES: in response to the fragmented and uncoordinatedresearch production on Covid-19, the italian Association of Epidemiology (AIE) stimulated the formation of a working group (WG) with the aims of identifying the most important gaps in knowledge and to propose a structured research agenda of clinical and epidemiological studies considered at high priority on Covid-19, including recommendations on the preferable methodology. METHODS: the WG was composed by 25 subjects, mainly epidemiologists, statisticians, and other experts in specific fields, who have voluntarily agreed to the proposal. The agreement on a list of main research questions and on the structure of the specific documents to be produced were defined through few meetings and cycles of document exchanges. RESULTS: twelve main research questions on Covid-19 were identified, covering aetiology, prognosis,interventions, follow-up and impact on general and specific populations (children, pregnant women). For each of them, a two-page form was developed, structured in: background, main topics, methods (with recommendations on preferred study design and warnings for bias prevention) and an essential bibliography. CONCLUSIONS: this research agenda represents an initial contribution to direct clinical and epidemiological research efforts on high priority topics with a focus on methodological aspects. Further development and refinements of this agenda by Public Health Authorities are encouraged.

Objective To estimate the three-year cumulative risk of work-related upper limb disorders (WRULDs) in a cohort of automotive industry workers and to provide a first test of the ability of the European Assembly Worksheet (EAWS) methodology to predict WRULDs. Methods 292 workers were investigated by reviewing workers' medical records during the period from 2012-2015 to determine their exposure to biomechanical overload according to EAWS risk scores (0-25, low risk, Green zone; 26-50, medium risk, Yellow zone; >50, High risk; Red zone). Results The risks were 0.83%, 5.71%, and 11.88% for the Control (unexposed), Green and Yellow Groups, respectively. Only the comparison between the Yellow/Control Groups was significant (p = 0.0014). In total, we observed 17 cases of musculoskeletal disorders (MSDs) (14 symptomatic and 3 cases detected by physical examination). Conclusions The EAWS is a useful tool for the preliminary risk assessments of biomechanical overload among automotive industry workers. The finding of mainly non-specific disorders highly suggests that health surveillance should aim to identify not only full-blown diseases but also symptomatic cases.

Introduction Accurate estimates and reliable classification of maternal deaths are imperative steps in the chain of actions targeted at reducing avoidable maternal mortality. The aims of this study were to estimate the maternal mortality ratio (MMR) in 10 Italian regions covering 77% of total national births and to identify the most suitable approach to classify the causes of death. Material and methods Deaths during and within 1 year after pregnancy have been identified through linkage between death registry and hospital discharge database. Regional and national data sources from 2006 to 2012 were used. The MMR has been estimated and deaths were classified as direct or indirect and according to their primary causes. Results A total of 277 maternal deaths within 42 days after pregnancy were identified: 149 direct, 102 indirect causes and 26 unclassified-resulting in a MMR of 9.18 per 100 000 live births. The under-reporting rate of official MMR figures in the participating regions is 60.3%. Hemorrhage (MMR 1.92), hypertensive disorders of pregnancy and cardiac diseases (MMR 1.06) were the leading causes of deaths occurring within 42 days after pregnancy, whereas malignancy (39%) and violent deaths (17%) were the most frequent of the 543 late maternal deaths. Conclusions Record-linkage is an efficient and reliable method to estimate maternal mortality and to identify causes of maternal deaths. Both the indirect/direct and the classification by primary cause have a role in countries where direct deaths exceed indirect maternal mortality. Building upon linkage data, confidential enquiries further increase the likelihood of reducing maternal mortality.

A meta-analysis is presented of randomized controlled trials (RCTs) comparing free or fixed combinations of a glucagon-like peptide-1 receptor agonist plus basal insulin versus insulin intensification on metabolic control in patients with type 2 diabetes. Electronic databases were searched for RCTs assessing changes in HbA1c, proportion of patients at HbA1c target of 71%, P < 0.001). Results did not differ in either the free or fixed combination subgroups. Combination strategies, either free or fixed, represent a good option for intensifying basal insulin therapy in patients with type 2 diabetes who need amelioration of glycaemic control.

Introduction: Thromboembolic complications are due to a complex interplay between patients’ characteristics, device features and anticoagulation intensity. Subtle design and material differences in available prostheses imply different susceptibility to thrombosis. This post hoc sub analysis of the LOWERING-IT database tested the safety and feasibility of a low-level oral anticoagulant regime in low-risk patients with aortic LivaNova prosthetic valve replacement. Methods: Study population included 148 patients randomized to LOW-INR group, and 144 patients randomized to CONVENTIONAL-INR group. The non inferiority of thromboembolic events between LOW-INR and CONVENTIONAL-INR groups was tested. Results: The two groups were well matched. Cumulative follow-up reached 1,545 patient/years. The mean INR was 1.91 ± 0.23 in the LOW-INR group, and 2.59 ± 0.26 in the CONVENTIONAL-INR group (P

No study has assessed whether the prognosis of coexisting diabetes mellitus and chronic kidney disease (DM-CKD) is dictated by DM per se or by the extent of proteinuria.In this pooled analysis of four prospective studies in CKD patients treated with drugs inhibiting the renin-angiotensin system, we compared the risk of all-cause mortality, fatal and non-fatal cardiovascular (CV) events and end-stage renal disease (ESRD) between patients with (n = 693) and without diabetes (n = 1481) stratified by proteinuria level (0.15, 0.15-0.49, 0.5-1 and 1 g/day).The group with DM-CKD was older (69 ± 11 versus 65 ± 15 years), had a higher body mass index (29.6 ± 5.4 versus 27.5 ± 4.8 kg/m2) and systolic blood pressure (143 ± 19 versus 136 ± 18 mmHg), prevalent CV disease (48% versus 29%) and lower estimated glomerular filtration rate (34.5 ± 17.9 versus 36.6 ± 19.0 mL/min/1.73 m2). During 4.07 years of follow-up, there were 466 patients with ESRD, 334 deaths and 401 CV events occurred. In the subgroup with urine protein0.15 g/day (N = 662), the risks of ESRD, CV events and mortality were similar in diabetic and non-diabetic patients. Conversely, in DM-CKD patients, the mortality risk was higher in proteinuric patients {hazard ratio 1.92 [95% confidence interval (CI) 1.25-2.95); 1.99 (1.26-3.15) and 1.98 (1.28-3.06) for proteinuria 0.15-0.49, 0.5-1 and1 g/day, respectively}, whereas in non-diabetics the mortality risk increased only for proteinuria 0.5-1 g/day [HR 1.60 (95% CI 1.07-2.40)] and1 g/day [HR 1.69 (95% CI1.20-2.55)]. In both groups, CV risk had a trend similar to that of mortality. ESRD risk increased progressively across strata0.5 g/day independent of diabetic status.We provide evidence that patients with non-proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, in the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and CV events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes.

Background The risk of death in patients affected by ST-elevation segment myocardial infarction (STEMI) is well known, but more data are required to define the in-hospital mortality in special subsets. We sought to assess the prognostic value of indicators in patients with large anterior STEMI as a first acute coronary event, undergoing percutaneous coronary intervention (PCI) and intra-aortic balloon pump (IABP). Methods and results We evaluated 48 consecutive large anterior STEMI patients admitted as first acute coronary event, undergoing in acute phase both PCI and IABP. Patient demographics, clinical, noninvasive and invasive findings, together with in-hospital complications, were collected. Moreover, findings obtained after a 24-month follow-up were reported. The primary endpoint was in-hospital mortality, whereas the secondary endpoints were out of hospital mortality, rehospitalization for heart failure or reinfarction, and New York Heart Association (NYHA) class at least 2 at follow-up visit. The univariate analysis showed a significant association with symptom to balloon, left anterior descending coronary artery, myocardial blush grade, and wall motion score index. Results of the multivariable analysis revealed the strongest predictive power for in-hospital mortality of proximal left anterior descending coronary artery (odds ratio: 6.9; 95% confidence interval: 1.1-67.7) and of myocardial blush grade 0-1 (odds ratio: 5.5; 95% confidence interval: 1.0-38.8). In-hospital death occurred in 13 patients (27% of total cases), whereas, at follow-up, the mean of survival was 66.7 ± 7.0%. Conclusion The patients with large anterior STEMI as a first acute coronary event, undergoing PCI and IABP, had a very high in-hospital mortality, whereas the mortality rate over the follow-up period was lower. The involvement of a large territory at risk and the ineffective treatment in terms of myocardial reperfusion were the main predictors of in-hospital mortality.

Patients with masticatory muscle pain and migraine typically report that the intensity of pain fluctuates over time and is affected by weather changes. Weather variables, such as ambient temperature and humidity, may vary significantly depending on whether the individual is outdoor or indoor. It is, therefore, important to assess these variables at the individual level using portable monitors, during everyday life. This study aimed to determine and compare the temporal patterns of pain in individuals affected with facial and head pain and to investigate its relation with weather changes. Eleven patients (27·3 ± 7·4 years) with chronic masticatory muscle pain (MP) and twenty (33·1 ± 8·7 years) with migraine headache (MH) were asked to report their current pain level on a visual analogue scale (VAS) every hour over fourteen consecutive days. The VAS scores were collected using portable data-loggers, which were also used to record temperature, atmospheric pressure and relative humidity. VAS scores varied markedly over time in both groups. Pain VAS scores fluctuate less in the MP group than in the MH group, but their mean, minimum and maximum values were higher than those of migraine patients (all PÂ

Background. We evaluated whether cardiac autonomic changes could be associated with different extent of sympathetic nerve resection in the management of essential palmar hyperhidrosis.Methods. Sixty patients with essential palmar hyperhidrosis were randomly allocated to undergo excision of T3 ganglia (sympathicectomygroup; n = 30) or to interruption of sympathetic chain at the T2 to T3 level with ganglion sparing (sympathicotomy group; n = 30). Time and frequency domains were measured with a 24-Holter monitor during daytime, nighttime, and 24-hour periods at different interval points (7 days before operation; 24 hours; and 1, 3, and 6 months later), and the differences were statistically compared. Clinical outcomes were also evaluated.Results. Twenty-eight of 30 patients of the sympathectomy and 29 of 30 patients of the sympathicotomy group completed the study. In both groups, we observed a significant increase (p < 0.05) of vagal activity measurements as root mean square of the successive differences of heart period; proportion of adjacent normal R-R intervals > 50 ms; high frequency; and a significant decrease (p < 0.05) of adrenergic activity variables as heart rate, low frequency, and the ratio between low frequency and high frequency during daytime, nighttime, and 24-hour periods. These changes were significantly more evident (p < 0.05) in the sympathectomy group than in the sympathicotomy group. Clinical outcomes were similar between the two groups.Conclusions. Endoscopic thoracic sympathectomy caused a shift of sympathovagal balance toward parasympathetic tone that seems to be associated with the extent of denervation. (C) 2017 by The Society of Thoracic Surgeons

Medical treatment of advanced colorectal cancer is effective in prolonging the survival of patients. The aim of this study was to describe the most common skin toxicities that occur in those patients, analyzing the association between the type of reaction and the different chemotherapeutic drugs; and to evaluate the importance of an outpatient dermatologic service to improve quality of life.Seventy-two patients with skin reactions from advanced colorectal cancer chemotherapy were included. Each patient underwent physical examination and digital photographic imaging, and completed a quality-of-life questionnaire (Dermatology Life Quality Index [DLQI]).Papulopustular rash was the most common side effect observed. It was statistically associated with EGFRi + irinotecan, EGFRi + FOLFOX, and EGFRi. Xerosis occurred in 50% of patients during EGFRi therapy. Periungual pyogenic granuloma-like lesions occurred in 30% of patients during EGFRi therapy. Our data underline a statistically significant association between capecitabine, FOLFOX + EGFRi, FOLFIFI + EGFRi, and hand-foot syndrome (P .001). Because none of patients treated with EGFRi alone developed this kind of reaction, we suppose that it is associated with the use of 5-fluorouracil. Fifty percent of patients receiving anti-epidermal growth factor receptor (EGFR) therapy developed trichomegaly. These data underline a statistically significant association between these reactions and this specific drug.A dermatologic visit is useful, both for the correct diagnosis of and for the adequate therapy of chemotherapy side effects. The prevention and treatment of these toxicities are important, not only to improve quality of life but also to avoid unnecessary dose reduction or interruption, which can have a negative effect on treatment outcome.

BACKGROUND Continuous glucose monitoring (CGM) provides important information to aid in achieving glycemic targets in people with diabetes. PURPOSE We performed a meta-analysis of randomized controlled trials (RCTs) comparing CGM with usual care for parameters of glycemic control in both type 1 and type 2 diabetes. DATA SOURCES Many electronic databases were searched for articles published from inception until 30 June 2019. STUDY SELECTION We selected RCTs that assessed both changes in HbA1c and time in target range (TIR), together with time below range (TBR), time above range (TAR), and glucose variability expressed as coefficient of variation (CV). DATA EXTRACTION Data were extracted from each trial by two investigators. DATA SYNTHESIS All results were analyzed by a random effects model to calculate the weighted mean difference (WMD) with the 95% CI. We identified 15 RCTs, lasting 12–36 weeks and involving 2,461 patients. Compared with the usual care (overall data), CGM was associated with modest reduction in HbA1c (WMD −0.17%, 95% CI −0.29 to −0.06, I2 = 96.2%), increase in TIR (WMD 70.74 min, 95% CI 46.73–94.76, I2 = 66.3%), and lower TAR, TBR, and CV, with heterogeneity between studies. The increase in TIR was significant and robust independently of diabetes type, method of insulin delivery, and reason for CGM use. In preplanned subgroup analyses, real-time CGM led to the higher improvement in mean HbA1c (WMD −0.23%, 95% CI −0.36 to −0.10, P < 0.001), TIR (WMD 83.49 min, 95% CI 52.68–114.30, P < 0.001), and TAR, whereas both intermittently scanned CGM and sensor-augmented pump were associated with the greater decline in TBR. LIMITATIONS Heterogeneity was high for most of the study outcomes; all studies were sponsored by industry, had short duration, and used an open-label design. CONCLUSIONS CGM improves glycemic control by expanding TIR and decreasing TBR, TAR, and glucose variability in both type 1 and type 2 diabetes.

Introduction: Acne is a common skin disease with important psychosocial impact. Often inadequate compliance affects the efficacy of the therapy. Because of emerging use of mobile and electronic health technology, the recent literature evaluated the helpfulness of the tools in medication adherence. The first goal of our study was to evaluate the adherence to therapy with topical adapalene 0.3%/benzoyl peroxide (A-BPO) 2.5% in different groups of patients who received explicative information supported by different strategies. The second goal was to evaluate the patient’s quality of life and skin parameters. Materials and Methods: We enrolled 126 subjects with mild to severe acne vulgaris. They were randomized into 3 groups of 42 patients each and applied daily topical A-BPO (0.3%, 2.5%) for 12 weeks. The first group (G1) was trained on the gel application by an explicative leaflet. The second group (G2) received the same instructions as group 1 and a daily SMS to remind them of the application of the product. The third group (G3) only received standard instructions. Evaluations were performed at the beginning of treatment (T0) and after 12 weeks (T1): assessment of acne severity using the Investigator’s Global Assessment (IGA) Scale for Acne Severity, quality of life by the Cardiff Acne Disability Index (CADI) and the Patient-Doctor Relationship Depth-of-Relationship Scale (PDRDS), skin pH, grade of hydration and adherence to treatment with a 7-day recall calendar were also measured. Results: After 12 weeks of therapy, we observed a reduction in IGA in all groups confirming the clinical efficacy of the product. In the multiple comparison analysis of IGA score reduction, a significant difference was found in G2 versus G1 and G2 versus G3, while the G1 versus G3 comparison was not statistically significant. However, the leaflet group (G1) showed better results compared to the no-leaflet group (G3). Supporting these data, we observed that adherence days correlated positively with the improvement of the single parameters. Moreover, we observed that SMS and leaflet groups had a greater improvement in quality of life evaluated by CADI and PDRDS scores. Conclusions: According to our data, this experimental setup based on text message service and leaflet service is inexpensive and easy to use. Physicians could consider using these items in their practice to enhance patient adherence and satisfaction as well as treatment outcome.

Rationale & Objective: Data for the association of sex with chronic kidney disease (CKD) progression are conflicting, a relationship this study sought to examine. Study Design: Pooled analysis of 4 Italian observational cohort studies. Setting & Participants: 1,311 older men and 1,024 older women with estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 followed up in renal clinics. Predictor: Sex. Outcomes: End-stage kidney disease (ESKD), defined as maintenance dialysis or kidney transplantation, as the primary outcome; all-cause mortality and eGFR decline as secondary outcomes. Analytical Approach: Cox proportional hazard analysis to estimate the relative risk for ESKD and mortality and linear mixed models to estimate the rate of eGFR decline. Results: Age, systolic blood pressure, and use of renin-angiotensin system inhibitors were similar in men and women. Baseline eGFRs were 27.6 ± 10.2 in men and 26.0 ± 10.6 mL/min/1.73 m2 in women (P < 0.001), while median proteinuria was lower in women (protein excretion, 0.45 [IQR, 0.14-1.10] g/d) compared with men (0.69 [IQR 0.19-1.60] g/d; P < 0.001). During a median follow-up of 4.2 years, 757 developed ESKD (59.4% men) and 471 died (58.4% men). The adjusted risks for ESKD and mortality were higher in men (HRs of 1.50 [95% CI, 1.28-1.77] and 1.30 [95% CI, 1.06-1.60], respectively). This finding was consistent across CKD stages. We observed a significant interaction between sex and proteinuria, with the risk for ESKD in men being significantly greater than for women at a level of proteinuria of ∼0.5 g/d or greater. The slope of decline in eGFR was steeper in men (−2.09; 95% CI, −2.21 to −1.97 mL/min/1.73 m2 per year) than in women (−1.79; 95% CI, −1.92 to −1.66 mL/min/1.73 m2 per year; P < 0.001). Although sex differences in eGFR decline were not different across CKD stages (P = 0.3), the difference in slopes between men and women was progressively larger with proteinuria > 0.5 g/d (P = 0.04). Limitations: Residual confounding; only whites were included. Conclusions: Excess renal risk in men may, at least in part, be related to higher levels of proteinuria in men compared with women.

Cancer may impair sexual function in women. We provide an overview of studies that address Female Sexual Dysfunction (FSD) in women with cancer with a meta-analysis of observational studies that used a validated diagnostic tool. Searches included MEDLINE, Scopus, and Google Scholar for studies published from January 2000 to 31 December 2014. Every included study had to involve at least 30 cancer patients, to investigate FSD based on the Female Sexual Function Index (FSFI), and to have been published in peer-review journals. Duplicate independent data extraction and quality assessment were performed. Data were pooled using a random effects model if statistical heterogeneity was present. The main outcomes were FSFI total score and FSD prevalence. FSFI is a 19-item self-report instrument for assessing key dimensions of female sexual function. A value less than 26.55 is consistent with FSD. Thirty-five studies met the inclusion criteria. Among these, 27 reported FSFI scores, and 16 FSD prevalence. Most studies (56 %) had low to moderate quality. The mean value of FSFI was lower than 20 at all cancer sites: 16.25 (pooled random effect, 95 % CI 14.91-17.58, I (2) = 14.5 %) for colorectal cancer, 18.11 (95 % CI 14.45-21.77, I (2) = 97.8 %) for gynecological cancer, and 19.58 (95 % CI 17.64-21.53, I (2) = 90.9 %) for breast cancer. FSD prevalence was higher than 60 % at all cancer sites, with the highest value for gynecological cancer (78.44 %, 95 % CI 68.36-88.52 %, I (2) = 94.1 %). Women with cancer showed low FSFI scores with a high prevalence of FSD. Cancer may impair sexual function in women. We provide an overview of studies that address Female Sexual Dysfunction (FSD) in women with cancer with a meta-analysis of observational studies that used a validated diagnostic tool. Searches included MEDLINE, Scopus, and Google Scholar for studies published from January 2000 to 31 December 2014. Every included study had to involve at least 30 cancer patients, to investigate FSD based on the Female Sexual Function Index (FSFI), and to have been published in peer-review journals. Duplicate independent data extraction and quality assessment were performed. Data were pooled using a random effects model if statistical heterogeneity was present. The main outcomes were FSFI total score and FSD prevalence. FSFI is a 19-item self-report instrument for assessing key dimensions of female sexual function. A value less than 26.55 is consistent with FSD. Thirty-five studies met the inclusion criteria. Among these, 27 reported FSFI scores, and 16 FSD prevalence. Most studies (56 %) had low to moderate quality. The mean value of FSFI was lower than 20 at all cancer sites: 16.25 (pooled random effect, 95 % CI 14.91–17.58, I2 = 14.5 %) for colorectal cancer, 18.11 (95 % CI 14.45–21.77, I2 = 97.8 %) for gynecological cancer, and 19.58 (95 % CI 17.64–21.53, I2 = 90.9 %) for breast cancer. FSD prevalence was higher than 60 % at all cancer sites, with the highest value for gynecological cancer (78.44 %, 95 % CI 68.36–88.52 %, I2 = 94.1 %). Women with cancer showed low FSFI scores with a high prevalence of FSD.

Objectives: The Frankel manoeuvre is a procedure by which the mandible of Class II individuals is postured forward in dental Class I relationship. The evaluation of the resulting facial profile provides information concerning the components determining the sagittal discrepancy. Data concerning the reproducibility of its assessment are not available. This study aimed to evaluate the intra-observer and inter-observer reproducibility of the assessment of the manoeuvre and to assess whether the amount of clinical experience affects its reproducibility. Methods: Two lateral photographs, one in centric occlusion, and the other with the mandible postured forward (Frankel manoeuvre) of 100 Angle Class II individuals aged between 9 and 13 years were evaluated by six orthodontists (T0). Each examiner was asked whether the facial profile worsen or not with the manoeuvre after being trained by an expert orthodontist. The test was repeated after 2 weeks interval (T1). Intra-observer and inter-observer agreement were evaluated by computing the Cohen’s K . Results: The agreement ( K values) between observations (T0 versus T1) for each examiner ranged from 0.49 to 0.72. The overall agreement was 0.65 [95% confidence interval (CI) = 0.54–0.75]. The agreement in the group with less clinical experience was 0.61 (95% CI = 0.46–0.76), while it was 0.68 (95% CI = 0.53–0.83) in the more experienced group. The amount of clinical experience did not affect intra-observer agreement ( P = 0.50). The overall agreement between the examiners and the trainer was 0.74 (95% CI = 0.65–0.83) and 0.73 (95% CI = 0.64–0.83) at T0 and T1 respectively. Conclusion: The assessment of the Frankel manoeuvre is reproducible and it is not influenced by the amount of clinical experience.

The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]).

Aims: Sodium–glucose cotransporter-2 inhibitors (gliflozins) and statins are oral drugs that may have beneficial cardiovascular effects in patients with type 2 diabetes, especially in those with known cardiovascular disease. We planned a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) that evaluated the effect of gliflozins on MACE risk in patients with T2D stratified by age and by statin use. Methods: The electronic search was carried out until 20 January 2020. RCTs were included if they were CVOTs performed in adults with T2D, compared add-on therapy with any gliflozin versus placebo, and had major cardiovascular events (MACE) as primary outcome. We limited the evaluation to MACE in order to minimize the statistical impact of post-hoc analyses. We used a random-effect model to calculate hazard ratio (HR) and 95% CI. Results: The hazard ratio for MACE was 0.95 (95% CI, 0.86–1.05) in people

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

BACKGROUND Psoriasis is one of the most common inflammatory skin diseases. There seem to be an increasing interest in childhood psoriasis in recent years. METHODS We conducted a survey among pediatricians in Italy. 50 pediatricians from different areas in Italy (north, center and south) were invited to participate, 37 were responding and active in data collection. Doctors were asked to review their databases and to fill a form providing a series of information about all patients diagnosed with psoriasis attending their ambulatory. RESULTS The total number of patients referring to the responding doctors was 28086. Of these, 66 were diagnosed with psoriasis. Mean age was 5.7, (6.3 in males and 5.1 in females). The majority of patients presented plaque psoriasis (N.=44; 66.7%), followed by inverse (N.=9; 13.6%), and guttate psoriasis (N.=7; 10.6%). The main site of presentation was the trunk (51.5%), followed by scalp (15.2%) and napkin area (12.1%). Fifteen patients presented nail psoriasis (22.7%). In the majority of cases no family history was reported (83.3%), first degree relatives presented psoriatic lesions in only 7 cases (10.6%). The comorbidity most frequently reported was overweight (N.=16, 25.4%), followed by atopic dermatitis (N.=12; 18.2%). Differences in the main pattern of presentation were found between male and female patients, in particular, a plaque type psoriasis was more frequent in males (79.4% vs. 53.1%; P=0.048). Female patients presented psoriasis of the napkin area more frequently than males (21.9% vs. 2.9%, P=0.025). CONCLUSIONS Peculiar pattern of presentation can be detected in childhood psoriasis. Further studies are needed to validate these findings.

International Guidelines for mineral bone disorders recommend that in Non Dialytic-Chronic Kidney Disease (ND-CKD) clinical decisions should be based on the trend of serum PTH changes over time rather than on a single value. However, the prognostic impact of these changes in ND-CKD patients remains unknown. We performed a multicenter cohort study in ND-CKD patients (stage 1-5) followed for 36 months in 24 Italian Nephrology Units. PTH changes (ΔPTH) were defined as the absolute differences between all available PTH measurements following the first control and basal value. Primary endpoint in this subanalysis was renal death (End-Stage Renal Disease (ESRD) or all-causes death before ESRD). Association between renal death and ΔPTH was assessed by time-dependent Cox model for repeated measurements. Out of the original cohort (N = 884), we selected 543 patients (66.3±15.4 ys, 58.4% males) with at least two serum PTH measurements. At baseline, eGFR was 36 (IQR: 22.4-56.8) mL/min/1.73m2 and serum PTH 46 (IQR: 28-81) pg/mL. ΔPTH was in median 0 (IQR:-18/18) pg/mL. Basal predictors of longitudinal PTH increments were higher serum phosphate, more advanced CKD stages and lower serum PTH. Fully adjusted Cox model with ΔPTH quartiles as discrete time-dependent covariate showed a significant risk of renal death in the highest quartile (HR: 1.91; 95%CI:1.08-3.38; P = 0.026). Considering ΔPTH, as continuous time-dependent variable, (HR:1.02; 95%C.I.: 1.01-1.04; P = 0.004), risk of renal death progressively rose as ΔPTH increased. An increment in serum PTH over time is associated with a worse prognosis in ND-CKD patients, independently from baseline or any absolute concentration of serum PTH and phosphate.

Background. A clear evidence on the benefits of reducing salt in people with chronic kidney disease (CKD) is still lacking. Salt restriction in CKD may allow better control of blood pressure (BP) as shown in a previous systematic review while the effect on proteinuria reduction remains poorly investigated. Methods. We performed a meta-analysis of randomized controlled trials (RCTs) evaluating the effects of low versus high salt intake in adult patients with non-dialysis CKD on change in BP, proteinuria and albuminuria. Results. Eleven RCTs were selected and included information about 738 CKD patients (Stage 1–4); urinary sodium excretion was 104 mEq/day (95%CI, 76–131) and 179 mEq/day (95%CI, 165–193) in low- and high-sodium intake subgroups, respectively, with a mean difference of −80 mEq/day (95%CI from −107 to −53; p

BACKGROUND: Genotype has been implicated in the outcome of ovarian stimulation. The analysis of patient-specific genotypes might lead to an individualized pharmacogenomic approach to controlled ovarian stimulation (COS). However, the validity of such an approach remains to be established.OBJECTIVE AND RATIONALE: To define the impact of specific genotype profiles of follicle-stimulating hormone, luteinizing hormone and their receptors (FSHR, LHR and LHCGR) on ovarian stimulation outcome. Specifically, our aim was to identify polymorphisms that could be useful in clinical practice, and those that need further clinical investigation.SEARCH METHODS: A systematic review followed by a meta-analysis was performed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines without time restriction. We searched the PubMed/MEDLINE, Cochrane Library, SCOPUS and EMBASE databases to identify all relevant studies published before January 2017. Only clinical trials published as full-text articles in peer-reviewed journals were included. The primary outcome was the number of oocytes retrieved.OUTCOMES: Fifty-seven studies were assessed for eligibility, 33 of which were included in the qualitative and quantitative analyses. Data were independently extracted using quality indicators. COS outcomes related to seven polymorphisms (FSHR [rs6165], FSHR [rs6166], FSHR [rs1394205], LHB [rs1800447], LHB [rs1056917], LHCGR [rs2293275] and LHCGR [rs13405728]) were evaluated. More oocytes were retrieved from FSHR (rs6165) AA homozygotes (five studies, 677 patients, weighted mean difference [WMD]: 1.85, 95% CI: 0.85-2.85, P < 0.001; I2 = 0%) than from GG homozygotes and AG heterozygotes (four studies, 630 patients, WMD: 1.62, 95% CI: 0.28-2.95, P = 0.020; I2 = 56%). Moreover, stimulation duration was shorter in FSHR (rs6165) AA homozygotes than in AG carriers (three studies, 588 patients, WMD -0.48, 95% CI: -0.87 to -0.10, P = 0.010, I2 = 44%). A higher number of oocytes (21 studies, 2632 patients WMD: 0.84, 95% CI: 0.19 to 1.49, P = 0.01, I2 = 76%) and metaphase II oocytes (five studies, 608 patients, WMD: 1.03, 95% CI: 0.01-2.05, P = 0.050, I2 = 0%) was observed in AA than in GG homozygote carriers. FSH consumption was significantly lower in FSHR (rs1394205) GG homozygotes (three studies, 411 patients, WMD: -1294.61 IU, 95% CI: -593.08 to -1996.14 IU, P = 0.0003, I2 = 99%) and AG heterozygotes (three studies, 367 patients, WMD: -1014.36 IU, 95% CI: -364.11 to -1664.61 IU, P = 0.002, I2 = 99%) than in AA homozygotes.WIDER IMPLICATIONS: These results support the clinical relevance of specific genotype profiles on reproductive outcome. Further studies are required to determine their application in a pharmacogenomic approach to ovarian stimulation.

Background: Type 1 diabetic patients have high instability of daily glucose levels. The aim of this study was to evaluate the long-term effects of continuous subcutaneous insulin infusion (CSII) therapy, compared with multiple daily injections of insulin (MDI), on glucose variability, in young type 1 diabetic patients transitioned to the adult diabetes care. Methods: Patients aged 18-30 years and considered eligible for insulin pump therapy were included in the study. Ninety-eight patients who started CSII therapy and 125 who remained in MDI completed a 2-year follow-up. Glucose variability was assessed with continuous glucose monitoring using blood glucose standard deviation (BGSD), mean amplitude of glycemic excursion (MAGE), continuous overall net glycemic action (CONGA-2 h), low blood glucose index, high blood glucose index, and average daily risk range. Results: MAGE and BGSD decreased in both groups, with adjusted differences at 2 years of -0.74 mM (95% confidence interval [CI] -1.22 to -0.26, P = 0.003) and -0.3 (CI -0.52 to -0.1, P = 0.005) favoring the pump-therapy group. No significant differences between groups in the other variability indexes were observed. HbA1c decreased in both groups without significant difference (0.05%, -0.26, 0.35, P = 0.77); fasting glucose, insulin dose, and overall hypoglycemia (daily, nocturnal, and severe) decreased more in patients with CSII, compared with those with MDI. Conclusions: Among young adults with type 1 diabetes transitioning from the pediatric care, the use of CSII is associated with lower glucose variability, fasting glycemia, and overall hypoglycemic events than MDI during a 2-year period of follow-up.

In nondialysis chronic kidney disease, ambulatory blood pressure (ABP) performs better than clinic BP in predicting outcome, but whether repeated assessment of ABP further refines prognosis remains ill-defined. We recruited 182 consecutive hypertensive patients with nondialysis chronic kidney disease who underwent 2 ABPs 12 months apart to evaluate the enhancement in risk stratification provided by a second ABP obtained 1 year after baseline on the risk (hazard ratio and 95% confidence interval) of composite renal end point (death, chronic dialysis, and estimated glomerular filtration rate decline ≥40%). The difference in daytime and nighttime systolic BP between the 2 ABPs (daytime and nighttime bias) was added to a survival model including baseline ABP. Net reclassification improvement was also calculated. Age was 65.6±13.4 years; 36% had diabetes mellitus and 36% had previous cardiovascular event; estimated glomerular filtration rate was 42.2±19.6 mL/min per 1.73 m 2 , and clinic BP was 145±18/80±11 mm Hg. Baseline ABP (daytime, 131±16/75±10 and nighttime, 122±18/66±10 mm Hg) and daytime/nighttime BP goals (58.2% and 43.4%) did not change at month 12. Besides baseline ABP values, bias for daytime and nighttime systolic BP linearly associated with renal outcome (1.12, 1.04–1.21 and 1.18, 1.08–1.29 for every 5-mm Hg increase, respectively). Classification of patients at risk improved when considering nighttime systolic level at second ABP (net reclassification improvement, 0.224; 95% confidence interval, 0.005–0.435). Patients with first and second ABPs above target showed greater renal risk (2.15, 1.29–3.59 and 1.71, 1.07–2.72, for daytime and nighttime, respectively). In nondialysis chronic kidney disease, reassessment of ABP at 1 year further refines renal prognosis; such reassessment should specifically be considered in patients with uncontrolled BP at baseline.

OBJECTIVES: To evaluate if the pre-emptive administration of ketamine would potentiate the effect of intravenous morphine analgesia in the management of post-thoracotomy pain. METHODS: This was a unicentre, double-blind, placebo-controlled, parallel-group, prospective study. Patients were randomly assigned to receive 1 mg/kg ketamine (ketamine group) or an equivalent dose of normal saline (placebo group) before thoracotomy in 1:1 ratio. All patients received postoperatively intravenous morphine administration as additional analgesic regimen. Primary end-point was the pain relief measured with Visual Analogue Scale at rest. The secondary end-points were the reduction of inflammatory response expressed by plasma C-reactive protein levels, the morphine consumption and the rate of side effects. The measurements were carried out 6, 12, 24, 36 and 48 hours postoperatively. RESULTS: A total of 75 patients were randomized of whom 38 were allocated to ketamine group and 37 to placebo group. Baseline characteristics were comparable. Ketamine compared with placebo group showed a significant reduction of pain scores (P= 0.01), C-reactive protein (P< 0.001) and morphine consumption (P< 0.001). No acute psychological side effects related to the use of ketamine were registered. CONCLUSIONS: The administration of ketamine before surgery may be an effective adjunct to intravenous morphine analgesia in acute post-thoracotomy pain management. In ketamine group, satisfaction of pain relief was significantly higher with a significant reduction of inflammatory response and morphine consumption compared with placebo group. Our results, if confirmed by larger studies, may be of clinical relevance in situations where epidural analgesia or other analgesic procedures different from systemic opioid analgesia are unavailable or contraindicated.

Background To evaluate the incidence, predictors, and survival of unexpected pN2 disease in patients with clinical stage I non-small cell lung cancer. Methods This is a retrospective observational multicenter study on all consecutive patients operated for clinical stage I non-small cell lung cancer from January 2006 to December 2012. Medical records were reviewed to investigate the incidence and risk factors for unexpected pN2 disease. Then, the survival of patients with unexpected pN2 disease was statistically compared with that of patients with clinical N2 disease operated after induction therapy in the same period. Results Our study population counted 901 patients. An incidence of 12% (108/901) unexpected pN2 disease was found. Among 3,389 lymph nodes sampled, 124 distinct metastases were found. Of the 108 patients, 92 (85%) had metastases in single N2 station and 16 (15%) patients had disease in multiple N2 stations; 47 (44%) had pN2 disease without pN1 involvement (skip metastases) and 61/108 (56%) had also pN1 metastases. Factors associated with unexpected pN2 disease were central tumor location (p 4.0 (0.007). Patients with pN2 disease compared with patients with cN2 disease presented a better median overall survival (56 versus 20 months; p = 0.001) and disease-free survival (46 versus 11 months; p

Background: We investigated the effect of having clinic and/or ambulatory blood pressures (BPs) not at goal on cardiorenal risk in patients with non-dialysis-dependent chronic kidney disease (CKD). Study Design: Multicenter prospective study. Setting & Participants: 489 consecutive hypertensive patients with CKD (stages 1-5) with concomitant assessment of ambulatory and clinic BPs followed up in tertiary nephrology clinics. Predictors: Achievement of goal for ambulatory (day- and night-time BPs < 135/85 and < 120/70 mm Hg, respectively) and clinic (

Background: In hemodialysis (HD), switching from erythropoiesis-stimulating agent (ESA) originators to biosimilars is associated with the need for doses approximately 10% higher, according to industry-driven studies. Objective: The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice. Methods: We retrospectively selected consecutive HD patients receiving stable intravenous ESA doses, and who had not been transfused in the previous 6 months, from 12 non-profit Italian centers. Patients switched from originators to biosimilars (n = 163) were matched with those maintained on ESA originators (n = 163) using a propensity score approach. The study duration was 24 weeks, and the primary endpoint was the mean dose difference (MDD), defined as the difference between the switch and control groups of ESA dose changes during the study (time-weighted average ESA dose minus baseline ESA dose). Results: Age (70 ± 13 years), male sex (63%), diabetes (29%), history of cardiovascular disease (40%), body weight (68 ± 14 kg), vascular access (86% arteriovenous fistula), hemoglobin [Hb] (11.2 ± 0.9 g/dL) and ESA dose (8504 ± 6370 IU/week) were similar in the two groups. Hb remained unchanged during the study in both groups. Conversely, ESA dose remained unchanged in the control group and progressively increased in the switch group from week 8 to 24. The time-weighted average of the ESA dose was higher in the switch group than in the control group (10,503 ± 7389 vs. 7981 ± 5858 IU/week; p = 0.001), leading to a significant MDD of 2423 IU/week (95% confidence interval [CI] 1615–3321), corresponding to a 39.6% (95% CI 24.7–54.6) higher dose of biosimilars compared with originators. The time-weighted average of Hb was 0.2 g/dL lower in the switch group, with a more frequent ESA hyporesponsiveness (14.7 vs. 2.5%). Iron parameters and other resistance factors remained unchanged. Conclusions: In stable dialysis patients, switching from ESA originators to biosimilars requires 40% higher doses to maintain anemia control.

CKD patients with low-grade proteinuria (LP) are common in nephrology clinics. However, prevalence, characteristics, and the competing risks of ESRD and death as the specific determinants, are still unknown. We analyzed epidemiological features of LP status in a prospective cohort of 2,340 patients with CKD stage III-V referred from ≥6 months in 40 nephrology clinics in Italy. LP status was defined as proteinuria - ESRD; P = 0.002) versus CON (ESRD>death; P

Objectives: The effect of modifiable stroke risk factors in terms of prevented cases remains unclear due to sex-specific disease rate and risk factors prevalence. Our aim was to estimate their impact on stroke by gender through population-attributable fraction (PAF), preventive fraction (PF) and their combination in EPIC-Italian cohort. Methods: 43,976 participants, age 34–75, and free of cardiovascular disease at baseline (1993–1998) were followed up for almost 11 years. Adjusted hazard ratios and PAF were estimated using Cox models. Results: We identified 386 cases. In males, the burden for stroke was 17% (95% CI 4–28%) for smoking and 14% (95% CI 5–22%) for alcohol consumption. In females, hypertension was carrying the biggest burden with 18% (95% CI 9–26%) followed by smoking 15% (95% CI 7–22%). Their combination was 46% (95% CI 32–58%) in males and 48% (95% CI 35–59%) in females. PF for current smokers was gender unequal [males 21% (95% CI 15–27%) females 9% (95% CI 1–17%)]. Conclusions: Half of strokes are attributable to potentially modifiable factors. The proportion of prevented cases is gender unbalanced, encouraging sex-specific intervention.

BACKGROUND Very low-protein intake during chronic kidney disease (CKD) improves metabolic disorders and may delay dialysis start without compromising nutritional status, but concerns have been raised on a possible negative effect on survival during dialysis. This study aimed at evaluating whether a very low-protein diet during CKD is associated with a greater risk of death while on dialysis treatment. METHODS This is an historical, cohort, controlled study, enrolling patients at dialysis start previously treated in a tertiary nephrology clinic with a very low-protein diet supplemented with amino acids and ketoacids (s-VLPD group, n = 184) or without s-VLPD [tertiary nephrology care (TNC) group, n = 334] and unselected patients [control (CON) group, n = 9.092]. The major outcome was survival rate during end-stage renal disease associated to s-VLPD treatment during CKD. The propensity score methods and Cox regression model were used to match groups at the start of dialysis to perform survival analysis and estimate adjusted hazard ratio (HR). RESULTS In s-VLPD, TNC and CON groups, average age was 67.5, 66.0 and 66.3 years, respectively (P = 0.521) and male prevalence was 55, 55 and 62%, respectively (P = 0.004). Diabetes prevalence differed in the three groups (P < 0.001), being 18, 17 and 31% in s-VLPD, CON and TNC, respectively. A different prevalence of cardiovascular (CV) disease was found (P < 0.001), being similar in TNC and CON (31 and 25%) and higher in s-VLPD (41%). Median follow-up during renal replacement therapy (RRT) was 36, 32 and 36 months in the three groups. Adjusted HR estimated on matched propensity patients was 0.59 (0.45-0.78) for s-VLPD versus CON. Subgroup analysis showed a lower mortality risk in s-VLPD versus matched-CON in younger patients (