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Abstract Background BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence. Methods Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1‐ABRAXAS1 interaction was assessed using a GFP‐fragment reassembly‐based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2. Results Variant‐carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0–155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6–40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2–2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03–61.6) emerged, warranting further evaluation. Likelihood‐ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1‐ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule‐based model. Collectively, these findings allowed to classify the variant as pathogenic. Conclusion Pathogenicity of BRCA1:c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype.

Abstract Geolocating aquatic animals with acoustic tags has been ongoing for decades, relying on the detection of acoustic signals at multiple receivers with known positions to calculate a 2D or 3D position, and ultimately recreate the path of an aquatic animal from detections at fixed stations. This method of underwater geolocation is evolving with new software and hardware options available to help investigators design studies and calculate positions using solvers based predominantly on time‐difference‐of‐arrival and time‐of‐arrival. We provide an overview of the considerations necessary to implement positioning in aquatic acoustic telemetry studies, including how to design arrays of receivers, test performance, synchronize receiver clocks and calculate positions from the detection data. We additionally present some common positioning algorithms, including both the free open‐source solvers and the ‘black‐box’ methods provided by some manufacturers for calculating positions. This paper is the first to provide a comprehensive overview of methods and considerations for designing and implementing better positioning studies that will support users, and encourage further knowledge advances in aquatic systems.

Abstract Introduction Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection. Methods Participants treated for recent HCV in an international trial (enrolled 2017–2019) were followed at 3‐monthly intervals for up to 2 years to assess longitudinal behaviours. Population‐averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group‐based trajectory modelling. HCV reinfection incidence was calculated using person‐years (PY) of observation. Results During the follow‐up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population‐averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population‐averaged decreases in condomless anal intercourse with casual male partners (CAI‐CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group‐sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI‐CMP (23%) and group‐sex (59%) post‐treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories. Conclusions Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment.

Background The impact of complete revascularization (CR) on the development of heart failure (HF) in patients with acute coronary syndrome and multivessel coronary artery disease undergoing percutaneous coronary intervention remains to be elucidated. Methods and Results Consecutive patients with acute coronary syndrome with multivessel coronary artery disease from the CORALYS (Incidence and Predictors of Heart Failure After Acute Coronary Syndrome) registry were included. Incidence of first hospitalization for HF or cardiovascular death was the primary end point. Patients were stratified according to completeness of coronary revascularization. Of 14 699 patients in the CORALYS registry, 5054 presented with multivessel disease. One thousand four hundred seventy‐three (29.2%) underwent CR, while 3581 (70.8%) did not. Over 5 years follow‐up, CR was associated with a reduced incidence of the primary end point (adjusted hazard ratio [HR], 0.66 [95% CI, 0.51–0.85]), first HF hospitalization (adjusted HR, 0.67 [95% CI, 0.49–0.90]) along with all‐cause death and cardiovascular death alone (adjusted HR, 0.74 [95% CI, 0.56–0.97] and HR, 0.56 [95% CI, 0.38–0.84], respectively). The results were consistent in the propensity‐score matching population and in inverse probability treatment weighting analysis. The benefit of CR was consistent across acute coronary syndrome presentations (HR, 0.59 [95% CI, 0.39–0.89] for ST‐segment elevation myocardial infarction and HR, 0.71 [95% CI, 0.50–0.99] for non‐ST‐elevation acute coronary syndrome) and in patients with left ventricular ejection fraction >40% (HR, 0.52 [95% CI, 0.37–0.72]), while no benefit was observed in patients with left ventricular ejection fraction ≤40% (HR, 0.77 [95% CI, 0.37–1.10], P for interaction 0.04). Conclusions CR after acute coronary syndrome reduced the risk of first hospitalization for HF and cardiovascular death, as well as first HF hospitalization, and cardiovascular and overall death both in patients with ST‐segment elevation myocardial infarction and non‐ST‐elevation acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT 04895176.

Abstract This study verified whether mechanical variables influence the anaerobic capacity outcome on treadmill running and whether these likely influences were dependent of running experience. Seventeen physical active and 18 amateur runners, males, performed a graded exercise test and constant load exhaustive running efforts at 115% of intensity associated to maximal oxygen consumption. During the constant load were determined the metabolic responses (i.e., gas exchange and blood lactate) to estimate the energetic contribution and anaerobic capacity as well as kinematic responses. The runners showed higher anaerobic capacity (16.6%; p = 0.005), but lesser time to exercise failure (−18.8%; p = 0.03) than active subjects. In addition, the stride length (21.4%; p = 0.00001), contact phase duration (−11.3%; p = 0.005), and vertical work (−29.9%; p = 0.015). For actives, the anaerobic capacity did not correlate significantly with any physiologic, kinematic, and mechanical variables and no regression model was fitted using the stepwise multiple regression, while to runners the anaerobic capacity was significantly correlated with phosphagen energetic contribution (r = 0.47; p = 0.047), external power (r = −0.51; p = 0.031), total work (r = −0.54; p = 0.020), external work (r = −0.62; p = 0.006), vertical work (r = −0.63; p = 0.008), and horizontal work (r = −0.61; p = 0.008), and the vertical work and phosphagen energetic contribution presented a coefficient of determination of 62% (p = 0.001). Based on findings, it is possible to assume that for active subjects, the mechanical variables have no influence over the anaerobic capacity, however, for experienced runners, the vertical work and phosphagen energetic contribution have relevant effect over anaerobic capacity output.

Abstract Pulmonary arterial hypertension (PAH) is a severe and progressive disease characterized by increased pulmonary vascular resistance, ultimately leading to right heart failure and death. Registries are a valuable tool in the research of rare conditions such as PAH. Moreover, the risk assessment strategy has been validated in European and North American registries and has been reported to provide an accurate prediction of mortality and the clinical advantage of reaching low‐risk status. However, there is no available data from Brazil. Thus, the aim of the present study was to describe the characteristics of a sample of PAH from Southern Brazil and to retrospectively validate the risk assessment at our population. The RESPHIRAR is a retrospective and multicentric registry on pulmonary hypertension. With a join collaboration from nine centers in Southern Brazil, demographics, clinical presentation, and hemodynamics data of PAH were collected between 2007 and 2017. Moreover, the REVEAL 2.0 and REVEAL 2.0 Lite risk assessments were validated in our population. Overall, 370 PAH patients were included in the present study. Patients were predominantly female (78.5%) and had a mean age of 41.8 ± 18.8 years. Most patients (33.4%) had idiopathic PAH, 30.2% had PAH associated with congenital heart disease, and 23.5% had PAH associated with connective tissue disease. The low‐risk group showed significantly lower mortality than the intermediated‐ or high‐risk group at diagnosis (p

Summary Aedes albopictus transmits several arboviral infections. In the absence of vaccines, control of mosquito populations is the only strategy to prevent vector‐borne diseases. As part of the search for novel, biological and environmentally friendly strategies for vector control, the isolation of new bacterial species with mosquitocidal activity represents a promising approach. However, new bacterial isolates may be difficult to grow and genetically manipulate. To overcome these limits, here we set up a system allowing the expression of mosquitocidal bacterial toxins in the well‐known genetic background of Bacillus subtilis. As a proof of this concept, the ability of B. subtilis to express individual or combinations of toxins of Bacillus thuringiensis israelensis (Bti) was studied. Different expression systems in which toxin gene expression was driven by IPTG‐inducible, auto‐inducible or toxin gene‐specific promoters were developed. The larvicidal activity of the resulting B. subtilis strains against second‐instar Ae. albopictus larvae allowed studying the activity of individual toxins or the synergistic interaction among Cry and Cyt toxins. The expression systems here presented lay the foundation for a better improved system to be used in the future to characterize the larvicidal activity of toxin genes from new environmental isolates.

Abstract Aims A multicentre trial, ICOS‐ONE, showed increases above the upper limit of normality of cardiac troponin (cTn) in 27% of patients within 12 months after the end of cancer chemotherapy (CT) with anthracyclines, whether cardiac protection with enalapril was started at study entry in all (prevention arm) or only upon first occurrence on supra‐normal cTn (troponin‐triggered arm). The aims of the present post hoc analysis were (i) to assess whether anthracycline‐based treatment could induce cardiotoxicity over 36 month follow‐up and (ii) to describe the time course of three cardiovascular biomarkers (i.e. troponin I cTnI‐Ultra, B‐type natriuretic peptide BNP, and pentraxin 3 PTX3) and of left ventricular (LV) function up to 36 months. Methods and results Eligible patients were those prescribed first‐in‐life CT, without evidence of cardiovascular disease, normal cTn, LV ejection fraction (EF) >50%, not on renin‐angiotensin aldosterone system antagonists. Patients underwent echocardiography and blood sampling at 24 and 36 months. No differences were observed in biomarker concentration between the two study arms, ‘prevention' vs. ‘troponin‐triggered'. During additional follow‐up 13 more deaths occurred, leading to a total of 23 (9.5%), all due to a non‐cardiovascular cause. No new occurrences of LV‐dysfunction were reported. Two additional patients were admitted to the hospital for cardiovascular causes, both for acute pulmonary embolism. No first onset of raised cTnI‐Ultra was reported in the extended follow‐up. BNP remained within normal range: at 36 months was 23.4 ng/L, higher (N.S.) than at baseline, 17.6 ng/L. PTX3 peaked at 5.2 ng/mL 1 month after CT and returned to baseline values thereafter. cTnI‐Ultra peaked at 26 ng/L 1 month after CT and returned to 3 ng/L until the last measurement at 36 months. All echocardiographic variables remained stable during follow‐up with a median LVEF of 63% and left atrial volume index about 24 mL/m2. Conclusions First‐in‐life CT with median cumulative dose of anthracyclines of 180 mg/m2 does not seem to cause clinically significant cardiac injury, as assessed by circulating biomarkers and echocardiography, in patients aged 51 years (median), without pre‐existing cardiac disease. This may suggest either a 100% efficacy of enalapril (given as preventive or troponin‐triggered) or a reassuringly low absolute cardiovascular risk in this cohort of patients, which may not require intensive cardiologic follow‐up.

Background The COVID‐19–related pulmonary effects may negatively impact pulmonary hemodynamics and right ventricular function. We examined the prognostic relevance of right ventricular function and right ventricular‐to‐pulmonary circulation coupling assessed by bedside echocardiography in patients hospitalized with COVID‐19 pneumonia and a large spectrum of disease independently of indices of pneumonia severity and left ventricular function. Methods and Results Consecutive COVID‐19 subjects who underwent full cardiac echocardiographic evaluation along with gas analyses and computed tomography scans were included in the study. Measurements were performed offline, and quantitative analyses were obtained by an operator blinded to the clinical data. We analyzed 133 patients (mean age 69±12 years, 57% men). During a mean hospital stay of 26±16 days, 35 patients (26%) died. The mean tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio was 0.48±0.18 mm/Hg in nonsurvivors and 0.72±0.32 mm/Hg in survivors (P=0.002). For each 0.1 mm/mm Hg increase in TAPSE/PASP, there was a 27% lower risk of in‐hospital death (hazard ratio [HR], 0.73 [95% CI, 0.59–0.89]; P=0.003). At multivariable analysis, TAPSE/PASP ratio remained a predictor of in‐hospital death after adjustments for age, oxygen partial pressure at arterial gas analysis/fraction of inspired oxygen, left ventricular ejection fraction, and computed tomography lung score. Receiver operating characteristic analysis was used to identify the cutoff value of the TAPSE/PASP ratio, which best specified high‐risk from lower‐risk patients. The best cutoff for predicting in‐hospital mortality was TAPSE/PASP 4‐fold increased risk of in‐hospital death (HR, 4.8 [95% CI, 1.7–13.1]; P=0.007). Conclusions In patients hospitalized with COVID‐19 pneumonia, the assessment of right ventricular to pulmonary circulation coupling appears central to disease evolution and prediction of events. TAPSE/PASP ratio plays a mainstay role as prognostic determinant beyond markers of lung injury.

Background Proctoring represents a cornerstone in the acquisition of state‐of‐the‐art cardiovascular interventions. Yet, travel restrictions and containment measures during the COVID‐19 pandemic limited on‐site proctoring for training and expert support in interventional cardiology. Methods and Results We established a teleproctoring setup for training in a novel patent foramen ovale closure device system (NobleStitch EL, HeartStitch Inc, Fountain Valley, CA) at our institution using web‐based real‐time bidirectional audiovisual communication. A total of 6 patients with prior paradoxical embolic stroke and a right‐to‐left shunt of grade 2 or 3 were treated under remote proctorship after 3 cases were performed successfully under on‐site proctorship. No major device/procedure‐related adverse events occurred, and none of the patients had a residual right‐to‐left shunt of grade 1 or higher after the procedure. Additionally, we sought to provide an overview of current evidence available for teleproctoring in interventional cardiology. Literature review was performed identifying 6 previous reports on teleproctoring for cardiovascular interventions, most of which were related to the current COVID‐19 pandemic. In all reports, teleproctoring was carried out in similar settings with comparable setups; no major adverse events were reported. Conclusions Teleproctoring may represent a feasible and safe tool for location‐independent and cost‐effective training in a novel patent foramen ovale closure device system. Future prospective trials comparing teleproctoring with traditional on‐site proctoring are warranted.

Abstract Neuroblastoma (NB) arises from oncogenic disruption of neural crest (NC) differentiation. Treatment with retinoic acid (RA) to induce differentiation has improved survival in some NB patients, but not all patients respond, and most NBs eventually develop resistance to RA. Loss of the chromatin modifier chromatin assembly factor 1 subunit p150 (CHAF1A) promotes NB cell differentiation; however, the mechanism by which CHAF1A drives NB oncogenesis has remained unexplored. This study shows that CHAF1A gain‐of‐function supports cell malignancy, blocks neuronal differentiation in three models (zebrafish NC, human NC, and human NB), and promotes NB oncogenesis. Mechanistically, CHAF1A upregulates polyamine metabolism, which blocks neuronal differentiation and promotes cell cycle progression. Targeting polyamine synthesis promotes NB differentiation and enhances the anti‐tumor activity of RA. The authors' results provide insight into the mechanisms that drive NB oncogenesis and suggest a rapidly translatable therapeutic approach (DFMO plus RA) to enhance the clinical efficacy of differentiation therapy in NB patients.

Abstract Background Type 2 diabetes, a highly prevalent chronic disease, is associated with increasing frailty and functional decline in older people. We aimed to evaluate the effectiveness of a multimodal intervention on functional performance in frail and pre‐frail participants aged ≥70 years with type 2 diabetes mellitus. Methods The MID‐Frail study was a cluster‐randomized multicenter clinical trial conducted in 74 trial sites across seven European countries. The trial recruited 964 participants who were aged >70 years [mean age in intervention group, 78.4 (SD 5.6) years, 49.2% male and 77.6 (SD 5.29) years, 52.4% male in usual care group], with type diabetes mellitus and determined to be frail or pre‐frail using Fried's frailty phenotype. Participants were allocated by trial site to follow either usual care (UCG) or intervention procedures (IG). Intervention group participants received a multimodal intervention composed of (i) an individualized and progressive resistance exercise programme for 16 weeks; (ii) a structured diabetes and nutritional educational programme over seven sessions; and (iii) Investigator‐linked training to ensure optimal diabetes care. Short Physical Performance Battery (SPPB) scores were used to assess change in functional performance at 12 months between the groups. An analysis of the cost‐effectiveness of the intervention was undertaken using the incremental cost‐effectiveness ratio (ICER). Secondary outcomes included mortality, hospitalization, institutionalization, quality of life, burden on caregivers, the frequency and severity of hypoglycaemia episodes, and the cost‐effectiveness of the intervention. Results After 12 months, IG participants had mean SPPB scores 0.85 points higher than those in the UCG (95% CI, 0.44 to 1.26, P

Summary Febrile infection–related epilepsy syndrome (FIRES) is a severe epileptic encephalopathy with presumed inflammatory origin and lacking effective treatments. Anakinra is the human recombinant interleukin 1 receptor antagonist clinically used in autoinflammatory or autoimmune conditions. We report a case of FIRES for which the spatial and temporal match between electroencephalography (EEG) and magnetic resonance imaging (MRI) focal alterations provides support for the detrimental synergic interplay between seizures and inflammation that may evolve to permanent focal lesions and progressive brain atrophy in weeks to months. Brain biopsy showed aspects of chronic neuroinflammation with scarce parenchymal lymphocytes. We report the novel evidence that anakinra reduces the relapse of highly recurrent refractory seizures at 1.5 years after FIRES onset. Our evidence, together with previously reported therapeutic effects of anakinra administered since the first days of disease onset, support the hypothesis that interleukin 1β and inflammation‐related factors play a crucial role in seizure recurrence in both the acute and chronic stages of the disease.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by an excessive production of pro‐inflammatory cytokines resulting in chronic inflammation and genomic instability. Besides the driver mutations in JAK2, MPL, and CALR genes, the deregulation of miRNA expression may also contribute to the pathogenesis of PMF. To this end, we recently reported the upregulation of miR‐382‐5p in PMF CD34+ cells. In order to unveil the mechanistic details of the role of miR‐382‐5p in pathogenesis of PMF, we performed gene expression profiling of CD34+ cells overexpressing miR‐382‐5p. Among the downregulated genes, we identified superoxide dismutase 2 (SOD2), which is a predicted target of miR‐382‐5p. Subsequently, we confirmed miR‐382‐5p/SOD2 interaction by luciferase assay and we showed that miR‐382‐5p overexpression in CD34+ cells causes the decrease in SOD2 activity leading to reactive oxygen species (ROS) accumulation and oxidative DNA damage. In addition, our data indicate that inhibition of miR‐382‐5p in PMF CD34+ cells restores SOD2 function, induces ROS disposal, and reduces DNA oxidation. Since the pro‐inflammatory cytokine transforming growth factor‐β1 (TGF‐β1) is a key player in PMF pathogenesis, we further investigated the effect of TGF‐β1 on ROS and miR‐382‐5p levels. Our data showed that TGF‐β1 treatment enhances miR‐382‐5p expression and reduces SOD2 activity leading to ROS accumulation. Finally, inhibition of TGF‐β1 signaling in PMF CD34+ cells by galunisertib significantly reduced miR‐382‐5p expression and ROS accumulation and restored SOD2 activity. As a whole, this study reports that TGF‐β1/miR‐382‐5p/SOD2 axis deregulation in PMF cells is linked to ROS overproduction that may contribute to enhanced oxidative stress and inflammation. Our results suggest that galunisertib may represent an effective drug reducing abnormal oxidative stress induced by TGF‐β1 in PMF patients. Database linking GEO: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103464.

Abstract High costs of tree planting are a barrier to meeting global forest restoration targets. Natural forest regeneration is more cost‐effective than tree planting, but its potential to foster restoration at scale is poorly understood. We predict, map, and quantify natural regeneration potential within 75.5 M ha of deforested lands in the Brazilian Atlantic Forest. Of 34.1 M ha (26.4%) of current forest cover, 2.7 M ha (8.0%) regenerated naturally from 1996 to 2015. We estimate that another 2.8 M ha could naturally regenerate by 2035, and a further 18.8 M ha could be restored using assisted regeneration methods, thereby reducing implementation costs by US$ 90.6 billion (77%) compared to tree planting. These restored forests could sequester 2.3 GtCO2 of carbon, reduce the mean number of expected species at risk of extinction by 63.4, and reduce fragmentation by 44% compared to current levels. Natural regeneration planning is key for achieving cost‐effective large‐scale restoration.