ProfhEX: AI-based platform for small molecules liability profiling.

Off-target drug interactions are a major reason for candidate failure in the drug discovery process. Anticipating potential drug's adverse effects in the early stages is necessary to minimize health risks to patients, animal testing, and economical costs. With the constantly increasing size of virtual screening libraries, AI-driven methods can be exploited as first-tier screening tools to provide liability estimation for drug candidates. In this work we present ProfhEX, an AI-driven suite of 46 OECD-compliant machine learning models that can profile small molecules on 7 relevant liability groups: cardiovascular, central nervous system, gastrointestinal, endocrine, renal, pulmonary and immune system toxicities. Experimental affinity data was collected from public and commercial data sources. The entire chemical space comprised 289'202 activity data for a total of 210'116 unique compounds, spanning over 46 targets with dataset sizes ranging from 819 to 18896. Gradient boosting and random forest algorithms were initially employed and ensembled for the selection of a champion model. Models were validated according to the OECD principles, including robust internal (cross validation, bootstrap, y-scrambling) and external validation. Champion models achieved an average Pearson correlation coefficient of 0.84 (SD of 0.05), an R2 determination coefficient of 0.68 (SD = 0.1) and a root mean squared error of 0.69 (SD of 0.08). All liability groups showed good hit-detection power with an average enrichment factor at 5% of 13.1 (SD of 4.5) and AUC of 0.92 (SD of 0.05). Benchmarking against already existing tools demonstrated the predictive power of ProfhEX models for large-scale liability profiling. This platform will be further expanded with the inclusion of new targets and through complementary modelling approaches, such as structure and pharmacophore-based models. ProfhEX is freely accessible at the following address: https://profhex.exscalate.eu/ .

Budget impact of implementing platelet pathogen reduction into the Italian blood transfusion system.

BACKGROUND: Despite improvements in blood donor selection and screening procedures, transfusion recipients can still develop complications related to infections by known and emerging pathogens. Pathogen reduction technologies (PRT) have been developed to reduce such risks. The present study, developed whithin a wider health technology assessment (HTA) process, was undertaken to estimate the costs of the continuing increase in the use of platelet PRT in Italy. MATERIALS AND METHODS: A multidisciplinary team was established to perform the HTA and conduct a budget impact analysis. Quantitative data on platelet use were derived from the 2015 national blood transfusion report and from the Italian Platelets Transfusion Assessment Study (IPTAS). The current national fee of 60 Euro per platelet PRT procedure was used to quantify the costs to the Italian National Health Service (INHS). The analysis adopts a 3-year time-frame. In order to identify the impact on budget we compared a scenario representing an increased use of PRT platelets over time with a control scenario in which standard platelets are used. RESULTS: Progressive implementation of PRT for 20%, 40% and 66% of annual adult platelet doses could generate an increase in annual costs for the INHS amounting to approximately 7, 14 and 23 million Euros, respectively. Use of kits and devices suitable for the treatment of multiple adult platelet doses in one PRT procedure could lower costs. DISCUSSION: In order to fully evaluate the societal perspective of implementing platelet PRT, the increase in costs must be balanced against the expected benefits (prevention of transfusion-transmissible infections, white cell inactivation, extension of platelet storage, discontinuation of pathogen detection testing). Further studies based on actual numbers of platelet transfusion complications and their societal cost at a local level are needed to see the full cost to benefit ratio of platelet PRT implementation in Italy, and to promote equal treatment for all citizens.

The good, the bad and the ugly: Emys trinacris, Placobdella costata and Haemogregarina stepanowi in Sicily (Testudines, Annelida and Apicomplexa).

Endemic Sicilian pond turtles Emys trinacris Fritz, Fattizzo, Guicking, Tripepi, Pennisi, Lenk, Joger et Wink were examined for the presence of haemogregarine parasites. The presence of haemogregarines, occurring mainly in the microgametocyte stage (13.2 ± 0.12 µm in length and 6.4 ± 0.52 µm in width), was observed in approximately 9% of the sampled E. trinacris. Based on the observed morphology and on the sequencing of nuclear 18S rDNA, we identified the parasite as Haemogregarina stepanowi Danilewsky, 1885. Morphometric study of uninfected and infected red blood cells has shown that H. stepanowi induces different changes in erythrocyte shape depending on the infective stage. The differential count of leukocytes in specimens infected with H. stepanowi showed no significant difference compared with healthy specimens. However, considering the health problems which might be induced by H. stepanowi in the closely related European pond turtle Emys orbicularis (Linneaus), monitoring of the health status of the infected Sicilian populations of E. trinacris is desirable. The restricted distribution of populations of Emys infected with haemogregarines in Sicily is quite puzzling and the possible human-mediated introduction of the parasite in Sicily is briefly discussed.

Impact and natural history of postprocedural aortic regurgitation on early and midterm mortality following transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis.

BACKGROUND: Post-procedural aortic regurgitation (AR) negatively impacts the prognosis after trans-catheter aortic valve implantation. However, data evaluating the impact of different post-procedural AR grades (particularly mild) on clinical outcomes are still important. AIM AND METHODS: A retrospective cohort analysis was performed on all consecutive patients with severe aortic stenosis who underwent trans-catheter aortic valve implantation between July 2008 and August 2011 in a single Institution. Aim of the study was to evaluate the impact of different post-procedural AR grades on early and mid-term clinical outcomes. RESULTS: 322 consecutive patients were evaluated. At post-procedural echocardiographic evaluation: 105 (32.6%) patients had no AR, 204 (63.4%) mild AR and 13 (4%) moderate/severe AR. In-hospital mortality was higher in patients with moderate/severe AR than in those with absent or mild AR (38.5% vs. 2.6%, P < 0.001). At a median clinical follow-up of 342 days [interquartile range 93-485] cardiovascular mortality was 2.9% in patients without AR; 13.2% in the mild AR group (P = 0.004 vs. absent AR) and 46.2% in the moderate/severe AR group (P < 0.001 vs. mild or absent AR). On multivariable analysis, post-procedural AR (hazard ratio = 2.65 absent vs. present any grade, 95% confidence interval = 1.11-6.29; P = 0.027) was an independent predictor of mid-term mortality. CONCLUSIONS: The impact of post-procedural AR on outcomes after trans-catheter aortic valve implantation is proportional with its grade even in case of mild post-procedural AR compared to absent. This study confirms that every effort should be made to reduce the grade of post-procedural AR after trans-catheter aortic valve implantation with current devices.

Cardiac surgery for patients with heart failure due to structural heart disease in Uganda: access to surgery and outcomes.

OBJECTIVE: Few data are available on heart failure (HF) in sub-Saharan Africa. We aimed to provide a current picture of HF aetiologies in urban Uganda, access to heart surgery, and outcomes. METHODS: We prospectively collected clinical and echocardiographic data from 272 consecutive patients referred for suspected heart disease to a tertiary hospital in Kampala during seven non-governmental organisation (NGO) missions from 2009 to 2013. We focused the analysis on 140 patients who fulfilled standardised criteria of HF by echocardiography. RESULTS: Rheumatic heart disease (RHD) was the leading cause of HF in 44 (31%) patients. Among the 50 children included (age ≤ 16 years), congenital heart disease (CHD) was the first cause of HF (30 patients, 60%), followed by RHD (16 patients, 32%). RHD was the main cause of HF (30%) among the 90 adults. All 85 patients with RHD and CHD presented with an indication for heart surgery, of which 74 patients were deemed fit for intervention. Surgery was scheduled in 38 patients with RHD [86%, median age 19 years (IQR: 12-31)] and in 36 patients with CHD [88%, median age 4 years (IQR 1-5)]. Twenty-seven candidates (32%) were operated on after a median waiting time of 10 months (IQR 6-21). Sixteen (19%) had died after a median of 38 months (IQR 5-52); 19 (22%) were lost to follow up. CONCLUSION: RHD still represents the leading cause of HF in Uganda, in spite of cost-efficient prevention strategies. The majority of surgical candidates, albeit young, do not have access to treatment and present high mortality rates.

How should I treat a left main spontaneous dissection involving left anterior descending artery, intermediate branch artery and left circumflex artery?

BACKGROUND: A 45-year-old woman presented to the emergency department with ST-segment elevation myocardial infarction (STEMI). INVESTIGATION: Physical examination, electrocardiography, coronary angiography, echocardiography, cardiac computed tomography. DIAGNOSIS: STEMI due to spontaneous left main coronary artery dissection involving left anterior descending, intermediate and left circumflex arteries. TREATMENT: Percutaneous coronary intervention (PCI).

"Procedural trauma risks longitudinal shortening of the Promus Element™ stent platform".

This case series raises further awareness of the potential for longitudinal shortening with the Promus Element™ (Boston Scientific, MN) drug-eluting stent (DES) platform. With safety at the forefront of DES development, newer generation systems are utilizing thinner platforms with little or no polymer. Although these contemporary, ultrathin platforms also improve conformability and deliverability, specific design characteristics might inadvertently reduce longitudinal strength. To date, there are no randomized data addressing this issue in vivo for any stent platform, with opinion based on individual experience and bench testing. We report five cases of longitudinal shortening with the Promus Element stent occurring in our institution over a 15-month period. During the same period, we experienced only isolated cases with other second generation DES platforms. Our experience supports recently published bench-top data correlating the two-link design of this platform with the risk of compression.

Clinical outcome and quality of life in octogenarians following transcatheter aortic valve implantation (TAVI) for symptomatic aortic stenosis.

OBJECTIVE: TAVI is the alternative option in pts with AS deemed ineligible for surgery. Although mortality and morbidity are measures to assess the effectiveness of treatments, quality of life (QOL) should be an additional target. We assessed clinical outcome and QOL in octogenarians following TAVI. DESIGN: All octogenarians with a risk profile considered by the Heart Team to be unacceptable for surgery entered in this registry. QOL was assessed by questionnaires concerning physical and psychic performance. PATIENTS: A hundred forty-five octogenarians (age: 84.7 ± 3.4 years; male: 48.3%) underwent TAVI for AS (97.2%) or isolated AR (2.8%). NYHA class: 2.8 ± 0.6; Logistic EuroScore: 26.1 ± 16.7; STS score: 9.2 ± 7.7.Echocardiographic assessments included AVA (0.77 ± 0.21 cm2), mean/peak gradients (54.5 ± 12.2/88 ± 19.5 mm Hg), LVEF (21%=EF ≤ 40%), sPAP (43.1 ± 11.6 mmHg). INTERVENTIONS: All pts underwent successful TAVI using Edward-SAPIEN valve (71.2%) or Medtronic CoreValve (28.8%). MAIN OUTCOME MEASURES: Rates of mortality at 30 days, 6 months and 1 year were 2.8%, 11.2% and 17.5%. RESULTS: At 16-month follow up, 85.5% survived showing improved NYHA class (2.8 ± 0.6 vs 1.5 ± 0.7; p<0.001), decreased sPAP (43.1 ± 11.6 mm Hg vs 37.1 ± 7.7 mm Hg; p<0.001) and increased LVEF in those with EF ≤ 40% (34.9 ± 6% vs 43.5 ± 14.4%; p=0.006). Concerning QOL, 49% walked unassisted, 79% (39.5% among pts ≥ 85 years) reported self-awareness improvement; QOL was reported as "good" in 58% (31.4% among pts ≥ 85 years), "acceptable according to age" in 34% (16% among pts ≥ 85 years) and "bad" in 8%. CONCLUSION: TAVI procedures improve clinical outcome and subjective health-related QOL in very elderly patients with symptomatic AS.

Exogenous surfactant replacement: how to deliver it?

Exogenous surfactant is a therapeutic option for newborns, children and adults with acute respiratory distress disorders. Although tracheal instillation is still reputed as the classical method of surfactant delivery, alternative techniques have been investigated. Surfactant administration by using thin intra-tracheal catheters, bronchoscopy, laryngeal mask airway, or nebulisation, although variably effective, appear to be less invasive when compared to tracheal intubation. However, further research is still needed to better clarify this matter. (www.actabiomedica.it).

Calcified left ventricular endomyocardial fibrosis.

Endomyocardial fibrosis (EMF) is a rare condition, but in certain tropical countries it is a major cause of illness and death. Moreover, the etiology of the disease is unknown, it has no specific treatment, and it carries a poor prognosis. As both the heart and the peritoneum may be affected by the inflammation and deposition of fibrous tissue, even left ventricular EMF may present with gross ascites mimicking right-heart failure. Notwithstanding attempts to standardize the diagnostic criteria, the clinical presentation may still be challenging. The case is described of calcified left ventricular EMF presenting with right-heart failure in the absence of right ventricular fibrosis.

Transcatheter valve-in-valve implantation with the Edwards SAPIEN in patients with bioprosthetic heart valve failure: the Milan experience.

AIMS: Reoperation for bioprosthetic heart valve failure is associated with significant morbidity and mortality, particularly in high-risk patients. Transcatheter valve-in-valve (VIV) implantation may offer a less invasive alternative. The aim of this study was to report our initial experience with transcatheter VIV implantation to treat degenerated tissue valves. METHODS AND RESULTS: VIV implantation with the Edwards SAPIEN transcatheter heart valve (THV; Edwards Lifesciences Inc, Irvine, CA, USA) was performed in 18 high-risk patients (STS 8.2±5.2%; logistic EuroSCORE 37.4±20.8%) with symptomatic bioprosthetic failure (17 aortic, one mitral). Valve Academic Research Consortium (VARC) definitions were applied for endpoint adjudication. Transfemoral access was the preferred vascular approach (16 patients, with the mitral VIV delivered anterogradely through the femoral vein; one transaxillary and one transapical). The majority (83%) of procedures were performed under local anaesthesia and sedation. Device success was achieved in all but one patient who had a final transaortic gradient ≥20mmHg. Acute kidney injury occurred in three patients (Stage 3 in 1), life-threatening or major bleeding in four patients, while major vascular complications occurred in one patient. Permanent pacemaker implantation was required in two patients. There were no deaths or neurological events at 30-day follow-up. At a median follow-up of 11 months (interquartile range 6-16), the mortality rate was 5.6% and all patients were in NYHA class II or lower. CONCLUSIONS: Transcatheter implantation of the Edwards THV within a degenerated aortic bioprosthesis, performed predominantly via the transfemoral route, is feasible and associated with good periprocedural and clinical outcomes in high-risk surgical patients.

Echocardiographic patterns of incomplete Shone's syndrome in adults.

BACKGROUND AND AIM OF THE STUDY: Whilst several cases of complete Shone's complex have been reported in children, the incomplete form--characterized by two or three components--has rarely been described in adults. Because of the wide spectrum of severity of each pattern, the correct diagnosis may be challenging. Moreover, as the hemodynamic interdependence between defects is thought to be a major determinant of clinical outcome and long-term follow up, it is crucial to consider the lesions as part of the same Shone's syndrome. METHODS: Between May 2005 and December 2009, six male patients (mean age 38 +/- 8 years) were referred to the authors' institute with progressive worsening of heart failure symptoms related to valvular disease. All patients had a clinical history of surgery for coarctation of the aorta (CoA), and all but one had a bicuspid aortic valve. Standard transthoracic and transesophageal echocardiographies were performed in all patients to identify the valvular heart disease responsible for clinical deterioration. RESULTS: Unexpected findings of dysplastic mitral valvular apparatus compatible with parachute deformity of the mitral valve (PMV) or 'PMV-like' morphology were disclosed in all patients. The association with major anatomic abnormalities (bicuspid aortic valve, subaortic ridge, and previous CoA surgical repair) was highly suggestive of adult incomplete Shone's syndrome. CONCLUSION: The findings of the present case series emphasized the need for a greater awareness regarding the rare incomplete Shone's syndrome in adulthood, as it occurs far more frequently than might be expected following a random diagnosis. The findings also highlight the additional value of a carefully performed step-by-step echocardiographic study to support the clinical decision-making in this array of left heart anomalies.

New-onset atrial fibrillation as first clinical manifestation of latent Brugada syndrome: prevalence and clinical significance.

AIMS: To evaluate the prevalence, clinical significance, and prognosis of latent Brugada syndrome (BrS) in patients with new-onset atrial fibrillation (AF) unmasked by class 1C antiarrhythmic drugs. METHODS AND RESULTS: Between January 2000 and June 2008, all consecutive patients with new-onset AF, who after flecainide exhibited typical Brugada ECG pattern, underwent electrophysiologic, pharmacologic, and genetic testing. Among 346 patients [median age 53 years; interquartile range (IQR), 15], 11 (3.2%; median age 51 years; IQR, 19) diagnosed as lone AF exhibited typical Brugada ECG pattern. Genetic testing was negative. Ventricular tachycardia/ventricular fibrillation (VT/VF) was induced by electrophysiologic testing (five patients) or during flecainide infusion (one patient). Six patients with type 1 ECG pattern and inducible VT/VF underwent ICD implantation. During a median follow-up of 31.5 months (range: 10-85) after ICD implantation, three patients developed BrS and one of them experienced VF. Patients without ICD (five patients) remained asymptomatic during a median follow-up of 74 months. Persistent type 1 pattern occurred only in the three patients who developed BrS. CONCLUSION: This study, for the first time, reveals the prevalence of latent BrS in patients with new-onset lone AF, which may precede VT/VF. Persistence of type 1 and ventricular tachyarrhythmias inducibility represents a marker of electrical instability leading to sudden death.