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Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors

Context. Certain populations, such as socially marginalized individuals and late adolescents (i.e., aged 17-19), are more prone than others to experience severe alcohol- related harm. However, these populations are often not interested in attaining alcohol abstinence or reducing alcohol consumption to moderate levels. Thus, their needs are not met within traditional primarily abstinence-based service options. In response, harm- reduction approaches have begun to be applied with these populations. The overall aim of this thesis was to contribute to the research on alcohol-related harm reduction in these populations by conducting 5 distinct studies. The two first studies were conducted with chronically homeless individuals with alcohol problems in the US: Study 1 examined their perceptions of twelve-step mutual-help groups (TMGs) and their association with treatment attendance, motivation and alcohol outcomes, whereas study 2 examined this population's use of safer-drinking strategies. Study 3 evaluated substance-use and related problems following exposure to a harm-reduction drop-in center that allows alcohol consumption onsite among socially marginalized alcohol and other drug (AOD) users in Switzerland. Studies 4 and 5 were conducted among US and Swedish high school seniors and prospectively tested a) the moderating effect of drinking intentions on the association between use of protective behavioral strategies (PBS) and alcohol outcomes, and b) the moderating effect of PBS use on the link between alcohol expectancies and alcohol outcomes. Findings. Study 1 found that most chronically homeless individuals with alcohol problems endorsed negative perceptions of TMGs, which were in turn associated with less treatment attendance. Study 2 found that chronically homeless individuals with alcohol dependence were interested in drinking safer and were able to commit to using safer-drinking strategies. Study 3 showed that exposure to a harm-reduction drop-in center that allows alcohol consumption onsite was followed by significant decrease in alcohol use and related problems among socially marginalized AOD users in Switzerland, with greater attendance being related to additional improvement in mental health-related quality of life (QoL) and decrease in drug-related problem severity. Finally, studies 4 and 5 showed that use of PBS was related to future decreases in alcohol use and related consequences among US and Swedish high school seniors. Findings also showed significant interactions between drinking intentions and PBS use (study 4), and between alcohol expectancies and PBS use (study 5). Conclusion. Taken together, findings confirmed that socially marginalized individuals and high school seniors show low interest in traditional approaches aiming abstinence or use reduction. Findings documented, however, that these distinct populations embrace alcohol harm-reduction approaches and that these approaches appear to be related to decreases in alcohol-related harm. Taken together, these findings suggest that alcohol harm-reduction approaches are promising ways to decrease alcohol- related harm across different populations and different cultures (i.e., US, Sweden, Switzerland). -- Contexte. Malgré leurs besoins importants en matière de traitement alcoologique, les personnes socialement marginalisées sont souvent sous-traitées par les traitements visant l'abstinence ou la consommation modérée. Similairement, les approches préventives promouvant l'abstinence ne suscitent généralement que peu d'intérêts et d'effets positifs au sein des jeunes (gymnasiens par exemple), qui sont pourtant connus pour leur usage d'alcool à risque. En réponse, les interventions ciblant ces populations intègrent de plus en plus des principes de réduction des risques et des méfaits. L'objectif général de ce travail de thèse était de contribuer à la recherche dans ce domaine en réalisant 5 études distinctes. Les deux premières études ont été conduites au sein de personnes sans-abris chroniques présentant un problème d'alcool aux États-Unis: L'étude 1 a examiné leurs perceptions des groupes d'entraide mutuelle en douze étapes (GEMs), et l'association entre ces perceptions et la fréquentation des traitements, la motivation et l'usage d'alcool. L'étude 2 a examiné l'usage des stratégies de consommation plus sûre au sein de cette population. L'étude 3 a évalué l'évolution de l'usage de substances et des problèmes associés après l'exposition à un espace d'accueil de jour tolérant la consommation d'alcool au sein de personnes socialement marginalisées en Suisse. Enfin, les études 4 et 5 ont été conduites parmi des gymnasiens aux États-Unis et en Suède et ont testé prospectivement a) l'effet modérateur des intentions de consommer sur le lien entre l'utilisation de stratégies de protection comportementales (SPCs) et l'usage d'alcool, et b) l'effet modérateur de l'usage de SPCs sur le lien entre les attentes liées à l'usage d'alcool et la consommation d'alcool. Résultats. L'étude 1 a montré que la plupart des participants avaient des perceptions négatives des GEMs et que ces perceptions étaient associées négativement à la fréquentation des traitements. L'étude 2 a montré que les participants étaient intéressés à réduire les risques liés à leur usage d'alcool et qu'ils pouvaient s'engager à utiliser des stratégies de consommation plus sûre. L'étude 3 a montré que les participants ont diminué leur usage d'alcool et les problèmes associés au cours de l'évaluation et que chaque mois supplémentaire passé au sein de l'espace d'accueil était associé à une diminution supplémentaire de la sévérité des problèmes liés aux drogues et à une amélioration de la qualité de vie liée à la santé mentale. Les études 4 et 5 ont indiqué que l'usage de SPCs était prospectivement associé à une diminution de la consommation d'alcool et des conséquences associées. Les résultats ont également montré des interactions significatives entre l'usage des SPCs et a) les intentions de consommer (étude 4), et b) les attentes liées à l'alcool (étude 5). Conclusion. Globalement, les études comprises dans ce travail de thèse confirment que les approches visant l'abstinence et la consommation modérée ne suscitent que peu d'intérêt au sein des personnes socialement marginalisées et des gymnasiens. Notre travail indique toutefois que ces populations acceptent les approches visant la réduction des risques et des méfaits et que celles-ci semblent être associées à une diminution des méfaits liés à l'usage d'alcool. De manière générale, ces résultats suggèrent que ces approches sont prometteuses au sein de différentes populations issues de cultures diverses (États-Unis, Suède, Suisse).

Objective To analyze Italian Cardiac Surgery experience during the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) identifying risk factors for overall mortality according to coronavirus disease 2019 (COVID‐19) status. Methods From February 20 to May 31, 2020, 1354 consecutive adult patients underwent cardiac surgery at 22 Italian Centers; 589 (43.5%), patients came from the red zone. Based on COVID‐19 status, 1306 (96.5%) were negative to SARS‐CoV‐2 (COVID‐N), and 48 (3.5%) were positive to SARS‐CoV‐2 (COVID‐P); among the COVID‐P 11 (22.9%) and 37 (77.1%) become positive, before and after surgery, respectively. Surgical procedures were as follows: 396 (29.2%) isolated coronary artery bypass grafting (CABG), 714 (52.7%) isolated non‐CABG procedures, 207 (15.3%) two associate procedures, and three or more procedures in 37 (2.7%). Heart failure was significantly predominant in group COVID‐N (10.4% vs. 2.5%, p = .01). Results Overall in‐hospital mortality was 1.6% (22 cases), being significantly higher in COVID‐P group (10 cases, 20.8% vs. 12, 0.9%, p

Background The impact of the coronary artery bypass grafting ( CABG ) technique (on‐ versus off‐pump, single versus multiple aortic clamping) on postoperative neurological outcome remains a matter of controversy. The aim of this study was to assess the association between the incidence of postoperative stroke and the degree of aortic manipulation in one of the largest contemporary CABG series. Methods and Results A retrospective, multicenter, international study was conducted in 25 388 patients undergoing isolated CABG procedures with on‐pump CABG ( ONCAB ) or off‐pump CABG ( OPCAB ) technique including single or multiple aortic clamping. Postoperative stroke was defined as a postoperative neurological deficit lasting more than 24 hours and associated with evidence of a brain lesion on computed tomography. The degree of aortic manipulation was assumed to be higher for on‐pump versus off‐pump surgery and for multiple versus single or no aortic clamping. Logistic regression and propensity matching were used. ONCAB procedures were performed in 17 231 cases and OPCAB in 8157. The incidence of postoperative stroke was significantly lower in the OPCAB group even after propensity matching (0.4% OPCAB versus 1.2% ONCAB , P =0.02). In the ONCAB group (but not in the OPCAB arm) the use of single aortic clamping was associated with significantly reduced postoperative stroke rate (odds ratio, 0.05; 95% CI , 0.008 to 0.07 [ P Conclusions OPCAB and the use of single aortic clamping in the ONCAB arm were associated with a reduced incidence of postoperative stroke. Our data confirm a strong association between aortic manipulation and neurological outcome after CABG surgery.

The metabolic effects of low oxygen content on alcohol-dehydrogenase (ADH) activity and hemoglobin (Hb) concentration were investigated in IV-instar larvae of Chironomus riparius (Diptera: Chironomidae) from an Italian stream. Two series of short-term (48 h) experiments were carried out: exposure to (1) progressive hypoxia (95 to 5% of oxygen saturation) and (2) anoxia (at 50% and decreased significantly only after 48 h of treatment (= 2 gAFDW-1 h-1. ADH activity showed two phases of growth, within the first 14 h and over 18 h of exposure. Overall, we inferred that i) Hb might function as short-term oxygen storage, enabling animals to delay the on-set of anaerobiosis; and ii) alcoholic fermentation co-occurs for a short time with aerobic respiration, becoming the prevalent metabolic pathway below 5% of oxygen saturation (-1). These considerations were supported also by results from anoxia exposure (2). In such condition, larvae were visibly stressed, becoming immobile after few minutes of incubation, and ADH reached higher values than in the hypoxia treatment (2.03±0.15 UADH mg prot-1). Overall, this study showed a shift from aerobic to anaerobic activity in C. riparius larvae exposed to poorly oxygenated water with an associated alteration of ADH activity and the Hb amount. Such metabolites might be valid candidate biomarkers for the environmental monitoring of running waters.

a b s t r a c t Background: Specific bacterial infections or alterations of the gut microbiota likely trigger immuno- pathological phenomena associated with Crohn's disease and ulcerative colitis. Mycobacterium avium subspecies paratuberculosis is a candidate etiological agent of Crohn's disease. Definitive causal connec- tion between Mycobacterium avium subspecies paratuberculosis infection and Crohn's disease has not been demonstrated. Aims: To determine the circulation of Mycobacterium avium subspecies paratuberculosis in Crohn's disease patients and water supplies in an Italian region where this bacterium is endemic in cattle farms. Methods: Mycobacterium avium subspecies paratuberculosis screening was performed on biopsies from human patients, and from water samples, using two different PCR procedures. Results: In hospitals where multiple specimens were obtained from different sites in the intestine, the prevalence of Mycobacterium avium subspecies paratuberculosis infection was 82.1% and 40% respec- tively in Crohn's disease and ulcerative colitis patients; in another hospital, where single specimens were obtained from patients, the bacterium was not detected. Control subjects also harboured Mycobac- terium avium subspecies paratuberculosis, but at a lower prevalence. Tap water samples collected in the study area contained Mycobacterium avium subspecies paratuberculosis DNA. Discussion: The results of screenings for Mycobacterium avium subspecies paratuberculosis in humans are deeply influenced by both the number and location of the collected biopsies. There is a wide circulation of the organism in the study area, considering the prevalence in humans and its presence in drinking water.

Urinary tract infections (UTIs) are among the most frequent community-acquired infections worldwide.Escherichia coliis the most common UTI pathogen although underlying host factors such as patients’ age and gender may influence prevalence of causative agents. In this study, 61 273 consecutive urine samples received over a 22-month period from outpatients clinics of an urban area of north Italy underwent microbiological culture with subsequent bacterial identification and antimicrobial susceptibility testing of positive samples. A total of 13 820 uropathogens were isolated and their prevalence analyzed according to patient’s gender and age group. OverallEscherichia coliaccounted for 67.6% of all isolates, followed byKlebsiella pneumoniae(8.8%),Enterococcus faecalis(6.3%),Proteus mirabilis(5.2%), andPseudomonas aeruginosa(2.5%). Data stratification according to both age and gender showedE. coliisolation rates to be lower in both males aged ≥60 years (52.2%),E. faecalisandP. aeruginosabeing more prevalent in this group (11.6% and 7.8%, resp.), as well as in those aged ≤14 years (51.3%) in whomP. mirabilisprevalence was found to be as high as 21.2%.Streptococcus agalactiaeoverall prevalence was found to be 2.3% although it was shown to occur most frequently in women aged between 15 and 59 years (4.1%). Susceptibility ofE. colito oral antimicrobial agents was demonstrated to be as follows: fosfomycin (72.9%), trimethoprim/sulfamethoxazole (72.9%), ciprofloxacin (76.8%), ampicillin (48.0%), and amoxicillin/clavulanate (77.5%). In conclusion, both patients’ age and gender are significant factors in determining UTIs etiology; they can increase accuracy in defining the causative uropathogen as well as providing useful guidance to empiric treatment.

Transrectal microwave hyperthermia of the prostate was administered to 191 patients with bladder outlet obstruction due to benign prostatic hyperplasia who were either at poor operative risk or who refused surgery. Patients were divided in 2 groups according to age and they underwent either 5 or 10, 60-minute sessions of hyperthermia, with a calculated intraprostatic temperature of 42.5 plus or minus 0.5C. Light and electron microscopy showed no irreversible damage at the glandular epithelium but did demonstrate a significant increase in neoformed intraprostatic capillary-like vessels. At 1, 12 and 24 months residual urine volume was significantly decreased in the majority of patients but only a minor amelioration of urinary flow rates and subjective symptoms was observed. According to maximum flow nomograms all patients were still obstructed postoperatively. Transrectal hyperthermia cannot be considered a genuine alternative to surgery for patients with bladder outlet obstruction due to benign prostatic hyperplasia.