The Use of Brexpiprazole Combined With a Stimulant in Adults With Treatment-Resistant Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: This is the first controlled pharmacologic study in either adults or children with uncomplicated, treatment-resistant attention-deficit/hyperactivity disorder (ADHD). This study augmented stimulant therapy with the atypical antipsychotic brexpiprazole. The Food and Drug Administration preapproved primary outcome measure (Conners' Adult ADHD Rating Scale [CAARS]) showed no drug-placebo differences. Often studies showing no efficacy on the prestudy, defined primary outcome variable go unpublished. While this is decried, publishing studies with equivocal results remains rare. This reanalysis highlights trends in secondary measures having implications for treatment and research regarding treatment resistant ADHD. METHODS: Initially, 559 stimulant-naive and 174 prior stimulant nonresponders received methylphenidate osmotic-release oral system, dexmethylphenidate hydrochloride, lisdexamfetamine, or mixed amphetamine salts. After 5 weeks, 168 stimulant-naive patients and 68 prior stimulant nonresponders who failed treatment were randomized to brexpiprazole or placebo in a 2:1 ratio while the remaining were on the stimulant. Outcome was measured with the CAARS, Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Clinical Global Impression, and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). The WRAADDS contains 2 factors: attention and emotional dysregulation. RESULTS: Stimulant-naive patients showed no improvement with adjunctive brexpiprazole. Prior stimulant nonresponders displayed no brexpiprazole effect on the CAARS, Montgomery-Asberg Depression Rating Scale, or Beck Depression Inventory. In contrast, the WRAADDS detected a trend in treatment benefit, primarily through emotional dysregulation symptoms. Adverse effects on brexpiprazole and placebo were equivalent. CONCLUSIONS: Brexpiprazole might be effective in ADHD adults who are nonresponders to 2 or more stimulants. Future trials in treatment-resistant ADHD should use a 1:1 randomization and use a measure of ADHD symptoms that includes emotional dysregulation.

DNA and other strands: the making of a human geneticist.

This article--a mini-memoir--focuses on the first half of my half-century-long career as a human geneticist: its accidental beginnings; its early bad and then good fortunes at the National Institutes of Health; its serendipitous successes and career-making scientific productivity at Yale; and its incalculable fortuity in the form of the large number of talented and resourceful mentors, colleagues, postdoctoral fellows, graduate students, and technicians who worked with me. These years acted as a launchpad for positions of visibility and leadership that followed them. My personal odyssey, which began in Madison, Wisconsin, and meandered with no fixed plan to New York, Bethesda, New Haven, and Princeton, has offered me life views as a human and medical geneticist that are panoramic, splendid, and indelible. I doubt that many people have been as fortunate as I have been in the professional life I have lived--and continue to live.

Four children and Yale: the making of a human geneticist: the Grover Powers lecture 2014.

Dr. Leon E. Rosenberg delivered the following presentation as the Grover Powers Lecturer on May 14, 2014, which served as the focal point of his return to his "adult home" as a Visiting Professor in the Department of Pediatrics. Grover F. Powers, MD, was one of the most influential figures in American Pediatrics and certainly the leader who created the modern Department of Pediatrics at Yale when he was recruited in 1921 from Johns Hopkins and then served as its second chairman from 1927 to 1951. Dr. Powers was an astute clinician and compassionate physician and fostered and shaped the careers of countless professors, chairs, and outstanding pediatricians throughout the country. This lectureship has continued yearly since it first honored Dr. Powers in 1956. The selection of Dr. Rosenberg for this honor recognizes his seminal role at Yale and throughout the world in the fostering and cultivating of the field of human genetics. Dr. Rosenberg served as the inaugural Chief of a joint Division of Medical Genetics in the Departments of Pediatrics and Internal Medicine; he became Chair when this attained Departmental status. Then he served as Dean of the Medical School from 1984 to 1991, before he became President of the Pharmaceutical Research Institute at Bristol-Myers Squibb and later Senior Molecular Biologist and Professor at Princeton University, until his recent retirement. Dr. Rosenberg has received numerous honors that include the Borden Award from the American Academy of Pediatrics, the McKusick Leadership Award from the American Society for Human Genetics, and election to the Institute of Medicine and the National Academy of Sciences.

The Ham-D is not Hamilton's Depression Scale.

Introduction: This article will demonstrate that the most widely used versions of the Hamilton Rating Scale for Depression (HAM-D) used in randomized clinical trials, the Guy 1976 HAM-D1 and the SIGH-D,2 have response options that deviate sharply from Max Hamilton's 19603 and 19674 guidelines. For example, difficulty in concentration, one of the diagnostic criteria for a Major Depressive Episode according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) since 1980, in editions III, IV, IV-TR and 5,5 is something that Hamilton wrote should be measured in his scale, yet it is not measured in either of the presently used HAM-Ds. Method: A review was conducted of the four key papers related to the development of the Hamilton Rating Scale for Depression: the 1960 and 1967 papers by Max Hamilton; the HAM-D chapter in the 1976 ECDEU Assessment Manual for Psychopharmacology edited by William Guy; and the 1988 article on the Structured Interview Guide for the HAM-D (SIGH-D) by Janet Williams. Additionally, the Janet Williams updated 2013 SIGH-D6 is also reviewed. Results: When comparing the HAM-D and the SIGH-D with the gold standard Hamilton guidelines from his 1960 and 1967 articles, 13 of the 17 items contain significant errors. Conclusion: Significant differences between the currently used HAM-Ds and the guidelines set forth by Max Hamilton in 1960 and 1967 will be demonstrated. These discrepancies may produce inconsistencies in administration and scoring, leading to unreliable measurements of subjects' and patients' depressive symptoms and unreliable measurement of their progress over time.

A Quality Improvement Initiative to Decrease Time to Analgesia in Patients With Sickle Cell and Vaso-Occlusive Crisis: A Population With Disparities in Treatment.

INTRODUCTION: Vaso-occlusive crises (VOCs) are the leading cause of emergency department (ED) visits and hospitalizations in patients with sickle cell disease (SCD). Timely administration of analgesia, within 60 minutes of patient registration, is the standard of care for SCD patients with VOCs. Patients with VOCs have longer times to initial analgesia compared to similar painful conditions. The primary aim of the project is to have 75% of patients with VOCs receive initial analgesia within 60 minutes of being registered, the current recommended time frame from the National Heart, Lung, and Blood Institute (NHLBI). METHODS: A multi-disciplinary team used quality improvement (QI) methodology to develop a plan involving multiple Plan-Do-Study-Act (PDSA) cycles. A rapid evaluation process was employed which included notification of a patient with a VOC being placed in a room, rapid evaluation by all team members and use of an electronic order set. RESULTS: The aim was met 72% of the time during our intervention period, compared to 17% pre-intervention. Average time to initial analgesia was decreased from 61 minutes to 42 minutes (p-value < 0.001), while time to disposition was also decreased when time goals were achieved. CONCLUSION: Using a rapid evaluation process we were able to decrease time to initial analgesia in a patient population that has previously experienced delays in care and decrease overall time to disposition.

Prevalence and early identification of language delays among at-risk three year olds.

The aims of this study were fourfold: to document the prevalence of language delays in a sample of at-risk 3 year olds; to assess the effectiveness of a home visiting program in preventing early language delays; to determine how often parents, pediatric providers, and home visitors identified early language delays; and to assess the effectiveness of a home visiting program in improving early identification of language delays. The Preschool Language Scale, Third Edition (PLS-3) was administered to 513 at-risk 3 year olds participating in a randomized trial of home visiting services. Families randomized to home visiting were expected to receive weekly to quarterly visits throughout the 3 years of this study. The content of home visits included teaching parents about child development, role-modeling parenting skills, and linking families to a medical home. Identification of delays was measured using structured parent interviews and review of primary care and home visiting records. At age 3 years, 10% of children had severe language delays, defined as scoring >or=2 SD below the national mean on the PLS-3, whereas 49% scored >or=1 SD below the national mean. No differences in prevalence were seen between children who did and did not receive home visiting. Among children with severe delays, 42% were identified by parents, 33% by pediatric providers, and 24% by home visitors. Among children with any delays, 24% were identified by parents, 25% by pediatric providers, and 17% by home visitors. No differences in rates of identification were seen between children who did and did not receive home visiting. Thus, while language delays were highly prevalent among these at-risk children, rates of identification were low, even among children with severe delays. Home visiting was not effective in either preventing language delays or improving early identification. This suggests that pediatric providers and home visiting programs need to reexamine their approaches to recognizing and intervening with early language delays.

The physician-scientist career pipeline in 2005: build it, and they will come.

CONTEXT: Physician-scientists play a unique and critical role in medical research. Nonetheless, a number of trends followed during the 1980s and 1990s revealed that this career pathway was in serious jeopardy. Physician-scientists were declining in number and were getting older. A variety of factors were thought to contribute to this problem, including increasing indebtedness of medical school graduates caused by rapidly rising medical school tuition costs. OBJECTIVE: To evaluate the impact of recently initiated programs from the National Institutes of Health (NIH) and several not-for-profit institutions designed to revitalize the physician-scientist career pipeline. DESIGN: We assessed recent trends in the physician-scientist career pipeline using data obtained from the NIH, the American Medical Association, the Association of American Medical Colleges, and other sources. MAIN OUTCOME MEASURES: Total numbers of physicians performing research, grant application numbers and success rates for MDs, MD-PhDs, and PhDs at various stages in their careers, interest in research among medical students, medical school tuitions and postgraduate salaries, numbers and composition of applicants for NIH loan repayment programs, and gender distribution of young physician-scientists. RESULTS: The number of physician-scientists in the United States has been in a steady state for the past decade, but funded physician-scientists are significantly older than they were 2 decades ago. However, the study of early career markers over the past 7 to 10 years has demonstrated increasing interest in research careers by medical students, steady growth of the MD-PhD pool, and a new burst of activity in the "late bloomer" pool of MDs (individuals who choose research careers in medical school or in residency training), fueled by loan repayment programs that were created by the NIH in 2002. Several recent trends for more established physician-scientists have also suggested improvement. CONCLUSIONS: Although it is too early to assess the impact of these indicators on the long-term career pathway, the recent growth in activity in the physician-scientist career pipeline is an encouraging development. Continued funding of these new programs, coupled with sustained support for physician-scientists committed to the pathway, will be required to maintain these positive trends.

A gender gap in the next generation of physician-scientists: medical student interest and participation in research.

BACKGROUND: For 2 decades, the number of physician-scientists has not kept pace with the overall growth of the medical research community. Concomitantly, the number of women entering medical schools has increased markedly. We have explored the effect of the changing gender composition of medical schools on the present and future pipeline of young physician-scientists. METHODS: We analyzed data obtained from the Association of American Medical Colleges, the National Institutes of Health, and the Howard Hughes Medical Institute pertaining to the expressed research intentions or research participation of male and female medical students in the United States. RESULTS: A statistically significant decline in the percentage of matriculating and graduating medical students--both men and women-who expressed strong research career intentions occurred during the decade between 1987 and 1997. Moreover, matriculating and graduating women were significantly less likely than men to indicate strong research career intentions. Each of these trends has been observed for medical schools overall and for research-intensive ones. Cohort data obtained by tracking individuals from matriculation to graduation revealed that women who expressed strong research career intentions upon matriculation were more likely than men to decrease their research career intentions during medical school. Medical student participation in research supported the gender gap identified by assessing research intentions. Female medical student participation in the Medical Scientist Training Program and the Howard Hughes Medical Institute/National Institutes of Health-sponsored Cloisters Program has increased but lags far behind the growth in the female population in medical schools. CONCLUSION: Three worrisome trends in the research career intentions and participation of the nation's medical students (a decade-long decline for both men and women, a large and persistent gender gap, and a negative effect of the medical school experience for women) presage a further decline in the physician-scientist pipeline unless they are reversed promptly and decisively.

Risk of mother-reported child abuse in the first 3 years of life.

OBJECTIVE: The purpose of this research was to investigate, within an at-risk population, parent and child characteristics associated with a mother's self-reports of severe physical assault and assault on the self-esteem of the child in the first 3 years of life. DESIGN: The study population consisted of a community-based sample of mothers of newborns identified as at-risk for child maltreatment (n=595). Families were assessed annually from the child's birth through age 3 using instruments with established psychometric properties. Independent variables investigated included: family socio-demographics, parity, mother's social support, maternal depression, maternal problem drug or alcohol use, partner violence, child's age, child's sex, low birth weight/small for gestational age (SGA), and mother's perception of child's demand level. Associations with maltreatment were examined using multivariable methods for longitudinal data. RESULTS: Child severe physical assault was significantly associated with parent characteristics (maternal depression and partner violence); and child characteristics (SGA). Assault to the child's self-esteem was significantly associated with maternal depression, maternal illicit drug use, partner violence and mother's perception of child's demand level. Controlling for family sociodemographic characteristics did not change the associations. Likewise, while mother's perception of child demand level had an independent association with self-esteem assault, the associations described above persisted while demand level was held constant. In this high-risk sample, abuse was not associated with mother's age, education, race, parity, or household income level. CONCLUSIONS: While characteristics such as SGA can serve as markers for increased abuse risk, they are not amenable to intervention after the child is born. However, certain other risk factors, such as maternal depression and domestic violence are malleable and should be targeted for intervention with the goal of preventing child maltreatment.

Exceptional economic returns on investments in medical research.

The United States will invest nearly US$70 billion (US$260 per capita) on medical research this year, more than half of which will be sponsored by the biopharmaceutical industry. This investment has been shown to provide major gains in basic, disease-oriented and patient-oriented research. It also provides a huge economic return on investment--whether measured in terms of jobs created, health costs saved, or the dollar value of lives saved. Australia, whose investment in medical research is less than 10% that of the United States, should increase its national commitment.