Staged approach for the management of atrial septal defect in the presence of a small left ventricle and suprasystemic pulmonary pressure

A 29-year-old woman presented with a symptomatic large atrial septal defect, a small left ventricle with a modest left atrium, mild to moderate nonrheumatic mitral valve incompetence, an apex-forming very large right ventricle and suprasystemic pulmonary artery pressure. Following one year of preprocedural drug treatment to lower pulmonary hypertension, she underwent percutaneous closure of the atrial septal defect with a customized fenestrated device that enabled gradual adaptation to the occlusion of the interatrial communication. This special case demonstrates the benefits of using a fenestrated occluder device in patients with pulmonary hypertension and components of left ventricular diastolic dysfunction, which is considered to be high risk and not amenable to therapeutic intervention. is a safe and effective alternative to surgery (1). Complete occlusion of the defect is generally the desired procedural outcome. However, there are clinical and morphological circumstances in which acute complete occlusion may worsen hemodynamics because this atrial communication serves as a 'pop-off' valve (2). Such situations have been previously described in the literature, and include children and adults with pulmonary arterial hypertension as well as closure of an ASD in elderly patients (3). In these settings, the use of a fenestrated occluder device was demonstrated to be beneficial (3). We present a case involving a young woman with an interesting cardiac morphology of a small left ventricle and suprasystemic pulmonary artery pressure. A staged approach, comprised of medical therapy followed by fenestrated device implantation, enabled gradual occlusion of the interatrial communication, leading to clinical and hemodynamic improvement. CASe pReSenTATion A previously healthy 29-year-old woman, who was diagnosed with an ASD when she was 14 years of age, became breathless on minor physical activity during pregnancy and remained decapacitated six months after spontaneous vaginal delivery of a healthy baby. She was referred to the authors as a tourist after several well-known cardiac and cardiothoracic services abroad elected not to intervene because of her unfavourable condition. On echocardiography, her heart morphology revealed a very small left ventricle (LV) -left ventricular end diastolic diameter of only 26 mm ( With regard to the possible etiology of increased PAp, there were no clinical or laboratory features of pulmonary embolism or a systemic illness such as Sjögren syndrome or lupus erythematosus, and the thrombophilia workup was negative. The patient was started on a combined drug therapy of bosentan 125 mg twice/day, sildenanfil 20 mg three times/day, bisoprolol 2.5 mg/day and furosemide 20 mg/day. The addition of bosentan aimed to decrease pulmonary resistance, thus decreasing the right-to-left shunt caused by the tricuspid valve jet through the ASD. Marked clinical and symptomatic improvements were documented soon thereafter and she returned home. Being a tourist, the patient could return for a follow-up visit only one year after the initial evaluation. Following one year of treatment, her O 2 saturation on room air increased from 88% to 90% to 98%, and her subjective limited walking capability improved. Doppler interrogation of tricuspid valve regurgitation revealed a pressure gradient of 60 mmHg. After informed consent was obtained, a hemodynamic study was performed in the catheterization laboratory. The measured PAp was 78/28 mmHg (mean 44 mmHg); the pulmonary capillary wedge pressure was 12/7 mmHg (mean 10 mmHg); and the Qp:Qs ratio was 3:1. The interatrial septum measured 50 mm. The ASD stretched diameter was 24 mm, with a small inferior fenestration revealed by transesophageal echocardiography. Although the LV was small, its systolic function was good. There was a large, apex-forming RV with good function. A sizing balloon was inflated through the ASD, resulting in an increase in mean pulmonary capillary wedge pressure from 10 mmHg to 12 mmHg

Mycobacterium haemophilum and Lymphadenitis in Immunocompetent Children, Israel

The database of a major microbiology laboratory in Israel was searched to determine the prevalence of nontuberculous mycobacterial lymphadenitis in immunocompetent children. We observed a 4-fold increase in nontuberculous mycobacteria isolates during 1985–2006, which was attributable mainly to increased detection of Mycobacterium haemophilum starting in 1996

Modeling the scaling properties of human mobility

While the fat tailed jump size and the waiting time distributions characterizing individual human trajectories strongly suggest the relevance of the continuous time random walk (CTRW) models of human mobility, no one seriously believes that human traces are truly random. Given the importance of human mobility, from epidemic modeling to traffic prediction and urban planning, we need quantitative models that can account for the statistical characteristics of individual human trajectories. Here we use empirical data on human mobility, captured by mobile phone traces, to show that the predictions of the CTRW models are in systematic conflict with the empirical results. We introduce two principles that govern human trajectories, allowing us to build a statistically self-consistent microscopic model for individual human mobility. The model not only accounts for the empirically observed scaling laws but also allows us to analytically predict most of the pertinent scaling exponents

MuD: an interactive web server for the prediction of non-neutral substitutions using protein structural data

The discrimination between functionally neutral amino acid substitutions and non-neutral mutations, affecting protein function, is very important for our understanding of diseases. The rapidly growing amounts of experimental data enable the development of computational tools to facilitate the annotation of these substitutions. Here, we describe a Random Forests-based classifier, named Mutation Detector (MuD) that utilizes structural and sequence-derived features to assess the impact of a given substitution on the protein function. In its automatic mode, MuD is comparable to alternative tools in performance. However, the uniqueness of MuD is that user-reported protein-specific structural and functional information can be added at run-time, thereby enhancing the prediction accuracy further. The MuD server, available at http://mud.tau.ac.il, assigns a reliability score to every prediction, thus offering a useful tool for the prioritization of substitutions in proteins with an available 3D structure

A Myo6 Mutation Destroys Coordination between the Myosin Heads, Revealing New Functions of Myosin VI in the Stereocilia of Mammalian Inner Ear Hair Cells

Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or ‘gating’ in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI–impaired hair cells, and ultimately leading to deafness

Deciphering the Arginine-Binding Preferences at the Substrate-Binding Groove of Ser/Thr Kinases by Computational Surface Mapping

Protein kinases are key signaling enzymes that catalyze the transfer of γ-phosphate from an ATP molecule to a phospho-accepting residue in the substrate. Unraveling the molecular features that govern the preference of kinases for particular residues flanking the phosphoacceptor is important for understanding kinase specificities toward their substrates and for designing substrate-like peptidic inhibitors. We applied ANCHORSmap, a new fragment-based computational approach for mapping amino acid side chains on protein surfaces, to predict and characterize the preference of kinases toward Arginine binding. We focus on positions P−2 and P−5, commonly occupied by Arginine (Arg) in substrates of basophilic Ser/Thr kinases. The method accurately identified all the P−2/P−5 Arg binding sites previously determined by X-ray crystallography and produced Arg preferences that corresponded to those experimentally found by peptide arrays. The predicted Arg-binding positions and their associated pockets were analyzed in terms of shape, physicochemical properties, amino acid composition, and in-silico mutagenesis, providing structural rationalization for previously unexplained trends in kinase preferences toward Arg moieties. This methodology sheds light on several kinases that were described in the literature as having non-trivial preferences for Arg, and provides some surprising departures from the prevailing views regarding residues that determine kinase specificity toward Arg. In particular, we found that the preference for a P−5 Arg is not necessarily governed by the 170/230 acidic pair, as was previously assumed, but by several different pairs of acidic residues, selected from positions 133, 169, and 230 (PKA numbering). The acidic residue at position 230 serves as a pivotal element in recognizing Arg from both the P−2 and P−5 positions

Integration of Transcriptomics, Proteomics, and MicroRNA Analyses Reveals Novel MicroRNA Regulation of Targets in the Mammalian Inner Ear

We have employed a novel approach for the identification of functionally important microRNA (miRNA)-target interactions, integrating miRNA, transcriptome and proteome profiles and advanced in silico analysis using the FAME algorithm. Since miRNAs play a crucial role in the inner ear, demonstrated by the discovery of mutations in a miRNA leading to human and mouse deafness, we applied this approach to microdissected auditory and vestibular sensory epithelia. We detected the expression of 157 miRNAs in the inner ear sensory epithelia, with 53 miRNAs differentially expressed between the cochlea and vestibule. Functionally important miRNAs were determined by searching for enriched or depleted targets in the transcript and protein datasets with an expression consistent with the dogma of miRNA regulation. Importantly, quite a few of the targets were detected only in the protein datasets, attributable to regulation by translational suppression. We identified and experimentally validated the regulation of PSIP1-P75, a transcriptional co-activator previously unknown in the inner ear, by miR-135b, in vestibular hair cells. Our findings suggest that miR-135b serves as a cellular effector, involved in regulating some of the differences between the cochlear and vestibular hair cells

Effects of total fat intake on body fatness in adults

Background: The ideal proportion of energy from fat in our food and its relation to body weight is not clear. In order to prevent overweight and obesity in the general population, we need to understand the relationship between the proportion of energy from fat and resulting weight and body fatness in the general population. Objectives: To assess the effects of proportion of energy intake from fat on measures of body fatness (including body weight, waist circumference, percentage body fat and body mass index) in people not aiming to lose weight, using all appropriate randomised controlled trials (RCTs) of at least six months duration. Search methods: We searched CENTRAL, MEDLINE, Embase, Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) to October 2019. We did not limit the search by language. Selection criteria: Trials fulfilled the following criteria: 1) randomised intervention trial, 2) included adults aged at least 18 years, 3) randomised to a lower fat versus higher fat diet, without the intention to reduce weight in any participants, 4) not multifactorial and 5) assessed a measure of weight or body fatness after at least six months. We duplicated inclusion decisions and resolved disagreement by discussion or referral to a third party. Data collection and analysis: We extracted data on the population, intervention, control and outcome measures in duplicate. We extracted measures of body fatness (body weight, BMI, percentage body fat and waist circumference) independently in duplicate at all available time points. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity, funnel plot analyses and GRADE assessment. Main results: We included 37 RCTs (57,079 participants). There is consistent high-quality evidence from RCTs that reducing total fat intake results in small reductions in body fatness; this was seen in almost all included studies and was highly resistant to sensitivity analyses (GRADE high-consistency evidence, not downgraded). The effect of eating less fat (compared with higher fat intake) is a mean body weight reduction of 1.4 kg (95% confidence interval (CI) -1.7 to -1.1 kg, in 53,875 participants from 26 RCTs, I2 = 75%). The heterogeneity was explained in subgrouping and meta-regression. These suggested that greater weight loss results from greater fat reductions in people with lower fat intake at baseline, and people with higher body mass index (BMI) at baseline. The size of the effect on weight does not alter over time and is mirrored by reductions in BMI (MD -0.5 kg/m2, 95% CI -0.6 to -0.3, 46,539 participants in 14 trials, I2 = 21%), waist circumference (MD -0.5 cm, 95% CI -0.7 to -0.2, 16,620 participants in 3 trials; I2 = 21%), and percentage body fat (MD -0.3% body fat, 95% CI -0.6 to 0.00, P = 0.05, in 2350 participants in 2 trials; I2 = 0%). There was no suggestion of harms associated with low fat diets that might mitigate any benefits on body fatness. The reduction in body weight was reflected in small reductions in LDL (-0.13 mmol/L, 95% CI -0.21 to -0.05), and total cholesterol (-0.23 mmol/L, 95% CI -0.32 to -0.14), with little or no effect on HDL cholesterol (-0.02 mmol/L, 95% CI -0.03 to 0.00), triglycerides (0.01 mmol/L, 95% CI -0.05 to 0.07), systolic (-0.75 mmHg, 95% CI -1.42 to -0.07) or diastolic blood pressure(-0.52 mmHg, 95% CI -0.95 to -0.09), all GRADE high-consistency evidence or quality of life (0.04, 95% CI 0.01 to 0.07, on a scale of 0 to 10, GRADE low-consistency evidence). Authors' conclusions: Trials where participants were randomised to a lower fat intake versus a higher fat intake, but with no intention to reduce weight, showed a consistent, stable but small effect of low fat intake on body fatness: slightly lower weight, BMI, waist circumference and percentage body fat compared with higher fat arms. Greater fat reduction, lower baseline fat intake and higher baseline BMI were all associated with greater reductions in weight. There was no evidence of harm to serum lipids, blood pressure or quality of life, but rather of small benefits or no effect

The data-driven time-dependent orienteering problem with soft time windows

In this paper, we study an extension of the orienteering problem where travel times are random and time-dependent and service times are random. Additionally, the service at each selected customer is subject to a soft time window; that is, violation of the window is allowed but subject to a penalty that increases in the delay. A solution is a tour determined before the vehicle departs from the depot. The objective is to maximize the sum of the collected prizes net of the expected penalty. The randomness of the travel and service times is modeled by a set of scenarios based on historical data that can be collected from public geographical information services. We present an exact solution method for the problem based on a branch-and-bound algorithm enhanced by a local search procedure at the nodes. A numerical experiment demonstrates the merits of the proposed solution approach. This study is the first to consider an orienteering problem with stochastic travel times and soft time windows, which are more relevant than hard time windows in stochastic settings

Symptoms and clinical parameters of pediatric and adolescent migraine, by gender - a retrospective cohort study

Abstract Background The available data on gender differences in clinical migraine parameters among pediatric patients are based on relatively few studies, which did not use the current version of the International Classification of Headache Disorders (ICHD) of the International Headache Society. The aim of the present study was to compare between males and females, demographic and clinical characteristics of children and adolescents with migraines diagnosed according to the ICDIII-beta version. Methods The electronic database of a tertiary pediatric headache clinic was searched for all children and adolescents diagnosed with migraine headaches in 2010–2016. Data on demographics, symptoms, and headache-related parameters were collected from the medical files. Findings were compared by gender. Results The cohort included 468 children and adolescents of mean age 11.3 ± 3.6 years; 215 males (45.9%) and 253 females (54.1%). Migraine without aura was documented in 313 patients (66.9%), and migraine with aura in 127 (27.1%); 28 patients (6.0%) had probable migraines. The female patients had significantly higher values than the male patients for the following parameters: age at admission (p = 0.042, Cohen’s d 0.8303, 95% CI 0.614–0.992); age at migraine onset (p = 0.021, Cohen’s d 0.211, 95% CI 0.029–0.394); rate of migraine with aura (OR 2.01, 95% CI 1.29–3.16, p = 0.0056); headache frequency (p = 0.0149, Cohen’s d 0.211, 95% CI 0.029–0.3940); rate of chronic migraine (p = 0.036, OR 1.54, 95% CI 1.02–2.34); and puberty (OR 3.51, 95% CI 2.01–6.35, p = <0.001). Males had a higher rate of vomiting (OR 0.62, 95% CI 0.41–0.93, p = 0.018). Further analysis by pubertal stage revealed that pubertal females, but not prepubertal females, had a significantly higher rate of migraine with aura than did males (41.1% versus 28.9%; OR 1.42, 95% CI 0.85–2.37, p = 0.039). Conclusion Female children and adolescents with migraine treated in a tertiary pediatric headache clinic were characterized by a higher rate of chronic migraine and migraine with aura, a lower rate of vomiting, and older age at onset relative to males. These findings might be influenced by the better description of migraine symptoms by females owing to their better verbal ability