The quality of a cluster analysis of unlabeled units depends on the quality of the between units dissimilarity measures. Data dependent dissimilarity is more objective than data independent geometric measures such as Euclidean distance. As suggested by Breiman, many data driven approaches are based on decision tree ensembles, such as a random forest (RF), that produce a proximity matrix that can easily be transformed into a dissimilarity matrix. A RF can be obtained using labels that distinguish units with real data from units with synthetic data. The resulting dissimilarity matrix is input to a clustering program and units are assigned labels corresponding to cluster membership. We introduce a General Iterative Cluster (GIC) algorithm that improves the proximity matrix and clusters of the base RF. The cluster labels are used to grow a new RF yielding an updated proximity matrix which is entered into the clustering program. The process is repeated until convergence. The same procedure can be used with many base procedures such as the Extremely Randomized Tree ensemble. We evaluate the performance of the GIC algorithm using benchmark and simulated data sets. The properties measured by the Silhouette Score are substantially superior to the base clustering algorithm. The GIC package has been released in R: https://cran.r-project.org/web/packages/GIC/index.html.

ImportanceAlthough classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown.ObjectiveTo evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy.Design, Setting, and ParticipantsIn this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD.InterventionsStudy medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy.Main Outcomes and MeasuresThe primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance.ResultsA total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0–24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin.Conclusions and RelevancePsilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD.Trial RegistrationClinicalTrials.gov Identifier: NCT02061293

Abstract Background The TAPS Tool is a substance use screening and brief assessment instrument that was developed for use in primary care medical settings. It is one of the first screening instruments to provide rapid assessment of all commonly used substance classes, including illicit and prescription opioids, and is one of the only available screeners designed and validated in an electronic self-administered format (myTAPS). This secondary analysis of data from the TAPS Tool validation study describes the feasibility and acceptability of the myTAPS among primary care patients. Methods Adult patients (N = 2000) from five primary care clinics completed the TAPS Tool on a tablet computer (myTAPS), and in an interviewer-administered format. Requests for assistance and time required were tracked, and participants completed a survey on ease of use, utilization of audio guidance, and format preference. Logistic regression was used to examine outcomes in defined subpopulations, including groups that may have greater difficulty completing an electronic screener, and those that may prefer an electronic self-administered approach. Results Almost all participants (98.3%) reported that the myTAPS was easy to use. The median time to complete myTAPS screening was 4.0 min (mean 4.48, standard deviation 2.57). More time was required by participants who were older, Hispanic, Black, or reported non-medical prescription drug use, while less time was required by women. Assistance was requested by 25% of participants, and was more frequently requested by those who with lower education (OR = 2.08, 95% CI 1.62–2.67) or age > 65 years (OR = 2.79, 95% CI 1.98–3.93). Audio guidance was utilized by 18.3%, and was more frequently utilized by participants with lower education (OR = 2.01, 95% CI 1.54–2.63), age > 65 years (OR = 1.79, 95% CI 1.22–2.61), or Black race (OR = 1.30, 95% 1.01–1.68). The myTAPS format was preferred by women (OR = 1.29, 95% CI 1.00–1.66) and individuals with drug use (OR = 1.43, 95% CI 1.09–1.88), while participants with lower education preferred the interviewer-administered format (OR = 2.75, 95% CI 2.00–3.78). Conclusions Overall, myTAPS screening was feasible and well accepted by adult primary care patients. Clinics adopting electronic screening should be prepared to offer assistance to some patients, particularly those who are older or less educated, and should have the capacity to use an interviewer-administered approach when required.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC=0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

A timely determination of the risk of post-traumatic stress disorder (PTSD) is a prerequisite for efficient service delivery and prevention. We provide a risk estimate tool allowing a calculation of individuals' PTSD likelihood from early predictors. Members of the International Consortium to Predict PTSD (ICPP) shared individual participants' item-level data from ten longitudinal studies of civilian trauma survivors admitted to acute care centers in six countries. Eligible participants (N=2,473) completed an initial clinical assessment within 60 days of trauma exposure, and at least one follow-up assessment 4-15 months later. The Clinician-Administered PTSD Scale for DSM-IV (CAPS) evaluated PTSD symptom severity and diagnostic status at each assessment. Participants' education, prior lifetime trauma exposure, marital status and socio-economic status were assessed and harmonized across studies. The study's main outcome was the likelihood of a follow-up PTSD given early predictors. The prevalence of follow-up PTSD was 11.8% (9.2% for male participants and 16.4% for females). A logistic model using early PTSD symptom severity (initial CAPS total score) as a predictor produced remarkably accurate estimates of follow-up PTSD (predicted vs. raw probabilities: r=0.976). Adding respondents' female gender, lower education, and exposure to prior interpersonal trauma to the model yielded higher PTSD likelihood estimates, with similar model accuracy (predicted vs. raw probabilities: r=0.941). The current model could be adjusted for other traumatic circumstances and accommodate risk factors not captured by the ICPP (e.g., biological, social). In line with their use in general medicine, risk estimate models can inform clinical choices in psychiatry. It is hoped that quantifying individuals' PTSD risk will be a first step towards systematic prevention of the disorder.

Real-time functional magnetic resonance imaging (rt-fMRI) has revived the translational perspective of neurofeedback (NF)(1). Particularly for stress management, targeting deeply located limbic areas involved in stress processing(2) has paved new paths for brain-guided interventions. However, the high cost and immobility of fMRI constitute a challenging drawback for the scalability (accessibility and cost-effectiveness) of the approach, particularly for clinical purposes(3). The current study aimed to overcome the limited applicability of rt-fMRI by using an electroencephalography (EEG) model endowed with improved spatial resolution, derived from simultaneous EEG-fMRI, to target amygdala activity (termed amygdala electrical fingerprint (Amyg-EFP))(4-6). Healthy individuals (n = 180) undergoing a stressful military training programme were randomly assigned to six Amyg-EFP-NF sessions or one of two controls (control-EEG-NF or NoNF), taking place at the military training base. The results demonstrated specificity of NF learning to the targeted Amyg-EFP signal, which led to reduced alex-ithymia and faster emotional Stroop, indicating better stress coping following Amyg-EFP-NF relative to controls. Neural target engagement was demonstrated in a follow-up fMRI-NF, showing greater amygdala blood-oxygen-level-dependent downregulation and amygdala-ventromedial prefrontal cortex functional connectivity following Amyg-EFP-NF relative to NoNF. Together, these results demonstrate limbic specificity and efficacy of Amyg-EFP-NF during a stressful period, pointing to a scalable non-pharmacological yet neuroscience-based training to prevent stress-induced psychopathology.

57 ABSTRACT Novel analgesic and anti-inflammatory compositions of matter for use in eliciting an analgesic or anti-inflamma tory response, said compositions comprising caffeine together with a selected non-narcotic analgesic/non steroidal anti-inflammatory drug or a selected narcotic analgesic, or both, are disclosed. When used in combi nation with the selected drugs, caffeine enhances the analgesic or anti-inflammatory response and also has tens its onset.

O. Evans, "The Potentiation of Opiate-induced Anal gesia by Stimulant Drugs, I., The Effect of Monoamine Oxidase Inhibitors and Caffeine'. Unlisted Drugs, vol. 32, No. 3, (Mar. 1980), p. 41j, “Kofesil'. Unlisted Drugs, vol. 29, No. 6, (Jun. 1977), p. 91t, “Nurodol'. Unlisted Drugs, vol. 24, No. 6, (Jun. 1972), p. 84p, "Cof foset'. Unlisted Drugs, vol. 28, No. 3, (Mar. 1976), p. 37e, 'Albaton'. Unlisted Drugs, vol. 16, No. 8, (Aug. 1964), p. 56L, "Femadol Co.'. Unlisted Drugs, vol. 25, No. 7, (Jul. 1973), p. 110h, “Ergoffen'. Dictionnaire Vidal, (1982), O.V.P., (Paris, FR), p. 716, "Lamaline au Paracétamol'. Rote Liste (1961), Editio Cantor, (Aulendorf/Wurtt., DE), p. 716, "Phenacodin'.

Armas & Valencia, "Eficacia Terapeutica de la Asocia cion Naproxen-Carisoprodol en Ciertas Enfermedader Musculoesqueleticas"Therapeutic Effectiveness of Na proxen-Carisoprodol Association in Certain Musculo skeletal Disorders, in Investigation Medica Interna cional, pp. 350-356, (1983), and English translation thereof. Goti & Valencia, "Caracterizacion Clinica de Una Nueva Asociacion (Naproxen -Carisoprodol) en Padecimientos del Aparato Musculoesqueletico'Clini cal Description of a New Association (Naproxen -Carisoprodol) in Ailments of the Musculoskeletal Ap paratus, Investigation Medica Internacional, pp. 475-478, (1983), and English translation thereof. Socialist Republic of Romania Description of Invention 4,722,938

OBJECTIVE:This study estimated the proportions of Hispanic and non-Hispanic white and black children ages three to 17 with a diagnosis of attention-deficit hyperactivity disorder (ADHD) receiving services from the New York State public mental health system (NYS PMHS) and their annual treated ADHD prevalence rates. Findings were compared with those of recent national studies of general population samples.METHODS:Data were from a 2011 survey of users of NYS PMHS nonresidential services. Adjusted odds ratios compared the probability of an ADHD diagnosis among the groups by age, gender, and insurance type. Prevalence rates were compared among groups by age and gender.RESULTS:An estimated 133,091 children used the NYS PMHS, of whom 31% had an ADHD diagnosis. The prevalence rate of ADHD among whites was significantly lower than that among Hispanics or blacks in all gender and age groups except Hispanic females ages 13 to 17. White children were significantly less likely than black children to receive an ADHD diagnosis.CONCLUSIONS:National studies have reported higher ADHD rates among white children. Compared with children in the NYS PMHS, those in national studies had multiple access points to care, including private psychiatrists and clinicians and primary care practitioners. The higher reported ADHD rates in national studies may reflect higher rates of private insurance among white children, which would increase the likelihood of their using private practitioners. Cultural factors that influence whether and where care is sought and whether practitioners appropriately diagnosis ADHD may also explain the difference in findings.

Objectives: We examined whether the cut-point 10 for the Patient Health Questionnaire-9 (PHQ9) depression screen used in primary care populations is equally valid for Mexicans (M), Ecuadorians (E), Puerto Ricans (PR) and non-Hispanic whites (W) from inner-city hospital-based primary care clinics; and whether stressful life events elevate scores and the probability of major depressive disorder (MDD).Methods: Over 18-months, a sample of persons from hospital clinics with a positive initial PHQ2 and a subsequent PHQ9 were administered a stressful life event questionnaire and a Structured Clinical Interview to establish an MDD diagnosis, with oversampling of those between 8 and 12: (n = 261: 75 E, 71M, 51 PR, 64W). For analysis, the sample was weighted using chart review (n = 368) to represent a typical clinic population. Receiver Operating Characteristics analysis selected cut-points maximizing sensitivity (Sn) plus specificity (Sp).Results: The optimal cut-point for all groups was 13 with the corresponding Sn and Sp estimates for E = (Sn 73%, Sp 71%), M = (76%, 81%), PR = (81%, 63%) and W = (80%, 74%). Stressful life events impacted screen scores and MDD diagnosis.Conclusions: Elevating the PHQ9 cut-point for inner-city Latinos as well as whites is suggested to avoid high false positive rates leading to improper treatment with clinical and economic consequences. (C) 2016 Elsevier Inc. All rights reserved.

OBJECT:The purpose of the current study is to determine the sensitivity and specificity of an eye tracking method as a classifier for identifying concussion.METHODS:Brain injured and control subjects prospectively underwent both eye tracking and Sport Concussion Assessment Tool 3. The results of eye tracking biomarker based classifier models were then validated against a dataset of individuals not used in building a model. The area under the curve (AUC) of receiver operating characteristics was examined.RESULTS:An optimal classifier based on best subset had an AUC of 0.878, and a cross-validated AUC of 0.852 in CT- subjects and an AUC of 0.831 in a validation dataset. The optimal misclassification rate in an external dataset (n = 254) was 13%.CONCLUSION:If one defines concussion based on history, examination, radiographic and Sport Concussion Assessment Tool 3 criteria, it is possible to generate an eye tracking based biomarker that enables detection of concussion with reasonably high sensitivity and specificity.

d-Cycloserine (DCS) has been shown to enhance memory and, in a previous trial, once-weekly DCS improved negative symptoms in schizophrenia subjects. We hypothesized that DCS combined with a cognitive remediation (CR) program would improve memory of a practiced auditory discrimination task and that gains would generalize to performance on unpracticed cognitive tasks. Stable, medicated adult schizophrenia outpatients participated in the Brain Fitness CR program 3-5 times per week for 8weeks. Subjects were randomly assigned to once-weekly adjunctive treatment with DCS (50mg) or placebo administered before the first session each week. Primary outcomes were performance on an auditory discrimination task, the MATRICS cognitive battery composite score and the Scale for the Assessment of Negative Symptoms (SANS) total score. 36 subjects received study drug and 32 completed the trial (average number of CR sessions=26.1). Performance on the practiced auditory discrimination task significantly improved in the DCS group compared to the placebo group. DCS was also associated with significantly greater negative symptom improvement for subjects symptomatic at baseline (SANS score ≥20). However, improvement on the MATRICS battery was observed only in the placebo group. Considered with previous results, these findings suggest that DCS augments CR and alleviates negative symptoms in schizophrenia patients. However, further work is needed to evaluate whether CR gains achieved with DCS can generalize to other unpracticed cognitive tasks.

Recently, a maximally selected normalized Wilcoxon, whose asymptotic distribution is a Brownian Bridge, was proposed for testing symmetry of a distribution about zero. The test sequentially discards observations whose absolute value is below increasing thresholds. The Wilcoxon is obtained at each threshold, and the maximum is the test statistic. We develop a recursive function for the exact distribution of a modification of the Max Wilcoxon test (MW) and provide critical values and a program for computing the p-value for a sample. A new hybrid test that combines the sign and MW tests is introduced. The power of MW and the new hybrid test are compared with Modarres and Gastwirth's hybrid test (MGH) and the Max McNemar (MM), under the generalized lambda distributions (GLD) family and two normal mixture models. The MW and the new hybrid test outperform the MGH, which is superior to the MM test in the GLD family. In one mixture model, MM is the least powerful test and the remaining three are essentially equivalent. In the second mixture model, when the zero median assumption is nearly valid, the MW test does well; its performance degrades when this assumption is violated. In the latter case, the MM performs better than MW for the same degree of skewness because the MM simultaneously tests both symmetry and zero median. Data from a genetic study of monozygotic twins discordant for major depressive disorder is used to illustrate the new tests.

Study Objective: To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST).Design: Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study.Setting: Maastricht University, The Netherlands.Participants: Forty healthy volunteers (20 females).Interventions: Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo.Measurements: Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) - an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment.Result: For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone.Conclusion: Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning = 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated.Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet; http://clinicaltrials.gov/ct2/show/NCT01106859.

Objective: Nationwide studies contrasting service use of racial-ethnic groups provide an overview of disparities, but because of variation in populations and service systems, local studies are required to identify specific targets for remedial action. The authors report on the use of noninpatient services regulated in New York State (NYS) and report use by the state's larger cultural groups. Methods: Data from the NYS Patient Characteristics Survey were used to estimate annual treated prevalence and treatment intensity, defined as the average number of annual weeks in service for non-Hispanic blacks, Hispanics, Asians, and non-Hispanic whites. The latter rates were obtained for specific types of treatment use, by person's age and diagnosis, for the state and for population density-defined regions. Statistical methods contrasted rates of whites with other groups. Results: A total of 578,496 individuals in these racial-ethnic groups were served in 2,500 programs, and 51% of those served were nonwhite. Treated prevalence rates of whites were lower than those of blacks and Hispanics and were substantially higher than prevalence rates for Asians. Statewide treatment intensity rates of all racial-ethnic and age groups were comparable except for lower use among Asians >65. Key findings from granular analyses were lower treatment intensity rates for black youths with disruptive disorders, Hispanic adults with anxiety disorders, and Asians >65 with depression compared with white counterparts. In upstate metropolitan areas, black youths and Hispanic adults received services in fewer weeks than whites, and in the New York City metropolitan area, whites >65 had higher treatment intensity rates than contrast groups. Conclusions: Findings suggest a need for assistance to black families in negotiating the multiple systems used by their children, clinical training focusing on cultural symptom presentation, screening of Asians in community settings, and mandated cultural competency assessments for all programs.

BACKGROUND:Falling duration of psychiatric inpatient stays over the past 2 decades and recent recommendations to tighten federal regulation of electroconvulsive therapy (ECT) devices have focused attention on trends in ECT use, but current national data have been unavailable.METHODS:We calculated the annual number of inpatient stays involving ECT and proportion of general hospitals conducting the procedure at least once in the calendar year with a national sample of discharges from 1993 to 2009. We estimated adjusted probabilities that inpatients with severe recurrent major depression (n = 465,646) were treated in a hospital that conducts ECT and, if so, received the procedure.RESULTS:The annual number of stays involving ECT fell from 12.6 to 7.2/100,000 adult US residents, driven by dramatic declines among elderly persons, whereas the percentage of hospitals conducting ECT decreased from 14.8% to 10.6%. The percentage of stays for severe recurrent major depression in hospitals that conducted ECT fell from 70.5% to 44.7%, whereas receipt of ECT where conducted declined from 12.9% to 10.5%. For depressed inpatients, the adjusted probability that the treating hospital conducts ECT fell 34%, whereas probability of receiving ECT was unchanged for patients treated in facilities that conducted the procedure. Adjusted declines were greatest for elderly persons. Throughout the period inpatients from poorer neighborhoods or who were publicly insured or uninsured were less likely to receive care from hospitals conducting ECT.CONCLUSIONS:Electroconvulsive therapy use for severely depressed inpatients has fallen markedly, driven exclusively by a decline in the probability that their hospital conducts ECT.