Risk of breakthrough infection and hospitalisation after COVID-19 primary vaccination by HIV status in four Italian regions during 2021.

BACKGROUND: As of 2024, vaccination remains the main mitigation measure against COVID-19, but there are contradictory results on whether people living with HIV (PLWH) are less protected by vaccines than people living without HIV (PLWoH). In this study we compared the risk of SARS-CoV-2 infection and COVID-19 hospitalisation following full vaccination in PLWH and PLWoH. METHODS: We linked data from the vaccination registry, the COVID-19 surveillance system and from healthcare/pharmacological registries in four Italian regions. We identified PLWH fully vaccinated (14 days post completion of the primary cycle) and matched them at a ratio of 1:4 with PLWoH by week of vaccine administration, age, sex, region of residence and comorbidities. Follow-up started on January 24, 2021, and lasted for a maximum of 234 days. We used the Kaplan-Meier estimator to calculate the cumulative incidence of infection and COVID-19 hospitalisation in both groups, and we compared risks using risk differences and ratios taking PLWoH as the reference group. RESULTS: We matched 42,771 PLWH with 171,084 PLWoH. The overall risk of breakthrough infection was similar in both groups with a rate ratio (RR) of 1.10 (95% confidence interval (CI):0.80-1.53). The absolute difference between groups at the end of the study period was 8.28 events per 10,000 person-days in the PLWH group (95%CI:-18.43-40.29). There was a non-significant increase the risk of COVID-19 hospitalisation among PLWH (RR:1.90; 95%CI:0.93-3.32) which corresponds to 6.73 hospitalisations per 10,000 individuals (95%CI: -0.57 to 14.87 per 10,000). CONCLUSIONS: Our findings suggest PLWH were not at increased risk of breakthrough SARS-CoV-2 infection or COVID-19 hospitalisation following a primary cycle of mRNA vaccination.

The Italian national survey on Coronavirus disease 2019 epidemic spread in nursing homes.

INTRODUCTION: Residents in facilities such as nursing homes (NHs) are particularly vulnerable to Coronavirus disease 2019 (COVID-19). A national survey was carried out to collect information on the spreading and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in nursing homes, and on how suspected and/or confirmed cases were managed. We carried out a survey between 25 March 2020 and 5 May 2020. MATERIALS AND METHODS: All Italian nursing homes either public or providing services both privately and within the NHS were included in the study. An on-line questionnaire was sent to 3292 nursing homes across all Italian regions. Nursing homes were also contacted by telephone to provide assistance in completing the questionnaire. RESULTS: A total of 1356 nursing homes voluntarily participated to the survey, hosting a total of 100,806 residents. Overall, 9154 residents died due to any cause from February 1 to the time when the questionnaire was completed (from March 25 to May 5). Of these, 7.4% had COVID-19 and 33.8% had flu-like symptoms, corresponding to a cumulative incidence of 0.7 and 3.1, respectively. Lack of personnel, difficulty in transferring patients to hospital or other facility, isolating residents with COVID-19, number of beds and geographical area were the main factor positively associated to the presence of COVID-19 in nursing homes. DISCUSSION: This survey showed the dissemination and impact of SARS-CoV-2 infection in Italian nursing homes and on how older and potentially chronically ill people residing in these long-term care facilities were managed.

Sex differences in factors associated with heart failure and diastolic left ventricular dysfunction: a cross-sectional population-based study.

BACKGROUND: Although sex differences in cardiovascular diseases are recognised, including differences in incidence, clinical presentation, response to treatments, and outcomes, most of the practice guidelines are not sex-specific. Heart failure (HF) is a major public health challenge, with high health care expenditures, high prevalence, and poor clinical outcomes. The objective was to analyse the sex-specific association of socio-demographics, life-style factors and health characteristics with the prevalence of HF and diastolic left ventricular dysfunction (DLVD) in a cross-sectional population-based study. METHODS: A random sample of 2001 65-84 year-olds underwent physical examination, laboratory measurements, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrocardiography, and echocardiography. We selected the subjects with no missing values in covariates and echocardiographic parameters and performed a complete case analysis. Sex-specific multivariable logistic regression models were used to identify the factors associated with the prevalence of the diseases, multinomial logistic regression was used to investigate the factors associated to asymptomatic and symptomatic LVD, and spline curves to display the relationship between the conditions and both age and NT-proBNP. RESULTS: In 857 men included, there were 66 cases of HF and 408 cases of DLVD (77% not reporting symptoms). In 819 women, there were 51 cases of HF and 382 of DLVD (79% not reporting symptoms). In men, the factors associated with prevalence of HF were age, ischemic heart disease (IHD), and suffering from three or more comorbid conditions. In women, the factors associated with HF were age, lifestyles (smoking and alcohol), BMI, hypertension, and atrial fibrillation. Age and diabetes were associated to asymptomatic DLVD in both genders. NT-proBNP levels were more strongly associated with HF in men than in women. CONCLUSIONS: There were sex differences in the factors associated with HF. The results suggest that prevention policies should consider the sex-specific impact on cardiac function of modifiable cardiovascular risk factors.

Integrated care pathways on dementia in Italy: a survey testing the compliance with a national guidance.

Dementias are chronic, degenerative neurological disorders with a complex management that require the cooperation of different healthcare professionals. The Italian Ministry of Health produced the document "Guidance on Integrated Care pathway for People with Dementia" (GICPD) with the specific objective of providing a standardized framework for the definition, development, and implementation of integrated care pathways (ICP) dedicated to people with dementia. We searched all available Italian territorial ICPs. Two raters assessed the retrieved ICPs with a 2-point scale on a 43-item checklist based on the GICPD. Only 5 out of 21 regions and 5 out of 101 local health authorities had an ICP, with most ICPs having a moderate compliance to the GICPD, in particular for the items referring to the development and implementation of the care pathways. A low to moderate inter-rater agreement was observed, mainly due to a lack of standardized models to describe ICPs for dementias. Results suggest that policy- and decision-makers should pay more attention to the GICPD when producing ICPs. The direct communication with clinicians, and the implementation of more precise and appropriate clinical outcomes, could increase the involvement of clinicians, whose participation is crucial to guarantee that ICPs meet needs of patients and their carers.

Prevalence and Incidence of Multiple Sclerosis in the City of Biancavilla.

BACKGROUND: It is common that the epidemiology of multiple sclerosis (MS) varies with geography and ethnicity. Recent studies show a continuous growth of incidence and prevalence in Sicily, despite the controversial "latitude gradient theory." OBJECTIVES: The aim of our study is to ascertain incidence and prevalence rates of MS in the city of Biancavilla, Sicily, Southern Italy. METHOD: Case ascertainment approach and a clinical database collecting data of MS cases to Biancavilla, according to McDonald 2011 and Thompson 2018 criteria, from 1992 to 2018, have been used to the study. We further collected information regarding the familiarity of patients with Mesothelioma, highly incident in this geographic area. RESULTS: The results showed an increase of the mean annual incidence for the period 2012-2018 (16.8/100,000) compared to 1992-1996 (4.5/100,000), and a standardized incidence ratio of 1.41 (95% CI 0.74-2.45). On December 31, 2018, 70 patients suffering from definite MS and living in Biancavilla yielded a crude prevalence of 292.3 per 100,000 (198.2/100,000 for men; 380.7/100,000 for women) with a standardized morbidity ratio of 2.3 (95% CI 1.8-2.9). CONCLUSIONS: Our data confirmed Biancavilla is an area at high risk for MS, ascribable to increased survival, improved ascertainment, or maybe related to a genetic or environmental risk. At the time, any relation with mesothelioma was excluded.

Predictors of Oral Feeding Resumption after Stroke in a Rehabilitation Hospital: A Retrospective Study.

BACKGROUND: Dysphagia is common after stroke, requiring exclusive enteral feeding in 20% of patients. Recovery of oral feeding is associated with increased quality of life, better functional outcomes, and decreased mortality rates. However, evidence is heterogeneous and not conclusive on which factors are predictive of oral feeding recovery for stroke patients in rehabilitation units. AIM: To investigate predictors of complete oral feeding recovery. DESIGN: Retrospective study. SETTING: Intensive inpatient rehabilitation hospital. POPULATION: Poststroke dysphagic individuals with enteral feeding. METHODS: Retrospective chart review of demographic, clinical, rehabilitation, and swallowing factors. Univariate analysis and multivariate regression analysis were used to compare variables between the oral feeding recovery group and the enteral feeding group at discharge. RESULTS: One hundred thirty-nine patients were included in the analysis. A total of 61.9% of the sample population resumed complete oral intake at discharge. There were statistically significant differences between the 2 groups in Functional Independence Measure cognitive score, clinical swallow evaluation, and instrumental swallow evaluation at admittance, and dysphagia rehabilitation. Multiple logistic regression analysis identified the absence of aspiration signs with liquids associated with a higher probability of the resumption of complete oral feeding (odds ratio [OR] 3.57; 95% confidence interval [CI] 1.07-11.89). Age between 73 and 79 years (OR .96; 95% CI .01-.58), the presence of aspiration and/or penetration (OR .22; 95% CI .07-.72), and the presence of residue (OR .14; 95%CI .04-.43) during fiberoptic endoscopic evaluation of swallowing presented lower probability of returning to complete oral feeding. CONCLUSION: Several demographic and swallowing characteristics predicted oral feeding recovery. Absence of dysphagia signs documented on fiberoptic endoscopic evaluation of swallowing was the strongest predictor of complete oral feeding resumption.

Free and cued selective reminding test predicts progression to Alzheimer's disease in people with mild cognitive impairment.

INTRODUCTION: To assess the diagnostic accuracy of the free and cued selective reminding test (FCSRT) for the development of Alzheimer's disease (AD) in people with mild cognitive impairment (MCI). METHODS: We enrolled 187 consecutive MCI outpatients from a memory clinic that were evaluated at baseline and every 6 to 12 months through an extensive clinical and neuropsychological protocol. For each test, measures of diagnostic accuracy were obtained. To improve the overall specificity of the neuropsychological battery, we also used the diagnostic tests in parallel combination. The association between FCSRT indexes and AD was tested through proportional hazard regression models with other dementia subtypes as competing event. Laplace regression was used to model time-to-AD diagnosis as a function of FCSRT indexes. RESULTS: The area under the curve of the FCSRT indexes ranged from 0.69 (95% CI: 0.62-0.76) to 0.76 (95% CI: 0.70-0.82). The specificity peaked up to 100% when we combined the category fluency test with the delayed total recall index of the FCSRT. Participants who tested positive at the FCSRT, as compared with those with negative tests, presented a twofold to fivefold higher risk of developing AD (median follow-up time 2.5 years; p < 0.001) and were diagnosed with AD 2-3 years earlier (p < 0.001). DISCUSSION: The FCSRT assessment suite shows the best predictive performance in detecting AD in people with MCI. These findings might help to reliably and timely identify people at higher risk of AD that is crucial both for properly selecting participants to clinical trials and to fine tune an effective and patient-centered care.

[Impact of a Decree on ACE inhibitors/ARBs in cardiovascular secondary prevention in the Lazio Region (Central Italy): a pre-post analysis]. / Impatto di un decreto su ACE-Inibitori e Sartani in prevenzione secondaria nel Lazio: un'analisi pre-post.

OBJECTIVES: to evaluate the effect of the 2010 legal decree (DCA) in the Lazio Region (Central Italy), promoting appropriateness on use of agents acting on the renin-angiotensin system, and limiting use of angiotensin II receptor blockers (ARBs) within this drug group to levels below 30%. SETTING AND PARTICIPANTS: two cohorts of incident patients with diagnosis of cardiovascular disease (CVD) were enrolled from the regional hospital information system: the first cohort included patients discharged during the 12 months before DCA (35,917 patients), and the second one patients discharged during the 12 months after DCA (35,491 patients). DESIGN: the first prescriptions of angiotensin- converting enzyme inhibitors (ACEIs) and ARBs in the 30 days after discharge were collected from the drug claims registry. The trends of monthly prescription proportions for the two drug groups were compared through a segmented regression analysis. MAIN OUTCOMES MEASURES: comparison between the pre- and post-DCA periods, distinguishing between prescription made by hospital physicians and by general practitioners, and between naïve and prevalent users. RESULTS: proportion of patients with CVD treated with ACEIs/ARBs after discharge was 50% in both pre-DCA (35,917 patients) and post-DCA (35,491 patients) cohorts, with the same share of ACEIs (60%) and ARBs (40%). ARB proportions met the threshold only for hospital prescriptions. Among naïve users, the target was met for both hospital physicians and general practitioners. CONCLUSIONS: the specific DCA has not led to an overall improvement in the appropriateness of prescribing of ACEIs/ARBs in secondary cardiovascular prevention. However, there is a suitable prescription choice for naïve patients and when the drug is dispensed in hospital pharmacies.

[Socioeconomic position and appropriate antiplatelet therapy after percutaneous coronary intervention: a population-based cohort study in Rome (Lazio Region, Central Italy)]. / Posizione socioeconomica e aderenza alla terapia antiaggregante post angioplastica coronarica: uno studio epidemiologico a Roma.

OBJECTIVES: to evaluate the association between socioeconomic position (SEP) and adherence to appropriate antiplatelet therapy (AAT) after percutaneous coronary intervention (PCI) in the year following the discharge. DESIGN: according to scientific guidelines, AAT for PCI patients consists of Clopidogrel for a minimum of 1 month and ideally up to 12 months after discharge, and with Acetylsalicylic Acid (ASA) indefinitely. For each patient, drug claims over a 1-year period after discharge were retrieved from Regional Drug Dispense Registry. Drug use was measured with Proportion of Days Covered (PDC). PDC was computed dividing the total number of dispensed Defined Daily Dose by each patient's follow-up time. Dual antiplatelet therapy with PDC ≥75% and single therapy based on Clopidogrel with PDC ≥75% were considered as AAT. We used a composite area-based index of socioeconomic position by census block of residence built using the 2001 census of Rome, assuming 5 levels (from 1 =High SEP to 5 =Low SEP). SETTING AND PARTICIPANTS: study population of 5,901 patients resident in Rome, who underwent their first PCI during 2006-2007 were selected from the Hospital Information System. MAIN OUTCOME MEASURES: proportions of patients treated with AAT by SEP was measured for the overall year and by semester. The association between SEP and adherence to AAT was estimated through logistic regression models adjusting for factors selected by a stepwise procedure (gender, age, comorbidities, discharged from cardiology or coronary care unit, new user of antiplatelet drugs). RESULTS: 76% of the study population were men, 96% were aged more than 44 years, and 63% belonged to medium-low SEP. In the 1-year follow-up, the proportion of patients adherent to appropriate antiplatelet therapy was 65%; SEP was associated with AAT (OR high vs. low SEP 1.26; 95%CI 1.05-1.51; p trend =0.002). CONCLUSIONS: during the year after discharge, adherence to AAT of PCI patients was unsatisfactory and it decreased overtime more in medium-low SEP patients than in high SEP patients. Strategies to improve adherence to AAT among patients who underwent PCI need to be identified taking into account the multifactorial nature of poor medication adherence, and in particular patients' socioeconomic position.

Pneumonia burden in elderly patients: a classification algorithm using administrative data.

BACKGROUND: Pneumonia has traditionally been classified into two subtypes: community-acquired pneumonia (CAP) and nosocomial pneumonia (NP). Recently, a new entity has been defined, called healthcare-associated pneumonia (HCAP). Few studies have investigated the potential of population-based, electronic, healthcare databases to identify the incidences of these three subtypes of pneumonia. The aim of this study was to estimate the burden of the three subtypes of pneumonia in elderly patients (aged 65+ years) in a large region of central Italy. METHODS: A retrospective cohort study was performed using linked regional Hospital Information System and Mortality Register. All episodes of pneumonia in elderly patients, who were discharged from the hospital in 2006-2008, were selected for the study. Following a validated ICD-9-coding algorithm, incidents of pneumonia events were classified into three groups (HCAP; probable nosocomial pneumonia, PNP; and CAP). Hospitalisation rates were calculated by age group (65-79, 80+), gender, and year, using the population from the Institute of Statistics (ISTAT) census estimates as denominators. RESULTS: A total of 26,239 pneumonia events occurred in 24,338 patients residing in the Lazio region, aged 65+ years: 2257 HCAP, 6775 PNP, and 17,107 CAP. For all subtypes, the proportion of males was greater than females. Comorbidity status was more severe in HCAP than in the other categories. In-hospital mortality, 30-day mortality, and length of hospital stay were twice higher in HCAP than in CAP episodes. The annual incidence rates were 0.7, 2.1, and 5.4 episodes per 1000 residents for HCAP, PNP, and CAP, respectively. From 2006 to 2008, incidence rates slightly increased for all three subtypes. CONCLUSION: Health care databases can be used to give a timely and inexpensive picture of the epidemiology of pneumonia. HCAP represents a distinct category of pneumonia, with the longest stay, highest mortality, and the greatest comorbidity.

A randomized double-blind clinical trial on safety and efficacy of tauroursodeoxycholic acid (TUDCA) as add-on treatment in patients affected by amyotrophic lateral sclerosis (ALS): the statistical analysis plan of TUDCA-ALS trial.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a highly debilitating neurodegenerative condition. Despite recent advancements in understanding the molecular mechanisms underlying ALS, there have been no significant improvements in therapeutic options for ALS patients in recent years. Currently, there is no cure for ALS, and the only approved treatment in Europe is riluzole, which has been shown to slow the disease progression and prolong survival by approximately 3 months. Recently, tauroursodeoxycholic acid (TUDCA) has emerged as a promising and effective treatment for neurodegenerative diseases due to its neuroprotective activities. METHODS: The ongoing TUDCA-ALS study is a double-blinded, parallel arms, placebo-controlled, randomized multicenter phase III trial with the aim to assess the efficacy and safety of TUDCA as add-on therapy to riluzole in patients with ALS. The primary outcome measure is the treatment response defined as a minimum of 20% improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R) slope during the randomized treatment period (18 months) compared to the lead-in period (3 months). Randomization will be stratified by country. Primary analysis will be conducted based on the intention-to-treat principle through an unadjusted logistic regression model. Patient recruitment commenced on February 22, 2019, and was closed on December 23, 2021. The database will be locked in September 2023. DISCUSSION: This paper provides a comprehensive description of the statistical analysis plan in order to ensure the reproducibility of the analysis and avoid selective reporting of outcomes and data-driven analysis. Sensitivity analyses have been included in the protocol to assess the impact of intercurrent events related to the coronavirus disease 2019. By focusing on clinically meaningful and robust outcomes, this trial aims to determine whether TUDCA can be effective in slowing the disease progression in patients with ALS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03800524 . Registered on January 11, 2019.

Decreasing trend in the incidence and prevalence of dementia: a systematic review.

INTRODUCTION: The progressive ageing of the population is one of the main socio-demographic phenomena, taking place at a global level. Several recent population-based studies conducted worldwide suggest that the age-specific risk of dementia may be changing in some countries and areas. EVIDENCE ACQUISITION: This systematic review was performed using the methodology proposed by the Cochrane handbook for systematic reviews and reported following the PRISMA statement. A structured bibliographic search was performed on the databases PubMed, ISI Web of Science and the Cochrane Database of Systematic Reviews. All included studies were qualitatively assessed using the Methodological Evaluation of Observational REsearch (MORE). EVIDENCE SYNTHESIS: The bibliographic search yielded 2394 records. Three more articles were retrieved from other sources. A total of ten studies were included, five reported data on a possible reduction in the prevalence of dementia, and five reported data on a possible reduction in its incidence. CONCLUSIONS: The present systematic review focused on the recent observations of a possible decrease in the frequency of dementia and cognitive impairment in some Western countries (USA, UK, Sweden, the Netherlands, France, Iceland) between 1977 and 2014. The included studies have a high heterogeneity in terms of the clinical criteria used to diagnose dementia, and of the criteria used to define the clinical condition preceding dementia, such as isolated cognitive impairment. Moreover, the methodological quality with which they were conducted was also heterogeneous, with scores ranging from 1 to 7 using the MORE tool.

A National Survey of Centers for Cognitive Disorders and Dementias in Italy.

BACKGROUND: Italy has one of the oldest populations in the World and more than one million dementia cases can be estimated at the national level. OBJECTIVE: The objectives of this national survey include: 1) to report the administrative features and the professional competencies of Centers for Cognitive Disorders and Dementias (CCDDs); 2) to document possible discrepancies by geographic macro-area; and 3) to identify the features of CCDDs that are associated with a better quality in the provision of care. METHODS: A survey of Italian CCDDs was conducted between February 2014 and December 2015. A list of CCDDs was obtained through direct interactions with designed delegates from each Italian region. A questionnaire was defined on five sections concerning: 1) location of the CCDD; 2) access to the CCDD; 3) organization of the CCDD; 4) services and treatments provided; and 5) quantitative data on the activities of the CCDD. RESULTS: Overall, 577 out of the 597 eligible CCDDs returned the completed survey questionnaire (response rate: 96.6%): 260 (45.1%) from Northern Italy, 103 (17.8%) from Central Italy, and 214 (37.1%) from Southern-Islands Italy. More than a third of CCDDs were open only once or twice weekly. A median of 450 (IQR: 200-800) patients regularly attended these services. Most patients (70%) were affected by dementia or mild cognitive impairment (19%). CONCLUSION: We have provided a snapshot of the organization and activities of CCDDs in Italy and documented existing inequalities in the provision of care.

Adverse Events in Italian Nursing Homes During the COVID-19 Epidemic: A National Survey.

Older people living in nursing homes (NHs) are particularly vulnerable in the ongoing COVID-19 pandemic, due to the high prevalence of chronic diseases and disabilities (e.g., dementia). The phenomenon of adverse events (AEs), intended as any harm or injury resulting from medical care or to the failure to provide care, has not yet been investigated in NHs during the pandemic. We performed a national survey on 3,292 NHs, either public or providing services both privately and within the national health system, out of the 3,417 NHs covering the whole Italian territory. An online questionnaire was addressed to the directors of each facility between March 24 and April 27, 2020. The list of NHs was provided by the Dementia Observatory, an online map of Italian services for people with dementia, which was one of the objectives of the implementation of the Italian National Dementia Plan. About 26% of residents in the Italian NHs for older people listed within the Dementia Observatory site had dementia. The objective of our study was to report the frequency of AEs that occurred during the months when SARS-CoV-2 spreading rate was at its highest in the Italian NHs and to identify which conditions and attributes were most associated with the occurrence of AEs by means of multivariate regression logistic analysis. Data are referred to 1,356 NHs that participated in the survey. The overall response rate was 41.2% over a time-period of six weeks (from March 24 to May 5). About one third of the facilities (444 out of 1,334) (33.3%) reported at least 1 adverse event, with a total of 2,000 events. Among the included NHs, having a bed capacity higher than the median of 60 beds (OR=1.57, CI95% 1.17-2.09; p=0.002), an observed increased in the use of psychiatric drugs (OR=1.80, CI95% 1.05-3.07; p=0.032), adopting physical restraint measures (OR=1.97, CI95% 1.47-2.64; p<0.001), residents hospitalized due to flu-like symptoms (OR =1.73, CI95% 1.28-2.32; p<0.001), and being located in specific geographic areas (OR=3.59, CI95% 1.81-7.08; OR = 2.90, CI95% 1.45-5.81 and OR = 4.02, CI05% 2.01-8.04 for, respectively, North-West, North-East and Centre vs South, p<0.001) were all factors positively associated to the occurrence of adverse events in the facility. Future recommendations for the management and care of residents in NHs during the COVID-19 pandemic should include specific statements for the most vulnerable populations, such as people with dementia.

Methodological Issues in the Clinical Validation of Biomarkers for Alzheimer's Disease: The Paradigmatic Example of CSF.

The use of biomarkers is profoundly transforming medical research and practice. Their adoption has triggered major advancements in the field of Alzheimer's disease (AD) over the past years. For instance, the analysis of the cerebrospinal fluid (CSF) and neuroimaging changes indicative of neuronal loss and amyloid deposition has led to the understanding that AD is characterized by a long preclinical phase. It is also supporting the transition towards a biology-grounded framework and definition of the disease. Nevertheless, though sufficient evidence exists about the analytical validity (i.e., accuracy, reliability, and reproducibility) of the candidate AD biomarkers, their clinical validity (i.e., how well the test measures the clinical features, and the disease or treatment outcomes) and clinical utility (i.e., if and how the test improves the patient's outcomes, confirms/changes the diagnosis, identifies at-risk individuals, influences therapeutic choices) have not been fully proven. In the present review, some of the methodological issues and challenges that should be addressed in order to better appreciate the potential benefits and limitations of AD biomarkers are discussed. The ultimate goal is to stimulate a constructive discussion aimed at filling the existing gaps and more precisely defining the directions of future research. Specifically, four main aspects of the clinical validation process are addressed and applied to the most relevant CSF biomarkers: (1) the definition of reference values; (2) the identification of reference standards for the disease of interest (i.e., AD); (3) the inclusion within the diagnostic process; and (4) the statistical process supporting the whole framework.

Anticancer drug prices and clinical outcomes: a cross-sectional study in Italy.

OBJECTIVE: To investigate whether the prices of new anticancer drugs correlated with their relative benefit despite negotiation. DESIGN: Retrospective cross-sectional study correlating new anticancer drugs prices with clinical outcomes. SETTING: We did a retrospective cross-sectional study including all new anticancer drugs approved by the European Medicines Agency (EMA) (2010-2016) and reimbursed in Italy. MAIN OUTCOMES AND MEASURES: Information on clinical outcomes-in terms of median overall survival (OS), median progression-free survival (PFS) and objective response rate (ORR)-was extracted from pivotal trials as reported in the European Public Assessment Reports available on the EMA website. Cost of a full course treatment was estimated on negotiated official and discounted prices. Regression coefficients ß, their levels of significance p and the coefficients of determination R2 were estimated adjusting by tumour type. RESULTS: Overall, 30 new anticancer drugs (with 35 indications) were available for analysis. Where data on OS were available, we observed no correlation between the improvement in median OS (in weeks) and negotiated price (R2=0.067, n=16 drugs for 17 indications). When the clinical outcomes were expressed as improvements in the median PFS or ORR, 25 drugs (29 indications) were available for the analysis, and again, there was no correlation with prices (R2=0.004 and 0.006, respectively). CONCLUSIONS AND RELEVANCE: Our results suggest that the prices of anticancer drugs in Italy do not reflect their therapeutic benefit. Drug price negotiations, which is mandatory by law in Italy, do not seem to ensure that prices correlate with clinical benefits provided by the cancer drugs. These results call for further efforts to establish the standard determinants of drug prices available at the time of negotiation. These findings need to be confirmed in other countries where price negotiations are in place. Moreover, further investigations may verify whether outcome data obtained after drug marketing would improve the correlation between prices and therapeutic benefit.

Safety and effectiveness of direct oral anticoagulants versus vitamin K antagonists: results from 3 Italian regions.

Background: In Italy, direct oral anticoagulant drugs (DOACs) were authorized for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) in 2013. There is conflicting evidence on their benefit-risk profile under real world conditions. Methods: The Italian Medicines Agency funded this study to investigate effectiveness and safety of DOACs compared to vitamin K antagonists (VKAs) in three Italian regions. An observational study was conducted with a sequential propensity-score-matched new user parallel-cohort design in the period July 2013-December 2015 using administrative health data. DOAC users with NVAF diagnosis were 1:1 matched to VKA users based on a PS which accounted for over 90 potential confounders at baseline. Applying an as-treated approach with a 90-day renewal grace time, patients were followed from the day after the first prescription of the study drug until occurrence of the outcome, death, discontinuation, switch, end of health plan enrolment, or study end. Outcomes were total and cardiovascular mortality, acute myocardial infarction, ischemic and haemorrhagic stroke, and gastrointestinal bleeding. Analyses were performed, using Cox proportional hazard models stratified by matched set. The results of the regional analyses were combined through a random-effects meta-analysis. Results: During the first 30 months of authorisation for NVAF, DOACs were increasingly prescribed. Overall, 72,434 new anticoagulant users were enrolled, 34% of whom received a DOAC. After PS matching, 37,266 patients contributed to the analysis. No differences between the study groups were found for total and cardiovascular mortality, myocardial infarction and ischemic stroke. DOAC users were at higher risk of gastrointestinal bleeding (HR 1.41, 95%CI 1.07-1.86) and at a not significant lower risk of haemorrhagic stroke (HR 0.36, 95%CI 0.10-1.33). Conclusions: The present study confirms findings from previous research regarding bleeding events, whereas we did not find a reduced risk of mortality in DOAC users. Further research on single active agents and specific populations is warranted.

MicroRNAs and mild cognitive impairment: A systematic review.

BACKGROUND: Mild cognitive impairment (MCI) is usually described as an intermediate phase between normal cognition and dementia. Identifying the subjects at a higher risk of progressing from MCI to AD is essential to manage this condition. The diagnosis of MCI is mainly clinical. Several biomarkers have been proposed, but mostly for research purposes, as they are based on an invasive procedure to obtain the sample, such as cerebrospinal fluid (CSF). As a consequence, rapid and non-invasive biomarkers are needed to improve diagnosis. The objective of this systematic review is to summarize available evidence on the use of miRNAs as biomarkers in subjects with MCI. METHODS: Relevant literature published up to June 2018 was retrieved searching the databases PubMed, ISI Web of Knowledge and the Cochrane Database. Only studies considering microRNAs (miRNAs) and a diagnosis of MCI were included. Data were extracted using a specifically-designed standardized form, and their methodological quality was assessed using QUADAS-2 and QUIPS. RESULTS: Twenty-one studies of 153 retrieved articles met the predefined inclusion/exclusion criteria. Studies included participants ranging from 6 to 330. More than 40 miRNAs resulted as dysregulated, and miR-206 was the only miRNA that was found as differentially expressed in patients with MCI by more than two studies. However, these results have either not yet been confirmed in other independent cohorts, or data are still inconsistent. Inconsistencies among included studies could be due to several issues including the selection of participants, pre-analytical and analytical procedures, and statistical analyses.

Drug Holiday of Interferon Beta 1b in Multiple Sclerosis: A Pilot, Randomized, Single Blind Study of Non-inferiority.

Introduction: To compare a schedule with cyclic withdrawal (CW) of interferon beta (IFN-b) 1b, respect to the full regimen (FR), in relapsing-remitting MS (RR-MS). Methods: Participants were randomly assigned to CW or FR schedule and monthly monitored with brain MRI scans for 12 months (three of run-in and 9 of treatment). CW schedule included drug withdrawal for 1 month after two of treatment for a total of three quarters over the 9-month treatment period. The assessing neurologist and the expert neuroradiologists were blind. After the blind phase of the study all participants took their indicated disease modifying therapies in a prospectively planned, open-label extension phase (up to 120 months). Results: Of 60 randomized subjects 56 (29 in FR and 27 in CW group) completed the single-blind phase: the two groups were comparable, except for a non-significant difference in the number of contrast-enhanced lesions (CEL) at the end of run-in. The two-sided 90% CI for the ratio between median number of cumulative CEL was 0.29-1.07, allowing to significantly reject the null hypothesis of a ratio ≥1.2 and to meet the primary end-point of non-inferiority (the threshold and the ratio between median were chosen according to the non-normal distribution of the data). The differences (CW vs. FR) were also non-significant for secondary end points: mean cumulative number of T2-weighted new and enlarging lesions (3.48 ± 5.34 vs. 3.86 ± 6.76); mean number and volume (cm3) of black holes (1.24 ± 1.61 vs. 2.71 ± 4.56; 489.11 ± 1488.12 vs. 204.48 ± 396.98); number of patients with at least an active scan (21 vs. 22); mean relapse rate (0.52 ± 0.89 vs. 0.34 ± 0.66), relapse risk ratio adjusted for baseline variables (2.15 [0.64-7.18]), EDSS score (1.0 [1-1.56] vs. 1.5 [1-1.78]), proportion of patients with antibodies anti-IFN (5 [21%] vs. 8 [36%]). Fifty-four patients (27 for each study arm) completed the open-label phase. The annualized RR, EDSS, proportion of patients shifting to progressive disease and hazard ratio of shifting, adjusting for baseline covariates, were comparable between the two study groups. Conclusions: A calendar with CW was non-inferior than FR at the beginning of IFN-b therapy, and may not affect the long-term outcome. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT00270816.

A Systematic Review and Meta-Analysis on the Prevalence of Dementia in Europe: Estimates from the Highest-Quality Studies Adopting the DSM IV Diagnostic Criteria.

BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer's Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe. OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria. METHODS: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool. RESULTS: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%. DISCUSSION: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV).