Thrombotic and hemorrhagic complications in idiopathic erythrocytosis

We report clinical features of a large cohort of patients with IE compared to a cohort of patients with PV, focusing on the thrombotic and hemorrhagic risk

Pediatric admissions to emergency departments of North-Western Italy during COVID-19 pandemic: A retrospective observational study

COVID-19 pandemic caused huge decrease of pediatric admissions to Emergency Department (ED), arising concerns about possible delays in diagnosis and treatment of severe disorders

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p < 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

The role of the oncogene ETV4 in the regulation of genes involved in prostate cancer pathogenesis

Prostate cancer is the second leading cause of death in the male population. In most prostate cancers, ETS proteins (ERG, ETV1, ETV4) are over-expressed because of recurrent chromosomal translocations that bring an ETS gene under the control of a promoter of a gene highly expressed in the prostate. The role of ERG and ETV1 in determining PC has been widely studied, but only little information is available about the tumorigenic role of ETV4. It has been previously demonstrated that ETV4 over-expression promotes neoplastic features in human prostate cell lines. In particular, ETV4 increases migration, invasion, proliferation, cell cycle progression, anchorage-independent growth, epithelial-mesenchymal transition and tumor growth in xenograft model. Moreover, ETV4 over-expression in prostate cell lines was associated with the deregulation of cell cycle progression and reduction of p21 and p27. In keeping, in two independent transgenic mouse lines that we have engineered to express human ETV4 in a prostate-specific manner, we have observed that half of 10 months old transgenic mice develop low-grade prostatic intraepithelial neoplasia (PIN) lesions. The first aim of this PhD work was to evaluate also in vivo the expression levels of p21 and p27 and to investigate the mechanisms through which ETV4 regulates p21 and p27. The proportion of Ki67+ prostate cells was significantly increased in 5 months-old ETV4-transgenic mice compared to wild type mice, confirming that also in vivo ETV4 is associated with increased proliferation. Moreover, in these mice cdkn1a (p21) was reduced at both mRNA and protein levels whereas p27 was reduced only at protein level. To determine how ETV4 regulates the expression of CDKN1A in human prostate cells, we performed ChIP and luciferase assays. In the 2 kb upstream the transcriptional start site of CDKN1A gene we identified 2 putative ETV4 binding sites (BS): distal (-1409/-1403) and proximal (-704/-696) BS. ChIP assay suggested that ETV4 binds the proximal but not the distal BS of CDKN1A promoter. The Luciferase assay performed in several cell lines using a vector, in which the firefly luciferase was expressed under the control of the WT proximal ETV4 BS, showed that ETV4 over-expression induces a reduction of the relative luciferase expression, while the normal level is restored when this site is either mutated or deleted. In addition, we found that ETV4 exerts also an indirect regulation of p21 expression through the downregulation of the protein level of p53. In order to further understand the molecular mechanisms by which ETV4 promotes prostate tumorigenesis, we compared, by micro-array analysis, the expression profile of prostate tissue of ETV4 mice with that of WT mice at 5 months of age. The second aim of this PhD work was to investigate, after validation, some of the genes found differentially expressed in ETV4 mice. In particular, we focused on the secretory leukocyte protease inhibitor (SLPI). SLPI is a serine protease that protects host tissues from the excessive damage by proteolytic enzymes released during inflammation and it has been found over-expressed in a variety of cancers. However, it is paradoxically reduced in localized PC, but it may increase during progression in patients resistant to androgen deprivation therapy. It is intriguing, that this is consistent with the reduced SLPI expression we found in our ETV4 mouse model of early PC. In order to demonstrate that ETV4 is responsible for SLPI downregulation we have studied two human prostate cell lines: (i) the PC3 prostate cancer cell line that express high levels of ETV4 and (ii) RWPE normal prostate cell line that does not express ETV4. In these mirror cellular models we found that ETV4 silencing in PC3 cells results in increased levels of SLPI mRNA and protein whereas their levels were reduced upon the overexpression of ETV4 in RWPE cells. Moreover, ETV4 reduces luciferase expression driven by the SLPI promoter in different cell lines but ChIP assay have not been able to demonstrate the direct binding of ETV4 to the SLPI promoter. In addition, we investigated ETV1, another ETS protein of Pea3 subfamily, and we found that also ETV1 reduces SLPI expression. In summary, this PhD work has clarified some of the oncogenic mechanisms of ETV4 in the prostate cancer. 1) ETV4 over-expression increases the proliferation rate of prostate cells leading to the development of Prostate Intraepithelial Neoplasia. This increased proliferation rate is associated with the down regulation of p21, that results from both the binding of ETV4 to the p21 promoter and from the ETV4-mediated reduction of p53. 2) ETV4 downregulates the expression of SLPI in mice and in human prostate cell lines. This role is likely shared with other ETS transcriptional factors, such as ETV1, as we demonstrated in human prostate cell lines; however, this regulation is not exerted by the direct regulation of the SLPI promoter. This negative regulation of SLPI exerted by ETS proteins could explain the clinical finding of the reduced levels of SLPI during the early phase of prostate cancer