Risk of major cardiovascular events in patients with psoriasis receiving biologic therapies: a prospective cohort study.

BACKGROUND: The cardiovascular safety profile of biologic therapies used for psoriasis is unclear. OBJECTIVES: To compare the risk of major cardiovascular events (CVEs; acute coronary syndrome, unstable angina, myocardial infarction and stroke) in patients with chronic plaque psoriasis treated with adalimumab, etanercept or ustekinumab in a large prospective cohort. METHODS: Prospective cohort study examining the comparative risk of major CVEs was conducted using the British Association of Dermatologists Biologics and Immunomodulators Register. The main analysis compared adults with chronic plaque psoriasis receiving ustekinumab with tumour necrosis-α inhibitors (TNFi: etanercept and adalimumab), whilst the secondary analyses compared ustekinumab, etanercept or methotrexate against adalimumab. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using overlap weights by propensity score to balance baseline covariates among comparison groups. RESULTS: We included 5468 biologic-naïve patients subsequently exposed (951 ustekinumab; 1313 etanercept; and 3204 adalimumab) in the main analysis. The secondary analyses also included 2189 patients receiving methotrexate. The median (p25-p75) follow-up times for patients using ustekinumab, TNFi, adalimumab, etanercept and methotrexate were as follows: 2.01 (1.16-3.21), 1.93 (1.05-3.34), 1.94 (1.09-3.32), 1.92 (0.93-3.45) and 1.43 (0.84-2.53) years, respectively. Ustekinumab, TNFi, adalimumab, etanercept and methotrexate groups had 7, 29, 23, 6 and 9 patients experiencing major CVEs, respectively. No differences in the risk of major CVEs were observed between biologic therapies [adjusted HR for ustekinumab vs. TNFi: 0.96 (95% CI 0.41-2.22); ustekinumab vs. adalimumab: 0.81 (0.30-2.17); etanercept vs. adalimumab: 0.81 (0.28-2.30)] and methotrexate against adalimumab [1.05 (0.34-3.28)]. CONCLUSIONS: In this large prospective cohort study, we found no significant differences in the risk of major CVEs between three different biologic therapies and methotrexate. Additional studies, with longer term follow-up, are needed to investigate the potential effects of biologic therapies on incidence of major CVEs

Characterizing problematic hypoglycaemia: iterative design and preliminary psychometric validation of the Hypoglycaemia Awareness Questionnaire (HypoA-Q)

AIMS: To design and conduct preliminary validation of a measure of hypoglycaemia awareness and problematic hypoglycaemia, the Hypoglycaemia Awareness Questionnaire. METHODS: Exploratory and cognitive debriefing interviews were conducted with 17 adults (nine of whom were women) with Type 1 diabetes (mean &plusmn; sd age 48&plusmn;10 years). Questionnaire items were modified in consultation with diabetologists/psychologists. Psychometric validation was undertaken using data from 120 adults (53 women) with Type 1 diabetes (mean &plusmn; sd age 44&plusmn;16 years; 50% with clinically diagnosed impaired awareness of hypoglycaemia), who completed the following questionnaires: the Hypoglycaemia Awareness Questionnaire, the Gold score, the Clarke questionnaire and the Problem Areas in Diabetes questionnaire. RESULTS: Iterative design resulted in 33 items eliciting answers on awareness of hypoglycaemia when awake/asleep and hypoglycaemia frequency, severity and impact (healthcare utilization). Psychometric analysis identified three subscales reflecting \u27impaired awareness\u27, \u27symptom level\u27 and \u27symptom frequency\u27. Convergent validity was indicated by strong correlations between the impaired awareness subscale and existing measures of awareness: (Gold: rs =0.75, P&lt;0.01; Clarke: rs =0.76, P&lt;0.01). Divergent validity was indicated by weaker correlations with diabetes-related distress (Problem Areas in Diabetes: rs =0.25, P&lt;0.01) and HbA1c (rs =-0.05, non-significant). The impaired awareness subscale and other items discriminated between those with impaired and intact awareness (Gold score). The impaired awareness subscale and other items contributed significantly to models explaining the occurrence of severe hypoglycaemia and hypoglycaemia when asleep. CONCLUSIONS: This preliminary validation shows the Hypoglycaemia Awareness Questionnaire has robust face and content validity; satisfactory structure; internal reliability; convergent, divergent and known groups validity. The impaired awareness subscale and other items contribute significantly to models explaining recall of severe and nocturnal hypoglycaemia. Prospective validation, including determination of a threshold to identify impaired awareness, is now warranted.<br /

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re‐emerging phenotype is associated with graft function

Islet transplantation is an effective therapy for life‐threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet‐specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty‐eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet‐specific T cell responses was not significantly different over time (pre‐Tx: 59%; 1–6 m posttransplant: 38%; 7–12 m: 44%; 13–24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN‐γ–dominated response in the pretransplant group replaced by IL‐10–dominated response in the 1–6 m posttransplant group, reverting to predominantly IFN‐γ–oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN‐γ and IL‐10 phenotypes, respectively. IL‐10–oriented posttransplant response was associated with relatively low graft function. Recipients within the IL‐10+ cluster had a significant decline in C‐peptide levels in the period preceding the IL‐10 response, but stable graft function following the response. In contrast, an IFN‐γ response was associated with subsequently decreased C‐peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet‐specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function

The effect of fear of falling on vestibular feedback control of balance

© 2017 The Authors. Vestibular sensation contributes to cervical-head stabilization and fall prevention. To what extent fear of falling influences the associated vestibular feedback processes is currently undetermined. We used galanic vestibular stimulation (GVS) to induce vestibular reflexes while participants stood at ground level and on a narrow walkway at 3.85 m height to induce fear of falling. Fear was confirmed by questionnaires and elevated skin conductance. Full-body kinematics was measured to differentiate the whole-body centre of mass response (CoM) into component parts (cervical, axial trunk, appendicular short latency, and medium latency). We studied the effect of fear of falling on each component to discern their underlying mechanisms. Statistical parametric mapping analysis provided sensitive discrimination of early GVS and height effects. Kinematic analysis revealed responses at 1 mA stimulation previously believed marginal through EMG and force plate analysis. The GVS response comprised a rapid, anode-directed cervical-head acceleration, a short-latency cathode-directed acceleration (cathodal buckling) of lower extremities and pelvis, an anode-directed upper thorax acceleration, and subsequently a medium-latency anode-directed acceleration of all body parts. At height, head and upper thorax early acceleration were unaltered, however, short-latency lower extremity acceleration was increased. The effect of height on balance was a decreased duration and increased rate of change in the CoM acceleration pattern. These results demonstrate that fear modifies vestibular control of balance, whereas cervical-head stabilization is governed by different mechanisms unaffected by fear of falling. The mechanical pattern of cathodal buckling and its modulation by fear of falling both support the hypothesis that short-latency responses contribute to regulate balance

Changes in prevalence of obesity and high waist circumference over four years across European regions: the European male ageing study (EMAS).

Diversity in lifestyles and socioeconomic status among European populations, and recent socio-political and economic changes in transitional countries, may affect changes in adiposity. We aimed to determine whether change in the prevalence of obesity varies between the socio-politically transitional North-East European (Łódź, Poland; Szeged, Hungary; Tartu, Estonia), and the non-transitional Mediterranean (Santiago de Compostela, Spain; Florence, Italy) and North-West European (Leuven, Belgium; Malmö, Sweden; Manchester, UK) cities. This prospective observational cohort survey was performed between 2003 and 2005 at baseline and followed up between 2008 and 2010 of 3369 community-dwelling men aged 40-79 years. Main outcome measures in the present paper included waist circumference, body mass index and mid-upper arm muscle area. Baseline prevalence of waist circumference ≥ 102 cm and body mass index ≥ 30 kg/m2, respectively, were 39.0, 29.5 % in North-East European cities, 32.4, 21.9 % in Mediterranean cities, and 30.0, 20.1 % in North-West European cities. After median 4.3 years, men living in cities from transitional countries had mean gains in waist circumference (1.1 cm) and body mass index (0.2 kg/m2), which were greater than men in cities from non-transitional countries (P = 0.005). North-East European cities had greater gains in waist circumference (1.5 cm) than in Mediterranean cities (P < 0.001). Over 4.3 years, the prevalence of waist circumference ≥ 102 cm had increased by 13.1 % in North-East European cities, 5.8 % in the Mediterranean cities, 10.0 % in North-West European cities. Odds ratios (95 % confidence intervals), adjusted for lifestyle factors, for developing waist circumference ≥ 102 cm, compared with men from Mediterranean cities, were 2.3 (1.5-3.5) in North-East European cities and 1.6 (1.1-2.4) in North-West European cities, and 1.6 (1.2-2.1) in men living in cities from transitional, compared with cities from non-transitional countries. These regional differences in increased prevalence of waist circumference ≥ 102 cm were more pronounced in men aged 60-79 years than in those aged 40-59 years. Overall there was an increase in the prevalence of obesity (body mass index  ≥ 30 kg/m2) over 4.3 years (between 5.3 and 6.1 %) with no significant regional differences at any age. Mid-upper arm muscle area declined during follow-up with the greatest decline among men from North-East European cities. In conclusion, increasing waist circumference is dissociated from change in body mass index and most rapid among men living in cities from transitional North-East European countries, presumably driven by economic and socio-political changes. Information on women would also be of value and it would be of interest to relate the changes in adiposity to dietary and other behavioural habits

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato–thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto–striato–parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto–striato–cerebellar dysregulation in ASD

Parenting-by-gender interactions in child psychopathology: attempting to address inconsistencies with a Canadian national database

<p>Abstract</p> <p>Background</p> <p>Research has shown strong links between parenting and child psychopathology. The moderating role of child gender is of particular interest, due to gender differences in socialization history and in the prevalence of psychiatric disorders. Currently there is little agreement on how gender moderates the relationship between parenting and child psychopathology. This study attempts to address this lack of consensus by drawing upon two theories (self-salience vs. gender stereotyped misbehaviour) to determine how child gender moderates the role of parenting, if at all.</p> <p>Methods</p> <p>Using generalized estimating equations (GEE) associations between three parenting dimensions (hostile-ineffective parenting, parental consistency, and positive interaction) were examined in relationship to child externalizing (physical aggression, indirect aggression, and hyperactivity-inattention) and internalizing (emotional disorder-anxiety) dimensions of psychopathology. A sample 4 and 5 year olds from the National Longitudinal Survey of Children and Youth (NLSCY) were selected for analysis and followed over 6 years (N = 1214). Two models with main effects (Model 1) and main effects plus interactions (Model 2) were tested.</p> <p>Results</p> <p>No child gender-by-parenting interactions were observed for child physical aggression and indirect aggression. The association between hostile-ineffective parenting and child hyperactivity was stronger for girls, though this effect did not reach conventional levels of statistical significance (<it>p </it>= .059). The associations between parenting and child emotional disorder did vary as a function of gender, where influences of parental consistency and positive interaction were stronger for boys.</p> <p>Discussion</p> <p>Despite the presence of a few significant interaction effects, hypotheses were not supported for either theory (i.e. self-salience or gender stereotyped misbehaviour). We believe that the inconsistencies in the literature regarding child gender-by-parenting interactions is due to the reliance on gender as an indicator of a different variable which is intended to explain the interactions. This may be problematic because there is likely within-gender and between-sample variability in such constructs. Future research should consider measuring and modelling variables that are assumed to explain such interactions when conducting gender-by-parenting research.</p

The effectiveness of interventions to change six health behaviours: a review of reviews

Background: Several World Health Organisation reports over recent years have highlighted the high incidence of chronic diseases such as diabetes, coronary heart disease and cancer. Contributory factors include unhealthy diets, alcohol and tobacco use and sedentary lifestyles. This paper reports the findings of a review of reviews of behavioural change interventions to reduce unhealthy behaviours or promote healthy behaviours. We included six different health-related behaviours in the review: healthy eating, physical exercise, smoking, alcohol misuse, sexual risk taking (in young people) and illicit drug use. We excluded reviews which focussed on pharmacological treatments or those which required intensive treatments (e. g. for drug or alcohol dependency). Methods: The Cochrane Library, Database of Abstracts of Reviews of Effectiveness (DARE) and several Ovid databases were searched for systematic reviews of interventions for the six behaviours (updated search 2008). Two reviewers applied the inclusion criteria, extracted data and assessed the quality of the reviews. The results were discussed in a narrative synthesis. Results: We included 103 reviews published between 1995 and 2008. The focus of interventions varied, but those targeting specific individuals were generally designed to change an existing behaviour (e. g. cigarette smoking, alcohol misuse), whilst those aimed at the general population or groups such as school children were designed to promote positive behaviours (e. g. healthy eating). Almost 50% (n = 48) of the reviews focussed on smoking (either prevention or cessation). Interventions that were most effective across a range of health behaviours included physician advice or individual counselling, and workplace- and school-based activities. Mass media campaigns and legislative interventions also showed small to moderate effects in changing health behaviours. Generally, the evidence related to short-term effects rather than sustained/longer-term impact and there was a relative lack of evidence on how best to address inequalities. Conclusions: Despite limitations of the review of reviews approach, it is encouraging that there are interventions that are effective in achieving behavioural change. Further emphasis in both primary studies and secondary analysis (e.g. systematic reviews) should be placed on assessing the differential effectiveness of interventions across different population subgroups to ensure that health inequalities are addressed.</p

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex