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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.

Introduction:Although there are multiple analgesia techniques, opioids remain the most widely used drug for pain control. Postoperative Nausea and Vomiting (PONV), sleepiness, respiratory, and gastrointestinal disorder are common complications of postoperative opioid use, which makes the decrease in opioid demand, through combination with non-opioid agents, desirable. Dexmedetomidine (DEX) is an alpha2-adrenergic agonist with sedative and anxiolytic effects. Recently, some studies proved the evidence of its notable opioid-sparing effect. Furthermore DEX, compared to opioids, seems to have the advantage of not inhibiting spontaneous breathing.Aim:This systematic review protocol aims to define the analgesic effect of perioperative DEX infusion and the cumulative opioid consumption of patients undergoing general anesthesia.Methods:The review will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta- Analysis Protocols (PRISMA- P) statement and the Cochrane recommendations for Systematic Reviews of Interventions.Results:The primary outcomes will be 1) The effect of DEX infusion, on pain control, compared to placebo or other treatments and 2) The opioid-sparing effect of DEX infusion compared to placebo or other treatments. The secondary outcome will be a) Respiratory depression, b) Hypotension requiring fluid infusion and/or amine, c) Bradycardia requiring vasoactive drugs, d) Needing of prolonged hospital stay, e) PONV and gastrointestinal disorders.Conclusion:A sub-analysis is planned for i) The type of surgery performed, ii) Patient’s gender, iii) Patients age. If possible, a meta- analysis (including sub-analysis and sensitivity analysis for all assessed outcomes) will be performed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be followed to create a Summary of Findings.The Registration Number for this Systematic Review is CRD42018086687.

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.

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

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.

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.

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.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the effects of implants versus autologous tissue flaps for breast reconstruction following mastectomy for breast cancer treatment or risk reduction, on women’s level of satisfaction, and quality of life, and surgical short- and long-term complications.

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.

A wave of new treatments and treatment combinations are becoming available for solid tumours. Trials performed to obtain registration establish a positive benefit-risk but unavoidably leave many questions unanswered on place-in-therapy and the relative efficacy of different treatment sequences. Such limitations create problems in terms of strength of treatment guidelines and reimbursement (in countries where a public payer exists). Data on new drugs arriving during the last 10 years for the treatment of hepatocellular carcinoma and renal cancer are reported as an example of how the fortunate condition of having new effective treatments may translate into uncertainty regarding the optimal treatment plan. We suggest that academic research should react to such limitations and propose a model of patient-journey study (PJS), where patients are followed from the initial diagnosis across subsequent lines of treatment. A PJS master protocol might include at each node of clinical decision either the possibility of choosing treatment according to guidelines (generating prospective real-world evidence) or the possibility to randomise where uncertainty exists (generating comparative effectiveness data). PJS protocols might be adaptively modified every time a new drug arrives on the market. Overall, methodologically sound analyses of PJS will produce knowledge on the efficacy and the effectiveness of different treatment pathways and might significantly optimise treatment of patients in clinical practice. PJS would represent a jump from a few snapshots (trials performed to get regulatory approval) to a full movie (evidence on the relative value of treatment pathways).

Objectives Several attempts have been made to test different drug-sparing strategies to reduce the drug-burden and drug-related toxicities. The objective of this meta-analysis was to evaluate the relative risk (RR) of failure of dual therapies compared to triple therapies in HIV-naive patients. Methods We searched MEDLINE, Google Scholar and the Cochrane Library. The following criteria were used: present data from original articles comparing the two treatment regimens; published from January 2007 up to January, 2020. No language or study design restriction was applied. Subjects were HIV-positive naive patients treated with dual or triple antiretroviral therapy (ART). A systematic review and meta-analysis was performed. Treatment failure (TF) was the primary outcome evaluated; heterogeneity was assessed using the Q statistic and I2. Results Fourteen studies were included, allowing a meta-analysis on 5205 patients. The meta-analysis performed on studies that presented data at 48 weeks showed that the RR of TF (RR > 1 favouring triple therapy) in 10 studies was 1.20 (95% confidence interval (CI): 0.91–1.59, I2: 49.2%); the RR of virological failure (VF) in eight studies was 1.54 (95% CI: 0.84–2.86, I2: 54%); the RR of adverse drug reaction leading to discontinuation of the regimen at 48 weeks in eight studies was 0.76 (95% CI: 0.43–1.33, I2: 17.7%). In patients with less than 200 CD4+, the RR of TF in two studies without maraviroc was 2.09 (95% CI: 1.05–4.17, I2: 0.0%). Regarding the studies at 96 weeks there was no difference except in rate of development of resistance, RR 1.94 (95% CI: 1.06–3.53, I2: 6.2%). Conclusion Dual therapies are as effective as those with three drugs, showing no difference according to the different dual therapies, except in patients with less than 200 CD4; however, they are associated with a higher selection of resistance-associated mutations at 96 weeks of therapy.

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.

Context: Fraudulent publication is a scourge of scientific research. Objectives: This scoping review was aimed at characterizing retracted publications for fraud or plagiarism in the field of anesthesia. Does the reputation of the journal (Quartile and Impact Factor, IF) protect the reader from the risk of having the manuscript he read withdrawn for fraud/plagiarism? Methods/Design: This scoping review was planned following the Joanna Briggs Institute recommendations. Data sources: PubMed and the Retraction Watch Database ( http://retractiondatabase.org/RetractionSearch.aspx? ). Study selection: All types of publications retracted. Data extraction: Year, first author nationality, journal name, journal category, IF, Quartile, H index. Data analysis: The association with Quartile and IF was investigated. Results: No significant association between retraction of papers published in no-Quartile journals and retractions published in journals placed in the highest quartile. Conclusions: The quality of the surveillance in paper submission is not higher in journals of the first Quartile than in journals not placed in other Quartiles. (The protocol was prospectively registered in the Open Science Framework https://doi.org/10.17605/OSF.IO/TGKNE )

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 Tocilizumab, an IL-6 receptor antagonist, was suggested as a possible treatment of severe or critical COVID-19 pneumonia in a small Chinese study. The TOCIVID-19 trial evaluates efficacy and tolerability of tocilizumab in the treatment of patients with severe or critical COVID-19 pneumonia. Methods TOCIVID-19 is an academic multicenter, single-arm, open-label, phase 2 study. All the patients are being offered a single shot of 8 mg/kg of Tocilizumab (up to a maximum of 800 mg), with an eventual second administration at the discretion of the Investigator. A companion prospective cohort, added to corroborate internal validity, includes either patients not eligible for phase 2 or subjects eligible for phase 2 but exceeding the planned sample size. 14- and 30-days lethality rates are the two co-primary endpoints in the intention-to-treat (ITT) population. Secondary objectives are to evaluate mortality and clinical improvement in the modified-ITT population of subjects who received the drug. Details of the methodological and statistical approaches are reported here reflecting the amendments impelled by the continuously increasing knowledge on COVID-19 progression and challenges in data collection. Conclusion This paper provides details of planned statistical analyses for TOCIVID19 trial to reduce the risk of reporting bias and increase validity of the study findings. TOCIVID-19 trial is registered in the EudraCT database with number 2020-001110-38 and in clinicaltrials.gov with ID NCT04317092.

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 Candidaemia remains associated with high mortality and increased costs worldwide. Objective To assess the changes over time in the relative prevalence of non-albicans candidaemia (NAC). Methods A systematic review, meta-analysis and meta-regression were performed. Observational studies investigating the epidemiology of consecutive, non-selected, candidaemia episodes were included. Two separated analyses were conducted: (a) whole hospital analysis and (b) intensive care unit (ICU) analysis. Results Starting from an initial total of 7726 records, 220 studies fulfilled inclusion criteria. The pooled prevalence of NAC in whole hospital analysis was 49.5% (95% confidence intervals [CI] 48.0-51.1, I2 93.1%), while the pooled prevalence in ICU analysis was 50.6% (95% CI 46.6-54.6; I2 86.7%). In meta-regression, a progressive increase in NAC prevalence was observed in whole hospital analysis, although it explained only a small portion of between-study variance (estimated yearly prevalence change +0.3%, 95% CI from +0.1% to +0.5%, P = .003; adjusted R2 3.42%) and was observed only in some continents in subgroup analyses. No relevant changes over time were observed in NAC prevalence for ICU studies. Conclusions We registered an increasing trend in the relative prevalence of NAC, which, nonetheless, seems to be limited to some continents and to contribute only minimally to explain the observed differences in NAC prevalence across studies.

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.

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 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.

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

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 …