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Objectives To investigate the use of maintenance immunosuppressive treatments following liver transplantation and to compare their risk–benefit profiles in clinical practice.Design Retrospective multicentrer cohort study.Setting Four Italian regions (Lombardy, Veneto, Lazio, Sardinia).Methods Data were integrated from the national transplant information system and administrative claims data from four Italian regions. All adults who underwent incident liver transplantation between 2009 and 2019 were identified and categorised into two groups: cirrhosis or hepatocellular carcinoma (HCC). The trend of immunosuppressive treatment over years was analysed, and their effectiveness/safety profiles were compared using multivariate Cox models (HR; 95% CI).Main outcome measures Mortality, transplant reject/graft failure, incidence of severe infections, cancer, diabetes, major adverse cardiovascular events and lipid-modifying agents use.Results The study comprised 750 subjects in the cirrhosis cohort and 1159 in the HCC cohort. Over the study years, there was a decline in the use of cyclosporine-CsA, while combination therapy involving tacrolimus with other drugs increased compared with monotherapy. Overall, tacrolimus monotherapy use was slightly over 40% in both groups, followed by tacrolimus+mycophenolate (39.5%-cirrhosis; 30.6%-HCC) and tacrolimus+molecular target of rapamycin inhibitors (mTORi) (8.5%-cirrhosis; 13.3%-HCC). No significant differences emerged in risk–benefit profile of different tacrolimus-based therapies, except for a higher risk of mortality in cirrhosis subjects under tacrolimus monotherapy compared with tacrolimus+mycophenolate (HR: 2.07; 1.17 to 3.65).Conclusions The study highlights a shift over time in postliver transplant therapeutic patterns, favouring the use of tacrolimus in combination with mycophenolate or mTORi, rather than monotherapy. Moreover, a potential association between tacrolimus monotherapy and increased mortality in the cirrhosis cohort was identified. Further research is warranted to investigate these findings more deeply and to optimise treatment strategies for liver transplant recipients.

ObjectiveWe investigated whether there are differences in cancer incidence by geographical area of origin in North-eastern Italy.MethodsWe selected all incident cases recorded in the Veneto Tumour Registry in the period 2015-2019. Subjects were classified, based on the country of birth, in six geographical areas of origin (Italy, Highly Developed Countries-HDC, Eastern Europe, Asia, Africa, South-central America). Age-standardized incidence rates and incidence rate ratio (IRR) were calculated, for all cancer sites and for colorectal, liver, breast and cervical cancer separately.ResultsWe recorded 159,486 all-site cancer cases; 5.2% cases occurred in subjects born outside Italy, the majority from High Migratory Pressure Countries (HMPC) (74.3%). Incidence rates were significantly lower in subjects born in HMPC in both sexes. Immigrants, in particular born in Asia and Africa, showed lower rates of all site cancer incidence. The lowest IRR for colorectal cancer was observed in males from South-Central America (IRR 0.19, 95%CI 0.09-0.44) and in females from Asia (IRR 0.32, 95%CI 0.18-0.70). The IRR of breast cancer appeared significantly lower than Italian natives in all female populations, except for those coming from HDC. Females from Eastern Europe showed a higher IRR for cervical cancer (IRR 2.02, 95%CI 1.57-2.61).ConclusionCancer incidence was found lower in subjects born outside Italy, with differences in incidence patterns depending on geographical area of origin and the cancer type in question. Further studies, focused on the country of birth of the immigrant population, would help to identify specific risk factors influencing cancer incidence.

Abstract Background Very scanty evidence is available on factors influencing the choice of immunosuppressive drug therapy after kidney transplantation. Methods An Italian multiregional real-world study was conducted integrating national transplant information system and claims data. All patients undergoing kidney transplantation for the first time during 2009–2019 (incident patients) were considered. Multilevel logistic models were used to estimate Odds Ratio (OR) and corresponding 95% Confidence intervals. Factors with statistically significance were identified as characteristics associated with treatment regimens: cyclosporin-CsA vs tacrolimus-Tac and, within the latter group, mTOR inhibitors vs mycophenolate-MMF. Results We identified 3,622 kidney patients undergoing transplantation in 17 hospitals located in 4 Italian regions, 78.3% was treated with TAC-based therapy, of which 78% and 22% in combination with MMF and mTOR, respectively. For both comparison groups, the choice of immunosuppressive regimens was mostly guided by standard hospital practices. Only few recipient and donor characteristics were found associated with specific regimen (donor/receipt age, immunological risk and diabetes). Conclusions The choice of post-renal transplant immunosuppressive therapy seems to be mostly driven by standard Centre practices, while only partially based on patient’s characteristics and recognized international guidelines.

Maintenance immunosuppressive therapy used in kidney transplantation typically involves calcineurin inhibitors, such as tacrolimus or cyclosporine, in combination with mycophenolate or mechanistic target of rapamycin (mTORi) with or without corticosteroids. An Italian retrospective multicentre observational study was conducted to investigate the risk-benefit profile of different immunosuppressive regimens. We identified all subjects who underwent kidney transplant between 2009 and 2019, using healthcare claims data. Patients on cyclosporine and tacrolimus-based therapies were matched 1:1 based on propensity score, and effectiveness and safety outcomes were compared using Cox models (HR; 95%CI). Analyses were also conducted comparing mTORi versus mycophenolate among tacrolimus-treated patients. Patients treated with cyclosporine had a higher risk of rejection or graft loss (HR:1.69; 95%CI:1.16-2.46) and a higher incidence of severe infections (1.25;1.00-1.55), but a lower risk of diabetes (0.66;0.47-0.91) compared to those treated with tacrolimus. Among tacrolimus users, mTORi showed non-inferiority to MMF in terms of mortality (1.01;0.68-1.62), reject/graft loss (0.61;0.36-1.04) and severe infections (0.76;0.56-1.03). In a real-life setting, tacrolimus-based immunosuppressive therapy appeared to be superior to cyclosporine in reducing rejection and severe infections, albeit with an associated increased risk of diabetes. The combination of tacrolimus and mTORi may represent a valid alternative to the combination with mycophenolate, although further studies are needed to confirm this finding.

Introduction Off-label, under-, and overdosed direct oral anticoagulants (DOACs) are commonly prescribed to patients with atrial fibrillation (AF), but real-world evidence on their effectiveness and safety is limited. Methods MEDLINE, Embase, and Cochrane Library databases were systematically searched from 01 July 2020 to 28 February 2022 to update a previous systematic review with the same search strategy from the inception to 30 June 2020. Eligible studies were those that reported effectiveness (stroke/systemic embolism and myocardial infarction) or safety (gastrointestinal or major bleeding and death) outcomes of off-label doses of DOACs compared to on-label doses in AF patients. A random-effects meta-analysis was performed to estimate the pooled hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were performed by specific DOACs and geographic regions. Results Twenty-two studies were included. Off-label, underdosed DOACs, compared to on-label doses, were not associated with an increased risk of stroke (HR 1.03, 95%CI: 0.88-1.17) but were associated with an increased risk of death (HR 1.26, 95%CI: 1.09-1.43). However, risk varied depending on the active ingredient. No other safety outcomes were associated with underdosed DOACs. No significant differences were observed by geographic regions. Compared to on-label DOACs, overdosing increased the risk of stroke (HR 1.17, 95%CI: 1.04-1.31), major bleeding (HR 1.18, 95%CI: 1.05-1.31), and death (HR 1.19, 95%CI: 1.03-1.35). Risk varied between geographical regions. Conclusions Off-label underdoses, compared to on-label dosing of DOACs, did not increase the risk of stroke but did increase overall mortality. Overdosed DOACs, compared to on-label doses, were associated with an increased risk of stroke, major bleeding, and death. Future studies must examine these associations, focusing on specific active ingredients and geographic settings.

The goal of post-transplant immunosuppressive drug therapy is to prevent organ rejection while minimizing drug toxicities. In clinical practice, a multidrug approach is commonly used and involves drugs with different mechanisms of action, including calcineurin inhibitors (CNI) (tacrolimus or cyclosporine), antimetabolite (antimet) (mycophenolate or azathioprine), inhibitors of mechanistic target of rapamycin (mTOR) (sirolimus or everolimus), and/or steroids. Although evidence based on several randomized clinical trials is available, the optimal immunosuppressive therapy has not been established and may vary among organ transplant settings. To improve the knowledge on this topic, a multiregional research network to Compare the Effectiveness and Safety of Immunosuppressive drugs in Transplant patients (CESIT) has been created with the financial support of the Italian Medicines Agency. In this article, we describe the development of this network, the framework that was designed to perform observational studies, and we also give an overview of the preliminary results that we have obtained. A multi-database transplant cohort was enrolled using a common data model based on healthcare claims data of four Italian regions (Lombardy, Veneto, Lazio, and Sardinia). Analytical datasets were created using an open-source tool for distributed analysis. To link the National Transplant Information System to the regional transplant cohorts, a semi-deterministic record linkage procedure was performed. Overall, 6,914 transplant patients from 2009–19 were identified: 4,029 (58.3%) for kidney, 2,219 (32.1%) for liver, 434 (6.3%) for heart, and 215 (3.1%) for lung. As expected, demographic and clinical characteristics showed considerable variability among organ settings. Although the triple therapy in terms of CNI + antimet/mTOR + steroids was widely dispensed for all settings (63.7% for kidney, 33.5% for liver, 53.3% for heart, and 63.7% for lung), differences in the active agents involved were detected. The CESIT network represents a great opportunity to study several aspects related to the use, safety, and effectiveness of post-transplant maintenance immunosuppressive therapy in real practice.

Background: DOACs are characterized by a higher incidence of gastrointestinal bleeding and this may be different among males and females. Female patients were underrepresented in the DOAC pivotal trials. We aimed to assess real-world differences in gastrointestinal bleeding with oral anticoagulants (DOACs and VKAs) among males and females with atrial fibrillation. Methods: We performed a population-based retrospective analysis on linked administrative claims. Atrial fibrillation patients of 65 years and above were considered. Bleeding risk factors were assessed through HASBED and previous history of gastrointestinal disease. A time-to-event analysis compared gastrointestinal bleeding between males and females. Results: The overall cohort consisted of 15338 (55% female) DOAC and 44542 (50% female) VKA users. Most of the patients showed HASBED ≥2. Incidence rate of GI bleeding was higher in females as compared to males among DOAC users (0.90% vs 0.59%), and significant gender difference in GI bleeding was found, after adjustment, in the Cox regression analysis (HR 1.48, 95%CI 1.02-2.16). In the VKA group, no significant difference among genders was found in the time-to-event analysis. Conclusions: Our data suggest that female patients treated with DOACs have a higher risk of GI bleeding versus male patients; this difference is not observed in VKA patients.

Abstract Public health strategies for malaria in endemic countries aim to prevent transmission of the disease and control the vector. This historical analysis considers the strategies for vector control developed during the first four decades of the twentieth century. In 1925, policies and technological advances were debated internationally for the first time after the outbreak of malaria in Europe which followed World War I. This dialogue had implications for policies in Europe, Russia and the Middle East, and influenced the broader international control agenda. The analysis draws on the advances made before 1930, and includes the effects of mosquito-proofing of houses; the use of larvicides (Paris Green) and larvivorous fish (Gambusia); the role of large-scale engineering works; and the emergence of biological approaches to malaria. The importance of strong government and civil servant support was outlined. Despite best efforts of public health authorities, it became clear that it was notoriously difficult to interrupt transmission in areas of moderately high transmission. The importance of combining a variety of measures to achieve control became clear and proved successful in Palestine between 1923 and 1925, and improved education, economic circumstances and sustained political commitment emerge as key factors in the longer term control of malaria. The analysis shows that the principles for many of the present public health strategies for malaria have nearly all been defined before 1930, apart from large scale usage of pesticides, which came later at the end of the Second World War. No single intervention provided an effective single answer to preventing transmission, but certainly approaches taken that are locally relevant and applied in combination, are relevant to today’s efforts at elimination.

Background: Sparse population-based data are available on the prevalence and etiology of chronic liver disease (CLD) in Italy. The study aims to assess the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in CLD according to age, gender and ethnicity. Methods: Clinically diagnosed CLD in the general population aged 20–59 years in the Veneto Region (North-Eastern Italy) were identified through the Adjusted Clinical Groups System, by record linkage of the archive of subjects enrolled in the Regional Health System with Hospital Discharge Records, Emergency Room visits, Chronic disease registry for copayment exemptions, and the Home care database. Age-standardized prevalence rates (PR) were computed in Italians and immigrants, based on country of citizenship. Results: Overall 22,934 subjects affected by CLD in 2016 were retrieved, 21% related to HBV and 43% to HCV infection. The prevalence of HCV-related CLD was higher in males, peaking at 50–54 years (males = 11/1000; females = 4/1000). The PR of HBV-related CLD was almost negligible in the Italian population (1/1000), and higher among immigrants, especially from East Asia (males = 17/1000; females = 11/1000) and Sub-Saharan Africa (males = 13/1000; females = 10/1000). Conclusion: Specific population sub-groups identified by age, gender, and ethnicity, were demonstrated to be at increased risk, and these trends are in line with global epidemiological patterns of viral hepatitis.

Background. Despite massive immigration towards Southern Europe in the last two decades, data on mortality by cause among immigrants in Italy are scarce. The aim of this study was to investigate mortality from all and from specific causes of death among immigrants residing in the Veneto Region (Northeastern Italy).Methods. Mortality records for the period 2008–2013 were extracted from the regional archive of causes of death, whereas population data were obtained from the 2011 Italian census. Immigrants were grouped by area of provenience based on the information on country of citizenship available both in mortality and census data. Standardized Mortality Ratios (SMR) with 95% Confidence Intervals (CI) were computed for the period 2008–2013 in subjects aged 20–59 years, with rates of Italian citizens as a reference.Results. Overall mortality was reduced both in male (SMR 0.86, CI [0.80–0.92]) and female immigrants (SMR 0.72, CI [0.65–0.78]), although an increased risk was observed for subjects from Sub-Saharan Africa. Significantly raised SMR for circulatory diseases were found among Sub-Saharan Africans and Southern Asians in both genders. Sub-Saharan Africans experienced a higher risk of death, especially from cerebrovascular diseases: SMR 4.78 (CI [2.67–7.89]) and SMR 6.09 (CI [1.96–14.2]) in males and females, respectively. Among Southern Asians, the increase in mortality from ischemic heart diseases reached statistical significance in males (SMR 2.53, CI [1.42–4.18]). In spite of a lower risk of death for all neoplasms combined, mortality from cancer of cervix uteri was increased among immigrants (SMR 2.61, CI [1.35–4.56]), as well as for other cancer sites in selected immigrant groups. A raised mortality was found for infectious diseases in Sub-Saharan Africans (both genders), and for transport accidents among females from Eastern Europe.Conclusion. Our study showed great variations in mortality by cause and area of provenience among immigrants resident in the Veneto Region and highlighted specific health issues that should be addressed through tailored efforts in chronic diseases prevention.

Antecedentes: Durante las últimas cuatro décadas, las vacunas han sido la principal arma global para disminuir la repercusión de la gripe en las personas de edad avanzada, y a nivel mundial se recomiendan para los individuos de 65 años o más de edad. El objetivo principal de la vacunación contra la gripe en las personas de edad avanzada es reducir el riesgo de complicaciones en quienes son más vulnerables. Objetivos: Evaluar la efectividad de las vacunas sobre la prevención de la gripe, la enfermedad similar a la gripe, los ingresos hospitalarios, las complicaciones y la mortalidad en las personas de edad avanzada. Identificar y evaluar los estudios comparativos que evalúan los efectos de las vacunas para la gripe en las personas de edad avanzada. Documentar los tipos y la frecuencia de los efectos adversos asociados con las vacunas contra la gripe en las personas de edad avanzada. Estrategia de búsqueda: Se realizaron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL), que contiene el Registro Especializado de Ensayos Controlados del Grupo Cochrane de Infecciones Respiratorias Agudas (Cochrane Acute Respiratory Infections [ARI]) (The Cochrane Library número 4 de 2009), MEDLINE (enero de 1966 hasta la primera semana de octubre de 2009); EMBASE (1974 hasta octubre de 2009) y Web of Science (1974 hasta octubre de 2009). Criterios de selección: Ensayos controlados aleatorios (ECAs), ensayos controlados cuasialeatorios, estudios de cohortes y estudios de casos y controles que evalúan la eficacia contra la gripe (casos confirmados por laboratorio), la efectividad contra la enfermedad similar a la gripe (ESG) o la seguridad. Se consideró cualquier vacuna administrada de forma independiente, en cualquier dosis, preparación o cronograma de administración, comparada con placebo o ninguna intervención. Obtención y análisis de los datos: Los informes se agruparon en primer lugar según el contexto del estudio (comunidad o establecimientos de atención a largo plazo) y luego por el nivel de circulación vírica y de pareamiento de la vacuna. Se estratificó adicionalmente por la administración concomitante de la vacuna de polisacárido antineumocócico (PPV) y por diferentes tipos de vacunas contra la gripe. Se analizaron los siguientes resultados: gripe, enfermedad similar a la gripe, ingresos hospitalarios, complicaciones y muertes. Resultados principales: Se incluyeron 75 estudios. En general se identificaron 100 conjuntos de datos. Se identificó un ECA que evaluó la eficacia y la efectividad. Aunque el mismo pareció mostrar un efecto contra los síntomas de la gripe no tuvo poder estadístico suficiente para detectar efectos sobre las complicaciones (1348 participantes). La base de pruebas restante incluyó ensayos controlados no aleatorios. Debido a la baja calidad general de los ensayos controlados no aleatorios y la probable presencia de sesgos, que dificultan la interpretación de estos datos y hacen que cualquier conclusión sólida se torne potencialmente engañosa, no fue posible establecer conclusiones claras acerca de los efectos de las vacunas en las personas de edad avanzada. Conclusiones de los autores: Las pruebas disponibles son de calidad deficiente y no proporcionan orientación con respecto a la seguridad, la eficacia o la efectividad de las vacunas contra la gripe en las personas de 65 años de edad o más. Para resolver la incertidumbre se debe realizar un ensayo aleatorio controlado con placebo, con financiamiento público y con poder estadístico adecuado, durante varias estaciones.