Kevin R. Murphy

Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials

BACKGROUND Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of reslizumab in patients with inadequately controlled, moderate-to-severe asthma. METHODS We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12-75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous reslizumab (3·0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (reslizumab or matching placebo) on the basis of the patients body weight and randomly assigned treatment group. Additionally, the sponsors clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2). FINDINGS Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0·50 [95% CI 0·37-0·67]; study 2: 0·41 [0·28-0·59]; both p<0·0001) compared with those receiving placebo. Common adverse events on reslizumab were similar to placebo. The most common adverse events were worsening asthma symptoms (127 [52%] for placebo and 97 [40%] for reslizumab in study 1; 119 [51%] for placebo and 67 [29%] for reslizumab for study 2), upper respiratory tract infections (32 [13%] and 39 [16%]; 16 [7%] and eight [3%]), and nasopharyngitis (33 [14%] and 28 [11%]; 56 [24%] and 45 [19%]). Two patients in the reslizumab group had anaphylactic reactions; both responded to standard treatment at the study centre and resolved, and the patients were withdrawn from the study. INTERPRETATION These results support the use of reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. FUNDING Teva Branded Pharmaceutical Products R&D.

Young Adults With Attention Deficit Hyperactivity Disorder: Subtype Differences In Comorbidity, Educational, And Clinical History

The present study sought to examine subtype differences in comorbidity and in antisocial, educational, and treatment histories among young adults (ages 17–27) with attention deficit hyperactivity disorder (ADHD). Comparisons were made between ADHD Combined Type (ADHD-C;N = 60) and Predominantly Inattentive Type (ADHD-I;N = 36) relative to each other and to a community control group of 64 adults. Both ADHD groups had significantly less education, were less likely to have graduated from college, and were more likely to have received special educational placement in high school. Both groups also presented with a greater likelihood of dysthymia, alcohol dependence/abuse, cannabis dependence/abuse, and learning disorders, as well as greater psychological distress on all scales of the SCL-90-R than the control group. Both ADHD groups were more likely to have received psychiatric medication and other mental health services than control adults. In comparison with ADHD-I, adults with ADHD-C differed in only a few respects. The C-type adults were more likely to have oppositional defiant disorder, to experience interpersonal hostility and paranoia, to have attempted suicide, and to have been arrested than the ADHD-I adults. These results are generally consistent with previous studies of ADHD in children, extend these findings to adults with ADHD, and suggest that the greater impulsivity associated with the ADHD-C subtype may predispose toward greater antisocial behavior and its consequences than does ADHD-I type in adults.

Prevalence of DSM-IV symptoms of ADHD in adult licensed drivers: Implications for clinical diagnosis

The present study reports on the prevalence of the DSM-IV symptoms for attention deficit hyperactivity disorder (ADHD) in a sample of 720 adults applying for or renewing their drivers licenses in central Massachusetts (ages 17-84 years). Symptoms were assessed using two self- report rating scales: One for current symptoms and a second for retrospective recall of child hood symptoms (ages 5-12 yrs.). Three age groups were created: 17-29, 30-49, and 50+ years. All scores and symptom counts for both scales declined significantly with age for both disorders. Males and females did not differ significantly on scores for current symptoms. However, for recall of childhood symptoms, males obtained higher scores than females. Requiring that DSM-IV diagnostic thresholds be met for both current and childhood symptoms, the prevalence of adult ADHD was found to be 1.3% for the Inattentive Type, 2.5% for the Hyperactive-Impulsive Type, and 0.9% for the Combined Type. The prevalence of all subtypes was below that found in most studies of children. While these results imply that ADHD subtypes may be less prevalent in adults, the lower prevalence could also have been due to DSM-IV diagnostic thresholds being too restrictive (i.e., >99th percentile) for use in the diagnosis of adults with ADHD. Further research is recommended to evaluate whether future DSMs should consider establishing thresholds that are developmentally (age) referenced rather than fixed across the lifespan.

Driving in young adults with attention deficit hyperactivity disorder: knowledge, performance, adverse outcomes, and the role of executive functioning

Past studies find that attention deficit hyperactivity disorder (ADHD) creates a higher risk for adverse driving outcomes. This study comprehensively evaluated driving in adults with ADHD by comparing 105 young adults with the disorder (age 17-28) to 64 community control (CC) adults on five domains of driving ability and a battery of executive function tasks. The ADHD group self-reported significantly more traffic citations, particularly for speeding, vehicular crashes, and license suspensions than the CC group, with most of these differences corroborated in the official DMV records. Cognitively, the ADHD group was less attentive and made more errors during a visual reaction task under rule-reversed conditions than the CC group. The ADHD group also obtained lower sceres on a test of driving rules and decision-making but not on a simple driving simulator. Both self- and other-ratings showed the CC group employed safer routine driving habits than the ADHD group. Relationships between the cognitive and driving measures and the adverse outcomes were limited or absent, calling into question their use in screening ADHD adults for driving risks. Several executive functions also were significantly yet modestly related to accident frequency and total traffic violations after controlling for severity of ADHD. These results are consistent with earlier studies showing significant driving problems are associated with ADHD. This study found that these driving difficulties were not a function of comorbid oppositional defiant disorder, depression, anxiety, or frequency of alcohol or illegal drug use. Findings to date argue for the development of interventions to reduce driving risks among adults with ADHD.

Impairment in occupational functioning and adult ADHD: the predictive utility of executive function (EF) ratings versus EF tests.

Attention deficit hyperactivity disorder (ADHD) is associated with deficits in executive functioning (EF). ADHD in adults is also associated with impairments in major life activities, particularly occupational functioning. We investigated the extent to which EF deficits assessed by both tests and self-ratings contributed to the degree of impairment in 11 measures involving self-reported occupational problems, employer reported workplace adjustment, and clinician rated occupational adjustment. Three groups of adults were recruited as a function of their severity of ADHD: ADHD diagnosis (n = 146), clinical controls self-referring for ADHD but not diagnosed with it (n = 97), and community controls (n = 109). Groups were combined and regression analyses revealed that self-ratings of EF were significantly predictive of impairments in all 11 measures of occupational adjustment. Although several tests of EF also did so, they contributed substantially less than did the EF ratings, particularly when analyzed jointly with the ratings. We conclude that EF deficits contribute to the impairments in occupational functioning that occur in conjunction with adult ADHD. Ratings of EF in daily life contribute more to such impairments than do EF tests, perhaps because, as we hypothesize, each assesses a different level in the hierarchical organization of EF as a meta-construct.

Executive functioning and olfactory identification in young adults with attention deficit-hyperactivity disorder

Young adults with attention deficit-hyperactivity disorder (ADHD; N = 105) were compared with a control group (N = 64) on 14 measures of executive function and olfactory identification using a 2 (group) X 2 (sex) design. The ADHD group performed significantly worse on 11 measures. No Group X Sex interaction was found on any measures. No differences were found in the ADHD group as a function of ADHD subtype or comorbid oppositional defiant disorder. Comorbid depression influenced the results of only 1 test (Digit Symbol). After IQ was controlled for, some group differences in verbal working memory, attention, and odor identification were no longer significant, whereas those in inhibition, interference control, nonverbal working memory, and other facets of attention remained so. Executive function deficits found in childhood ADHD exist in young adults with ADHD and are largely not influenced by comorbidity but may be partly a function of low intelligence.

Time perception and reproduction in young adults with attention deficit hyperactivity disorder.

Adults with attention deficit hyperactivity disorder (ADHD; n = 104) were compared with a control group (n = 64) on time estimation and reproduction tasks. Results were unaffected by ADHD subtype or gender. The ADHD group provided larger time estimations than the control group, particularly at long intervals. This became nonsignificant after controlling for IQ. The ADHD group made shorter reproductions than did the control group (15- and 60-s intervals) and greater reproduction errors (12-, 45-, 60-s durations). These differences remained after controlling for IQ and comorbid oppositional defiant disorder, depression, and anxiety. Only the level of anxiety contributed to errors (at 12-s duration) beyond the level of ADHD. Results extended findings on time perception in ADHD children to adults and ruled out comorbidity as the basis of the errors.

When your top choice turns you down: Effect of rejected offers on the utility of selection tests.

A system for purifying bodies of water, such as swimming pools, includes a prefilter upstream of a catalytic filter, and a pump for periodically circulating water to be treated through the prefilter and then through the catalytic filter. The catalytic filter includes a series of horizontally disposed filter elements each having a stationary layer of a permeable water-purifying biocatalyst composition. The preferred biocatalyst is a microbicidal surface compound formed by wet processing finely divided silver oxide, zinc oxide and lampblack. Water circulated through the prefilter is filtered to remove suspended solids or algae which would clog or otherwise disturb the biocatalyst filter cake. Water circulated through the catalytic filter is purified by surface contact with the biocatalyst. Repeated pool water contact with the biocatalyst generates a residual microbicidal condition in the pool water. The biocatalyst layer, the water circulated to it, and the water circulated away from it are constantly maintained at a pH above 7 and at a temperature between about 70 DEG F to about 98 DEG F to prevent deactivating the biocatalyst and to constantly maintain the residual microbicidal condition.

Why Don't Measures of Broad Dimensions of Personality Perform Better As Predictors of Job Performance?

Despite recent enthusiasm for the use of personality inventories in personnel selection, many of the problems cited in Guion and Gottiers (1965) review have yet to be resolved. The validity of measures of broad personality traits is still low, personality tests used in organizations are still poorly chosen, and links between personality and jobs are poorly understood. Personality measures are unlikely to achieve the degree of acceptance given to cognitive tests because of differences in the domains, differences in the tests, and differences in the environments in which cognitive tests versus personality inventories are developed.

The Relation Between Personality and Contextual Performance in "Strong" Versus "Weak" Situations

Both a laboratory and field study investigated the extent to which the strength of behavioral cues in simulated and actual job performance situations moderate the relation between measures of broad personality dimensions and contextual performance behaviors. Extending Mischels (1977) conceptualization of strong and weak situations, it was hypothesized that personality and contextual performance behavior would be most strongly correlated when there were only weak cues, and less correlated when there were strong cues. Results indicated that personality-contextual performance correlations varied across situations with different expectations for performance.