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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.

Introduction: Progastrin-releasing peptide (proGRP), a precursor of GRP, has been recently reported as a putative circulating biomarker for differential diagnosis between non–small cell lung cancer (NSCLC) and SCLC. We evaluated the diagnostic effectiveness of proGRP to differentiate patients with NSCLC and SCLC and the usefulness of combined measurement of proGRP and neuron-specific enolase (NSE) for diagnosing SCLC. Methods: Serum proGRP, NSE, cytokeratin 19 fragment 21-1 (CYFRA 21.1), squamous cell carcinoma antigen (SCC Ag) and carcinoembryonic antigen (CEA) were prospectively collected and measured in patients with a new diagnosis of lung cancer. Serum proGRP was also measured in healthy subjects. The serum proGRP, NSE, CYFRA 21.1 and CEA concentrations were determined by an electrochemiluminescence immunoassay and the serum SCC Ag concentration was determined by an automated immunofluorescence assay. Differences between proGRP and NSE in patients with SCLC and NSCLC were evaluated and compared using Mann-Whitney test. Results: A total of 77 patients affected by SCLC (n = 17) and NSCLC (n = 60) were enrolled in the present study. Moreover, 50 cases of healthy subjects were analyzed for proGRP. SCLC patients showed a significantly higher proGRP (1,484 pg/mL; range 168-3,777) levels compared to NSCLC patients (45 pg/mL; range 31.7-60.6), p

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.

The incidence of cutaneous melanoma has been increasing over the past few decades. The introduction of dermoscopy has enriched the diagnostic armamentarium of dermatologists improving diagnostic accuracy. The involvement of General Practitioners (GPs) and the use of telemedicine systems could constitute a new resource to make available early diagnosis to a larger population and to rationalize health resources in favor of patients at high risk of developing skin tumors. Aims: Primary aim of this study is to assess the feasibility of a “hub and spoke” model for the cooperation between high-specialty hospital units and GPs, using a new online teledermatology platform (I3DermoscopyApp®), that recently has been proved as a valid semiautomatic diagnostic image-based measurement system. Secondary aim is to evaluate the reliability of this semiautomatic diagnostic system in a clinical model of real life. Methods: An observational cross-sectional study using a “hub and spoke” model, was conducted at Dermatology Unit of Department of Clinical Medicine and Surgery of University Federico II of Naples. GPs and dermatologists were involved in this study after a demormoscopy traninig. Results: The system proved to be reliable in the triage phase and useful in the rationalization of highly specialized medical resources. Comparing patients diagnosed with malignant skin tumors through teledermoscopy system with patients with the same skin lesions of our department not participating to the study, we noticed that latency time between diagnosis and surgical excision were significantly decreased demonstrating the reliability of this semiautomatic diagnostic system in a clinical model of real life. Discussion: This study demonstrating the feasibility of a hub and spoke system based on a teledermatology cooperation between GPs and dermoscopy trained dermatologists. The use of teledermoscopy improves the ability of GPs selecting lesions suggestive of skin cancer without increasing the number of unnecessary expert consultations.

Background The relation of dairy product consumption to health and mortality is controversial. Objectives We investigated associations of consumption of various dairy products with mortality in the Italian cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Italy study. Methods Dairy product consumption was assessed by validated semiquantitative FFQs. Multivariable Cox models stratified by center, age, and sex and adjusted for confounders estimated associations of milk (total, full fat, and reduced fat), yogurt, cheese, butter, and dairy calcium consumption with mortality for cancer, cardiovascular disease, and all causes. Nonlinearity was tested by restricted cubic spline regression. Results After a median follow-up of 14.9 y, 2468 deaths were identified in 45,009 participants: 59% from cancer and 19% from cardiovascular disease. No significant association of consumption of any dairy product with mortality was found in the fully adjusted models. A 25% reduction in risk of all-cause mortality was found for milk intake from 160 to 120 g/d (HR: 0.75; 95% CI: 0.61, 0.91) but not for the highest (>200 g/d) category of intake (HR: 0.95; 95% CI: 0.84, 1.08) compared with nonconsumption. Associations of full-fat and reduced-fat milk consumption with all-cause and cause-specific mortality were similar to those for milk as a whole. Conclusions In this Italian cohort characterized by low to average milk consumption, we found no evidence of a dose-response association between milk consumption and mortality and also no association of consumption of other dairy products investigated with mortality.

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.

Background Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients’ selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. Methods/design CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses’ duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients’ cetuximab-mediated ADCC and characterize the tumor microenvironment. Discussion The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results’ interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. Trial registration The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number (NCT03874062).

A meta-analysis of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta-analysis of available trial data was undertaken, using a random-effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP-1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80-0.96; P = 0.011) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP-1RA also reduced the risk of cardiovascular death by 12%, of non-fatal stroke by 16%, of hospitalization for heart failure by 9%, of all-cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68-0.86]; P = 0.003). GLP-1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease.

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.

Simple Summary Epithelial ovarian cancers (EOC) have an unpredictable frequent recurrence often associated with incurable chemo-resistant disease. Basing on the miRNA expression profile of 892 EOC patients, we previously developed a 35 miRNA-based classifier, MiROvaR, able to predict EOC risk of early relapse. Further independent analysis of prediction accuracy represents a crucial step in the test-validation phase. Here we exploited an external and independently collected, handled and profiled EOC cohort, to challenge MirovaR accuracy. Our analysis confirmed the MiROvaR prognostic power, thus opening the way to its prospective validation as a clinical grade assay entering into clinical practice to help in the refinement of therapeutic intervention for high risk EOC patients. Abstract Epithelial ovarian cancer (EOC) remains the second most common cause of gynecological cancer deaths. To improve patients’ outcomes, we still need reliable biomarkers of early relapse, of which external independent validation is a crucial process. Our previously established prognostic signature, MiROvaR, including 35 microRNAs (miRNA) able to stratify EOC patients for their risk of relapse, was challenged on a new independent cohort of 197 EOC patients included in the Pelvic Mass Study whose miRNA profile was made publically available, thus resulting in the only accessible database aside from the EOC TCGA collection. Following accurate data matrix adjustment to account for the use of different miRNA platforms, MiROvaR confirmed its ability to discriminate early relapsing patients. The model’s original cutoff separated 156 (79.2%) high- and 41 (20.8%) low-risk patients with median progression free survival (PFS) of 16.3 months and not yet reached (NYR), respectively (hazard ratio (HR): 2.42–95% Confidence Interval (CI) 1.49–3.93; Log-rank p = 0.00024). The MiROvaR predictive accuracy (area under the curve (AUC) = 0.68; 95% Cl 0.57–0.79) confirms its prognostic value. This external validation in a totally independently collected, handled and profiled EOC cohort suggests that MiROvaR is a strong and reliable biomarker of EOC early relapse, warranting prospective validation.

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)

Simple Summary The possibility to identify, with appropriate biomarkers, patients that might mostly benefit from any given treatment is the basis of personalized oncology. Cancer biomarkers should be properly identified and validated on a large number of patients possibly enrolled in dedicated clinical trials. Here, we report the first molecular results of the MITO16A-ManGo-OV2 phase IV trial that was specifically designed to identify prognostic biomarkers of survival in epithelial ovarian cancer patients treated in first line with carboplatin-paclitaxel plus Bevacizumab (NCT01706120), a treatment for which validated predictive or prognostic biomarkers are still lacking. With this work we propose not only novel possible biomarkers for Bevacizumab-treated patients but also a way through which they can be properly collected, analyzed and statistically evaluated in the frame of large multicenter clinical trials. Abstract Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients’ survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.

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.

Objectives A growing amount of evidence suggests that the rifampicin dosing currently recommended for tuberculosis treatment could be associated with inadequate exposure and unfavourable outcomes. We aimed to compare clinical and microbiological efficacy and safety outcomes of standard and higher rifampicin dosing. Methods Data sources were MEDLINE, Google Scholar and the Cochrane Library. This was a systematic review and meta-analysis that included experimental or observational studies comparing 8-week sputum culture conversion, treatment failure, or safety outcomes in naive patients with pulmonary tuberculosis treated with standard (10 mg/kg) or higher doses of rifampicin. Results Of a total of 9683 citations screened, eight randomized controlled trials were included, accounting for 1897 subjects; the risk of bias was low in three studies, high in two and intermediate in three. At week 8 a higher proportion of patients in the high-dose group obtained a sputum culture conversion than those in the standard dose group (83.7% versus 80.6%, RR 1.06; 95%CI 1.01–1.12, p 0.028); this result was confirmed in the sub-analysis including patients treated with a rifampicin dose of ≥20 mg/kg, but not in those treated with 11–19 mg/kg. Events of treatment failure at end of treatment showed no significant difference between the two groups (RR 0.84; 95%CI 0.59–1.21, p 0.362). In the analysis evaluating safety outcome, the difference in the occurrence of a grade 3 or 4 liver toxicity or adverse drug reactions leading to discontinuation was not significant at the statistical analysis among the groups (7.2% versus 5.4%, RR 1.19; 95%CI 0.81–1.73, p 0.370, and 1.5% versus 0.6%, RR 2.31; 95%CI 0.65–8.21, p 0.195, respectively). No statistical heterogeneity among studies was observed for each outcome. Conclusions High doses of rifampicin were associated with an increased rate of sputum culture conversion at 8 weeks of treatment, particularly in patients receiving ≥20 mg/kg.

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.

Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.

BackgroundTocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients.MethodsA multicentre, single-arm, hypothesis-driven phase 2 trial was planned to study the effect of Tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints). A cohort of patients consecutively enrolled after phase 2 was used as a validation dataset. A multivariable logistic regression was performed to generate hypotheses, while controlling for possible confounders.Resultsout of 301 patients in phase 2 intention-to-treat (ITT) analysis, 180 (59.8%) received tocilizumab. With 67 death events, lethality rates were 18.4% (97.5%CI: 13.6-24.0, P=0.52) and 22.4% (97.5%CI: 17.2-28.3, PConclusionsTocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Such result support the use of tocilizumab while waiting for ongoing phase 3 trials.RegistrationEudraCT (2020-001110-38);clinicaltrials.gov(NCT04317092)

Cardiovascular outcome trials (CVOTs) have demonstrated a significant reduction of major adverse cardiovascular events (MACE) in patients with type 2 diabetes (T2D) treated by SGLT-2 inhibitors. This holds true in the presence of background therapy with statins in most patients. Noteworthy, this SGLT-2 inhibitors effect is unique because, at variance with other components of cardiorenal protection, MACE prevention does not appear to be a class effect. Here, we present meta-analysis of the four key CVOTs indicating a major role of renal function in determining the extent of MACE prevention, with the benefit increasing in more severe kidney disease, that is, a high-risk condition where effectiveness of the traditional approach with statins is reduced.

Aim In order to disclose relations between reduction of haemoglobin A1c (HbA1c) levels and risk of major cardiovascular events (MACE), we performed a meta-analysis with metaregression of all cardiovascular outcome trials (CVOTs) so far published in patients with type 2 diabetes (T2D).Materials and Methods An electronic search up to February 10, 2020 was conducted to determine eligible trials. 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 15 CVOTs included evaluated 138,250 patients. In the pooled analysis, the risk of MACE was significantly reduced by 9% (hazard ratio, HR = 0.91, 0.87-0.95, P

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 and Purpose— The purpose of this study was to conduct a meta-analysis of CVOTs (cardiovascular outcome trials) to evaluate the effect of glucagon-like peptide-1 receptor agonists therapy in reducing the risk of stroke in patients with type 2 diabetes mellitus. Methods— PubMed and other electronic sources were searched until June 20, 2019, to identify relevant studies. Hazard ratios with 95% CIs were used as a measure of the association between use of glucagon-like peptide-1 receptor agonists and risk of stroke after pooling data across trials. Results— Seven CVOTs with 56 004 participants were identified. Use of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus was associated with 15% lower risk of nonfatal stroke ( P =0.002), 19% lower risk of fatal stroke ( P =0.150), and 16% lower risk of total stroke ( P =0.001). There was no association between reductions of hemoglobin A1c levels or body weight and risk of stroke. Conclusions— Glucagon-like peptide-1 receptor agonists reduce the risk of nonfatal stroke in patients with T2D.

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 Spontaneous bacterial peritonitis (SBP) is a common complication among cirrhotic patients. Guidelines recommend third-generation cephalosporins (3GCs) as empiric antibiotic therapy (EAT) of SBP. Recently, a broad-spectrum EAT was shown to be more effective than cephalosporins in the treatment of nosocomial spontaneous bacterial peritonitis (N-SBP); however, the prevalence of 3GCs-resistant bacteria is high in the nosocomial setting and broad-spectrum EAT cannot be used in all cases of SBP. Aim The aim of this study was to evaluate the 3GCs resistance distribution between N-SBP and community-Acquired spontaneous bacterial peritonitis (CA-SBP) to clarify whether 3GCs are still an effective therapeutic intervention for CA-SBP. Methods We searched for studies that reported the aetiology of SBP and the resistance profile of both gram-positive and gram-negative bacteria in MEDLINE and Google Scholar databases (since 1 January 2000 to 30 April 2017). A meta-Analysis was carried out to estimate the risk difference [relative risk (RR) and 95% confidence intervals (CIs)] for 3GCs resistance in N-SBP and CA-SBP. Heterogeneity was assessed using the I 2-test. Results A total of eight studies were included, including 1074 positive cultures of ascitic fluid in cirrhotic patients; 462 positive cultures were from N-SBP and, among these, 251 (54.3%) were 3GCs resistant. Six hundred and twelve positive cultures were from CA-SBP and, among these, 207 (33.8%) were 3GCs-resistant SBP. A pooled RR of 3GCs resistance in N-SBP compared with CA-SBP showed a significant difference (RR=1.67, 95% CI: 1.14-2.44; P=0.008). We carried out two subgroup analyses: the first according to the median year of study observation (before vs. since 2008) and the second according to the country of the study (China vs. others). The studies carried out before 2008 (327 SBP-positive culture) showed a significantly higher risk for 3GCs-resistant strains in N-SBP compared with CA-SBP (RR=2.36, 95% CI: 1.39-3.99; P=0.001), whereas this was not found in SBP acquired after 2008 (RR=1.24, 95% CI: 0.83-1.84; P=0.29). N-SBP occurring in China had no significantly higher risk for 3GCs-resistant strains compared with CA-SBP (RR=1.44, 95% CI: 0.87-2.37; P=0.16). Conclusion Our findings suggest that although the pooled RR of 3GCs resistance in N-SBP compared with CA-SBP show that 3GCs are still an effective option for the treatment of CA-SBP, the subanalysis of studies that enroled patients in the last decade did not show a significant higher RR of 3GCs resistance in N-SBP compared with CA-SBP. Therefore, in centres where local patterns of antimicrobial susceptibility (with low rates of 3GCs resistance) are not available, 3GCs should not be used initially for CA-SBP treatment. Future studies are needed to confirm this trend of 3GCs resistance.

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.

Obesity and chronic kidney disease (CKD) are public health priorities that share core pathophysiological mechanisms. However, whether high body mass index (BMI) increases risk of CKD de novo remains ill-defined. To evaluate the role of BMI in predicting CKD onset in the general adult population, we performed a systematic review and meta-analysis of PubMed and ISI Web of Science databases articles published between January 2000 and August 2016 without language restriction. We selected studies in adult individuals from a general population with normal renal function at baseline that reported the risk of low estimated glomerular filtration (eGFR) (under 60 mL/min/1.73m 2 ) and/or albuminuria (1+ at dipstick or an albumin creatinine ratio of 3.4 mg/mmol or more) as hazard ratio, odds ratio or relative risk related to obesity, overweight, or BMI as continuous value. A total of 39 cohorts covering 630, 677 participants with a mean follow-up of 6.8 years were selected. Obesity increased the relative risk, 95% confidence interval and heterogeneity (I 2 ) of developing low eGFR (1.28, 1.07–1.54, [I 2 : 95.0%]) and albuminuria (1.51, 1.36–1.67, [I 2 : 62.7%]). Increase of BMI unit was also associated with higher risk of low eGFR (1.02, 1.01–1.03, [I 2 : 24.3%]) and albuminuria (1.02, 1.00–1.04, [I 2 : 0%]). Conversely, overweight did not predict onset of either low eGFR (1.06, 0.94–1.21, [I 2 : 50.0%]) or albuminuria (1.24, 0.98–1.58, [I 2 : 49.4%]). Thus, a high BMI predicts onset of albuminuria without kidney failure (CKD stages 1–2) as well as CKD stages 3 and higher, the effect being significant only in obese individuals. Hence, our findings may have implications to improve risk stratification and recommendations on body weight control in the general population.

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

OBJECTIVE The combination of basal insulin plus a glucagon-like peptide 1 receptor agonist (GLP-1RA) has been proposed as a treatment option to intensify insulin therapy in type 2 diabetes. We performed a meta-analysis of randomized controlled trials (RCTs) comparing this combination strategy to other injectable antidiabetes treatments on metabolic control in adult patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted an electronic search until November 2016 on many electronic databases to identify RCTs assessing changes in HbA1c, proportion of patients at HbA1c target ≤7% (53 mmol/mol), hypoglycemia, and weight change. We used a random-effect model to calculate the weighted mean difference (WMD) or relative risk (RR) with the 95% CI. RESULTS We identified 26 RCTs, lasting 12–52 weeks, and involving 11,425 patients. When the combination strategy was compared with other injectable treatments (overall data), there were reductions in HbA1c (WMD = −0.47%, 95% CI −0.59 to −0.35), more patients at HbA1c target (RR = 1.65, 95% CI 1.44–1.88), similar hypoglycemic events (RR = 1.14, 95% CI 0.93–1.39) and a reduction in weight (WMD = −2.5 kg, 95% CI −3.3 to −1.7), with high heterogeneity (I2 > 89%, P < 0.001) and a significant publication bias for three outcomes. In preplanned subgroup analyses, the combination treatment was similar to basal-bolus insulin regimens for glycemic control, with less hypoglycemia (RR = 0.66, 95% CI 0.46–0.93) and reduced weight (WMD = −4.7 kg, 95% CI −6.9 to −2.4). Fixed-ratio combinations yielded results similar to the overall analysis (HbA1c WMD = −0.56%, 95% CI −0.72 to −0.40). CONCLUSIONS GLP-1RAs alone or as titratable fixed-ratio combinations with basal insulin may represent a promising option to advance basal insulin therapy or to initiate injectable therapy in patients with type 2 diabetes inadequately controlled on oral agents. Longer studies are needed to assess durability and tolerability.

As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, profound changes in daily lives have occurred. In Italy, the exponential spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection required extraordinary measures to limit viral transmission, leading to an almost complete lockdown of the country (1). The mandatory lockdown significantly affected patients with chronic diseases, including people with diabetes and diabetic foot ulceration (DFU), which represents a heavy burden for health care systems in terms of mortality and reduced quality of life (1,2). The interruption of preventive education, early treatment, and diagnosis may have led to increased hospitalization of patients with severe DFU at high amputation risk (3). The aim of this study was to evaluate clinical features and amputation risk of individuals with diabetes and DFU admitted to a tertiary care center during the COVID-19 lockdown compared with a population admitted in the first 5 months of 2019. Patients with diabetes and DFU admitted to the Division of Endocrinology and Metabolic Diseases at the Teaching Hospital of University of Campania “Luigi Vanvitelli” (Naples, Italy) from 9 March 2020 to 18 May 2020 were included in this study. This cohort was compared with a population of patients admitted …

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.

Data on the prevalence of occult HBV infection (OBI) in Western Europe and in Northern America are few; hence, we conducted a systematic review and meta-analysis. All studies included had to fulfil the following inclusion criteria: (a) they investigated the prevalence of OBI (HBV DNA in liver tissue in HBsAg-negative subjects), (b) were carried out in Western Europe and in Northern America; (c) were available as a full-text manuscript, (d) written in English and (e) published up to December 2018. The exclusion criteria were as follows: (a) meta-analyses, letters, reviews, meeting abstracts or editorial comments; (b) studies investigating HBsAg-positive patients; (c) those investigating OBI outside Western Europe and in Northern America; and (d) to avoid small sample bias in the random-effects model, those enrolling less than five subjects. Thirty-four studies met the inclusion criteria, allowing a meta-analysis on 2729 patients. The overall prevalence of OBI was 34% (95% CI=26%-42%), 28% (CI 95%: 12%-48%) in 329 subjects without chronic liver disease and 35% (95% CI 26%-44%) in 2400 patients with chronic liver disease. The prevalence of OBI was 51% (95% CI 40%-62%) in the 823 anti-HBc-positive subjects and 19% (95% CI 10%-30%) in the 1,041 anti-HBc-negative subjects. Evaluating the data from 17 studies comparing anti-HBc-positive and negative subjects, the prevalence of OBI was higher in the 641 anti-HBc-positive subjects than in the 1041 anti-HBc-negative (prevalence ratio=2.29; 95% CI=1.61-3.26, P&nbsp

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.

The purpose of this review is to evaluate the effectiveness and safety of dexmedetomidine as adjunctive therapy to the standard of care (benzodiazepines) compared to either the standard of care or other adjunctive treatment approaches (e.g. benzodiazepines plus propofol) for the treatment of alcohol withdrawal syndrome (AWS).Benzodiazepines have been the cornerstone of AWS therapy, but in some patients, AWS is refractory to high doses. Moreover, benzodiazepine use is burdened by excessive sedation, confusion and respiratory depression. Options for management of refractory AWS include the addition of phenobarbital, propofol and, more recently, dexmedetomidine to benzodiazepines therapy. The possible advantage of dexmedetomidine compared to benzodiazepines is that it does not cause respiratory depression, thus reducing the risk of intubation and hospitalization in the intensive care unit.This review will consider studies including patients who are 18 years or older and are diagnosed with AWS. The exclusion criteria are a history of psychoactive substances or withdrawal states and/or severe neurologic disorder (e.g. traumatic brain injury, acute stroke, severe dementia, seizure disorder).This review will include only studies published in English, with no restrictions on the year of publication. Both randomized controlled trials and observational studies (including cohort and case-control studies) assessing the drug effectiveness and safety will be included. The databases utilized will include: PubMed, Embase and Cochrane Central Register of Controlled Trials. In addition, the trial registers to be searched will include: World Health Organization International Clinical Trials Registry Platform (ICTRP), U.S. National Library of Medicine Drug Information Portal and ClinicalTrials.gov.PROSPERO CRD42018084370.

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.

We provided an updated systematic review with meta-analysis of randomized controlled trials (RCTs) assessing the metabolic effects of combination therapy of insulin and GLP-1RA (combo) in comparison with other injectable therapy. We searched PubMed, Cochrane Register of Controlled Trials, Scholar, and ClinicalTrials.gov for RCTs evaluating changes in HbA1c (primary outcome), proportion of patients at HbA1c target

Introduction: We aimed to evaluate adherence to the EAU guidelines (GL) on penile cancer (PC) with regard to primary surgical treatment and management of lymph nodes and to estimate the influence of adherence to GL on clinical outcome. Materials and methods: This is a retrospective multicenter study (PEnile Cancer ADherence study, PECAD Study) on PC patients treated at 12 European and American centers between 2010 and 2016. Adherence to the EAU GL on the surgical management of the primary penile tumor and lymphadenectomy was evaluated. Descriptive analyses were performed, and survival curves were estimated. Results: Data on 425 patients were considered for the analysis. The EAU GL on surgical treatment of the primary tumor and lymphadenectomy were respected in 74.8% and 73.7% of cases, respectively. Survival analysis showed that adherence to the GL on primary penile surgery was significantly associated with a good overall survival [adjusted HR 0.40 (95% CI 0.20-0.83, p value = 0.014)]. Also, the adherence to the GL on lymphadenectomy was statistically significantly associated with overall survival [adjusted HR 0.48 (95% CI 0.24-0.96, p value = 0.038)]. Limited follow-up and retrospective design represent limitations of this study. Conclusions: Our findings suggest that there is a good adherence to the EAU GL on PC. However, this should be further reinforced, endorsed and encouraged as it might translate into better clinical outcomes for PC patients.

We did a meta-analysis with meta-regression to evaluate the relationship between hemoglobin A1c (A1C) reduction and the primary CV outcome of cardiovascular outcome trials (CVOTs). We used a random effects meta-analysis of the 12 CVOTs to quantify the effect of A1C reduction on major cardiovascular events (MACE) risk by stratifying the difference in achieved A1C (drug vs placebo) in three strata: A1c

Federica Dall’Oglio,1 Gabriella Fabbrocini,2 Aurora Tedeschi,1 Marianna Donnarumma,2 Paolo Chiodini,3 Giuseppe Micali1 1Dermatology Clinic, University of Catania, Catania, Italy; 2Section of Dermatology, Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy; 3Medical Statistics Unit, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Giuseppe MicaliDermatology Clinic, University of Catania, A.O.U. Policlinico -Vittorio Emanuele, via Santa Sofia, 78, Catania 95123, ItalyTel +39 095321705Fax +39 0953782425Email cldermct@gmail.comPurpose: Topical cosmetic agents if correctly prescribed and used may improve outcomes in acne therapy. The aim of this study was to assess the efficacy and tolerability of a new daily cosmetic regimen in the treatment of mild facial acne.Patients and methods: A multicenter, prospective, observational, clinical study was conducted on 91 adult patients with mild acne. Subjects were instructed to apply a fluid containing Licochalcone A/Salicylic acid/L-Carnitine in the morning and a cream with Licochalcone A/Hydroxy-Complex 10% at bedtime for 8 weeks. The efficacy was clinically evaluated by Global Acne Grading System (GAGS) score and by comedones/papules lesions count and by instrumental assessment (SebutapeTMand Reveal Photo Imager/VISIA-CR™ imaging) at baseline, at 4 and 8 weeks.Results: At 4 weeks a statistically significant reduction from baseline of GAGSwas observed. In addition, the mean total count of comedones and papules was significantly reduced by 41% and 45%, respectively, from baseline along with a significant reduction of mean sebum of 47%. At 8 weeks, a further statistically significant reduction from baseline of GAGS, total count of comedones and papules (64% and 71%, respectively), along with an additional sebum reduction of about 52% was also recorded.Conclusion: Our results suggest that the daily regimen based on Licochalcone A with Salicylic acid/L-Carnitine as fluid or with Hydroxy-Complex 10% as cream represent an interesting cosmetic approach for treating mild acne.Keywords: mild acne, topical cosmetic, licochalcone A, salicylic acid, hydroxyl-complex

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.

Background: The intensive study of predictive factors has strongly ameliorated the therapeutic flow-chart of metastatic colorectal cancer (mCRC) by allowing the selection of patients who benefit from specific therapies. For instance, in mRAS (mutated RAS) mCRC patients, anti-EGFR drugs (cetuximab and panitumumab) are not recommended; in this group of patients, the use of anti-angiogenic drugs (bevacizumab and aflibercept) is predominant. However, at progression to standard bevacizumab-based first-line chemotherapy, still to date, there are no studies to guide oncologists in the choice of the best second-line anti-angiogenic drug (bevacizumab beyond progression versus aflibercept). Methods: ARBITRATION is a prospective, observational study assessing efficacy differences between second-line fluorouracil/irinotecan (FOLFIRI)/bevacizumab versus FOLFIRI/aflibercept at progression to fluoropyrimidines, oxaliplatin and bevacizumab in mRAS mCRC patients. A test power of 80%, a median survival of 9 months from second-line treatment start and a hazard ratio of 0.67 between the two schedules were the basis for statistical design. The final sample will be 220 patients (110 per treatment). The significance will be verified with a two-tailed log-rank test with an alpha value of the I-type error of 5%. Time-to-outcome will be described by Kaplan–Meier curves and prognostic factors studied through multivariable analyses based on the Cox model. Secondary objectives include safety, responses’ duration and progression-free survival. A translational research will be conducted to measure several angiogenic proteins in patients’ serum before starting the therapy in order to evidence any angiogenic factor patterns related to outcome. Discussion: We present a large, prospective, observational study aiming to answer two scientific questions: (1) outcome differences between second-line treatments with FOLFIRI/bevacizumab beyond progression versus FOLFIRI/aflibercept in mRAS mCRC patients, (2) angiogenic factors’ patterns that could associate with efficacy and help oncologists to apply best the therapeutic anti-angiogenic strategies. Trial registration: The ARBITRATION trial (version 0.0, 13 April 2020) has been registered into the clinicaltrials.gov registry on 20 May 2020 with identifier NCT04397601.

In this study, we investigated whether minocycline, a second-generation tetracycline proposed as an add-on to antipsychotics in treatment-resistant schizophrenia (TRS), may affect the expression of Homer and Arc postsynaptic density (PSD) transcripts, implicated in synaptic regulation. Minocycline was administered alone or with haloperidol in rats exposed or not to ketamine, mimicking acute glutamatergic psychosis or naturalistic conditions, respectively. Arc expression was significantly reduced by minocycline compared with controls. Minocycline in combination with haloperidol also significantly reduced Arc expression compared with both controls and haloperidol alone. Moreover, haloperidol/minocycline combination significantly affected Arc expression in cortical regions, while haloperidol alone was ineffective on cortical gene expression. These results suggest that minocycline may strongly affect the expression of Arc as mediated by haloperidol, both in terms of quantitative levels and of topography of haloperidol-related expression. It is noteworthy that no significant pre-treatment effect was found, suggesting that pre-exposure to ketamine did not grossly affect gene expression. Minocycline was not found to significantly affect haloperidol-related Homer1a expression. No significant changes in Homer1b/c expression were observed. These results are consistent with previous observations that minocycline may modulate postsynaptic glutamatergic transmission, affecting distinct downstream pathways initiated by N-methyl-D-aspartate (NMDA) receptor modulation, i.e. Arc-mediated but not Homer1a-mediated pathways.