Understanding Patterns of Adherence to Antifibrotic Treatment in Idiopathic Pulmonary Fibrosis: Insights from an Italian Prospective Cohort Study.

Background: Pirfenidone and Nintedanib have significantly improved the prognosis of patients with idiopathic pulmonary fibrosis (IPF), reducing mortality risk and exacerbations. This study aimed to analyze antifibrotic treatment utilization and its association with clinical outcomes (i.e., acute exacerbation or death) during 2014-2021 in newly diagnosed IPF patients, using Healthcare Utilization Databases of the Marche Region, Italy. Methods: The first 12-month adherence to antifibrotic was estimated using the Proportion of Days Covered (PDC), defining adherence as PDC ≥ 75%. State Sequence Analysis over the initial 52 weeks of treatment was used to identify adherence patterns. The role of adherence patterns on acute exacerbations/death, adjusted by demographic, clinical features, and monthly adherence after the 52-week period (time-dependent variable), was assessed with Cox regression. Results: Among 667 new IPF cases, 296 received antifibrotic prescriptions, with 62.8% being adherent in the first year. Three antifibrotic utilization patterns emerged-high adherence (37.2%), medium adherence (42.5%), and low adherence (20.3%)-with median PDCs of 95.3%, 79.5%, and 18.6%, respectively. These patterns did not directly influence three-year mortality/exacerbation probability, but sustained adherence reduced risk over time. Conclusions: Good adherence was observed in in this population-based study, emphasizing the importance of continuous antifibrotics therapy over time to mitigate adverse outcomes.

Cost-effectiveness of outpatient adherence to recommendations for monitoring of patients hospitalized for heart failure.

AIMS: A set of indicators to assess the quality of care for patients hospitalized for heart failure was developed by an expert working group of the Italian Health Ministry. Because a better performance profile measured using these indicators does not necessarily translate to better outcomes, a study to validate these indicators through their relationship with measurable clinical outcomes and healthcare costs supported by the Italian National Health System was carried out. METHODS AND RESULTS: Residents of four Italian regions (Lombardy, Marche, Lazio, and Sicily) who were newly hospitalized for heart failure (irrespective of stage and New York Heart Association class) during 2014-2015 entered in the cohort and followed up until 2019. Adherence to evidence-based recommendations [i.e. renin-angiotensin-aldosterone system (RAS) inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and echocardiograms (ECCs)] experienced during the first year after index discharge was assessed. Composite clinical outcomes (cardiovascular hospital admissions and all-cause mortality) and healthcare costs (hospitalizations, drugs, and outpatient services) were assessed during the follow-up. The restricted mean survival time at 5 years (denoted as the number of months free from clinical outcomes), the hazard of clinical outcomes (according to the Cox model), and average annual healthcare cost (expressed in euros per person-year) were compared between adherent and non-adherent patients. A non-parametric bootstrap method based on 1000 resamples was used to account for uncertainty in cost-effectiveness estimates. A total of 41 406 patients were included in this study (46.3% males, mean age 76.9 ± 9.4 years). Adherence to RAS inhibitors, beta-blockers, MRAs, and ECCs were 64%, 57%, 62%, and 20% among the cohort members, respectively. Compared with non-adherent patients, those who adhered to ECCs, RAS inhibitors, beta-blockers, and MRAs experienced (i) a delay in the composite outcome of 1.6, 1.9, 1.6, and 0.6 months and reduced risks of 9% (95% confidence interval, 2-14%), 11% (7-14%), 8% (5-11%), and 4% (-1-8%), respectively; and (ii) lower (€262, €92, and €571 per year for RAS inhibitors, beta-blockers, and MRAs, respectively) and higher costs (€511 per year for ECC). Adherence to RAS inhibitors, beta-blockers, and MRAs showed a delay in the composite outcome and a saving of costs in 98%, 84%, and 93% of the 1000 bootstrap replications, respectively. CONCLUSIONS: Strict monitoring of patients with heart failure through regular clinical examinations and drug therapies should be considered the cornerstone of national guidelines and audits.

A study protocol for identifying aging trajectories toward chronic neurodegenerative diseases by means of Marche regional administrative databases - TREND project.

Background: People are living longer but an increasing number of older people experience chronicity and disability in the latest years of their life. The Marche region is one of the Italian regions where people live the longest lives; therefore, the number of people with age-related chronic diseases is expected to be at least similar, if not higher, compared to the rest of Italy. The identification of the aging trajectories is of huge interest in the arena of public health. Administrative healthcare databases represent valuable reservoirs for reconstructing the trajectories of aging. Here, we present the protocol for a study (TREND project) aimed to integrate existing administrative databases into a Marche regional dataset in order to estimate the prevalence and incidence rates of age-related neurodegenerative diseases (ND), with a specific focus on Parkinsonism and Dementia. Methods: The TREND Project is a retrospective cross-sectional study. The source population includes permanent residents in the Marche region aged 40 years and older. A minimal dataset has been built up linking data on drug prescriptions, outpatient services, and diagnosis for hospital admission, from 2014 to 2021 in the Marche Region. Data on clinical outcomes (re-hospitalization, mortality, comorbidities), and therapeutic approaches (drugs and medicines) have been integrated with state-of-the-art statistical methods to define patients into different risk clusters and to analyze the aging trend by assessing the Comorbidity Index (CI) as a proxy for chronicity. Discussion: Our research contributes to the integration of existing administrative databases on ND to create a Marche regional ND database, support regional health policy, and better understand patients' needs and their aging trajectories. This approach could be implemented also at the National level. Moreover, by linking different administrative data sources, this study sheds light on important issues related to ND, such as early-onset dementia; ethical aspects such as anticipated wills; problems of dementia in patients still in the job market, etc. The results of this study will contribute to the successful implementation of integrated care for patients affected by ND at regional or national levels.

Incidence of amyotrophic lateral sclerosis before and during the COVID-19 pandemic: evidence from an 8-year population-based study in Central Italy based on healthcare utilization databases.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder with a high multidimensional burden, with an obscure etiopathogenesis. METHODS: We designed a longitudinal, population-based study of people residing in Central Italy (Marche Region) who were beneficiaries of the National Health System. People with an unprecedented ALS hospitalization (335.20 ICD-9 CM) or tagged with an ALS exemption between 2014 and 2021 were considered incident cases. ALS cases residing in the region for <3 years or with an active ALS exemption or hospitalized for ALS before 2014 were excluded. We used secondary sources to identify new ALS diagnoses. The regional referral center for ALS's database was used to test the accuracy of secondary sources in detecting cases. ALS mean incidence was compared to that reported in similar studies conducted in Italy. The incidence rate trend adjusted by sex and age was evaluated using the Poisson regression model. RESULTS: We detected 425 new ALS cases (median age: 70y) in the 2014-2021 period, with a mean incidence of 3.5:100,000 py (95%CI: 3.2-3.8; M:F = 1.2), similar to that reported in similar studies conducted in Italy. No trend was observed during 2014-2019. After including 2020-2021 in the model, we observed a mean decrease in incidence of 5.8% (95% CI 2.0%; 9.5%, p = 0.003). CONCLUSION: We show a decrease in the incidence rate of ALS in Marche, during the 2014-2021 period, as a possible outcome of a delayed neurological assessment and diagnosis during the pandemic. An ad hoc developed identification algorithm, based on healthcare utilization databases, is a valuable tool to assess the health impact of global contingencies.

Epidemiology of listeriosis in a region in central Italy from 2010 to 2019: Estimating the real incidence and space-time analysis for detecting cluster of cases.

BACKGROUND: Contamination and transmission of different Listeria monocytogenes strains along food chain are a serious threat to public health and food safety. Understanding the distribution of diseases in time and space-time is fundamental in the epidemiological study and in preventive medicine programs. The aim of this study is to estimate listeriosis incidence along 10-years period and to perform space-time cluster analysis of listeriosis cases in Marche Region, Italy. METHODS: The number of observed listeriosis cases/year was derived from regional data of surveillance of notifiable diseases and hospital discharge form. The capture and recapture method (C-R method) was applied to estimate the real incidence of listeriosis cases in Marche Region and the space-time scan statistics analysis was performed to detect clusters of space-time of listeriosis cases and add precision to the conventional epidemiological analysis. RESULTS: The C-R method estimation of listeriosis cases was 119 in the 10- year period (2010-2019), with an average of 31.93 % of unobserved cases (lost cases). The estimated mean annual incidence of listeriosis was 0.77 per 100,000 inhabitants (95 %CI 0.65-0.92), accounting for 6.07 % of additional listeriosis cases per year than observed cases. Using the scan statistic, the two most likely clusters were identified, one of these was statistically significant (p < 0.05). The underdiagnosis and under-reporting in addition to listeriosis incidence variability suggested that the surveillance system of Marche Region should be improved. CONCLUSIONS: This study provides evidence of the ability of space-time cluster analysis to complement traditional surveillance of food-borne diseases and to understand the local risk factors by implementing timely targeted interventions.

Rhythmic oscillations in the midbrain dopaminergic nuclei in mice.

Introduction: Dopamine release in the forebrain by midbrain ventral tegmental nucleus (VTA) and substantia nigra pars compacta (SNc) neurons is implicated in reward processing, goal-directed learning, and decision-making. Rhythmic oscillations of neural excitability underlie coordination of network processing, and have been reported in these dopaminergic nuclei at several frequency bands. This paper provides a comparative characterization of several frequencies of oscillations of local field potential and single unit activity, highlighting some behavioral correlates. Methods: We recorded from optogenetically identified dopaminergic sites in four mice training in operant olfactory and visual discrimination tasks. Results: Rayleigh and Pairwise Phase Consistency (PPC) analyses revealed some VTA/SNc neurons phase-locked to each frequency range, with fast spiking interneurons (FSIs) prevalent at 1-2.5 Hz (slow) and 4 Hz bands, and dopaminergic neurons predominant in the theta band. More FSIs than dopaminergic neurons were phase-locked in the slow and 4 Hz bands during many task events. The highest incidence of phase-locking in neurons was in the slow and 4 Hz bands, and occurred during the delay between the operant choice and trial outcome (reward or punishment) signals. Discussion: These data provide a basis for further examination of rhythmic coordination of activity of dopaminergic nuclei with other brain structures, and its impact for adaptive behavior.

Long-term near-continuous recording with Neuropixels probes in healthy and epileptic rats.

Neuropixels probes have become a crucial tool for high-density electrophysiological recordings. Although most research involving these probes is in acute preparations, some scientific inquiries require long-term recordings in freely moving animals. Recent reports have presented prosthesis designs for chronic recordings, but some of them do not allow for probe recovery, which is desirable given their cost. Others appear to be fragile, as these articles describe numerous broken implants.Objective.This fragility presents a challenge for recordings in rats, particularly in epilepsy models where strong mechanical stress impinges upon the prosthesis. To overcome these limitations, we sought to develop a new prosthesis for long-term electrophysiological recordings in healthy and epileptic rats.Approach.We present a new prosthesis specifically designed to protect the probes from strong shocks and enable the safe retrieval of probes after experiments.Main results.This prosthesis was successfully used to record from healthy and epileptic rats for up to three weeks almost continuously. Overall, 10 out of 11 probes could be successfully retrieved with a retrieval and reuse success rate of 91%.Significance.Our design and protocol significantly improved previously described probe recycling performances and prove usage on epileptic rats.

Prognosis and Survival in Idiopathic Pulmonary Fibrosis in the Era of Antifibrotic Therapy in Italy: Evidence from a Longitudinal Population Study Based on Healthcare Utilization Databases.

The aim was to evaluate the determinants of acute exacerbation (AE) and death in new cases of idiopathic pulmonary fibrosis (IPF) using administrative databases in the Marche Region. Adults at their first prescription of antifibrotics or hospitalization with a diagnosis of IPF occurring in 2014-2019 were considered as new cases. Multiple Cox regression was used to estimate the risk of AE and of all-cause mortality adjusted by demographic and clinical characteristics, stratifying patients according to antifibrotic treatment. Overall, 676 new cases of IPF were identified and 276 deaths and 248 AE events occurred. In never-treated patients, the risk of AE was higher in patients with poor health conditions at diagnosis; the risk of death was higher in males, in patients aged ≥75 and in those with poor health conditions at baseline. The increasing number of AEs increased the risk of death in treated and never-treated patients. Within the limits of an observational study based on secondary data, the combined use of healthcare administrative databases allows the accurate analysis of progression and survival of IPF from the beginning of the antifibrotic therapy era, suggesting that timely and early diagnosis is critical to prescribing the most suitable treatment to increase survival and maintain a healthy life expectancy.

Development and Validation of a Novel Pre-Pregnancy Score Predictive of Preterm Birth in Nulliparous Women Using Data from Italian Healthcare Utilization Databases.

Background: Preterm birth is a major worldwide public health concern, being the leading cause of infant mortality. Understanding of risk factors remains limited, and early identification of women at high risk of preterm birth is an open challenge. Objective: The aim of the study was to develop and validate a novel pre-pregnancy score for preterm delivery in nulliparous women using information from Italian healthcare utilization databases. Study Design: Twenty-six variables independently able to predict preterm delivery were selected, using a LASSO logistic regression, from a large number of features collected in the 4 years prior to conception, related to clinical history and socio-demographic characteristics of 126,839 nulliparous women from Lombardy region who gave birth between 2012 and 2017. A weight proportional to the coefficient estimated by the model was assigned to each of the selected variables, which contributed to the Preterm Birth Score. Discrimination and calibration of the Preterm Birth Score were assessed using an internal validation set (i.e., other 54,359 deliveries from Lombardy) and two external validation sets (i.e., 14,703 and 62,131 deliveries from Marche and Sicily, respectively). Results: The occurrence of preterm delivery increased with increasing the Preterm Birth Score value in all regions in the study. Almost ideal calibration plots were obtained for the internal validation set and Marche, while expected and observed probabilities differed slightly in Sicily for high Preterm Birth Score values. The area under the receiver operating characteristic curve was 60%, 61% and 56% for the internal validation set, Marche and Sicily, respectively. Conclusions: Despite the limited discriminatory power, the Preterm Birth Score is able to stratify women according to their risk of preterm birth, allowing the early identification of mothers who are more likely to have a preterm delivery.

Post-trauma behavioral phenotype predicts the degree of vulnerability to fear relapse after extinction in male rats.

Current treatments for trauma-related disorders remain ineffective for many patients.1,2 Fear extinction deficiency is a prominent feature of these diseases,3 and many behavioral treatments rely on extinction training.4,5 However, in many patients, therapy is followed by a relapse of symptoms, and the underpinnings of such interindividual variations in vulnerability to relapse remain unknown.6-8 Here, we modeled interindividual differences in post-therapy fear relapse with an ethologically relevant trauma recovery paradigm. After fear conditioning, male rats underwent fear extinction while foraging in a large enriched arena, permitting the expression of a wide spectrum of behaviors. An automated multidimensional behavioral assessment revealed that post-conditioning fear response profiles clustered into two groups: some animals expressed fear by freezing more, whereas others darted more, as if fleeing from danger. Remarkably, the tendency of an animal to dart or to freeze after CS presentation during the first extinction session was, respectively, associated with stronger or weaker fear renewal. Moreover, genome-wide transcriptional profiling revealed that these groups differentially regulated specific sets of genes, some of which were previously implicated in anxiety and trauma-related disorders. Our results suggest that post-trauma behavioral phenotypes and the associated gene expression landscapes can serve as markers of fear relapse susceptibility and thus may be instrumental for future development of more effective treatments for psychiatric patients.

Discriminating Sleep From Freezing With Cortical Spindle Oscillations.

In-vivo longitudinal recordings require reliable means to automatically discriminate between distinct behavioral states, in particular between awake and sleep epochs. The typical approach is to use some measure of motor activity together with extracellular electrophysiological signals, namely the relative contribution of theta and delta frequency bands to the Local Field Potential (LFP). However, these bands can partially overlap with oscillations characterizing other behaviors such as the 4 Hz accompanying rodent freezing. Here, we first demonstrate how standard methods fail to discriminate between sleep and freezing in protocols where both behaviors are observed. Then, as an alternative, we propose to use the smoothed cortical spindle power to detect sleep epochs. Finally, we show the effectiveness of this method in discriminating between sleep and freezing in our recordings.

Assessing the Impact of Off-the-Job and On-the-Job Training on Employment Outcomes: A Counterfactual Evaluation of the PIPOL Program.

BACKGROUND: This article studies the effect of PIPOL, an integrated program of active labor policies launched by the Friuli Venezia Giulia, an Italian region, in 2014. OBJECTIVES: To understand the impact of training in a classroom setting (off-the-job) and work-related training (on-the-job) on employment integration of benefit recipients. RESEARCH DESIGN: We adopt a counterfactual approach by comparing a target group (treated) against a control group (19,899) extracted by means of propensity score matching and Mahalanobis distance matching among subjects who, while registered in the program over the years 2014-2016, had never benefited from it. The selection of about 7,175 recipients in the program and in each type of intervention was random. Subjects: About 30,000 job seekers made up of 3,911 interns, 2,945 trainees, and 319 recipients of training and internship within PIPOL. Target: Young people, Not in Education Employment or Trainings, and over 30s. MEASURES: We look at different outcomes: employment tout court and employment in open-ended contracts. RESULTS: The overall net impact of PIPOL was equal to +5 pp on average. Specifically, impact results were classroom training none, internship sizable (+14.1 pp), and training combined with an internship, quite sizable (+9.6 pp). Furthermore, training to gain a qualification was the most effective (+6.4 pp) among those receiving combined training and internship. Internship also increased the chance to find permanent employment (+3 pp). Among recipients, women, immigrants, and low-skilled recipients registered the most sizable impact on finding employment and training in manufacturing and construction was more effective than elsewhere. CONCLUSIONS: Italian young people have ever-increasing academic attainment but, due to the sequential nature of the education system, little work-related competences. This could explain the greater success of internships on classroom training.

Incidence of pertussis in the province of Pesaro-Urbino (Italy).

Pertussis vaccination coverage in the Marche region is one of the lowest in Italy, with the province of Pesaro-Urbino remaining stable below 95% coverage since at least 2013. In this paper, we retrospectively analyzed all whooping cough notification cards arriving at the prevention department of the Area Vasta 1 Health Office in the Marche region and relating to the Pesaro-Urbino province (Italy). Between 2012 and 2017, there were 28 reported cases of pertussis with a peak in 2016 (11 cases, of which seven were in Urbino). The 28 patients were mostly male (65%), and had a mean age of 9 years. Three of these were not Italian. Between 2012 and 2017, the district of Pesaro reported the highest number of cases (almost 46.5% of the total), followed by Urbino (28.5%) and Fano (25%). The average incidence in the province in the period in question, still under 2 cases/100,000 inhabitants, arrived in 2016 at 4 cases/100,000 inhabitants. In particular, in Urbino there was an unforeseen incidence >8 cases/100,000 inhabitants. There were no deaths, although two children (both under 12 months of age) were hospitalized. Our data confirm that in 2016 there was a pertussis epidemic in Urbino (Italy).

Wireless inertial measurement of head kinematics in freely-moving rats.

While miniature inertial sensors offer a promising means for precisely detecting, quantifying and classifying animal behaviors, versatile inertial sensing devices adapted for small, freely-moving laboratory animals are still lacking. We developed a standalone and cost-effective platform for performing high-rate wireless inertial measurements of head movements in rats. Our system is designed to enable real-time bidirectional communication between the headborne inertial sensing device and third party systems, which can be used for precise data timestamping and low-latency motion-triggered applications. We illustrate the usefulness of our system in diverse experimental situations. We show that our system can be used for precisely quantifying motor responses evoked by external stimuli, for characterizing head kinematics during normal behavior and for monitoring head posture under normal and pathological conditions obtained using unilateral vestibular lesions. We also introduce and validate a novel method for automatically quantifying behavioral freezing during Pavlovian fear conditioning experiments, which offers superior performance in terms of precision, temporal resolution and efficiency. Thus, this system precisely acquires movement information in freely-moving animals, and can enable objective and quantitative behavioral scoring methods in a wide variety of experimental situations.