Variable importance and prediction methods for longitudinal problems with missing variables.

We present prediction and variable importance (VIM) methods for longitudinal data sets containing continuous and binary exposures subject to missingness. We demonstrate the use of these methods for prognosis of medical outcomes of severe trauma patients, a field in which current medical practice involves rules of thumb and scoring methods that only use a few variables and ignore the dynamic and high-dimensional nature of trauma recovery. Well-principled prediction and VIM methods can provide a tool to make care decisions informed by the high-dimensional patient's physiological and clinical history.

Structure-activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators.

A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure-activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC₅₀ value of 79 nM which is ∼2.

Role of Titanium in the Development of Yellow Nail Syndrome.

Yellow nail syndrome (YNS) is characterized by the triad of nail changes, lymphedema and respiratory tract involvement. Several hypotheses have been postulated to explain the findings in YNS including lymphatic drainage abnormalities along with microvasculopathy. The most recent hypothesis, proposed by Berglund and Calmark [Biol Trace Elem Res 2011;143:1-7], suggests a role of titanium dioxide in the development of YNS.

Evolving beyond the vicious triad: Differential mediation of traumatic coagulopathy by injury, shock, and resuscitation.

Background: A subset of trauma patients with critical injury present with coagulopathy, portending markedly worse outcomes. Clinical practice is evolving to treat the classical risk factors of hypothermia, hemodilution, and acidosis; however, coagulopathy persists even in the absence of these factors. We sought to determine the relative importance of injury- and shock-specific factors compared with resuscitation-associated factors in coagulopathy after trauma.

Effect of 1-substitution on tetrahydroisoquinolines as selective antagonists for the orexin-1 receptor.

Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline.

[New protocol combining orthodontics and implant therapy for partially edentulous adult patients. Part I: Description of the Decker protocol].

Introduction: The treatment of adult malocclusion is usually complex and pluridisciplinary. Its prognosis is not reliable. We present a new clinical protocol to improve the management and final result.

Usual energy and macronutrient intakes in 2-9-year-old European children.

Objective: Valid estimates of population intakes are essential for monitoring trends as well as for nutritional interventions, but such data are rare in young children. In particular, the problem of misreporting in dietary data is usually not accounted for. Therefore, this study aims to provide accurate estimates of intake distributions in European children.

Alpha-ethyltryptamines as dual dopamine-serotonin releasers.

The dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporter releasing activity and serotonin-2A (5-HT2A) receptor agonist activity of a series of substituted tryptamines are reported. Three compounds, 7b, (+)-7d and 7f, were found to be potent dual DA/5-HT releasers and were >10-fold less potent as NE releasers. Additionally, these compounds had different activity profiles at the 5-HT2A receptor.

Diarylureas as allosteric modulators of the cannabinoid CB1 receptor: structure-activity relationship studies on 1-(4-chlorophenyl)-3-{3-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (PSNCBAM-1).

The recent discovery of allosteric modulators of the CB1 receptor including PSNCBAM-1 (4) has generated significant interest in CB1 receptor allosteric modulation. Here in the first SAR study on 4, we have designed and synthesized a series of analogs focusing on modifications at two positions. Pharmacological evaluation in calcium mobilization and binding assays revealed the importance of alkyl substitution at the 2-aminopyridine moiety and electron deficient aromatic groups at the 4-chlorophenyl position for activity at the CB1 receptor, resulting in several analogs with comparable potency to 4.

Recent violence in a community-based sample of homeless and unstably housed women with high levels of psychiatric comorbidity.

Objectives: We determined associations between co-occurring psychiatric conditions and violence against homeless and unstably housed women.

Methods: Between 2008 and 2010, we interviewed homeless and unstably housed women recruited from community venues about violence, socioeconomic factors, and psychiatric conditions. We used multivariable logistic regression to determine independent correlates of violence.

Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics.

As part of our program to study neurotransmitter releasers, we report herein a class of hybrid dopamine reuptake inhibitors that display serotonin releasing activity. Hybrid compounds are interesting since they increase the design potential of transporter related compounds and hence represent a novel and unexplored strategy for therapeutic drug discovery. A series of N-alkylpropiophenones was synthesized and assessed for uptake inhibition and release activity using rat brain synaptosomes.

Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes.

Rationale: Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT₂A) receptors.

Objectives: This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects.

Synthesis, pharmacological characterization, and structure-activity relationship studies of small molecular agonists for the orphan GPR88 receptor.

GPR88 is an orphan G-protein-coupled receptor (GPCR) enriched in the striatum. Genetic deletion and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in psychiatric disorders. The signal transduction pathway and receptor functions of GPR88, however, are still largely unknown due to the lack of endogenous and synthetic ligands.

Truncated Orexin Peptides: Structure-Activity Relationship Studies.

Orexin receptors are involved in many processes including energy homeostasis, wake/sleep cycle, metabolism and reward. Development of potent and selective ligands is an essential step for defining the mechanism(s) underlying such critical processes. The goal of this study was to further investigate the structure-activity relationships of these peptides and to identify truncated form of the orexin peptides active at OX.

Registration of aggressive incidents in an adolescent forensic psychiatric unit and implications for further practice.

Although aggression is part of daily life in psychiatric units for adolescents, empirical data on its prevalence are sparse. Only few studies have described prevalence of aggressive incidents in adolescent psychiatric wards, and data in forensic psychiatric care are even more limited. Available studies reported high prevalence rates of aggression, ranging from 0.

Semiparametric Estimation of the Impacts of Longitudinal Interventions on Adolescent Obesity using Targeted Maximum-Likelihood: Accessible Estimation with the ltmle Package.

While child and adolescent obesity is a serious public health concern, few studies have utilized parameters based on the causal inference literature to examine the potential impacts of early intervention. The purpose of this analysis was to estimate the causal effects of early interventions to improve physical activity and diet during adolescence on body mass index (BMI), a measure of adiposity, using improved techniques. The most widespread statistical method in studies of child and adolescent obesity is multi-variable regression, with the parameter of interest being the coefficient on the variable of interest.

Ratio of primary episcleral buckling surgery versus primary vitrectomy for rhegmatogenous retinal detachment.

Purpose: To assess the ratio of the frequency of primary scleral buckling procedures versus the frequency of vitrectomies performed as treatment for rhegmatogenous retinal detachments in a primary retinal surgical department.

Methods: The study included all patients with rhegmatogenous retinal detachments who underwent retinal or vitreoretinal surgery in the study period from 2002 to 2006. The size of the retinal defect and the amount of proliferative vitreoretinopathy were not exclusion criteria.

Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern.

Transient receptor potential, melastatin-like 7 (Trpm7) is a combined ion channel and kinase implicated in the differentiation or function of many cell types. Early lethality in mice and frogs depleted of the corresponding gene impedes investigation of the functions of this protein particularly during later stages of development. By contrast, zebrafish trpm7 mutant larvae undergo early morphogenesis normally and thus do not have this limitation.

Considerations for normalization of DNA methylation data by Illumina 450K BeadChip assay in population studies.

Analysis of epigenetic mechanisms, particularly DNA methylation, is of increasing interest for epidemiologic studies examining disease etiology and impacts of environmental exposures. The Infinium HumanMethylation450 BeadChip(®) (450K), which interrogates over 480,000 CpG sites and is relatively cost effective, has become a popular tool to characterize the DNA methylome. For large-scale studies, minimizing technical variability and potential bias is paramount.

Time-dependent prediction and evaluation of variable importance using superlearning in high-dimensional clinical data.

Background: Prediction of outcome after injury is fraught with uncertainty and statistically beset by misspecified models. Single-time point regression only gives prediction and inference at one time, of dubious value for continuous prediction of ongoing bleeding. New statistical machine learning techniques such as SuperLearner (SL) exist to make superior prediction at iterative time points while evaluating the changing relative importance of each measured variable on an outcome.

Exposure to parental smoking and child growth and development: a cohort study.

Background: Studies on adverse childhood health and development outcomes associated with parental smoking have shown inconsistent results. Using a cohort of Belarusian children, we examined differences in cognition, behaviors, growth, adiposity, and blood pressure at 6.5 years according to prenatal and postnatal exposure to parental smoking.

Changes of cytokine profiles during electroconvulsive therapy in patients with major depression.

Objectives: Electroconvulsive therapy (ECT) is an effective treatment of depression, but its mechanism of action still remains unknown. Some studies emphasize that epileptic seizures result in cerebral production of cytokines, including the cytokine network in association with the pathophysiology of depression. We hypothesized that depressed patients would show a dysregulated profile of peripheral cytokines before and after ECT treatment.

Fetal alcohol spectrum disorders: knowledge and screening practices of university hospital medical students and residents.

Background: Fetal alcohol spectrum disorder (FASD) is the leading cause of preventable intellectual disabilities in the United States and a significant public health issue.

Objectives: The purpose of this study is to evaluate the knowledge and screening practices of pre-clinical medical students and clinical providers on FAS, FASD, and alcohol consumption.

Methods: A short survey sent to medical students and residents on the campus of a large medical school and university hospital.

A novel nutrition medicine education model: the Boston University experience.

Most deaths in the United States are preventable and related to nutrition. Although physicians are expected to counsel their patients about nutrition-related health conditions, a recent survey reported minimal improvements in nutrition medicine education in US medical schools in the past decade. Starting in 2006, we have developed an educational plan using a novel student-centered model of nutrition medicine education at Boston University School of Medicine that focuses on medical student-mentored extracurricular activities to develop, evaluate, and sustain nutrition medicine education.

A novel SERPINA1 mutation causing serum alpha(1)-antitrypsin deficiency.

Mutations in the SERPINA1 gene can cause deficiency in the circulating serine protease inhibitor α(1)-Antitrypsin (α(1)AT). α(1)AT deficiency is the major contributor to pulmonary emphysema and liver disease in persons of European ancestry, with a prevalence of 1 in 2500 in the USA. We present the discovery and characterization of a novel SERPINA1 mutant from an asymptomatic Middle Eastern male with circulating α(1)AT deficiency.