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.

Identification of dementia and MCI cases in health information systems: An Italian validation study.

Introduction: The identification of dementia cases through routinely collected health data represents an easily accessible and inexpensive method to estimate the prevalence of dementia. In Italy, a project aimed at the validation of an algorithm was conducted. Methods: The project included cases (patients with dementia or mild cognitive impairment [MCI]) recruited in centers for cognitive disorders and dementias and controls recruited in outpatient units of geriatrics and neurology. The algorithm based on pharmaceutical prescriptions, hospital discharge records, residential long-term care records, and information on exemption from health-care co-payment, was applied to the validation population. Results: The main analysis was conducted on 1110 cases and 1114 controls. The sensitivity, specificity, and positive and negative predictive values in discerning cases of dementia were 74.5%, 96.0%, 94.9%, and 79.1%, respectively, whereas in detecting cases of MCI these values were 29.7%, 97.5%, 92.2%, and 58.1%, respectively. The variables associated with misclassification of cases were also identified. Discussion: This study provided a validated algorithm, based on administrative data, which can be used to identify cases with dementia and, with lower sensitivity, also early onset dementia but not cases with MCI.

The Italian fund for Alzheimer's and other dementias: strategies and objectives to face the dementia challenge.

The Italian Fund for Alzheimer's and other dementias was approved and signed in December 2021. The Fund is financed with 15 million euros in three years. The main goal is to provide new strategies in the field of dementia with a Public Health perspective. The Fund includes eight main activities that will be monitored and supervised by the Italian National Institute of Health: 1) development of a guideline for the assessment, management and support for people with dementia and their families/carers; 2) updating of the Dementia National Plan (DNP); 3) implementation of the documents of the DNP; 4) conducting surveys dedicated to the Italian Dementia Services; 5) promotion of dementia prevention strategies; 6) training strategies for healthcare professionals, families and caregivers; 7) creation of a National Electronic Record for Dementia; 8) evaluation and monitoring of activities promoted by Regions and Autonomous Provinces in the field of dementia, together with the dementia National Permanent Table. These activities are outlined in detail in the present paper.

Safety and Efficacy of Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Published and Unpublished Clinical Trials.

BACKGROUND: Monoclonal antibodies (mAbs) are currently among the most investigated targets for potential disease-modifying therapies in Alzheimer's disease (AD). OBJECTIVE: Our objectives were to identify all registered trials investigating mAbs in MCI due to AD or AD at any stage, retrieve available published and unpublished data from all registered trials, and analyze data on safety and efficacy outcomes. METHODS: A systematic search of all registered trials on ClinicalTrials.gov and EUCT was performed. Available results were searched on both platforms and on PubMed, ISI Web of Knowledge, and The Cochrane Library. RESULTS: Overall, 101 studies were identified on 27 mAbs. Results were available for 50 trials investigating 12 mAbs. For 18 trials, data were available from both published and unpublished sources, for 21 trials only from published sources, and for 11 trials only from unpublished sources. Meta-analyses of amyloid-related imaging abnormalities (ARIA) events showed overall risk ratios of 10.65 for ARIA-E and of 1.75 for ARIA-H. The meta-analysis of PET-SUVR showed an overall significant effect of mAbs in reducing amyloid (SMD -0.88), but when considering clinical efficacy, data on CDR-SB showed that treated patients had a statistically significant but clinically non-relevant lower worsening (MD -0.15). CONCLUSION: Our results suggest that the risk-benefit profile of mAbs remains unclear. Research should focus on clarifying the effect of amyloid on cognitive decline, providing data on treatment response rate, and accounting for minimal clinically important difference. Research on mAbs should also investigate the possible long-term impact of ARIA events, including potential factors predicting their onset.

Risk Factors for Liver Decompensation and HCC in HCV-Cirrhotic Patients after DAAs: A Multicenter Prospective Study.

BACKGROUND: Prospective studies on predictors of liver-related events in cirrhotic subjects achieving SVR after DAAs are lacking. METHODS: We prospectively enrolled HCV cirrhotic patients in four Italian centers between November 2015 and October 2017. SVR and no-SVR cases were compared according to the presence or absence of liver-related events during a 24-month follow-up. Independent predictors of liver-related events were evaluated by Cox regression analysis. RESULTS: A total of 706 subjects started DAAs therapy. SVR was confirmed in 687 (97.3%). A total of 61 subjects (8.9%) in the SVR group and 5 (26.3%) in the no-SVR group had liver-related events (p < 0.03). The incidence rate x 100 p/y was 1.6 for HCC, 1.7 for any liver decompensation, and 0.5 for hepatic death. Baseline liver stiffness (LSM) ≥ 20 kPa (HR 4.0; 95% CI 1.1-14.1) and genotype different from 1 (HR 7.5; 95% CI 2.1-27.3) were both independent predictors of liver decompensation. Baseline LSM > 20 KPa (HR 7.2; 95% CI 1.9-26.7) was the sole independent predictor of HCC. A decrease in liver stiffness (Delta LSM) by at least 20% at the end of follow-up was not associated with a decreased risk of liver-related events. CONCLUSION: Baseline LSM ≥ 20 kPa identifies HCV cirrhotic subjects at higher risk of liver-related events after SVR.

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.

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.

Lower extremity amputations in persons with and without diabetes in Italy: 2001-2010.

OBJECTIVE: To analyze hospitalization for lower extremity amputations (LEAs) and amputee rates in persons with and without diabetes in Italy. RESEARCH DESIGN AND METHODS: All patients with LEAs in the period 2001-2010 were identified analyzing the National Hospital Discharge Record database. For each year, amputee and hospitalization rates for LEAs were calculated either for persons with diabetes or without. Time trend for major and minor amputations were analysed. RESULTS: From 2001 to 2010 a mean annual number of 11,639 individuals underwent a lower extremity amputation: 58.6% had diabetes accounting for 60.7% of total hospitalizations. In 2010, the crude amputee rate for LEAs was 20.4 per 100,000 inhabitants: 247.2 for 100.000 persons with diabetes, and 8.6 for those without diabetes. Having diabetes was associated to an increased risk of amputation (Poisson estimated RR 10.9, 95%CI 9.4-12.8). Over the whole period, a progressive reduction of amputee rates was observed for major amputations either among persons with diabetes (-30.7%) or without diabetes (-12.5%), while the rates of minor amputations increased progressively (+22.4%) among people without diabetes and were nearly stable in people with diabetes (-4.6%). A greater number of minor amputations were performed among persons with than without diabetes: in 2010, the minor-to-major ratio among persons with diabetes (2.5) was more than twice than in those without diabetes (1.0). CONCLUSIONS: The nationwide analyses confirm a progressive reduction of hospitalization and amputee rates for major LEAs, suggesting an earlier and more diffuse approach aimed at limb salvage.

Dementia and lower blood pressure in Latin America, India, and China: a 10/66 cross-cohort study.

OBJECTIVE: To study the relationship between dementia and blood pressure (BP) in 8 low- and middle-income countries. METHODS: In identical cross-sectional surveys of older adults (aged 65 years and older) conducted in Cuba, Dominican Republic, Peru, Venezuela, Mexico, Puerto Rico, China, and India (n = 15,746), we measured systolic and diastolic BP and used the 10/66 prevalidated algorithms to adjudicate dementia diagnosis and quantify dementia severity (Clinical Dementia Rating [CDR]). RESULTS: BP levels, dementia prevalence, and participants' sociodemographic and health characteristics varied across sites. In fixed-effect meta-analyses of site-specific linear regression coefficients adjusted for potential confounders, dementia and CDR were cross-sectionally associated with lower systolic BP (ß = -1.7, 95% confidence interval [CI]: -2.8, -0.6; and ß = -1.1, 95% CI: -1.5, -0.7) and diastolic BP (ß = -0.4, 95% CI: -1.1, 0.2; and ß = -0.4, 95% CI: -0.7, -0.2). Associations were heterogeneous across sites for both dementia (I(2) < 47%) and CDR (I(2) < 75%), and were strongest in Cuba, where prevalence of hypertension was highest. Results were robust to alternative model specifications that accounted for hypertensive status, antihypertensive treatment, and leanness (i.e., smaller waist circumference). CONCLUSION: The association between dementia and lower BP was heterogeneous across geographically diverse samples, strongest where prevalent hypertension was highest (in Cuba), and relatively small compared with that found in Western settings. Both the mechanisms and the extent to which different levels of lifetime hypertensive disease explain this heterogeneity remain uncertain. However, because rapid increments in both dementia and hypertension are predicted in low- and middle-income countries, closer monitoring is warranted.

Social and Cultural Factors Affecting Complementary and Alternative Medicine (CAM) Use during Menopause in Sydney and Bologna.

Background. Previous surveys found CAM use during menopause to be popular. This paper compares the results from two surveys (Sydney and Bologna) to examine factors that determine the extent and pattern of CAM use to alleviate menopausal symptoms. Methods. Women, aged 45-65 years, who were symptomatic when transitioning through menopause or asymptomatic but taking menopause-specific treatments, were recruited in Sydney (n=1,296) and Bologna (n=1,106) to complete the same voluntary, anonymous, and self-administered questionnaire. The results were reanalysed using stratified analyses to determine similarities and differences. Results. Demographics of the two cohorts differed significantly. CAM was more popular in Sydney. The most significant determinants of CAM use were the use of CAM for other conditions besides menopause and the severity of vasomotor symptoms. Occupational status was a determinant of CAM use amongst Bologna respondents only. In order to relieve symptoms, Australian and Italian women used different CAM modalities whose effectiveness was generally perceived as good. Conclusion. CAM use is popular amongst menopausal women from Sydney and Bologna. Differences in the patterns of CAM use seem to depend on CAM availability and on the educational level and professional status of users. The complex interaction between market, social, and cultural factors of CAM use seems to be more influential on women's choice of CAM than the available evidence of their effectiveness.

No association between fish intake and depression in over 15,000 older adults from seven low and middle income countries--the 10/66 study.

BACKGROUND: Evidence on the association between fish consumption and depression is inconsistent and virtually non-existent from low- and middle-income countries. Using a standard protocol, we aim to assess the association of fish consumption and late-life depression in seven low- and middle-income countries. METHODOLOGY/FINDINGS: We used cross-sectional data from the 10/66 cohort study and applied two diagnostic criteria for late-life depression to assess the association between categories of weekly fish consumption and depression according to ICD-10 and the EURO-D depression symptoms scale scores, adjusting for relevant confounders. All-catchment area surveys were carried out in Cuba, Dominican Republic, Venezuela, Peru, Mexico, China, and India, and over 15,000 community-dwelling older adults (65+) were sampled. Using Poisson models the adjusted association between categories of fish consumption and ICD-10 depression was positive in India (p for trend = 0.001), inverse in Peru (p = 0.025), and not significant in all other countries. We found a linear inverse association between fish consumption categories and EURO-D scores only in Cuba (p for trend = 0.039) and China (p<0.001); associations were not significant in all other countries. Between-country heterogeneity was marked for both ICD-10 (I(2)>61%) and EURO-D criteria (I(2)>66%). CONCLUSIONS: The associations of fish consumption with depression in large samples of older adults varied markedly across countries and by depression diagnosis and were explained by socio-demographic and lifestyle variables. Experimental studies in these settings are needed to confirm our findings.