Whole exome sequencing in an Italian family with isolated maxillary canine agenesis and canine eruption anomalies

Objective: The aim of this study was the clinical and molecular characterization of a family segregating a trait consisting of a phenotype specifically involving the maxillary canines, including agenesis, impaction and ectopic eruption, characterized by incomplete penetrance and variable expressivity. Design: Clinical standardized assessment of 14 family members and a whole-exome sequencing (WES) of three affected subjects were performed. WES data analyses (sequence alignment, variant calling, annotation and prioritization) were carried out using an in-house implemented pipeline. Variant filtering retained coding and splice-site high quality private and rare variants. Variant prioritization was performed taking into account both the disruptive impact and the biological relevance of individual variants and genes. Sanger sequencing was performed to validate the variants of interest and to carry out segregation analysis. Results: Prioritization of variants “by function” allowed the identification of multiple variants contributing to the trait, including two concomitant heterozygous variants in EDARADD (c.308C>T, p.Ser103Phe) and COL5A1 (c.1588G>A, p.Gly530Ser), specifically associated with a more severe phenotype (i.e. canine agenesis). Differently, heterozygous variants in genes encoding proteins with a role in the WNT pathway were shared by subjects showing a phenotype of impacted/ectopic erupted canines. Conclusions: This study characterized the genetic contribution underlying a complex trait consisting of isolated canine anomalies in a medium-sized family, highlighting the role of WNT and EDA cell signaling pathways in tooth development

An Utstein-based model score to predict survival to hospital admission: The UB-ROSC Score

Abstract Aims To develop and validate a multi-parametric practical score to predict the probability of survival to hospital admission of an out-of-hospital cardiac arrest (OHCA) victim by using Utstein Style-based variables. Methods All consecutive OHCA cases occurring from 2015 to 2017 in two regions, Pavia Province (Italy) and Canton Ticino (Switzerland) were included. We used random effect logistic regression to model survival to hospital admission after an OHCA. We computed the model area under the ROC curve (AUC ROC) for discrimination and we performed both internal and external validation by considering all OHCAs occurring in the aforementioned regions in 2018. The Utstein-Based ROSC (UB-ROSC) score was derived by using the coefficients estimated in the regression model. The score value was obtained adding the pertinent score components calculated for each variable. The score was then plotted against the probability of survival to hospital admission. Results 1962 OHCAs were included (62% male, mean age 73 ± 16 years). Age, aetiology, location, witnessed OHCA, bystander CPR, EMS arrival time and shockable rhythm were independently associated with survival to hospital admission. The model showed excellent discrimination (AUC 0.83, 95%CI 0.81–0.85) for predicting survival to hospital admission, also at internal cross-validation (AUC 0.82, 95%CI 0.80–0.84). The model maintained good discrimination after external validation by using the 2018 OHCA cohort (AUC 0.77, 95%CI 0.74–0.80). Conclusions UB-ROSC score is a novel score that predicts the probability of survival to hospital admission of an OHCA victim. UB-ROSC shall help in setting realistic expectations about sustained ROSC achievement during resuscitation manoeuvres

Real-life time and distance covered by lay first responders alerted by means of smartphone-application: Implications for early initiation of cardiopulmonary resuscitation and access to automatic external defibrillators

AIM OF THE STUDY To investigate the distance covered by lay first responders (LFR) alerted for an out-of- hospital cardiac arrest (OHCA), evaluate the time elapsed between mission acceptance and arrival at the OHCA site, as well as the distance between the LFRs to the closest automatic external defibrillator (AED). METHODS The LFR route, thus time, distance information, and the average speed of each responder were estimated. The same methodology was used to calculate the distance between the closest AED and the LFRs, as well as the distance between the AED and OHCA site. RESULTS Between June 1st, 2014 and December 31st, 2017, the LFR network was activated in occasion of 484 suspected OHCAs. 710 LFRs were automatically selected by the application and accepted the mission. On average 1.5 LFRs arrived at the OHCA site. LFRs covered a distance of 1196 m (IQR 596-2314) at a median speed of 6.9 m/s (IQR 4.5-9.8) or 24.8 Km/h. In 4.4% of the cases the speed of the LFRs was compatible with a brisk walk activity (<1.5 m/sec). The total intervention time of an LFR, who first retrieved an AED and then went to the OHCA site, was longer (275 s, IQR: 184 s-414 s) compared to the total intervention time of a LFR (197 s, IQR: 120 s-306 s; p < 0.001), who went to the OHCA site directly without retrieving an AED. CONCLUSIONS The dispatch of LFRs directly to the OHCA site instead of first retrieving the AED, significantly decreases the time to CPR initiation. More studies are needed to assess the prognostic implications on survival and neurological outcome

Integrated Assessment of Left Ventricular Electrical Activation and Myocardial Strain Mapping in Heart Failure Patients: A Holistic Diagnostic Approach for Endocardial Cardiac Resynchronization Therapy, Ablation of Ventricular Tachycardia, and Biological Therapy

Objectives This study sought to test the accuracy of strain measurements based on anatomo-electromechanical mapping (AEMM) measurements compared with magnetic resonance imaging (MRI) tagging, to evaluate the diagnostic value of AEMM-based strain measurements in the assessment of myocardial viability, and the additional value of AEMM over peak-to-peak local voltages. Background The in vivo identification of viable tissue, evaluation of mechanical contraction, and simultaneous left ventricular activation is currently achieved using multiple complementary techniques. Methods In 33 patients, AEMM maps (NOGA XP, Biologic Delivery Systems, Division of Biosense Webster, a Johnson & Johnson Company, Irwindale, California) and MRI images (Siemens 3T, Siemens Healthcare, Erlangen, Germany) were obtained within 1 month. MRI tagging was used to determine circumferential strain (Ecc) and delayed enhancement to obtain local scar extent (%). Custom software was used to measure Ecc and local area strain (LAS) from the motion field of the AEMM catheter tip. Results Intertechnique agreement for Ecc was good (R2 = 0.80), with nonsignificant bias (0.01 strain units) and narrow limits of agreement (−0.03 to 0.06). Scar segments showed lower absolute strain amplitudes compared with nonscar segments: Ecc (median [first to third quartile]: nonscar −0.10 [−0.15 to −0.06] vs. scar −0.04 [−0.06 to −0.02]) and LAS (−0.20 [−0.27 to −0.14] vs. −0.09 [−0.14 to −0.06]). AEMM strains accurately discriminated between scar and nonscar segments, in particular LAS (area under the curve: 0.84, accuracy = 0.76), which was superior to peak-to-peak voltages (nonscar 9.5 [6.5 to 13.3] mV vs. scar 5.6 [3.4 to 8.3] mV; area under the curve: 0.75). Combination of LAS and peak-to-peak voltages resulted in 86% accuracy. Conclusions An integrated AEMM approach can accurately determine local deformation and correlates with the scar extent. This approach has potential immediate application in the diagnosis, delivery of intracardiac therapies, and their intraprocedural evaluation

Out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation in patients with normal electrocardiograms:results from a multicentre long-term registry

AIMS : To define the clinical characteristics and long-term clinical outcomes of a large cohort of patients with idiopathic ventricular fibrillation (IVF) and normal 12-lead electrocardiograms (ECGs). METHODS AND RESULTS: Patients with ventricular fibrillation as the presenting rhythm, normal baseline, and follow-up ECGs with no signs of cardiac channelopathy including early repolarization or atrioventricular conduction abnormalities, and without structural heart disease were included in a registry. A total of 245 patients (median age: 38 years; males 59%) were recruited from 25 centres. An implantable cardioverter-defibrillator (ICD) was implanted in 226 patients (92%), while 18 patients (8%) were treated with drug therapy only. Over a median follow-up of 63 months (interquartile range: 25-110 months), 12 patients died (5%); in four of them (1.6%) the lethal event was of cardiac origin. Patients treated with antiarrhythmic drugs only had a higher rate of cardiovascular death compared to patients who received an ICD (16% vs. 0.4%, P = 0.001). Fifty-two patients (21%) experienced an arrhythmic recurrence. Age ≤16 years at the time of the first ventricular arrhythmia was the only predictor of arrhythmic recurrence on multivariable analysis [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.18-0.92; P = 0.03]. CONCLUSION : Patients with IVF and persistently normal ECGs frequently have arrhythmic recurrences, but a good prognosis when treated with an ICD. Children are a category of IVF patients at higher risk of arrhythmic recurrences

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Key lessons from the ELECTRa registry in the modern era of transvenous lead extraction

The implantation rate of cardiac electronic devices has grown over the past decades. The number of treated patients has increased in parallel with the complexity of the patient population treated, being older, frailer, having more complex devices (in particular, cardiac resynchronisation therapy) and presenting with a greater comorbidity burden. As a consequence, there is a rising number of related implanted system complications, including malfunction and infection. Thus, the demand for transvenous lead extraction (TLE) has also substantially increased. To identify the indication to TLE by various operators and centres, techniques used to perform TLE, and the safety and efficacy of the current clinical practice of TLE, a large prospective registry has been started in Europe - the European Lead Extraction Controlled (ELECTRa) Registry. The key findings of the ELECTRa Registry are discussed in the present review and placed in the context of previous knowledge. The ELECTRa Registry confirms that the TLE procedure is a safe and effective treatment, with an acceptable risk-benefit ratio that is comparable with other well-known cardiological invasive procedures. Of course, TLE is accompanied by potential life-threatening complications; the vast majority of these can be managed by an experienced multidisciplinary team. Multiple factors predict complications, including patient/lead profile, centre experience and procedure volumes, which may suggest caution when accepting a patient for TLE

Gender-specific differences in return-to-spontaneous circulation and outcome after out-of-hospital cardiac arrest: Results of sixteen-year-state-wide initiatives

Aim Several studies reported a lower proportion of laypeople cardio-pulmonary resuscitation (CPR) in female victims of out-of-hospital cardiac arrest (OHCA). We aimed to verify how sixteen-years of state-wide initiatives impacted on gender-differences in OHCA treatment and survival. Methods All the 2481 consecutive OHCAs of presumed cardiac origin occurred between 2002 and 2018 in the Swiss Ticino Canton and in which a resuscitation was attempted, were included. Emergency medical system (EMS)-witnessed OHCAs were excluded. Results Time from call to CPR decreased from 9-min in 2002–2006 to 5-min in 2015–2018 (p < 0.01) and until 2014, it was longer in women. Survival to discharge increased overall from 11% in 2002–2006 to 23% in 2015–2018 (p < 0.001) related to telephone-assisted CPR development (period 2011–2014) and first responder and layperson recruitment via a mobile application (period 2015–2018). In males, survival increased from 12% to 25% (p = 0.001) with a statistically significant increase in odds of survival in 2007–2010 (OR 1.6 95%CI 1.1–2.3; p = 0.001), in 2011–2014 (OR 2 95%CI 1.4–2.8; p = 0.001), and in 2015–2018 (2.4 95%CI 1.7–3.3; p = 0.001) compared to 2002–2006. On the other hand, in females, survival increased from 7% to 18% (p < 0.001), with a corresponding increase in the odds of survival of almost 3 times from 2002–2006 to 2015–2018 time period (OR 2.9 95%CI 1.5–5.8, p = 0.001). No difference in survival probability was observed according to gender when adjusted for age, presenting rhythm, year-groups, OHCA location, EMS arrival time, witnessed status and laypeople-CPR. Conclusions State-wide initiatives can significantly increase the chances of survival in both male and female victims of OHCAs, by increasing the probability to receive CPR in a shorter time span