Working memory deficits in adults with ADHD: is there evidence for subtype differences?

BACKGROUND: Working memory performance is important for maintaining functioning in cognitive, academic and social activities. Previous research suggests there are prevalent working memory deficits in children with attention deficit hyperactivity disorder (ADHD). There is now a growing body of literature characterizing working memory functioning according to ADHD subtypes in children. The expression of working memory deficits in adults with ADHD and how they vary according to subtype, however, remains to be more fully documented. METHODS: This study assessed differences in working memory functioning between Normal Control (NC) adults (N = 18); patients with ADHD, Combined (ADHD-CT) Type ADHD (N = 17); and ADHD, Inattentive (ADHD-IA) Type (N = 16) using subtests from the Wechsler Adult Intelligence Scale-III and Wechsler Memory Scale-III and the Paced Auditory Serial Addition Task (PASAT). RESULTS: The ADHD groups displayed significant weaknesses in contrast to the NC group on working memory tests requiring rapid processing and active stimulus manipulation. This included the Letter-Number-Sequencing test of the Wechsler scales, PASAT omission errors and the longest sequence of consecutive correct answers on the PASAT. No overall ADHD group subtype differences emerged; however differences between the ADHD groups and the NC group varied depending on the measure and the gender of the participants. Gender differences in performance were evident on some measures of working memory, regardless of group, with males performing better than females. CONCLUSION: In general, the data support a dimensional interpretation of working memory deficits experienced by the ADHD-CT and ADHD-IA subtypes, rather than an absolute difference between subtypes. Future studies should test the effects of processing speed and load on subtype performance and how those variables interact with gender in adults with ADHD

Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations

Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Multicountry survey of emergency and critical care medicine physicians' fluid resuscitation practices for adult patients with early septic shock

Evidence to guide fluid resuscitation evidence in sepsis continues to evolve. We conducted a multicountry survey of emergency and critical care physicians to describe current stated practice and practice variation related to the quantity, rapidity and type of resuscitation fluid administered in early septic shock to inform the design of future septic shock fluid resuscitation trials.Using a web-based survey tool, we invited critical care and emergency physicians in Canada, the UK, Scandinavia and Saudi Arabia to complete a self-administered electronic survey.A total of 1097 physicians responses were included. 1 L was the most frequent quantity of resuscitation fluid physicians indicated they would administer at a time (46.9%, n=499). Most (63.0%, n=671) stated that they would administer the fluid challenges as quickly as possible. Overall, normal saline and Ringers solutions were the preferred crystalloid fluids used often or always in 53.1% (n=556) and 60.5% (n=632) of instances, respectively. However, emergency physicians indicated that they would use normal saline often or always in 83.9% (n=376) of instances, while critical care physicians said that they would use saline often or always in 27.9% (n=150) of instances. Only 1.0% (n=10) of respondents indicated that they would use hydroxyethyl starch often or always; use of 5% (5.6% (n=59)) or 20-25% albumin (1.3% (n=14)) was also infrequent. The majority (88.4%, n=896) of respondents indicated that a large randomised controlled trial comparing 5% albumin to a crystalloid fluid in early septic shock was important to conduct.Critical care and emergency physicians stated that they rapidly infuse volumes of 500-1000 mL of resuscitation fluid in early septic shock. Colloid use, specifically the use of albumin, was infrequently reported. Our survey identifies the need to conduct a trial on the efficacy of albumin and crystalloids on 90-day mortality in patients with early septic shock

The value of episodic, intensive blood glucose monitoring in non-insulin treated persons with type 2 diabetes: Design of the Structured Testing Program (STeP) Study, a cluster-randomised, clinical trial [NCT00674986]

<p>Abstract</p> <p>Background</p> <p>The value and utility of self-monitoring of blood glucose (SMBG) in non-insulin treated T2DM has yet to be clearly determined. Findings from studies in this population have been inconsistent, due mainly to design differences and limitations, including the prescribed frequency and timing of SMBG, role of the patient and physician in responding to SMBG results, inclusion criteria that may contribute to untoward floor effects, subject compliance, and cross-arm contamination. We have designed an SMBG intervention study that attempts to address these issues.</p> <p>Methods/design</p> <p>The Structured Testing Program (STeP) study is a 12-month, cluster-randomised, multi-centre clinical trial to evaluate whether poorly controlled (HbA1c ≥ 7.5%), non-insulin treated T2DM patients will benefit from a comprehensive, integrated physician/patient intervention using structured SMBG in US primary care practices. Thirty-four practices will be recruited and randomly assigned to an active control group (ACG) that receives enhanced usual care or to an enhanced usual care group plus structured SMBG (STG). A total of 504 patients will be enrolled; eligible patients at each site will be randomly selected using a defined protocol. Anticipated attrition of 20% will yield a sample size of at least 204 per arm, which will provide a 90% power to detect a difference of at least 0.5% in change from baseline in HbA1c values, assuming a common standard deviation of 1.5%. Differences in timing and degree of treatment intensification, cost effectiveness, and changes in patient self-management behaviours, mood, and quality of life (QOL) over time will also be assessed. Analysis of change in HbA1c and other dependent variables over time will be performed using both intent-to-treat and per protocol analyses. Trial results will be available in 2010.</p> <p>Discussion</p> <p>The intervention and trial design builds upon previous research by emphasizing appropriate and collaborative use of SMBG by both patients and physicians. Utilization of per protocol and intent-to-treat analyses facilitates a comprehensive assessment of the intervention. Use of practice site cluster-randomisation reduces the potential for intervention contamination, and inclusion criteria (HbA1c ≥ 7.5%) reduces the possibility of floor effects. Inclusion of multiple dependent variables allows us to assess the broader impact of the intervention, including changes in patient and physician attitudes and behaviours.</p> <p>Trial Registration</p> <p>Current Controlled Trials NCT00674986.</p

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Coping resources, coping strategies and adaptation to organisational change : direct or buffering effects?

This study examined the effects of personal and social resources, coping strategies and appraised stress on employees' levels of anxiety and depression. In relation to the effects of resources and coping strategies, two different models were tested. The main effects model proposes that, irrespective of the level of stress, coping resources and coping strategies have direct effects on well-being. In contrast, the buffering model predicts that the buffering effects of coping resources and strategies are only evident at high levels of stress. One hundred lawyers completed a structured self-administered questionnaire that measured their personal and social resources, use of problem-focused and emotion-focused coping strategies, and appraisals of the stressfulness of the situation. Results revealed generally strong support for the main effects model in the prediction of employee levels of anxiety and depression. Lower levels of anxiety were linked to judgements of lower levels of organizational change, greater self-confidence, greater internality of control beliefs and less use of emotion-focused coping strategies. Lower levels of depression in employees were also linked to judgements of lower levels of organizational change, greater use of resources and less appraised stress. There was only limited support for the buffering effects model. Due to the small size of the sample, the findings need to be explored further in other contexts