Effectiveness and cost effectiveness of cardiovascular disease prevention in whole populations: modelling study

Objective To estimate the potential cost effectiveness of a population-wide risk factor reduction programme aimed at preventing cardiovascular disease

Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant

[Background] Inherited chronic mucocutaneous candidiasis (CMC) is often caused by inborn errors of immunity, impairing the response to, or the production of IL-17A and IL-17F. About half of the cases carry STAT1 gain-of-function (GOF) mutations. Only few patients have been reported with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential for IL-17 receptor(R) signaling. We investigated a 10-year-old girl with CMC, carrying a heterozygous variant of STAT1 and compound heterozygous variants of TRAF3IP2.[Methods] By flow cytometry, STAT1 levels and phosphorylation (CD14+) as well as IL-17A, IL-22, IFN-γ, and IL-4 production (memory CD4+ T cells) were determined. ACT1 expression and binding to IL-17RA were assessed by Western blot and co-immunoprecipitation in HEK-293T cells transfected with plasmids encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We evaluated IL-17A responses by measuring luciferase induction under a NF-κB-driven reporter system in HEK-293T cells and Gro-α secretion in fibroblasts. [Results] A STAT1 variant (c.1363G>A/p.V455I) was identified by next-generation sequencing and classified as likely non-pathogenic as functional testing revealed normal STAT1 expression and phosphorylation upon IFN-γ. We also found compound heterozygous variants (c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2. By overexpression, despite normal protein expression, and impaired (K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant alleles resulted in impaired NF-κB activation. Patient's fibroblasts displayed abolished GRO-α secretion upon IL-17A stimulation. Finally, ex vivo CD4+ T cells showed increased IL-17A, IL-22, and IL-4 and normal low IFN-γ expression upon stimulation. [Conclusion] We identify novel compound heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1 deficiency in a child with CMC and provide a review of the current literature

Successive translocation into and out of the mitochondrial matrix

We investigated the import and sorting pathways of cytochrome b2 and cytochrome c1, which are functionally located in the intermembrane space of mitochondria. Both proteins are synthesized on cytoplasmic ribosomes as larger precursors and are processed in mitochondria in two steps upon import. The precursors are first translocated across both mitochondrial membranes via contact sites into the matrix. Processing by the matrix peptidase leads to intermediate-sized forms, which are subsequently redirected across the inner membrane. The second proteolytic processing occurs in the intermembrane space. We conclude that the hydrophobic stretches in the presequences of the intermediate-sized forms do not stop transfer across the inner membrane, but rather act as transport signals to direct export from the matrix into the intermembrane space

Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study)

Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).BackgroundHyperphosphatemia underlies development of hyperparathyroidism, osteodystrophy, extraosseous calcification, and is associated with increased mortality in hemodialysis patients.MethodsTo determine whether calcium acetate or sevelamer hydrochloride best achieves recently recommended treatment goals of phosphorus ≤5.5mg/dL and Ca × P product ≤55mg2/dL2, we conducted an 8-week randomized, double-blind study in 100 hemodialysis patients.ResultsComparisons of time-averaged concentrations (weeks 1 to 8) demonstrated that calcium acetate recipients had lower serum phosphorus (1.08mg/dL difference, P = 0.0006), higher serum calcium (0.63mg/dL difference, P < 0.0001), and lower Ca × P (6.1mg2/dL2 difference, P = 0.022) than sevelamer recipients. At each week, calcium acetate recipients were 20% to 24% more likely to attain goal phosphorus [odds ratio (OR) 2.37, 95% CI 1.28–4.37, P = 0.0058], and 15% to 20% more likely to attain goal Ca × P (OR 2.16, 95% CI 1.20–3.86, P = 0.0097). Transient hypercalcemia occurred in 8 of 48 (16.7%) calcium acetate recipients, all of whom received concomitant intravenous vitamin D. By regression analysis hypercalcemia was more likely with calcium acetate (OR 6.1, 95% CI 2.8–13.3, P < 0.0001). Week 8 intact PTH levels were not significantly different. Serum bicarbonate levels were significantly lower with sevelamer hydrochloride treatment (P < 0.0001).ConclusionCalcium acetate controls serum phosphorus and calcium-phosphate product more effectively than sevelamer hydrochloride. Cost-benefit analysis indicates that in the absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in hemodialysis patients

Parent Agreement on Ratings of Children's Attention Deficit/Hyperactivity Disorder and Broadband Externalizing Behaviors

Mothers and fathers often disagree in their ratings of child behavior, as evidenced clinically and as supported by a substantial literature examining parental agreement on broadband rating scales. The present study examined mother-father agreement on Diagnostic and Statistical Manual-based symptom-specific ratings of Attention-Deficit/Hyperactivity Disorder (ADHD), as compared to agreement on broadband ratings of externalizing behavior. Based on mother and father ratings of 324 children who participated in the Multimodal Treatment Study of Children with ADHD (MTA), parental agreement was computed and patterns of disagreement examined. Mother-father ratings were significantly correlated; however, a clear pattern of higher ratings by mothers was present. Agreement on attention-deficit/hyperactivity disorder symptom-specific ratings was significantly lower than that for broadband externalizing behaviors and oppositional defiant disorder symptoms. Of several moderator variables tested, parental stress was the only one that predicted the discrepancy in ratings. Disagreement between parents is clinically significant and may pose complications to the diagnostic process

Number preferences in lotteries

We explore people's preferences for numbers in large proprietary data sets from two different lottery games. We find that choice is far from uniform, and exhibits some familiar and some new tendencies and biases. Players favor personally meaningful and situationally available numbers, and are attracted towards numbers in the center of the choice form. Frequent players avoid winning numbers from recent draws, whereas infrequent players chase these. Combinations of numbers are formed with an eye for aesthetics, and players tend to spread their numbers relatively evenly across the possible range

Interference control in children with attention deficit/hyperactivity disorder

The view that Attention Deficit/Hyperactivity Disorder (ADHD) is associated with a diminished ability to control interfference is controversial and based exclusively on results of (verbal)-visual interference tasks, primarily the Stroop Color Word task. The present study compares medication-naïve children with ADHD (n∈=∈35 and n∈=∈51 in Experiments 1 and 2, respectively) with normal controls (n∈=∈26 and n∈=∈32, respectively) on two interference tasks to assess interference control in both the auditory and the visual modality: an Auditory Stroop task and a Simon task. Both groups showed reliable but equal degrees of interference on both tasks, suggesting that children with ADHD do not differ from normal controls in their ability to control interference in either modality. © 2008 The Author(s)

Serotonergic Contribution to Boys' Behavioral Regulation

Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure.Participants were 23 boys (age 10 years) with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered.Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter.The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors

Systematic review of quality of life and functional outcomes in randomized placebo-controlled studies of medications for attention-deficit/hyperactivity disorder

Children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD) experience functional impairment and poor health-related quality of life (HRQoL) in addition to symptoms of inattention/hyperactivity-impulsivity. To synthesize qualitatively the published evidence from randomized, double-blind, placebo-controlled trials of the effectiveness of pharmacotherapy on functional impairment or HRQoL in patients with ADHD, a systematic PubMed searching and screening strategy was designed to identify journal articles meeting pre-specified criteria. Post hoc analyses and meta-analyses were excluded. HRQoL outcomes, functional outcomes and the principal ADHD symptom-based outcome were extracted from included studies. An effect size of 0.5 versus placebo was used as a threshold for potential clinical relevance (unreported effect sizes were calculated when possible). Of 291 records screened, 35 articles describing 34 studies were included. HRQoL/functioning was usually self-rated in adults and proxy-rated in children/adolescents. Baseline data indicated substantial HRQoL deficits in children/adolescents. Placebo-adjusted effects of medication on ADHD symptoms, HRQoL and functioning, respectively, were statistically or nominally significant in 18/18, 10/12 and 7/9 studies in children/adolescents and 14/16, 9/11 and 9/10 studies in adults. Effect sizes were ≥0.5 versus placebo for symptoms, HRQoL and functioning, respectively, in 14/16, 7/9 and 4/8 studies in children/adolescents; and 6/12, 1/6 and 1/8 studies in adults. Effect sizes were typically larger for stimulants than for non-stimulants, for symptoms than for HRQoL/functioning, and for children/adolescents than for adults. The efficacy of ADHD medication extends beyond symptom control and may help reduce the related but distinct functional impairments and HRQoL deficits in patients with ADHD

Designing microenvironments for optimal outcomes in tissue engineering and regenerative medicine: From biopolymers to culturing conditions

Bone marrow mesenchymal stem cells have been extensively used for tissue engineering and regenerative medicine applications due to their ease of isolation and expansion and their ability to differentiate towards various lineages of mesodermal origin. Despite these properties, their clinical potential is often hampered by the simplicity of the in vitro environment and its inability to resemble the complex in vivo niche. Herein, different microenvironmental cues (e.g. surface topography, substrate stiffness, mechanical stimulation, oxygen tension and co-culture systems) that have been utilised to enhance the therapeutic efficacy of bone marrow mesenchymal stem cells are discussed.The authors would like to acknowledge the following entities for financial support: H2020, Marie Skłodowska-Curie Actions, Innovative Training Networks 2015 Tendon Therapy Train project (Grant No. 676338); Science Foundation Ireland (SFI) / European Regional Development Fund (Grant Number 13/RC/2073); and SFI Career Development Award (Grant Number 15/CDA/3629)