Ambulatory Systolic Blood Pressure and Obesity are Independently Associated with Left Ventricular Hypertrophic Remodeling in Children

Background: Children with obesity have hypertrophic cardiac remodeling. Hypertension is common in pediatric obesity, and may independently contribute to hypertrophy. We hypothesized that both the degree of obesity and ambulatory blood pressure (ABP) would independently associate with measures of hypertrophic cardiac remodeling in children. Methods: Children, aged 8–17 years, prospectively underwent cardiovascular magnetic resonance (CMR) and ABP monitoring. Left ventricular (LV) mass indexed to height2.7(LVMI), myocardial thickness and end-diastolic volume were quantified from a 3D LV model reconstructed from cine balanced steady state free precession images. Categories of remodeling were determined based on cutoff values for LVMI and mass/volume. Principal component analysis was used to define a “hypertrophy score” to study the continuous relationship between concentric hypertrophy and ABP. Results: Seventy-two children were recruited, and 68 of those (37 healthy weight and 31 obese/overweight) completed both CMR and ABP monitoring. Obese/overweight children had increased LVMI (27 ± 4 vs 22 ± 3 g/m2.7, p \u3c 0.001), myocardial thickness (5.6 ± 0.9 vs 4.9 ± 0.7 mm, p \u3c 0.001), mass/volume (0.69 ± 0.1 vs 0.61 ± 0.06, p \u3c 0.001), and hypertrophy score (1.1 ± 2.2 vs −0.96 ± 1.1, p \u3c 0.001). Thirty-five percent of obese/overweight children had concentric hypertrophy. Ambulatory hypertension was observed in 26% of the obese/overweight children and none of the controls while masked hypertension was observed in 32% of the obese/overweight children and 16% of the controls. Univariate linear regression showed that BMI z-score, systolic BP (24 h, day and night), and systolic load correlated with LVMI, thickness, mass/volume and hypertrophy score, while 24 h and nighttime diastolic BP and load also correlated with thickness and mass/volume. Multivariate analysis showed body mass index z-score and systolic blood pressure were both independently associated with left ventricular mass index (β=0.54 [p \u3c 0.001] and 0.22 [p = 0.03]), thickness (β=0.34 [p \u3c 0.001] and 0.26 [p = 0.001]) and hypertrophy score (β=0.47 and 0.36, both p \u3c 0.001). Conclusions: In children, both the degree of obesity and ambulatory blood pressures are independently associated with measures of cardiac hypertrophic remodeling, however the correlations were generally stronger for the degree of obesity. This suggests that interventions targeted at weight loss or obesity-associated co-morbidities including hypertension may be effective in reversing or preventing cardiac remodeling in obese children

Whirlpool: Improving Dynamic Cache Management with Static Data Classification

Cache hierarchies are increasingly non-uniform and difficult to manage. Several techniques, such as scratchpads or reuse hints, use static information about how programs access data to manage the memory hierarchy. Static techniques are effective on regular programs, but because they set fixed policies, they are vulnerable to changes in program behavior or available cache space. Instead, most systems rely on dynamic caching policies that adapt to observed program behavior. Unfortunately, dynamic policies spend significant resources trying to learn how programs use memory, and yet they often perform worse than a static policy. We present Whirlpool, a novel approach that combines static information with dynamic policies to reap the benefits of each. Whirlpool statically classifies data into pools based on how the program uses memory. Whirlpool then uses dynamic policies to tune the cache to each pool. Hence, rather than setting policies statically, Whirlpool uses static analysis to guide dynamic policies. We present both an API that lets programmers specify pools manually and a profiling tool that discovers pools automatically in unmodified binaries. We evaluate Whirlpool on a state-of-the-art NUCA cache. Whirlpool significantly outperforms prior approaches: on sequential programs, Whirlpool improves performance by up to 38% and reduces data movement energy by up to 53%; on parallel programs, Whirlpool improves performance by up to 67% and reduces data movement energy by up to 2.6x.National Science Foundation (U.S.) (grant CCF-1318384)National Science Foundation (U.S.) (CAREER-1452994)Samsung (Firm) (GRO award

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562

Differentiation of the Lateral Compartment of the Cochlea Requires a Temporally Restricted FGF20 Signal

FGF20 signaling in mice is required specifically for the differentiation of cochlear outer hair cells, the cells most often damaged during age-related hearing loss

Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly

<p>Abstract</p> <p>Background</p> <p>Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in <it>CDK5RAP2 </it>gene at MCPH3 locus have been least involved in causing MCPH phenotype.</p> <p>Methods</p> <p>All coding exons and exon/intron splice junctions of <it>CDK5RAP2 </it>gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.</p> <p>Results</p> <p>A previously described nonsense mutation [243 T>A (S81X)] in exon 4 of <it>CDK5RAP2 </it>gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).</p> <p>Conclusion</p> <p>Recurrent observation of Y82X mutation in <it>CDK5RAP2 </it>gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.</p

Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

10.2337/db08-1514Diabetes5861403-1410DIAE

The epidemiology of suicide and attempted suicide in Dutch general practice 1983–2003

BACKGROUND: Many patients attempting or committing suicide consult their general practitioner (GP) in the preceding period, indicating that GPs might play an important role in prevention. The aim of the present study was to analyse the epidemiology of suicidal behaviour in Dutch General Practice in order to find possible clues for prevention. METHOD: Description of trends in suicide and suicide attempts occurring from 1983–2003 in the Dutch General Practice Sentinel Network, representing 1% of the Dutch population. The data were analysed with regard to: 1) suicidal behaviour trends and their association with household situation; 2) presence of depression, treatment of depression and referral rate by GPs; 3) contact with GP before suicide or suicide attempt and discussion of suicidal ideation. RESULTS: Between 1983 and 2003 the annual number of suicide and suicide attempts decreased by 50%. Sixty percent of the patients who committed or attempted suicide were diagnosed as depressed, of whom 91% were treated by their GP with an antidepressant. Living alone was a risk factor for suicide (odds ratio 1.99; 95% CI 1.50 to 2.64), whereas living in a household of 3 or more persons was a relative risk for a suicide attempt (odds ratio 1.81; 95% CI 1.34 to 2.46). Referral to a psychiatrist or other mental health professionals occurred in 65% of the cases. GPs recalled having discussed suicidal ideation in only 7% of the cases, and in retrospect estimated that they had foreseen suicide or suicide attempts in 31% and 22% of the cases, respectively, if there had been contact in the preceding month. CONCLUSION: With regard to the prescription of antidepressants and referral of suicidal patients to a psychiatrist, Dutch GPs fulfil their role as gatekeeper satisfactorily. However, since few patients discuss their suicidal ideation with their GP, there is room for improvement. GPs should take the lead to make this subject debatable. It may improve early recognition of depressed patients at risk and accelerate their referral to mental health professionals