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Biological sex and sociocultural gender matter when it comes to health and diseases. They have been both proposed as the undeniable gateways towards a personalized approach in care delivery. The Gender Working Group of the Italian Society of Internal Medicine (SIMI) was funded in 2019 with the aim of promoting good practice in the integration of sex and gender domains in clinical studies. Starting from a narrative literature review and based on regular meetings which led to a shared virtual discussion during the national SIMI congress in 2021, the members of the WG provided a core operational framework to be applied by internal medicine (IM) specialists to understand and implement their daily activity as researchers and clinicians. The SIMI Gender '5 Ws' Rule for clinical studies has been conceptualized as follows: Who (Clinical Internal Medicine Scientists and Practitioners), What (Gender-related Variables-Gender Core Dataset), Where (Clinical Studies/Translational Research), When (Every Time It Makes Sense) and Why (Explanatory Power of Gender and Opportunities). In particular, the gender core dataset was identified by the following domains (variables to collect accordingly): relations (marital status, social support, discrimination); roles (occupation, caregiver status, household responsibility, primary earner, household dimension); institutionalized gender (education level, personal income, living in rural vs urban areas); and gender identity (validated questionnaires on personality traits). The SIMI Gender '5 Ws' Rule is a simple and easy conceptual framework that will guide IM for the design and analysis of clinical studies., (© 2022. The Author(s).)

Rare diseases represent a numerous (more than 30 million patients throughout Europe), diverse (more than 6000 disease ascertained), and complex group of genetic, metabolic, neurologic, congenital and other type of disorders presenting both in pediatric and adult age. Research, education and care are the mainstay of the national rare disease plans of the member states, including Italy. Early diagnosis and multidisciplinary care, particularly in severe or progressive disorder, are mandatory to treat disorders (when a specific treatment is available) and/or avoid life-threatening complications. According to the catchphrase "you can only diagnose what you know", it is intuitive how important is education and the "culture of suspect" in rare disease. In the last decade, a pre- and post-graduate academic planning on rare disease have been set up in Italy, with the aim to be comprehensive and up-to-date with the literature, traversal to both general physicians and all the specialties, longitudinal during all the study courses.

Background: There is a growing literature on how medical education adapts to the COVID-19 pandemic. However, there is a need to examine the facilitators and barriers of these adaptations. This study explores the strengths, weaknesses, opportunities, and threats (SWOT) of how Italian medical schools adapted their curricula to the COVID -19 pandemic., Methods: The authors conducted an online survey of directors of medical curricula in Italy. Free-text responses to open-ended questions about curricular adaptations and reflections on these adaptations were analysed using qualitative thematic analysis., Results: Twenty out of 60 Italian medical school directors completed the survey. Strengths identified were rapid responses and a spirit of cooperation. Weaknesses included dependency on clinical facilities, teachers' limited skills to use technology, and lack of mental health support for staff. Opportunities highlighted were clear government rules, new ways of teaching and a renewed focus on underrepresented topics. Threats expressed included impaired relationships, difficulties related to online assessment, lack of IT access, and legal and insurance issues., Conclusions: This study, in documenting the curricular adaptations of Italian medical schools during an active global pandemic, and recording the perspectives of medical education leaders, offers important lessons for the future.

Objectives: To analyze the relationship between atrial fibrillation (AF) and Charlson comorbidity index (CCI) in a population-based cohort study over a long-term follow-up period, in relation to oral anticoagulant (OAC) prescriptions and outcomes., Patients and Methods: We used data from the administrative health databases of Lombardy. All patients with AF and age 40 years and older and who were admitted to the hospital in 2002 were considered for analysis and followed up to 2014. AF diagnosis and CCI were established according to codes from the International Classification of Diseases, Ninth Revision., Results: In 2002, 24,040 patients were admitted with a diagnosis of AF. CCI was higher in patients with AF than in those without AF (1.8±2.1 vs 0.2±0.9; P<.001). Over 12 years of follow-up, AF was associated with an increased risk of higher CCI (beta coefficient, 1.69; 95% CI, 1.67-1.70). In patients with AF, CCI was inversely associated with OAC prescription at baseline (P<.001) and at the end of the follow-up (P=.03). Patients with AF and a high CCI (≥4) had a higher cumulative incidence of stroke, major bleeding, and all-cause death (all P<.001), compared with those with low CCI (range, 0-3). Adjusted Cox regression analysis revealed that time-dependent continuous CCI was associated with an increased risk for stroke, major bleeding, and all-cause death (all P<.001)., Conclusions: In hospitalized patients, AF is associated with an increase in CCI that is inversely associated with OAC prescriptions during follow-up. CCI is independently associated with an increased risk of stroke, major bleeding, and all-cause death., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: Tobacco smoking is the leading cause of preventable death in developed countries and smokers should be encouraged to quit. Physicians are instrumental in this, but recent reports suggest inadequate training in medical school. We aimed to assess the knowledge of nicotine dependence and its treatment among Italian medical students., Study Design: Prospective observational study., Methods: We developed an online course consisting of 11 Didactic Modules (6 for Tobacco Dependence I, TDI, and 5 for TDII) on nicotine dependence and treatment. The course was administered to 4th and 5th year medical students in Italy in Academic Years 2016-17 (Course A) and 2017-18 (Course B). A validated questionnaire was used before and after each part in order to measure knowledge of smoking epidemiology, health effects and benefits of giving up smoking ("Score 1", TDI), and effectiveness of cessation treatments ("Score 2", TDII)., Results: 324 students took both TDI and TDII and completed all questionnaires (Course A, n = 245; Course B, n = 79). 55 students were current smokers (17%). A significant increase in score 1 and 2 was observed at the end of both TDI (pre-course 47.2±13.1, post-course 66.0±12.3, p <0.0001) and TDII (pre-course 55.6±11.5, post-course 68.1±10.9, p <0.0001). The prevalence of students wishing for a smoke-free medical school significantly increased between the beginning of TDI (74.4%, 241/324) and the end of TDII (88%, 285/324; p <0.0001)., Conclusions: This e-learning course has proven to be an effective tool in teaching students on nicotine dependence and treatment.

Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear., Methods: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years., Results: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 10 3 /μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events., Conclusions: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients.

Background & Aims: Patients with cirrhosis display enhanced blood levels of factor VIII, which may result in harmful activation of the clotting system; however, the underlying mechanism is unknown., Methods: We performed a cross-sectional study in patients with cirrhosis (n=61) and matched controls (n=61) comparing blood levels of factor VIII, von Willebrand factor (vWf), lipopolysaccharide (LPS) and positivity for Escherichia coli DNA. Furthermore, we performed an in vitro study to investigate if LPS, in a concentration range similar to that found in the peripheral circulation of cirrhotic patients, was able to elicit factor VIII secretion from human umbilical vein endothelial cells (HUVEC)., Results: Patients with cirrhosis displayed higher serum levels of LPS (55.8 [42.2-79.9] vs. 23.0 [7.0-34.0]pg/ml, p<0.001), factor VIII (172.0 [130.0-278.0] vs. 39.0 [26.0-47.0]U/dl, p<0.0001), vWf (265.0 [185.0-366.0] vs. 57.0 [48.0-65.0]U/dl, p<0.001) and positivity for Escherichia coli DNA (88% vs. 3%, p<0.001, n=34) compared to controls. Serum LPS correlated significantly with factor VIII (r=0.80, p<0.001) and vWf (r=0.63, p<0.001). Only LPS (beta-coefficient=0.70, p<0.0001) independently predicted factor VIII levels. The in vitro study showed that LPS provoked factor VIII and vWf release from HUVEC via formation and secretion of Weibel-Palade bodies, a phenomenon blunted by pre-treating HUVEC with an inhibitor of Toll-like receptor 4., Conclusions: The study provides the first evidence that LPS derived from gut microbiota increases the systemic levels of factor VIII via stimulating its release by endothelial cells. Lay summary: Cirrhosis is associated with thrombosis in portal and systemic circulation. Enhanced levels of factor VIII have been suggested to play a role but the underlying mechanism is still unclear. Here we show that patients with cirrhosis display a concomitant increase of factor VIII and lipopolysaccharide (LPS) from Escherichia coli and suggest that LPS contributes to the release of factor VIII from endothelial cells., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the relationship between Ankle-Brachial Index (ABI) and renal function progression in patients with atrial fibrillation (AF)., Design: Observational prospective multicentre cohort study., Setting: Atherothrombosis Center of I Clinica Medica of 'Sapienza' University of Rome; Department of Medical and Surgical Sciences of University Magna Græcia of Catanzaro; Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study., Participants: 897 AF patients on treatment with vitamin K antagonists., Main Outcome Measures: The relationship between basal ABI and renal function progression, assessed by the estimated Glomerular Filtration Rate (eGFR) calculated with the CKD-EPI formula at baseline and after 2 years of follow-up. The rapid decline in eGFR, defined as a decline in eGFR >5 mL/min/1.73 m(2)/year, and incident eGFR<60 mL/min/1.73 m(2) were primary and secondary end points, respectively., Results: Mean age was 71.8±9.0 years and 41.8% were women. Low ABI (ie, ≤0.90) was present in 194 (21.6%) patients. Baseline median eGFR was 72.7 mL/min/1.73 m(2), and 28.7% patients had an eGFR<60 mL/min/1.73 m(2). Annual decline of eGFR was -2.0 (IQR -7.4/-0.4) mL/min/1.73 m(2)/year, and 32.4% patients had a rapid decline in eGFR. Multivariable logistic regression analysis showed that ABI ≤0.90 (OR 1.516 (95% CI 1.075 to 2.139), p=0.018) and arterial hypertension (OR 1.830 95% CI 1.113 to 3.009, p=0.017) predicted a rapid eGFR decline, with an inverse association for angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (OR 0.662 95% CI 0.464 to 0.944, p=0.023). Among the 639 patients with AF with eGFR >60 mL/min/1.73 m(2), 153 (23.9%) had a reduction of the eGFR <60 mL/min/1.73 m(2). ABI ≤0.90 was also an independent predictor for incident eGFR<60 mL/min/1.73 m(2) (HR 1.851, 95% CI 1.205 to 2.845, p=0.005)., Conclusions: In patients with AF, an ABI ≤0.90 is independently associated with a rapid decline in renal function and incident eGFR<60 mL/min/1.73 m(2). ABI measurement may help identify patients with AF at risk of renal function deterioration., Trial Registration Number: NCT01161251., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Non-valvular atrial fibrillation (NVAF) represents a major health-care problem, needing an extensive and strict thrombosis prevention for stroke and cardiovascular (CV) disease risks. NVAF management guidelines recommend adequate antithrombotic and anti-atherosclerotic therapies. Medication adherence has been recognized as a pivotal element in health quality promotion and in the achievement of better clinical outcomes. We conducted a post-hoc analysis of the "Atrial fibrillation Registry for Ankle-brachial index Prevalence Assessment-Collaborative Italian Study (ARAPACIS)" with the aim of discerning differences in pharmacological management and medication adherence among NVAF Italian patients. Furthermore, data were analysed according to Italian geographical macro-regions (North, Center, South) to evaluate whether socioeconomic conditions might also influence medication adherence. Thus, we selected 1,366 NVAF patients that fulfilled the Morisky Medication Adherence Scale-4 items. Regional disparities in drug prescriptions were observed. In particular, in high-risk patients (CHA2DS2-VASc ≥2) oral anticoagulants were more prescribed in Northern and Center patients (61 and 60 %, respectively) compared to 53 % of high-risk Southern patients. Also, medication adherence showed a progressive decrease from North to South (78 vs. 60 %, p < 0.001). This disparity was independent of the number of drugs consumed for any reason, since prevalence of poly-therapy among the three macro-regions was similar. Our results show regional differences in NVAF patients' antithrombotic management and medication adherence, potentially reflecting well-known disparities in socioeconomic status among Italian regions. Future interventions promoting campaigns to global health-care education may be desirable to improve clinical outcomes in NVAF patients.

Objectives: To reduce the increase of oxidative stress and the upregulation of CD40L during stenting procedure using ascorbic acid infusion., Background: CD40L upregulation occurring after coronary percutaneous coronary intervention predicts vascular events but the underlying mechanism is still unclear., Methods: Fifty-six patients undergoing elective coronary stenting were randomly allocated to intravenous infusion of the antioxidant ascorbic acid or placebo. Platelet CD40L and plasma levels of soluble CD40L and of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, were measured before and after coronary stenting. In vitro study was also done to measure reactive oxidant species and CD40L expression in platelets exposed to anoxia-reoxygenation., Results: Placebo-treated patients showed a significant increase of platelet CD40L, soluble CD40L and 8-hydroxy-2'-deoxyguanosine compared to baseline values. Patients given ascorbic acid showed no change of soluble CD40L and platelet CD40L but a significant decrease of 8-hydroxy-2'-deoxyguanosine. After 60 and 120 min, soluble CD40L, platelet CD40L and 8-hydroxy-2'-deoxyguanosine were significantly lower in the ascorbic acid-treated group compared to the placebo-treated one. A significant correlation between platelet CD40L and soluble CD40L and between soluble CD40L and 8-hydroxy-2'-deoxyguanosine was observed. Platelets, in vitro exposed to anoxia-reoxygenation, had a burst of ROS and an upregulation of CD40L that were inhibited by ascorbic acid or apocynin, an inhibitor of NADPH oxidase., Conclusions: This study shows that in patients undergoing coronary stenting CD40L is upregulated with a mechanism which is likely mediated by oxidative stress., (© 2010 Blackwell Publishing Ltd.)

The aim of this study was to investigate the relationship between serum tumor necrosis factor alpha (TNF-alpha) levels and single nucleotide polymorphisms (SNPs) of the TNFA gene promoter (-376G/A, -308G/A, and -238G/A) in 100 Italian Caucasian women with reproductive failure and 100 fertile controls. Molecular analysis of TNFA SNPs showed higher frequencies of -238G allele (P = .028) as well as the presence of a 3-loci haplotype (-376G/-308A/-238G; P = .020) in fertile controls compared to women with reproductive failure. Serum TNF-alpha levels were higher in study women compared to controls ( P = .001). Of interest, the TNFA -376G/-308A/-238G haplotype was an independent predictor of low TNF-alpha levels (P = .021) and miscarriage (P = .023) in multivariate analyses. In conclusion, these findings support the concept of an association of TNFA polymorphisms and recurrent pregnancy loss (RPL). In particular, the TNFA -238GG variant and the TNFA -376G/-308A/-238G haplotype might represent protective factors, probably through reduced TNF-alpha production and/or mediated responses.

Background: Between extra-hepatic manifestations of hepatitis C virus (HCV) infection particular interest is focused on some dermatological diseases such as: leukocytoclastic vasculitis, oral lichen planus, pruritus-urticaria, psoriasis, etc. The aim of this study was to determine the prevalence of some dermatoses in our population of patients with HCV infection and describe the more characteristics clinical pictures., Methods: Ninety-six patients (36 men and 60 women) aged from 35 to 74 years with HCV documented by 3rd generation ELISA and RIBA tests were prospectively examined for 3 years to determine the prevalence of some skin disorders, reported as associated with HCV infection. All patients were also studied for presence and quantification of HCV-RNA by polymerase chain reaction and genotyping when possible. Eighty-one underwent a liver biopsy. Routine laboratory tests and some immunological investigations (ANA, AMA, SMA, LKM, ANCA, ICC, crioglobulins) were performed using standard procedures and indirect immunofluorescence, nephelometric, RIA methods., Results: Twelve of 96 patients (12.5%) presented skin disorders in progress of chronic virus C hepatitis: 5 cases of leukocytoclastic vasculitis (LCV) by mixed cryoglobulinemia, 1 case of pruritus, 2 cases of oral lichen planus (OLP), 2 cases of alopecia areata, 1 case of urticaria, 1 case of psoriasis., Conclusions: Our findings show a calculated prevalence of clinical dermatoses in HCV infected patients around 12.5%. These findings confirm however the importance of liver examination in presence of skin diseases not related to other pathogenetic mechanisms.

Background and Objective: Prospective studies have shown that high plasma levels of fibrinogen are independently associated with the risk of cardiovascular complications. In patients suffering from peripheral vascular disease (PVD) fibrinogen has been shown to be an independent predictor of cardiovascular disease but its determinants have never been examined in this clinical setting., Design and Methods: Fibrinogen levels were related to clinical and laboratory variables in 2,111 patients suffering from PVD. We also analyzed whether there was a regional distribution of risk factors., Results: The median values of fibrinogen was 312 mg/dL. The clinical variables examined did not differentiate patients with elevated or normal fibrinogen levels. In particular, patients with ankle/arm pressure ratio < 0.8 did not show a higher prevalence of fibrinogen > 312 mg/dL. Conversely, white blood cell (WBC) count and serum cholesterol levels were significantly associated with high fibrinogen levels (p < 0.0001). Multiple logistic regression analysis demonstrated that areas of Italy were differently associated with high plasma fibrinogen levels (p < 0.03): subjects in the north and middle of Italy having significantly higher values of fibrinogen than subjects in the south of Italy (p < 0.01). A similar regional distribution was observed for WBC count and serum cholesterol levels., Interpretation and Conclusions: The regional distribution of risk factors raises the question as to whether the already reported large variability of cardiovascular events so in PVD may be attributed to a non homogeneous distribution of risk factors.

The relation between coagulation indexes and survival rate was studied and analyzed in 46 patients with advanced liver cirrhosis (grade B and C Child-Pugh Classification), during a follow-up of 1 year. Twenty-four patients (52%) died of liver failure or fatal haemorrhage within 12 months of follow-up. Prothrombin activity, fibrinogen, fibrin(ogen) degradation products, prekallikrein and factor VII, serum bilirubin, and the degree of liver insufficiency, scored by Child-Pugh classification, proved to be significantly correlated with survival by univariate analysis. A multivariate survival analysis (Cox regression model) disclosed two variables, prekallikrein and factor VII, that predicted survival. The rate ratios of death increased to 2.8 and 7.6 with values of prekallikrein < 26% and factor VII < 39%, respectively. This study shows that some simple laboratory tests exploring the clotting system may identify patients with poor prognosis in severe liver failure.