Sounding the Alarm: Sex Differences in Rat Ultrasonic Vocalizations during Pavlovian Fear Conditioning and Extinction.

Pavlovian fear conditioning is a prevalent tool in the study of aversive learning, which is a key component of stress-related psychiatric disorders. Adult rats can exhibit various threat-related behaviors, including freezing, motor responses, and ultrasonic vocalizations (USVs). While these responses can all signal aversion, we know little about how they relate to one another. Here we characterize USVs emitted by male and female rats during cued fear acquisition and extinction, and assess the relationship between different threat-related behaviors. We found that males consistently emitted >22 kHz calls (referred to here as "alarm calls") than females, and that alarm call frequency in males, but not females, related to the intensity of the shock stimulus. Interestingly, 25% of males and 45% of females did not emit any alarm calls at all. Males that did make alarm calls had significantly higher levels of freezing than males who did not, while no differences in freezing were observed between female Alarm callers and Non-alarm callers. Alarm call emission was also affected by the predictability of the shock; when unpaired from a tone cue, both males and females started emitting alarm calls significantly later. During extinction learning and retrieval sessions, males were again more likely than females to emit alarm calls, which followed an extinction-like reduction in frequency. Collectively these data suggest sex dependence in how behavioral readouts relate to innate and conditioned threat responses. Importantly, we suggest that the same behaviors can signal sex-dependent features of aversion.

Darting across space and time: parametric modulators of sex-biased conditioned fear responses.

Pavlovian fear conditioning is a widely used behavioral paradigm for studying associative learning in rodents. Despite early recognition that subjects may engage in a variety of both conditioned and unconditioned responses, the last several decades have seen the field narrow its focus to measure freezing as the sole indicator of conditioned fear. We previously reported that female rats were more likely than males to engage in darting, an escape-like conditioned response that is associated with heightened shock reactivity. To determine how experimental parameters contribute to the frequency of darting in both males and females, we manipulated factors such as chamber size, shock intensity, and number of trials. To better capture fear-related behavioral repertoires in our animals, we developed ScaredyRat, an open-source custom Python tool that analyzes Noldus Ethovision-generated raw data files to identify darters and quantify both conditioned and unconditioned responses. We found that, like freezing, conditioned darting occurrences scale with experimental alterations. While most darting occurs in females, we found that with an extended training protocol, darting can emerge in males as well. Collectively, our data suggest that darting reflects a behavioral switch in conditioned responding that is a product of an individual animal's sex, shock reactivity, and experimental parameters, underscoring the need for careful consideration of sex as a biological variable in classic learning paradigms.

Direct Reimplantation Procedure in Anomalous Aortic Origin of the Right Coronary Artery: Long-Term Single Center Outcomes.

BACKGROUND: Anomalous aortic origin of the right coronary artery is known to be a cause of sudden cardiac death in athletes. There are no specific guidelines concerning treatment strategy in the literature. The aim of this study is to describe and report our experience of direct reimplantation technique in the treatment of this anomaly. METHODS: This was a retrospective single center study of 30 patients who underwent surgery in the congenital heart disease unit of Louis Pradel Heart and Lung Hospital between January 2003 and December 2016. The mean follow-up was seven years (3 months-17 years). RESULTS: Thirty patients underwent surgery. The median age was 17 years (0.2-52 years). There were 24 males. The median weight was 58 kg (3.6-118 kg). Fourteen patients were actively engaged in sports. Twenty-six patients had exertional chest pain or syncope. The median time lapse between diagnosis and intervention was 4.5 months (0.5-179 months). Twenty-seven (90%) patients underwent reimplantation of the anomalous coronary artery without transverse aortotomy, while in 3 (10%) patients transverse aortotomy was used to facilitate reimplantation to avoid tension at the anastomosis. There was no early death; one late death occurred in the third postoperative month. At the last follow-up, all patients had returned to normal physical activity without evidence of ischemia. CONCLUSIONS: Direct reimplantation allows for a complete restoration of the coronary anatomy and enables patients to return to normal physical activity. Our study shows encouraging results using a direct reimplantation technique without aortotomy.

Diagnosis and treatment of anomalous aortic origin of coronary artery: A twenty-year retrospective study of experience and decision-making in children and young adults.

BACKGROUND: Anomalous aortic origin of a coronary artery, particularly in the presence of inter-arterial course between the great arteries, has been found to be associated with sudden death in young people. METHODS: This study reports a single-center experience in the management of anomalous aortic origin of a coronary artery, with or without inter-arterial course, by focusing specifically on presentation, diagnosis, and patient outcome. RESULTS: From March 1993 to February 2018, 100 patients (70 males) were diagnosed with anomalous aortic origin of a coronary artery, including 27 left coronary artery from the right sinus, 60 right coronary artery from the left sinus, and 13 other anomalies. Patients with inter-arterial course between the great arteries presented more frequently with syncope and/or sudden death compared to patients without (23.4% vs. 0%, p = 0.026). Diagnosis was reached using first-line transthoracic echocardiography in 65% of cases. Surgical repair was performed in 61 patients (61%). All operated patients (60 direct implantations, 1 unroofing) had been diagnosed with inter-arterial course between the great arteries, and were asymptomatic at a mean (±SD) postoperative follow-up of 4.9 ± 5.3 years. CONCLUSIONS: An inter-arterial course of the anomalous right or left coronary arteries arising from the opposite sinus is associated with life-threatening events. Direct reimplantation of coronary artery is reliable, and should be discussed even in asymptomatic patients.

Quality of life of adult Fontan patients.

BACKGROUND: Progress in the management of complex congenital heart disease (CHD) led to an improvement in survival rates of adults with a Fontan-like circulation. The objective of this study was to assess the subjective health status and quality of life of this population. METHODS AND RESULTS: Patients aged more than 18 years at the time of the study, who underwent a Fontan-like procedure. Subjective health status was assessed by the SF-36 questionnaire and a linear analog scale was used to score patients' self-perception of their quality of life; cardiac and demographic parameters were collected. RESULTS: Among 65 eligible patients, 60 (23 females; mean ± SD age: 25.7 ± 7.2 years) answered the SF-36 questionnaire and 46 of these were interviewed to evaluate their perceived quality of life. Among them, 20 (33.3%) were working full-time and 21 (35%) experienced arrhythmias. The physical SF-36 scores were lower in patients than in the general population (p ≤ 0.05). The New York Hear Association (NYHA) class and occupation were correlated with SF-36 scores of physical activity (respectively, p = 0.0001 and p = 0.025). SF-36 scores of psychological status were associated with the number of drugs and occupation (respectively, p = 0.0001 and p = 0.02). The mean ± SD quality of life score measured using a linear analog scale was 7.02 ± 1.6 and was linked to education and occupation (p ≤ 0.05) but not with cardiac parameters. CONCLUSION: Adult Fontan patients perceive an impaired physical health but report a good overall quality of life. Education and occupation impacts significantly on Fontan patients' quality of life.

Correction of Tetralogy of Fallot Associated With Anomalous Coronary Artery Without Extracardiac Conduit.

Between 1983 and 2016, we operated on 14 children with tetralogy of Fallot with an anomalous coronary artery crossing the pulmonary infundibulum, which is an anomaly that makes the repair complex. The technique used was the enlargement of the right ventricular outflow tract underneath the mobilized coronary artery. All patients had right ventricular outflow tract relief without coronary artery injury. Only one patient required the use of an extracardiac conduit. There was neither in-hospital mortality nor coronary anomaly requiring reintervention. Mobilizing the anomalous coronary artery in tetralogy of Fallot repair often allows relief of obstruction without using an extracardiac conduit.

Feasibility of improving vascular imaging in the presence of metallic stents using spectral photon counting CT and K-edge imaging.

Correct visualization of the vascular lumen is impaired in standard computed tomography (CT) because of blooming artifacts, increase of apparent size, induced by metallic stents and vascular calcifications. Recently, due to the introduction of photon-counting detectors in the X-ray imaging field, a new prototype spectral photon-counting CT (SPCCT) based on a modified clinical CT system has been tested in a feasibility study for improving vascular lumen delineation and visualization of coronary stent architecture. Coronary stents of different metal composition were deployed inside plastic tubes containing hydroxyapatite spheres to simulate vascular calcifications and in the abdominal aorta of one New Zealand White (NZW) rabbit. Imaging was performed with an SPCCT prototype, a dual-energy CT system, and a conventional 64-channel CT system (B64). We found the apparent widths of the stents significantly smaller on SPCCT than on the other two systems in vitro (p < 0.01), thus closer to the true size. Consequently, the intra-stent lumen was significantly larger on SPCCT (p < 0.01). In conclusion, owing to the increased spatial resolution of SPCCT, improved lumen visualization and delineation of stent metallic mesh is possible compared to dual-energy and conventional CT.

Supravalvular Aortic Stenosis Caused by a Familial Chromosome 7 Inversion Disrupting the ELN Gene Uncovered by Whole-Genome Sequencing.

Apparently, balanced chromosomal rearrangements usually have no phenotypic consequences for the carrier. However, in some cases, they may be associated with an abnormal phenotype. We report herein the case of a 4-year-old boy presenting with clinically isolated supravalvular aortic stenosis (SVAS). No chromosomal imbalance was detected by array CGH. The karyotype showed a balanced paracentric chromosome 7 inversion. Breakpoint characterization using paired-end whole-genome sequencing (WGS) revealed an ELN gene disruption in intron 1, accounting for the phenotype. Family study showed that the inversion was inherited, with incomplete penetrance. To our knowledge, this is the first case of a disruption of the ELN gene characterized by WGS. It contributes to refine the genotype-phenotype correlation in ELN disruption. Although this disruption is a rare etiology of SVAS, it cannot be detected by the diagnostic tests usually performed, such as array CGH or sequencing methods (Sanger, panel, or exome sequencing). With the future perspective of WGS as a diagnostic tool, it will be important to include a structural variation analysis in order to detect balanced rearrangements and gene disruption.

Assessing the adoption of clinical trial results summary disclosure to patients and the public.

Introduction: There is a broad global acknowledgment that the timely and effective communication of clinical trial results is not only essential to the development, diagnosis, and treatment of medical conditions but also meets an ethical obligation to inform patients and the public. Areas covered: At this time, less than 2% of all clinical trials completed or terminated within the past three years returned plain language summaries to study volunteers. This estimate is far below our forecast made 10 years ago when we evaluated a pilot effort to demonstrate a feasible and efficient process for communicating summary results to patients. At that time, we anticipated that research sponsors would embrace the obligation and in so doing would improve their relationship with and trust among their study volunteers and patient communities. This article discusses why adoption remains low and suggests that the absence of clear regulatory requirements and their enforcement are the primary cause. Expert opinion: The authors anticipate that the regulatory environment will tighten and that public, patient and patient advocate appetite and expectation for the disclosure of clinical trial results summaries in plain language will intensify during the next 18 months. These pressures will compel research sponsors to accelerate adoption.

Strengthening partnerships between substance use researchers and policy makers to take advantage of a window of opportunity.

BACKGROUND: The National Institute on Drug Abuse has identified a persistent research-to-practice gap in the implementation of evidence-based prevention and treatment programs for substance use disorder. To identify mechanisms to close this gap, we sought to obtain and characterize the range of policy makers' perspectives on the use of research in substance use disorder treatment and coverage decisions. METHODS: We conducted open-ended, semi-structured interviews with a purposive sample of eighteen policy makers involved in the delivery of health services. The aim was to identify barriers and facilitators, attitudes, beliefs, and experiences surrounding the use of research related to the treatment and economics of substance use disorder. RESULTS: The analysis generated four themes: 1) policy maker engagement with evidence and researchers; 2) strategic use and usefulness of research; 3) scientific rigor versus relevance; and 4) communication of evidence. Within each theme, the participants identified barriers, facilitators, current practice, and gave their perspectives on "ideal conditions" for research design, conduct and communication. CONCLUSIONS: Recommendations for investigators are the following actionable steps: 1) partner with policy makers early in the research process, 2) formulate and use research designs to meet the strategic goals of end-users; 3) systematically test alternative phrasing of scientific terminology - particularly in the realm of cost effectiveness research - that allow end users to better understand and repurpose the data; 4) incorporate qualitative research methods to uncover the narratives that explain the context and relevance of evidence; 5) incorporate study designs that prioritize timeliness of results; and 6) promote and reward researcher involvement in policy discussions.

IMPACT OF REFLECTIVE SUPERVISION ON EARLY CHILDHOOD INTERVENTIONISTS' PERCEPTIONS OF SELF-EFFICACY, JOB SATISFACTION, AND JOB STRESS.

Despite widespread recognition of the importance of reflective practice in the field of infant mental health, little quantitative research exists regarding the impact of reflective supervision on professionals' self-efficacy, job satisfaction, and work-related stress. Thirty-three early childhood interventionists received approximately 9 months of reflective supervision and completed pre- and post-assessments of their job-related stress and self-efficacy using a modified version of the Reflective Supervision Self-Efficacy Scales for Supervisees (S. Shea, S. Goldberg, & D.J. Weatherston, 2012). At the post-assessment, participants also rated their overall experience of reflective supervision. Reported self-efficacy increased significantly from pre- to post-assessment, and participants reported a positive overall impact of reflective supervision with respect to a variety of indices, such as job satisfaction, professional development, and the ability to cope with job-related stress. These results provide necessary quantitative data demonstrating a positive impact of reflective supervision on early childhood professionals and suggest the value of reflective supervision for supporting workforce development.

Analysis of HOXB1 gene in a cohort of patients with sporadic ventricular septal defect.

Ventricular septal defect (VSD) including outlet VSD of double outlet right ventricle (DORV) and perimembranous VSD are among the most common congenital heart diseases found at birth. HOXB1 encodes a homeodomain transcription factor essential for normal cardiac outflow tract development. The aim of the present study was to investigate the possible genetic effect of sequence variations in HOXB1 on VSD. The coding regions and splice junctions of the HOXB1 gene were sequenced in 57 unrelated VSD patients. As a result, a homozygous c.74_82dup (p.Pro28delinsHisSerAlaPro) variant was identified in one individual with DORV. We also identified five previously reported polymorphisms (rs35114525, rs12946855, rs14534040, rs12939811, and rs7207109) in 18 patients (12 DORV and 6 perimembranous VSD). Our study did not show any pathogenic alterations in the coding region of HOXB1 among patients with VSD. To our knowledge this is the first study investigating the role of HOXB1 in nonsyndromic VSD, which provide more insight on the etiology of this disease.

Surgical repair of a pseudocoarctation with cervical aortic arch complicated by multiple aneurysms of the aorta: a case report.

Aortic pseudocoarctation is a rare congenital anomaly characterized by elongation and deformity of the aortic arch and is known to be associated with aneurysmal formation. Several studies unite to say it leads to a surgical sanction as soon as symptomatic or associated with aneurysms of the aortic arch. Our patient is a 12 years old boy, followed since birth for a little tight pseudocoarctation with a cervical aortic arch and transverse aortic arch hypoplasia. Close clinical and paraclinical monitoring including angioscans, showed the gradual enlargement of the superior mediastinum, in relation with the appearance of three aneurysms of the aortic arch. The intervention, performed by sternotomy, has consisted of the resection of the aneurysmal area and the interposition of a Dacron tube to repair the aortic arch and the reimplantation of the left subclavian artery into the left carotid artery. The postoperative course was uneventful. Management of pseudocoarctation associated with cervical aortic arch and aneurysms remains surgical. Close monitoring of patients with pseudocorctation, seems to be essential to avoid fatal complications such as aneurysmal rupture.

Total Anomalous Pulmonary Venous Connection: A 40 years' Experience Analysis.

Background Total anomalous pulmonary venous connection is a rare cardiac malformation associated with significant morbidity and mortality rates. We report a large surgical series study to evaluate mid-term and long-term results of conventional surgical techniques. Methods and Results We performed a retrospective analytic study of all patients operated on for simple total anomalous pulmonary venous connection in the University Hospital of Lyon, France, between January 1973 and June 2014. A total of 180 patients were included (43% supracardiac, 27% intracardiac, 19% infracardiac, and 11% mixed types). Mean cardiopulmonary bypass and aortic cross clamp times were respectively 66 and 39 minutes. Overall mortality was 27.1%, including 38 early deaths (21.1%) and 12 late deaths (6.1%). The percentage of early death greatly decreased over the eras, from 42.1% in the seventies to 7.4% after 2010. Besides the earlier era of intervention (p < 0.0001), significant risk factors for death in multivariate analysis were preoperative pulmonary hypertension, acidosis, and cardiopulmonary bypass time. There were 24 reoperations, including 7 for pulmonary venous obstruction; 6 died. Factors directly and independently associated with late complications were the anatomic type (mixed forms, p = 0.0023), and length of aortic cross clamp time (p = 0.01). Long-term results for survivals are excellent. We report 84.7% of asymptomatic patients with a mean follow-up of 10.8 years. Conclusions The overall prognosis of total anomalous pulmonary venous connection repair with conventional procedures has greatly improved over the years with excellent long-term results. A thorough evaluation of all preoperative characteristics is imperative to achieve the best outcome.

International normalized ratio self-testing and self-management: improving patient outcomes.

Long term oral anti-coagulation with vitamin K antagonists is a risk factor of hemorrhagic or thromebomlic complications. Periodic laboratory testing of international normalized ratio (INR) and a subsequent dose adjustment are therefore mandatory. The use of home testing devices to measure INR has been suggested as a potential way to improve the comfort and compliance of the patients and their families, the frequency of monitoring and, finally, the management and safety of long-term oral anticoagulation. In pediatric patients, increased doses to obtain and maintain the therapeutic target INR, more frequent adjustments and INR testing, multiple medication, inconstant nutritional intake, difficult venepunctures, and the need to go to the laboratory for testing (interruption of school and parents' work attendance) highlight those difficulties. After reviewing the most relevant published studies of self-testing and self-management of INR for adult patients and children on oral anticoagulation, it seems that these are valuable and effective strategies of INR control. Despite an unclear relationship between INR control and clinical effects, these self-strategies provide a better control of the anticoagulant effect, improve patients and their family quality of life, and are an appealing solution in term of cost-effectiveness. Structured education and knowledge evaluation by trained health care professionals is required for children, to be able to adjust their dose treatment safely and accurately. However, further data are necessary in order to best define those patients who might better benefit from this multidisciplinary approach.

Reimplantation of left coronary artery from pulmonary artery in a 65-year-old.

Anomalous left coronary artery to the pulmonary artery is a rare pathology with a mortality rate of 90% in the first year of life, directly related to left ventricular function and coronary perfusion, although several adult cases have been reported. Surgical correction consists of ligation of the anomalous left coronary artery associated with coronary artery bypass grafting. We describe the exceptional case of a 65-year-old woman who underwent reimplantation of the left coronary artery in the anatomical position without bridging.

Kommerell Diverticulum Should Be Removed in Children With Vascular Ring and Aberrant Left Subclavian Artery.

BACKGROUND: Right aortic arch with aberrant left subclavian artery is the most frequent cause of vascular ring. Ligamentum arteriosus division opens the ring but leaves the Kommerell diverticulum in place, with a risk of residual compression, aneurysmal dilation, dissection, or even rupture. A procedure consisting of translocation of the aberrant left subclavian artery to the left carotid artery with removal of the Kommerell diverticulum and division of the ligamentum is currently advocated. METHODS: Between September /2009 and August 2011, 12 consecutive patients underwent the foregoing procedure. Clinical findings, surgical procedure, complications, histopathologic findings, and follow-up data were retrospectively analyzed. RESULTS: Mean age at the time of operation was 7.7 years (median, 4.3 years, range, 0.9 to 18.9 years), and mean weight was 26 kg (median, 18 kg; range, 8.4 to 59 kg). All patients had symptoms. Computed tomography scan or magnetic resonance imaging, or both, had confirmed the diagnosis in all patients. Postoperative events, all transient, included chylothorax (1 patient), phrenic palsy (1 patient), pneumonia (1 patient), and the need for prolonged chest drainage (3 patients). Mean follow-up reached 19 months (median, 13 months; range, 12 to 41 months). Mild residual respiratory symptoms were noted in 3 patients. Echo-Doppler analysis showed a patent left subclavian-to-carotid artery anastomosis. Histopathologic analysis of the resected diverticulum (n = 6) showed cystic medial necrosis in four diverticula (focal in one). CONCLUSIONS: Translocation of the aberrant left subclavian artery with diverticulum resection and ligamentum division is an efficient procedure for symptom relief. Profound wall abnormalities such as medial necrosis in at least 50% of the analyzed diverticula encourage us to maintain this strategy, to reduce the risk of aneurysm formation and dissection.

Plasma neuronal specific enolase: a potential stage diagnostic marker in human African trypanosomiasis.

BACKGROUND: This study was carried out to determine the potential of neuronal specific enolase (NSE) as a stage diagnostic marker in human African trypanosomiasis. METHODS: Plasma and cerebrospinal fluid were obtained from a cohort of Trypanosoma brucei rhodesiense-infected patients and non-infected controls. Neuronal specific enolase concentrations were measured by ELISA and analysed in relation to diagnosis and disease-stage data. RESULTS: Plasma NSE concentration was significantly increased in late-stage patients (median 21 ng/ml), compared to the control (median 11 ng/ml), but not in early-stage patients (median 5.3 ng/ml). Cerebrospinal fluid NSE concentration did not vary between stages. CONCLUSION: Plasma NSE is a potential stage diagnostic in this cohort and merits further investigation.

Could anterior papillary muscle partial necrosis explain early mitral valve repair failure?

Standardized techniques of mitral valve repair (MVR) have recently witnessed the introduction of a 'respect rather than resect' concept, the strategy of which involves the use of artificial chordae. MVR displays several advantages over mitral valve replacement in degenerative mitral regurgitation (MR), but the risk of reoperation for MVR failure must be taken into account. Different mechanisms could be advocated as the leading cause of MVR failure; procedure-related mechanisms are usually involved in early MVR failure, while valve-related mechanisms are common in late failure. Here, the case is reported of an early failure of MVR using artificial chordae that could be explained by an unusual procedure-related mechanism, namely anterior papillary muscle necrosis. MVR failure is a well-known complication after surgical repair of degenerative MR, but anterior papillary muscle partial necrosis might also be considered a possible mechanism of procedure-related MVR failure, especially when considering the increasing use of artificial chordae. Owing to the encouraging results obtained, mitral valve re-repair might be considered a viable solution, but must be selected after only a meticulous evaluation of the underlying mechanism of MVR failure.