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• The prevalence of pSS in Italy may be consistent with the definition of rare disease. • Patients with pSS show higher rates of hospitalization, pharmacological treatment, and outpatient care needs. • Economic impact of pSS patients' health care is three-times higher than the general population. Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with significant impact on morbidity, mortality, and quality of life. This study aimed to evaluate epidemiology, healthcare needs and related costs of pSS patients from the Italian National Health Service perspective. From the Fondazione Ricerca e Salute's database (∼5 million inhabitants/year), pSS prevalence in 2018 was calculated. Demographics, mean healthcare consumptions and direct costs at one year following index date (first in-hospital diagnosis/disease waiver claim) were analysed through an individual direct matched pair case-control analysis (age, sex, residency). In Italy, 3.8/10,000 inhabitants were identified as affected by pSS (1,746 case: 1,746 controls) in 2018. In the year following index date, 53.7% of cases and 42.7% of controls received ≥1 drug (p <0.001); mean per capita cost was €501 and €161, respectively (p <0.01). At least one hospitalization occurred to 7.8% of cases and 3.9% of controls (p <0.001) with mean per capita costs of €416 and €129, respectively (p = 0.46). At least one outpatient specialist service was performed in 49.8% of cases and 30.6% of controls (p <0.001); mean per capita costs were €200 and €75, respectively (p <0.01). Overall, mean annual costs were €1,171 per case and €372 per control (p < 0.01). According to results of this population-based study, the prevalence of pSS in Italy appears to be consistent with the definition of rare disease. Patients with pSS have higher pharmacological, in-hospital and outpatient specialist care needs, leading to three-times higher overall cost for the INHS, compared to the general population. [ABSTRACT FROM AUTHOR]

Objectives: The PROtein-enriched MEDiterranean diet to combat undernutrition and promote healthy neuroCOGnitive ageing in older adults (PROMED-COG) is a European project that investigates the role of nutritional status on neurocognitive ageing. This methodological paper describes the harmonization process of dietary data from four Italian observational studies (Pro.V.A., ILSA, BEST-FU, and NutBrain). Methods: Portion sizes and food frequency consumption within different food frequency questionnaires were retrospectively harmonized across the datasets on daily food frequency, initially analyzing raw data using the original codebook and establishing a uniform food categorization system. Individual foods were then aggregated into 27 common food groups. Results: The pooled cohort consisted of 9326 individuals (40-101 years, 52.4% female). BEST-FU recruited younger participants who were more often smokers and less physically active than those of the other studies. Dietary instruments varied across the studies differing in the number of items and time intervals assessed, but all collected dietary intake through face-to-face interviews with a common subset of items. The average daily intakes of the 27 food groups across studies varied, with BEST-FU participants generally consuming more fruits, vegetables, red meat, and fish than the other studies. Conclusions: Harmonization of dietary data presents challenges but allows for the integration of information from diverse studies, leading to a more robust and statistically powerful dataset. The study highlights the feasibility and benefits of data harmonization, despite inherent limitations, and sets the stage for future research into the effects of diet on cognitive health and aging.

Background: An increasing number of observational studies combine large sample sizes with low participation rates, which could lead to standard inference failing to control the false-discovery rate. We investigated if the 'empirical calibration of P-value' method (EPCV), reliant on negative controls, can preserve type I error in the context of survival analysis.Methods: We used simulated cohort studies with 50% participation rate and two different selection bias mechanisms, and a real-life application on predictors of cancer mortality using data from four population-based cohorts in Northern Italy (n = 6976 men and women aged 25-74 years at baseline and 17 years of median follow-up).Results: Type I error for the standard Cox model was above the 5% nominal level in 15 out of 16 simulated settings; for n = 10 000, the chances of a null association with hazard ratio = 1.05 having a P-value < 0.05 were 42.5%. Conversely, EPCV with 10 negative controls preserved the 5% nominal level in all the simulation settings, reducing bias in the point estimate by 80-90% when its main assumption was verified. In the real case, 15 out of 21 (71%) blood markers with no association with cancer mortality according to literature had a P-value < 0.05 in age- and gender-adjusted Cox models. After calibration, only 1 (4.8%) remained statistically significant.Conclusions: In the analyses of large observational studies prone to selection bias, the use of empirical distribution to calibrate P-values can substantially reduce the number of trivial results needing further screening for relevance and external validity. [ABSTRACT FROM AUTHOR]

Background: Nabiximols (THC/CBD Oromucosal Spray, Sativex) is used as an add-on therapy to treat moderate to severe spasticity of Multiple Sclerosis (MS). Objectives: To examine the impact of physiotherapy (PT) programs on effectiveness and persistence of nabiximols treatment in people with MS-related spasticity. Methods: This is an observational multicenter study with a follow-up period of 12 weeks, conducted in routine care settings in Italy. Patients with moderate to severe MS-related spasticity who started nabiximols were included. Spasticity was evaluated by the patient-rated 0–10 numerical rating scale (NRS). Clinical data were collected at baseline (T0), 4 weeks (T1) and 12 weeks (T2) months after enrollment. Results: A total of 297 MS patients were selected, 290 completed the 3 months follow-up period. Mean NRS scores were 7.6 ± 1.1 at T0, 5.8 ± 1.4 at T1 and 5.5 ± 1.5 at T2. At T1, 77% of patients reached ≥20% improvement (initial response, IR); 22% reached ≥30% improvement (clinically relevant response, CRR). At T1, patients undergoing PT had a higher probability to reach CRR (Odds Ratio = 2.6 95% CI 1.3–5.6, p = 0.01). Nabiximols was discontinued in 30/290 (10.3%) patients at T1 (early discontinuers) and in 71/290 (24.5%) patients at T2 (late discontinuers). The probability of being late discontinuers was reduced in patients undergoing PT (Hazard Ratio = 0.41; 95% CI 0.23–0.69, p = 0.001). Conclusions: Our real-life study confirms nabiximols’ effectiveness in MS-related spasticity and suggests that the association of a PT program may improve overall response and persistence to nabiximols treatment. [ABSTRACT FROM AUTHOR]

The intake of Vitamin D against COVID-19 has theoretical bases. In the 3-year period of the pandemic, hundreds of favorable observational studies and some small randomized controlled trials (RCTs) have been produced.However, to date, RCTs of larger size and quality have unfavorable results and do not support its use, neither in oral form at various doses nor as injection boluses nor in prophylaxis nor in treatment of COVID-19, not even in severe or critical cases, nor to prevent deaths.The results of a recent sequential meta-analysis of a few RCTs, presented as 'definitive evidence', are biased by the weight of the improper inclusion of an observational study.Interference with correct information, both in the media and in scientific communication, risks obscuring in clinical practice the conclusions of the most valid studies available.

Objectives: We studied survival and associated risk factors in an Italian nationwide cohort of HIV-infected individuals after an AIDS-defining cancer (ADC) or non-AIDS-defining cancer (NADC) diagnosis in the modern cART era. Methods: Multi-center, retrospective, observational study of HIV patients included in the MASTER Italian Cohort with a cancer diagnosis from January 1998 to September 2012. Malignancies were divided into ADC or NADC on the basis of the Centre for Disease Control-1993 classification. Recurrence of cancer and metastases were excluded. Survivals were estimated according to the Kaplan-Meier method and compared according to the log-rank test. Statistically significant variables at univariate analysis were entered in a multivariate Cox regression model. Results: Eight hundred and sixty-six cancer diagnoses were recorded among 13,388 subjects in the MASTER Database after 1998: 435 (51%) were ADCs and 431 (49%) were NADCs. Survival was more favorable after an ADC diagnosis than a NADC diagnosis (10-year survival: 62.7%±2.9% vs. 46%±4.2%; p = 0.017). Non-Hodgkin lymphoma had lower survival rates than patients with Kaposi sarcoma or cervical cancer (10-year survival: 48.2%±4.3% vs. 72.8%±4.0% vs. 78.5%±9.9%; p<0.001). Regarding NADCs, breast cancer showed better survival (10-year survival: 65.1%±14%) than lung cancer (1-year survival: 28%±8.7%), liver cancer (5-year survival: 31.9%±6.4%) or Hodgkin lymphoma (10-year survival: 24.8%±11.2%). Lower CD4+ count and intravenous drug use were significantly associated with decreased survival after ADCs or NADCs diagnosis. Exposure to cART was found to be associated with prolonged survival only in the case of ADCs. Conclusions: cART has improved survival in patients with an ADC diagnosis, whereas the prognosis after a diagnosis of NADCs is poor. Low CD4+ counts and intravenous drug use are risk factors for survival following a diagnosis of ADCs and Hodgkin lymphoma in the NADC group. [ABSTRACT FROM AUTHOR]

Background: The relationship between hospital volumes and short-term patients’ outcomes of colon cancer (CC) surgery is not well established in the literature. Moreover, evidence about short-term outcomes of urgent compared with elective CC procedures is scanty. The aims of this study are 1) to determine whether caseloads and other hospital characteristics are associated with short-term outcomes of CC surgery; 2) to compare the outcomes of urgent and elective CC surgery. Methods: A total of 14,200 patients undergoing CC surgery between 2005 and 2010 in the General Surgery Units (GSUs) of the hospitals of Emilia-Romagna region, Northern Italy, were identified from the hospital discharge records database. The outcomes of interest were 30-day in-hospital mortality, re-intervention and 30-day re-admission. Using multilevel analysis, we analyzed the relationship of GSU volumes and focused practice, defined as the percentage of CC operations over total operations, with the three outcomes. Results: High procedure volumes were associated with a lower risk of 30-day in-hospital mortality, after adjusting for patients’ characteristics [aOR (95% CI) = 0.51 (0.33–0.81)]. Stratified analyses for elective and urgent surgery showed that high volumes were associated with a lower 30-day mortality for elective patients [aOR (95% CI) = 0.35 (0.17–0.71)], but not for urgent patients [aOR (95% CI) = 0.72 (0.42–1.24)]. Focused practice was an independent predictor of re-intervention [aOR (95% CI) = 0.67 (0.47–0.97)] and re-admission [aRR (95% CI) = 0.88 (0.78–0.98)]. Conclusions: The present study adds evidence in support of the notion that patients with CC undergoing surgery at high-volume and focused surgical units experience better short-term outcomes. [ABSTRACT FROM AUTHOR]

We evaluated the risk of worsening according to the length of exposure to interferon beta (IFNβ) in a large cohort of 2090 multiple sclerosis patients collected by the Italian MS Database Network. Overall 44 140 patient-visits with a follow-up of 22 143 patient-years were evaluated. Forty-one per cent of patients were exposed to IFNβ for up to 2 years, 39% for 2–4 years and 20% for more than 4 years. A Cox regression model was used to analyse two clinical outcomes: disability progression and worsening of relapse rate. The technique of propensity score was applied to reduce bias in the comparison of non-randomized groups. The risks of disability progression (HR=0.23; 95% CI: 0.17–0.30) and worsening of relapse rate (HR=0.19; 95% CI: 0.14–0.27) were reduced by about 4–5-fold in patients exposed to IFNβ for more than four years, compared with patients exposed for up to two years. The propensity score technique confirmed the findings. The proportion of days covered by IFNβ treatment was lower (p<0.0001) in patients exposed to IFNβ for up to two years than in other groups. A clinical stabilization over two years of IFNβ exposure may predict a subsequent good clinical response to treatment. [ABSTRACT FROM AUTHOR]

Background: The availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy., Methods: Demographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence., Results: Of 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among second-line DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation., Conclusion: The use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors., Competing Interests: Declaration of Competing Interest AM, GF, VV, SF, FC, FM, AF, FR, GS, MV and MDB have no conflicts of interest. AG received research support funding and advisory board honoraria from Merck., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Protopathic bias is a systematic error which occurs when measured exposure status may be affected by the latent onset of the target outcome. In this article, we aimed to discuss the benefits and drawbacks of the lag-time approach to address this type of bias., Study Design and Setting: The lag-time approach consists in excluding from exposure assessment the period immediately preceding the outcome detection date. With the help of simple causal diagrams, we illustrate the rationale and limitations of such strategy. The lag-time approach was illustrated in a case-crossover study, based on the health care utilization databases of the Italian Lombardy Region, on the real-world effectiveness of some respiratory drugs (exposure) in preventing asthma exacerbations (outcome)., Results: A total of 7,300 of patients who were admitted to an emergency department (ED) for asthma during 2010-2012 (cases) were included. Use (vs. nonuse) of short-acting beta-agonists (SABAs, an asthma reliever medication) during the 90 days before the ED admission date was associated with an increased risk of the outcome [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.72, 2.22]. This paradoxical finding may be explained by protopathic bias, as SABA use prior the ED admission may be affected by preceding respiratory distress. Indeed, when a 120-day period preceding the ED admission was ignored from drug exposure assessment (lag time), SABAs were found to be associated with a reduced risk of the outcome (OR: 0.81; 95% CI: 0.84, 0.92), as expected., Conclusions: The lag-time approach can be a useful strategy to circumvent protopathic bias in observational studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)