Septic AKI in ICU patients. diagnosis, pathophysiology, and treatment type, dosing, and timing: a comprehensive review of recent and future developments

Evidence is accumulating showing that septic acute kidney injury (AKI) is different from non-septic AKI. Specifically, a large body of research points to apoptotic processes underlying septic AKI. Unravelling the complex and intertwined apoptotic and immuno-inflammatory pathways at the cellular level will undoubtedly create new and exciting perspectives for the future development (e.g., caspase inhibition) or refinement (specific vasopressor use) of therapeutic strategies. Shock complicating sepsis may cause more AKI but also will render treatment of this condition in an hemodynamically unstable patient more difficult. Expert opinion, along with the aggregated results of two recent large randomized trials, favors continuous renal replacement therapy (CRRT) as preferential treatment for septic AKI (hemodynamically unstable). It is suggested that this approach might decrease the need for subsequent chronic dialysis. Large-scale introduction of citrate as an anticoagulant most likely will change CRRT management in intensive care units (ICU), because it not only significantly increases filter lifespan but also better preserves filter porosity. A possible role of citrate in reducing mortality and morbidity, mainly in surgical ICU patients, remains to be proven. Also, citrate administration in the predilution mode appears to be safe and exempt of relevant side effects, yet still requires rigorous monitoring. Current consensus exists about using a CRRT dose of 25 ml/kg/h in non-septic AKI. However, because patients should not be undertreated, this implies that doses as high as 30 to 35 ml/kg/h must be prescribed to account for eventual treatment interruptions. Awaiting results from large, ongoing trials, 35 ml/kg/h should remain the standard dose in septic AKI, particularly when shock is present. To date, exact timing of CRRT is not well defined. A widely accepted composite definition of timing is needed before an appropriate study challenging this major issue can be launched

Distorted Cognitive Processing in Youth: The Structure of Negative Cognitive Errors and Their Associations with Anxiety

The Children’s Negative Cognitive Error Questionnaire (CNCEQ) is commonly used to measure four errors in young people’s thinking, but research has failed to support the factorial validity of the measure. The primary objective of the present study was to examine the factor structure of a refined and extended version of the CNCEQ. Revision of the CNCEQ involved the exclusion of items rated as contaminated, and the addition of items measuring cognitive errors closely associated with anxiety (‘threat conclusion’ and ‘underestimation of the ability to cope’). A secondary objective was to determine the relation between the negative cognitive errors and anxiety. Principal component analysis of data from 481 children and adolescents indicated five distinct negative cognitive error subscales labeled ‘underestimation of the ability to cope’, ‘personalizing without mind reading’, ‘selective abstraction’, ‘overgeneralizing’, and ‘mind reading’ which contained the new ‘threat conclusion’ items. Confirmatory factor analysis in an independent sample of 295 children and adolescents yielded further support for the five-factor solution. All cognitive errors except ‘selective abstraction’ were correlated with anxiety. Multiple regression analysis indicated that the strongest predictors of anxiety were the two subscales containing new items, namely ‘underestimation of the ability to cope’ and ‘mind reading’. The results are discussed with respect to further development of the instrument so as to advance the assessment of distorted cognitive processing in young people with internalizing symptoms

Emergence of the Asian 1 Genotype of Dengue Virus Serotype 2 in Viet Nam: In Vivo Fitness Advantage and Lineage Replacement in South-East Asia

A better description of the extent and structure of genetic diversity in dengue virus (DENV) in endemic settings is central to its eventual control. To this end we determined the complete coding region sequence of 187 DENV-2 genomes and 68 E genes from viruses sampled from Vietnamese patients between 1995 and 2009. Strikingly, an episode of genotype replacement was observed, with Asian 1 lineage viruses entirely displacing the previously dominant Asian/American lineage viruses. This genotype replacement event also seems to have occurred within DENV-2 in Thailand and Cambodia, suggestive of a major difference in viral fitness. To determine the cause of this major evolutionary event we compared both the infectivity of the Asian 1 and Asian/American genotypes in mosquitoes and their viraemia levels in humans. Although there was little difference in infectivity in mosquitoes, we observed significantly higher plasma viraemia levels in paediatric patients infected with Asian 1 lineage viruses relative to Asian/American viruses, a phenotype that is predicted to result in a higher probability of human-to-mosquito transmission. These results provide a mechanistic basis to a marked change in the genetic structure of DENV-2 and more broadly underscore that an understanding of DENV evolutionary dynamics can inform the development of vaccines and anti-viral drugs

A New Approach to Monitoring Dengue Activity

Discusses informal surveillance tools for monitoring dengue activity, such as ProMED, GPHIN HealthMap and BioCaster

Physical activity and depression in adolescents: cross-sectional findings from the ALSPAC cohort

Purpose: Few studies have examined the association between physical activity (PA), measured objectively, and adolescent depressive symptoms. The aim of this study was to determine whether there is an association between objective measures of PA (total PA and time spent in moderate and vigorous PA (MVPA)) and adolescent depressive symptoms. Methods: Data on 2,951 adolescents participating in ALSPAC were used. Depressive symptoms were measured using the self-report Mood and Feelings Questionnaire (MFQ) (short version). Measures of PA were based on accelerometry. The association between PA and MFQ scores was modelled using ordinal regression. Results: Adolescents who were more physically active (total PA or minutes of MVPA) had a reduced odds of depressive symptoms [ORadj total PA (tertiles): medium 0.82 (95% CI: 0.69, 0.97); high 0.69 (95% CI: 0.57, 0.83)]; ORadj per 15 min MVPA: 0.92 (95% CI: 0.86, 0.98). In a multivariable model including both total PA and the percentage of time spent in MVPA, total PA was associated with depressive symptoms (ORadj total PA (tertiles): medium 0.82 (95% CI: 0.70, 0.98); high 0.70 (95% CI: 0.58, 0.85) but the percentage of time spent in MVPA was not independently associated with depressive symptoms [ORadj MVPA (tertiles) medium 1.05 (95% CI: 0.88, 1.24), high 0.91 (95% CI: 0.77, 1.09)]. Conclusions: The total amount of PA undertaken was associated with adolescent depressive symptoms, but the amount of time spent in MVPA, once total PA was accounted for, was not. If confirmed in longitudinal studies and randomised controlled trials, this would have important implications for public health messages.Nicola J. Wiles, Anne M. Haase, Debbie A. Lawlor, Andy Ness, Glyn Lewi

Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study

Rate-dependent effects on the Ca2+ sub-system in a rat ventricular myocyte are investigated. Here, we employ a deterministic mathematical model describing various Ca2+ signalling pathways under voltage clamp (VC) conditions, to better understand the important role of calmodulin (CaM) in modulating the key control variables Ca2+/calmodulin-dependent protein kinase-II (CaMKII), calcineurin (CaN), and cyclic adenosine monophosphate (cAMP) as they affect various intracellular targets. In particular, we study the frequency dependence of the peak force generated by the myofilaments, the force-frequency response (FFR). Our cell model incorporates frequency-dependent CaM-mediated spatially heterogenous interaction of CaMKII and CaN with their principal targets (dihydropyridine (DHPR) and ryanodine (RyR) receptors and the SERCA pump). It also accounts for the rate-dependent effects of phospholamban (PLB) on the SERCA pump; the rate-dependent role of cAMP in up-regulation of the L-type Ca2+ channel (ICa;L); and the enhancement in SERCA pump activity via phosphorylation of PLB.Our model reproduces positive peak FFR observed in rat ventricular myocytes during voltage-clamp studies both in the presence/absence of cAMP mediated -adrenergic stimulation. This study provides quantitative insight into the rate-dependence of Ca2+-induced Ca2+-release (CICR) by investigating the frequency-dependence of the trigger current (ICa;L) and RyR-release. It also highlights the relative role of the sodium-calcium exchanger (NCX) and the SERCA pump at higher frequencies, as well as the rate-dependence of sarcoplasmic reticulum (SR) Ca2+ content. A rigorous Ca2+ balance imposed on our investigation of these Ca2+ signalling pathways clarifies their individual roles. Here, we present a coupled electromechanical study emphasizing the rate-dependence of isometric force developed and also investigate the temperature-dependence of FFR. Our model provides mechanistic biophysically based explanations for the rate-dependence of CICR, generating useful and testable hypotheses. Although rat ventricular myocytes exhibit a positive peak FFR in the presence/absence of beta-adrenergic stimulation, they show a characteristic increase in the positive slope in FFR due to the presence of Norepinephrine or Isoproterenol. Our study identifies cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of ICa;L as the key mechanisms underlying the aforementioned positive FFR

Comparison of children's self-reports of depressive symptoms among different family interaction types in northern Taiwan

<p>Abstract</p> <p>Background</p> <p>Previous research has shown that family interactions are associated with depressive symptoms in children. However, detailed classifications of family interaction types have not been studied thoroughly. This study aims to understand the types of family interactions children experience and to identify the specific types of family interactions that are associated with a higher risk of depressive symptoms in children.</p> <p>Methods</p> <p>Data used in the study was collected as part of the Child and Adolescent Behavior in Long term Evolution (CABLE) project in 2003. CABLE is a longitudinal cohort study that commenced in 2001 and collects data annually from children in Taipei city and Hsinchu county in northern Taiwan. The data analyzed in this study was that obtained from the sixth graders (aged 11 to 12 years old) in 2003. Of the 2,449 sixth graders, 51.2% were boys and 48.8% were girls. Factor analysis and cluster analysis were used to investigate the types of family interactions. One way ANOVA was used to establish the relationship between family interaction types and children's self-reports of depressive symptoms.</p> <p>Results</p> <p>Based on the results of factor analysis, the latent factors for family interactions included supporting activities, psychological control, parental discipline, behavioral supervision, and family conflict. After conducting cluster analysis using factor scores, four types of family interactions were revealed: supervised (29.66%), disciplined (13.56%), nurtured (40.96%) and conflict (15.82%). Children from the disciplined or conflict families were more likely to report depressive symptoms. Children from the nurtured families were least likely to report depressive symptoms.</p> <p>Conclusion</p> <p>Family interactions can be classified into four different types, which are related to children's self-reports of depressive symptoms. The creation of a family interaction environment that is beneficial for children's mental health is an important issue for health education and health promotion professionals.</p

Protocol for a randomised controlled trial of a school based cognitive behaviour therapy (CBT) intervention to prevent depression in high risk adolescents (PROMISE)

<p>Abstract</p> <p>Background</p> <p>Depression in adolescents is a significant problem that impairs everyday functioning and increases the risk of severe mental health disorders in adulthood. Relatively few adolescents with depression are identified and referred for treatment indicating the need to investigate alternative preventive approaches.</p> <p>Study Design</p> <p>A pragmatic cluster randomised controlled trial evaluating the effectiveness of a school based prevention programme on symptoms of depression in "high risk" adolescents (aged 12-16). The unit of allocation is year groups (n = 28) which are assigned to one of three conditions: an active intervention based upon cognitive behaviour therapy, attention control or treatment as usual. Assessments will be undertaken at screening, baseline, 6 months and 12 months. The primary outcome measure is change on the Short Mood and Feeling Questionnaire at 12 months. Secondary outcome measures will assess changes in negative thoughts, self esteem, anxiety, school connectedness, peer attachment, alcohol and substance misuse, bullying and self harm.</p> <p>Discussion</p> <p>As of August 2010, all 28 year groups (n = 5023) had been recruited and the assigned interventions delivered. Final 12 month assessments are scheduled to be completed by March 2011.</p> <p>Trial Registration</p> <p>ISRCTN19083628</p

Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae.

Metabolic resistance to pyrethroid insecticides is widespread in Anopheles mosquitoes and is a major threat to malaria control. DNA markers would aid predictive monitoring of resistance, but few mutations have been discovered outside of insecticide-targeted genes. Isofemale family pools from a wild Ugandan Anopheles gambiae population, from an area where operational pyrethroid failure is suspected, were genotyped using a candidate-gene enriched SNP array. Resistance-associated SNPs were detected in three genes from detoxification superfamilies, in addition to the insecticide target site (the Voltage Gated Sodium Channel gene, Vgsc). The putative associations were confirmed for two of the marker SNPs, in the P450 Cyp4j5 and the esterase Coeae1d by reproducible association with pyrethroid resistance in multiple field collections from Uganda and Kenya, and together with the Vgsc-1014S (kdr) mutation these SNPs explained around 20% of variation in resistance. Moreover, the >20 Mb 2La inversion also showed evidence of association with resistance as did environmental humidity. Sequencing of Cyp4j5 and Coeae1d detected no resistance-linked loss of diversity, suggesting selection from standing variation. Our study provides novel, regionally-validated DNA assays for resistance to the most important insecticide class, and establishes both 2La karyotype variation and humidity as common factors impacting the resistance phenotype

The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer

© The Author 2015.Background: The management of NSCLC has been transformed by stratified medicine. The National Lung Matrix Trial (NLMT) is a UK-wide study exploring the activity of rationally selected biomarker/targeted therapy combinations. Patients and methods: The Cancer Research UK (CRUK) Stratified Medicine Programme 2 is undertaking the large volume national molecular pre-screening which integrates with the NLMT. At study initiation, there are eight drugs being used to target 18 molecular cohorts. The aim is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. A Bayesian adaptive design that gives a more realistic approach to decision making and flexibility to make conclusions without fixing the sample size was chosen. The screening platform is an adaptable 28-gene Nextera next-generation sequencing platform designed by Illumina, covering the range of molecular abnormalities being targeted. The adaptive design allows new biomarker-drug combination cohorts to be incorporated by substantial amendment. The pre-clinical justification for each biomarker-drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Discrete routes of pathway activation or inactivation determined by cancer genome aberrations are treated as separate cohorts. Key translational analyses include the deep genomic analysis of pre- and post-treatment biopsies, the establishment of patient-derived xenograft models and longitudinal ctDNA collection, in order to define predictive biomarkers, mechanisms of resistance and early markers of response and relapse. Conclusion: The SMP2 platform will provide large scale genetic screening to inform entry into the NLMT, a trial explicitly aimed at discovering novel actionable cohorts in NSCLC