A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.

There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson's disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson's disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson's disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson's disease (28 568 cases) were obtained from the International Parkinson's Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10-8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson's disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = -2.364, 95% confidence interval (CI) = -4.789-0.060; years difference per 1 log-unit increase = -2.011, 95% CI = -3.706 to -0.317; years difference per 1 log-unit increase = -1.569, 95% CI = -2.891 to -0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson's disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson's disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson's disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson's disease.

Increased risk of emergency department presentations for bronchiolitis in infants exposed to air pollution.

Air pollution has been linked to an increased risk of several respiratory diseases in children, especially respiratory tract infections. The present study aims to evaluate the association between pediatric emergency department (PED) presentations for bronchiolitis and air pollution. PED presentations due to bronchiolitis in children aged less than 1 year were retrospectively collected from 2007 to 2018 in Padova, Italy, together with daily environmental data. A conditional logistic regression based on a time-stratified case-crossover design was performed to evaluate the association between PED presentations and exposure to NO2 , PM2.5, and PM10. Models were adjusted for temperature, relative humidity, atmospheric pressure, and public holidays. Delayed effects in time were evaluated using distributed lag non-linear models. Odds ratio for lagged exposure from 0 to 14 days were obtained. Overall, 2251 children presented to the PED for bronchiolitis. Infants' exposure to higher concentrations of PM10 and PM2.5 in the 5 days before the presentation to the PED increased the risk of accessing the PED by more than 10%, whereas high concentrations of NO2 between 2 and 12 days before the PED presentation were associated with an increased risk of up to 30%. The association between pollutants and infants who required hospitalization was even greater. A cumulative effect of NO2 among the 2 weeks preceding the presentation was also observed. In summary, PM and NO2 concentrations are associated with PED presentations and hospitalizations for bronchiolitis. Exposure of infants to air pollution could damage the respiratory tract mucosa, facilitating viral infections and exacerbating symptoms.

Oversampling and replacement strategies in propensity score matching: a critical review focused on small sample size in clinical settings.

BACKGROUND: Propensity score matching is a statistical method that is often used to make inferences on the treatment effects in observational studies. In recent years, there has been widespread use of the technique in the cardiothoracic surgery literature to evaluate to potential benefits of new surgical therapies or procedures. However, the small sample size and the strong dependence of the treatment assignment on the baseline covariates that often characterize these studies make such an evaluation challenging from a statistical point of view. In such settings, the use of propensity score matching in combination with oversampling and replacement may provide a solution to these issues by increasing the initial sample size of the study and thus improving the statistical power that is needed to detect the effect of interest. In this study, we review the use of propensity score matching in combination with oversampling and replacement in small sample size settings. METHODS: We performed a series of Monte Carlo simulations to evaluate how the sample size, the proportion of treated, and the assignment mechanism affect the performances of the proposed approaches. We assessed the performances with overall balance, relative bias, root mean squared error and nominal coverage. Moreover, we illustrate the methods using a real case study from the cardiac surgery literature. RESULTS: Matching without replacement produced estimates with lower bias and better nominal coverage than matching with replacement when 1:1 matching was considered. In contrast to that, matching with replacement showed better balance, relative bias, and root mean squared error than matching without replacement for increasing levels of oversampling. The best nominal coverage was obtained by using the estimator that accounts for uncertainty in the matching procedure on sets of units obtained after matching with replacement. CONCLUSIONS: The use of replacement provides the most reliable treatment effect estimates and that no more than 1 or 2 units from the control group should be matched to each treated observation. Moreover, the variance estimator that accounts for the uncertainty in the matching procedure should be used to estimate the treatment effect.

Anomalous left coronary artery from pulmonary artery repair: Outcomes from the European Congenital Heart Surgeons Association Database.

INTRODUCTION: We sought to determine the surgical outcomes of patients with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) enrolled in the European Congenital Heart Surgeons Association (ECHSA) database. MATERIALS AND METHODS: From 1999 to 2019, 907 patients with ALCAPA underwent surgical repair and were included in the current study. The primary outcome was in-hospital mortality. Secondary outcomes included frequency and results of concomitant mitral valve surgery and postoperative mechanical circulatory support (MCS). RESULTS: The overall in-hospital mortality was 6% (54/907) and was significantly higher in neonates (p = .01), patients with lower body surface area (BSA) (p = .01), and those requiring postoperative MCS (p = .001). Associated mitral valve surgery was performed in 144 patients (15.9%) and was associated with longer cardiopulmonary bypass (CPB) and aortic cross-clamp times (AOX) (p ≤ .0001) but was not significantly related to an increase in in-hospital mortality. Postoperative MCS was required in 66 patients (7.3%). These patients were younger (p ≤ .001), had a lower BSA (p ≤ .001), and required a longer CPB (p ≤ .001) and AOX time (p ≤ .001). CONCLUSIONS: ALCAPA repair can be achieved successfully, and with low surgical risk. Concomitant mitral valve procedures can be performed without increasing operative mortality. The use of MCS remains a valuable option, especially in younger patients.

Dyspnea, effort and muscle pain during exercise in lung transplant recipients: an analysis of their association with cardiopulmonary function parameters using machine learning.

BACKGROUND: Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. METHODS: Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. RESULTS: Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (< 32) the higher the muscle effort perception. Muscle pain score was significantly associated with VO2 peak, arterial [HCO3-] at rest, and VE/VCO2 slope. In a subgroup analysis, muscle pain was the limiting symptom in LTx recipients with a lower VO2 peak (< 15 mL/Kg/min) and a higher VE/VCO2 slope (≥ 32). CONCLUSIONS: The majority of our LTx recipients reported peripheral limitation as the prevalent reason for exercise termination. Muscle pain at peak exercise was strictly associated with basal and exercise-induced metabolic altered pathways. The onset of dyspnea (breathing effort) was associated with the intensity of ventilatory response to meet metabolic demands for increasing WR. Our study suggests that only an accurate assessment of symptoms combined with cardio-pulmonary parameters allows a correct interpretation of exercise limitation and a tailored exercise prescription. The role and mechanisms of muscle pain during exercise in LTx recipients requires further investigations.

Similar effectiveness of dapagliflozin and GLP-1 receptor agonists concerning combined endpoints in routine clinical practice: A multicentre retrospective study.

AIMS: According to cardiovascular outcome trials, some sodium-glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are recommended for secondary cardiovascular prevention in type 2 diabetes (T2D). In this real-world study, we compared the simultaneous reductions in HbA1c, body weight and systolic blood pressure after initiation of dapagliflozin or GLP-1RA as second or a more advanced line of therapy. MATERIALS AND METHODS: DARWIN-T2D was a retrospective multi-centre study conducted at diabetes specialist clinics in Italy that compared T2D patients who initiated dapagliflozin or GLP-1RA (exenatide once weekly or liraglutide). Data were collected at baseline and at the first follow-up visit after 3 to 12 months. The primary endpoint was the proportion of patients achieving a simultaneous reduction in HbA1c, body weight and systolic blood pressure. To reduce confounding, we used multivariable adjustment (MVA) or propensity score matching (PSM). RESULTS: Totals of 473 patients initiating dapagliflozin and 336 patients initiating GLP-1RA were included. The two groups differed in age, diabetes duration, HbA1c, weight and concomitant medications. The median follow-up was 6 months in both groups. Using MVA or PSM, the primary endpoint was observed in 30% to 32% of patients, with no difference between groups. Simultaneous reduction of HbA1c, BP and SBP by specific threshold, as well as achievement of final goals, did not differ between groups. GLP-1RA reduced HbA1c by 0.3% more than the reduction achieved with dapagliflozin. CONCLUSION: In routine specialist care, initiation of dapagliflozin can be as effective as initiation of a GLP-1RA for attainment of combined risk factor goals.

Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study.

In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs.

Anticoagulation alone as an effective and safe antithrombotic therapy in LVAD: When less is more.

To evaluate the safety and effectiveness of anticoagulation alone in HeartMate3 patients. According to antithrombotic regimen, patients were divided into 2 groups: Group-1(warfarin+aspirin) and Group-2(warfarin). A comparison of hemocompatibility-related adverse events (HRAEs), hemocompatibility score (HCS), and hemocoagulative laboratory markers, both qualitative and quantitative, between the 2 groups were performed. Fifty patients were enrolled, 28 (56%) in Group-1 and 22 in Group-2 (44%), without statistical differences at baseline. Median time of follow-up was 590 days (IQR: 410.25-1007.50). Eighteen HRAEs (36.0%) occurred: 17 in Group-1 (34%) and 1 in Group-2 (2%) (P < 0.001). The net HCS for Group-1 versus Group-2 was 24 points and 1 point (OR 12.116[2.034-233.226], P = 0.023), respectively. Hemocoagulative values turned into the normality and remained stable during follow-up, without differences between groups, except for ASPI-test (P = 0.003). HeartMate3 showed a high hemocompatibility independently from antithrombotic therapy. Aspirin avoidance resulted a safe and effective strategy since it reduced hemorrhagic events, without increasing thrombotic risk.

Determinants of SARS-CoV-2 nasopharyngeal testing in a rural community sample susceptible of first infection: the CHRIS COVID-19 study.

To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four-week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandemic intensity and public health interventions, COVID-19-related symptoms (odds ratio, OR:8.26; 95% confidence interval, CI:6.04-11.31), contacts with infected individuals within home (OR:7.47, 95%CI:3.81-14.62) or outside home (OR:9.87, 95%CI:5.78-16.85), and being retired (OR:0.50, 95%CI:0.34-0.73). Symptoms and next within- and outside-home contacts were the leading determinants of swab testing predisposition in the most acute phase of the pandemics. Testing was not associated with age, sex, education, comorbidities, or lifestyle factors. In the study area, contextual determinants reflecting the course of the pandemic were predominant compared to individual sociodemographic characteristics in explaining the SARS-CoV-2 probability of testing. Decision makers should evaluate whether the intended target groups were correctly prioritized by the testing campaign.

Trends and symptoms of SARS-CoV-2 infection: a longitudinal study on an Alpine population representative sample.

OBJECTIVES: The continuous monitoring of SARS-CoV-2 infection waves and the emergence of novel pathogens pose a challenge for effective public health surveillance strategies based on diagnostics. Longitudinal population representative studies on incident events and symptoms of SARS-CoV-2 infection are scarce. We aimed at describing the evolution of the COVID-19 pandemic during 2020 and 2021 through regular monitoring of self-reported symptoms in an Alpine community sample. DESIGN: To this purpose, we designed a longitudinal population representative study, the Cooperative Health Research in South Tyrol COVID-19 study. PARTICIPANTS AND OUTCOME MEASURES: A sample of 845 participants was retrospectively investigated for active and past infections with swab and blood tests, by August 2020, allowing adjusted cumulative incidence estimation. Of them, 700 participants without previous infection or vaccination were followed up monthly until July 2021 for first-time infection and symptom self-reporting: COVID-19 anamnesis, social contacts, lifestyle and sociodemographic data were assessed remotely through digital questionnaires. Temporal symptom trajectories and infection rates were modelled through longitudinal clustering and dynamic correlation analysis. Negative binomial regression and random forest analysis assessed the relative importance of symptoms. RESULTS: At baseline, the cumulative incidence of SARS-CoV-2 infection was 1.10% (95% CI 0.51%, 2.10%). Symptom trajectories mimicked both self-reported and confirmed cases of incident infections. Cluster analysis identified two groups of high-frequency and low-frequency symptoms. Symptoms like fever and loss of smell fell in the low-frequency cluster. Symptoms most discriminative of test positivity (loss of smell, fatigue and joint-muscle aches) confirmed prior evidence. CONCLUSIONS: Regular symptom tracking from population representative samples is an effective screening tool auxiliary to laboratory diagnostics for novel pathogens at critical times, as manifested in this study of COVID-19 patterns. Integrated surveillance systems might benefit from more direct involvement of citizens' active symptom tracking.

Social skills and psychopathology are associated with autonomic function in children: a cross-sectional observational study.

In recent years, the increase of psychopathological disorders in the population has become a health emergency, leading to a great effort to understand psychological vulnerability mechanisms. In this scenario, the role of the autonomic nervous system (ANS) has become increasingly important. This study investigated the association between ANS, social skills, and psychopathological functioning in children. As an ANS status proxy, we measured heart rate variability (HRV). Infants admitted to the neonatal intensive care unit of the University Hospital of Padova because of preterm birth or neonatal hypoxic-ischemic encephalopathy were sequentially recruited from January 2011 to June 2013 and followed long-term up to school age in this cross-sectional observational study. We recorded 5 minutes of HRV immediately before measuring performance in social abilities tasks (affect recognition and theory of mind, NEPSY-II) in 50 children (mean age 7.4 ± 1.4 years) with and without risk factors for developing neuropsychiatric disorders due to pre-/perinatal insults without major sequelae. Children also completed extensive cognitive, neuropsychological, and psychosocial assessment. Parents were assessed with psychopathological interviews and a questionnaire (CBCL 6-18). Analysis in a robust Bayesian framework was used to unearth dependencies between HRV, social skills, and psychopathological functioning. Social task scores were associated with HRV components, with high frequency the most consistent. HRV bands were also associated with the psychopathological questionnaire. Only normalized HRV high frequency was able to distinguish impaired children in the affect recognition task. Our data suggest that ANS may be implicated in social cognition both in typical and atypical developmental conditions and that HRV has cross-disease sensitivity. We suggest that HRV parameters may reflect a neurobiological vulnerability to psychopathology. The study was approved by the Ethics Committee of the University Hospital of Padova (Comitato Etico per la Sperimentazione, Azienda Opedaliera di Padova, approval No. 1693P).

Assessment of Glucose Lowering Medications' Effectiveness for Cardiovascular Clinical Risk Management of Real-World Patients with Type 2 Diabetes: Targeted Maximum Likelihood Estimation under Model Misspecification and Missing Outcomes.

The results from many cardiovascular (CV) outcome trials suggest that glucose lowering medications (GLMs) are effective for the CV clinical risk management of type 2 diabetes (T2D) patients. The aim of this study is to compare the effectiveness of two GLMs (SGLT2i and GLP-1RA) for the CV clinical risk management of T2D patients in a real-world setting, by simultaneously reducing glycated hemoglobin, body weight, and systolic blood pressure. Data from the real-world Italian multicenter retrospective study Dapagliflozin Real World evideNce in Type 2 Diabetes (DARWINT 2D) are analyzed. Different statistical approaches are compared to deal with the real-world-associated issues, which can arise from model misspecification, nonrandomized treatment assignment, and a high percentage of missingness in the outcome, and can potentially bias the marginal treatment effect (MTE) estimate and thus have an influence on the clinical risk management of patients. We compare the logistic regression (LR), propensity score (PS)-based methods, and the targeted maximum likelihood estimator (TMLE), which allows for the use of machine learning (ML) models. Furthermore, a simulation study is performed, resembling the structure of the conditional dependencies among the main variables in DARWIN-T2D. LR and PS methods do not underline any difference in the effectiveness regarding the attainment of combined CV risk factor goals between the two treatments. TMLE suggests instead that dapagliflozin is significantly more effective than GLP-1RA for the CV risk management of T2D patients. The results from the simulation study suggest that TMLE has the lowest bias and SE for the estimate of the MTE.

Systematic review of Mendelian randomization studies on Parkinson's disease.

Background: Parkinson's disease (PD) is known to be associated with non-genetic factors. To infer causality, Mendelian randomization (MR) studies are increasingly used. Here, genetic variants are used as instrumental variables for the risk factor but have no direct effect on PD themselves. Methods: We performed a systematic literature review on MR studies for PD. Studies were identified searching the PubMed database. Upon data extraction, we evaluated the methodological quality and summarized the evidence. Results: Twelve articles were included. Most studies showed "good" methodological quality, but most did not report proper power estimations. Twelve analyses yielded nominally significant effects. Conclusions: Our systematic review shows that most MR studies were well performed and allow to identify causal exposures, which may inform further studies on the prevention and early intervention of PD.

Identifying Predictors of Anal HPV Status in HPV-Vaccinated MSM: A Machine Learning Approach.

Anal human papillomavirus (HPV) infection has a high prevalence in men who have sex with men (MSM), resulting in an increased risk for anal cancer. The present work aimed to identify factors associated with HPV in a prospective cohort of HPV-vaccinated MSM using a random forest (RF) approach. This observational study enrolled MSM patients admitted to an Italian (sexually transmitted infection) STI-AIDS Unit. For each patient, rectal swabs for 28 different HPV genotype detection were collected. Two RF algorithms were applied to evaluate predictors that were most associated with HPV. The cohort included 135 MSM, 49% of whom were HIV-positive with a median age of 39 years. In model 1 (baseline information), age, age sexual debut, HIV, number of lifetime sex partners, STIs, were most associated with the HPV. In model 2 (follow-up information), age, age sexual debut, HIV, STI class, and follow-up. The RF algorithm exhibited good performances with 61% and 83% accuracy for models 1 and 2, respectively. Traditional risk factors for anal HPV infection, such as drug use, receptive anal intercourse, and multiple sexual partner, were found to have low importance in predicting HPV status. The present results suggest the need to focus on HPV prevention campaigns.

Whole Exome Sequencing Enhanced Imputation Identifies 85 Metabolite Associations in the Alpine CHRIS Cohort.

Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.

A Device Strategy-Matched Comparison Analysis among Different Intermacs Profiles: A Single Center Experience.

Background: The present study evaluates outcomes of LVAD patients, taking into account the device strategy and the INTERMACS profile. Methods: We included 192 LVAD-patients implanted between January 2012 and May 2021. The primary and secondary end-points were survival and major adverse events between Profiles 1-3 vs. Profile 4, depending on implantation strategies (Bridge-to-transplant-BTT; Bridge-to-candidacy-BTC; Destination-Therapy-DT). Results: The overall survival was 67% (61-75) at 12 months and 61% (54-70) at 24 months. Profile 4 patients showed significantly higher survival (p = 0.018). Incidences of acute right-ventricular-failure (RVF) (p = 0.046), right-ventricular-assist-device (RVAD) implantation (p = 0.015), and continuous-venovenous-hemofiltration (CVVH) (p = 0.006) were higher in Profile 1-3 patients, as well as a longer intensive care unit stays (p = 0.050) and in-hospital-mortality (p = 0.012). Twelve-month and 24-month survival rates were higher in the BTT rather than in BTC (log-rank = 0.410; log-rank = 0.120) and in DT groups (log-rank = 0.046). In the BTT group, Profile 1-3 patients had a higher need for RVAD support (p = 0.042). Conclusions: LVAD implantation in elective patients was associated with better survival and lower complications incidence. LVAD implantation in BTC patients has to be considered before their conditions deteriorate. DT should be addressed to elective patients in order to guarantee acceptable results.

Propensity Score Analysis with Partially Observed Baseline Covariates: A Practical Comparison of Methods for Handling Missing Data.

(1) Background: Propensity score methods gained popularity in non-interventional clinical studies. As it may often occur in observational datasets, some values in baseline covariates are missing for some patients. The present study aims to compare the performances of popular statistical methods to deal with missing data in propensity score analysis. (2) Methods: Methods that account for missing data during the estimation process and methods based on the imputation of missing values, such as multiple imputations, were considered. The methods were applied on the dataset of an ongoing prospective registry for the treatment of unprotected left main coronary artery disease. The performances were assessed in terms of the overall balance of baseline covariates. (3) Results: Methods that explicitly deal with missing data were superior to classical complete case analysis. The best balance was observed when propensity scores were estimated with a method that accounts for missing data using a stochastic approximation of the expectation-maximization algorithm. (4) Conclusions: If missing at random mechanism is plausible, methods that use missing data to estimate propensity score or impute them should be preferred. Sensitivity analyses are encouraged to evaluate the implications methods used to handle missing data and estimate propensity score.

Phenomapping of Patients with Primary Breast Cancer Using Machine Learning-Based Unsupervised Cluster Analysis.

Primary breast cancer (PBC) is a heterogeneous disease at the clinical, histopathological, and molecular levels. The improved classification of PBC might be important to identify subgroups of the disease, relevant to patient management. Machine learning algorithms may allow a better understanding of the relationships within heterogeneous clinical syndromes. This work aims to show the potential of unsupervised learning techniques for improving classification in PBC. A dataset of 712 women with PBC is used as a motivating example. A set of variables containing biological prognostic parameters is considered to define groups of individuals. Four different clustering methods are used: K-means, self-organising maps, hierarchical agglomerative (HAC), and Gaussian mixture models clustering. HAC outperforms the other clustering methods. With an optimal partitioning parameter, the methods identify two clusters with different clinical profiles. Patients in the first cluster are younger and have lower values of the oestrogen receptor (ER) and progesterone receptor (PgR) than patients in the second cluster. Moreover, cathepsin D values are lower in the first cluster. The three most important variables identified by the HAC are: age, ER, and PgR. Unsupervised learning seems a suitable alternative for the analysis of PBC data, opening up new perspectives in the particularly active domain of dissecting clinical heterogeneity.

A Machine Learning Approach for Investigating Delirium as a Multifactorial Syndrome.

Delirium is a psycho-organic syndrome common in hospitalized patients, especially the elderly, and is associated with poor clinical outcomes. This study aims to identify the predictors that are mostly associated with the risk of delirium episodes using a machine learning technique (MLT). A random forest (RF) algorithm was used to evaluate the association between the subject's characteristics and the 4AT (the 4 A's test) score screening tool for delirium. RF algorithm was implemented using information based on demographic characteristics, comorbidities, drugs and procedures. Of the 78 patients enrolled in the study, 49 (63%) were at risk for delirium, 32 (41%) had at least one episode of delirium during the hospitalization (38% in orthopedics and 31% both in internal medicine and in the geriatric ward). The model explained 75.8% of the variability of the 4AT score with a root mean squared error of 3.29. Higher age, the presence of dementia, physical restraint, diabetes and a lower degree are the variables associated with an increase of the 4AT score. Random forest is a valid method for investigating the patients' characteristics associated with delirium onset also in small case-series. The use of this model may allow for early detection of delirium onset to plan the proper adjustment in healthcare assistance.

Epidemiology and Trends over Time of Foreign Body Injuries in the Pediatric Emergency Department.

This paper presents the epidemiology of foreign body injuries in the Pediatric Emergency Department (PED) of Padova (Italy) along with its trends over an eleven-year period based on administrative data. Annual incidence rates (IRs) of PED presentations for foreign body (FB) injuries per 1000 person-years were calculated. Univariable and multivariable generalized linear (GLM) Poisson models were estimated to evaluate the relationship between FB injury incidence and year, triage priority, nationality, injury site, and FB type. During the study period, there were 217,900 presentations of pediatric residents in the province of Padova; of these, 3084 (1.5%) reported FB injuries involving the ears, nose, throat, gastrointestinal tract or eyes. The annual IR of FB injury episodes increased from 10.45 for 1000 residents in 2007 (95% CI, 9.24, 11.77) to 12.66 for 1000 residents in 2018 (95% CI, 11.35, 14.08). Nonfood items were the FBs that were most frequently reported. The intermediate urgent triage code was the most represented for FB injuries, with IRs ranging from 5.44 (95% CI: 4.59, 6.40) in 2008 to 8.56 in 2018 (95% CI: 7.50, 9.74). A total of 170 patients who presented for FB injuries were hospitalized (5.5%). The annual FB-related injury IR has increased over time, although most episodes are not life threatening. Educational and prevention programs on FB-related injuries should be promoted and dedicated to childcare providers.