A Pediatric Patient with Severe Obstructive Sleep Apnea and Comorbid Depression and Substance Abuse.

Obstructive sleep apnea (OSA), depression, and substance abuse problems share similar symptomatology and have significant interplay. An underlying diagnosis of OSA can often be overlooked in patients with significant psychiatric illness and polysubstance use. Pediatric OSA is often associated with adenotonsillar hypertrophy and frequently requires surgical intervention for resolution of symptoms. Untreated OSA can worsen mental status and encourage polysubstance abuse as a form of self-medication. Proper identification and management of OSA plays an important role in treating psychiatric conditions. We report a 16-year-old with major depressive disorder (MDD), suicide attempts, polysubstance use disorder, and severe OSA admitted to an inpatient psychiatric facility. History included sleep and mood disturbances started at age 12. Patient presented with apnea-hypopnea index greater than 50 and started on bilevel-positive airway pressure (BiPAP) prior to admission. Management of OSA led to significant improvement of MDD, insomnia, and polysubstance abuse. OSA can often be overlooked in patients with MDD or substance abuse. Among adolescent patients with poorly managed psychiatric conditions, significant sleep disturbances, and polysubstance abuse, providers should maintain a high degree of suspicion for OSA, as its proper management will aid in the management of the other conditions.

Covid19 impact screening of patients undergoing medication treatment for opioid use disorder.

BACKGROUND: Populations with addiction are considered at-risk for both medical and financial effects of the COVID19 outbreak. Patients receiving medication treatment for opioid use disorder (MOUD) were screened to assess need, vulnerability factors and potential clinical impact of the pandemic for referral and allocation of resources. Methods: A 31-item quality improvement survey of COVID19-related factors (e.g. engagement in social distancing, food and financial security) and clinical benchmarks of anxiety, craving, and treatment response was administered between March 24 and April 29, 2020. Anonymized data were compiled for study. Frequencies and means were evaluated for gender, age and financial effects on anxiety and craving ratings. Results: A total of 200 (N = 117 male; N = 80 female; N = 1 transgender) patients (age 42 ± 13 years) were screened. Medical risk factors known to predict severe COVID19 reactions reported in 33% of patients did not contribute significantly to distress. While 95% of patients reported stable food and housing, personal financial and employment instability reported in 40% of patients was associated with significantly increased anxiety and craving rating, particularly for women. Conclusions: Financial ramifications of the COVID19 pandemic were the most salient concerns reported by patients engaged in MOUD in the early phases of the outbreak, particularly for women.

Relationship Between Body Habitus and Aggression Subtypes Among Healthy Young Adults from the American Midwest.

This study examined associations between body habitus and functions of aggression, in a sample of 474 college students from the Midwestern region of the United States (age range = 18-25y; 73% Caucasian). Two instruments of aggression, the Reactive-Proactive Aggression Questionnaire from Dodge & Coie 1987 (DC) and Raine et al. 2006 (RPQ) were given as self-assessments. Body habitus measures standardized by age and gender specific weight and height were collected. Subjects considered to have a large body habitus in our study had both weight and height measures above the 75th percentile. Large body habitus was positively correlated with both proactive and reactive functions of aggression among adult males but not females; however, regression analyses indicated that body habitus was most strongly and robustly associated with proactive aggression. Findings suggest that even in a healthy homogeneous population, large body size in males is associated with aggression, particularly proactive aggression including bullying rather than retaliatory aggression. The presence of a large body physique may reinforce aggressive behavioral traits acquired through life experiences and activities evoking physical dominance. Alternatively, the relationship may reflect neurological processes related to size influenced by genetic factors and hormones leading to antisocial behaviors requiring future research on the role of genes for aggression.

Impostorism in American medical students during early clinical training: gender differences and intercorrelating factors.

OBJECTIVES: This study examined the incidence and severity of impostorism in third-year medical students as they transitioned from the preclinical to clinical phases of training. METHODS: A cross-sectional study was conducted in third-year medical students (N=215).  Respondents completed a voluntary, anonymous, 60-item survey that included the Clance Impostor Phenomenon Scale and the Perceived Stress Scale.  Student's-t, Mann-Whitney, and Chi-Square tests and Pearson correlation were used to determine differences between subgroups of students and relationships between instruments scores and demographic parameters. RESULTS: Fifty-nine percent of students responded with N=112 (59% female) completing at least one instrument. The mean impostor score was 63.0 ± 14.6 (moderate-to-frequent impostor feelings) and was 9% higher in females (U=1181, p = .046). Perceived Stress scores for females were 17% higher than males (t(109)=2.87, p=.005).  Females had lower United States Medical Licensing Examination (USMLE) Step 1 scores (t(107)= 3.06,  p=.003).  Impostor and perceived stress scores were correlated for males (r(46)=.47, p=.002) and females (r(64)=.54,p<.0001). Impostor and USMLE Step 1 scores were negatively correlated for males (r(45) =-.32, p= .034) but not females (r(63) = -.11, p=.40). CONCLUSIONS:  These findings demonstrate the intercorrelation between impostorism and stress in male and female medical students and raise interesting questions regarding the contributions of gender and other factors involved with medical training.

Impostorism in third-year medical students: an item analysis using the Clance impostor phenomenon scale.

INTRODUCTION: Impostorism, feelings of distrust in one's abilities and accomplishments despite evidence to the contrary, is frequent in medical students and negatively affects student wellness. METHODS: The aspects of impostorism that were most prevalent in medical students during the transition from the preclinical to clinical phases of their training were assessed using an anonymous, voluntary 60-item survey that included the Clance Impostor Phenomenon Scale (CIPS) and a 2-item burnout assessment administered in October-November 2018. Ratings of individual CIPS items were compared between items for the entire sample and in subpopulations of students. The correlation of individual CIPS items with CIPS total score was also determined. RESULTS: A total of 127 of 215 (59%) surveyed students responded, with 112 completing the CIPS with mean score of 63.0 ± 14.6 (moderate-to-frequent impostor feelings). Ratings of individual CIPS items differed significantly between items. Responses also differed depending on gender and perceived burnout or depersonalization. DISCUSSION: Third-year medical students identified most strongly with items related to unfounded fear of failure, hesitance to share recognition before it is announced, remembering failures rather than successes, believing themselves less capable than others, and worrying about succeeding. In contrast, attribution of accomplishments to luck was not prominent for these students. Responses to certain items also differed depending on gender and perceived burnout or depersonalization, but not self-reported under-represented minority status. This observation may inform the development of interventions tailored to foster wellness as students negotiate the transition from the preclinical to clinical phases of their training.

Age Distribution, Comorbidities and Risk Factors for Thrombosis in Prader-Willi Syndrome.

: Prader-Willi syndrome (PWS) is an imprinting disorder caused by lack of expression of the paternally inherited 15q11.2-q13 chromosome region. The risk of death from obesity-related complications can worsen with age, but survival trends are improving. Comorbidities and their complications such as thrombosis or blood clots and venous thromboembolism (VTE) are uncommon but reported in PWS. Two phases of analyses were conducted in our study: unadjusted and adjusted frequency with odds ratios and a regression analysis of risk factors. Individuals with PWS or non-PWS controls with exogenous obesity were identified by specific International Classification of Diseases (ICD)-9 diagnostic codes reported on more than one occasion to confirm the diagnosis of PWS or exogenous obesity in available national health claims insurance datasets. The overall average age or average age per age interval (0-17yr, 18-64yr, and 65yr+) and gender distribution in each population were similar in 3136 patients with PWS and 3945 non-PWS controls for comparison purposes, with exogenous obesity identified from two insurance health claims dataset sources (i.e., commercial and Medicare advantage or Medicaid). For example, 65.1% of the 3136 patients with PWS were less than 18 years old (subadults), 33.2% were 18-64 years old (adults), and 1.7% were 65 years or older. After adjusting for comorbidities that were identified with diagnostic codes, we found that commercially insured PWS individuals across all age cohorts were 2.55 times more likely to experience pulmonary embolism (PE) or deep vein thrombosis (DVT) than for obese controls (p-value: 0.013; confidence interval (CI) :1.22-5.32). Medi caid-insured individuals across all age cohorts with PWS were 0.85 times more likely to experience PE or DVT than obese controls (p-value: 0.60; CI: 0.46-1.56), with no indicated age difference. Age and gender were statistically significant predictors of VTEs, and they were independent of insurance coverage. There was an increase in occurrence of thrombotic events across all age cohorts within the PWS patient population when compared with their obese counterparts, regardless of insurance type.

Kratom (Mitragyna speciosa): Friend or Foe?

Increased use of the opioid-related plant kratom as an alternative treatment for opioid withdrawal symptoms has raised concerns regarding its potential for abuse and severe adverse effects. A review of the literature was performed to characterize kratom's pharmacology, clinical efficacy, and adverse effects to increase understanding and evaluate potential use as an alternative treatment for opioid dependence. Kratom use initiated as self-medication for an opioid use disorder or pain syndrome in the absence of effective alternatives is associated with a risk of kratom dependence, withdrawal, and life-threatening toxicity. The potential for a serious adverse reaction should discourage unregulated use of kratom products.

Venous Thromboembolism in Prader-Willi Syndrome: A Questionnaire Survey.

Prader-Willi Syndrome Association (USA) monitors the ongoing health and welfare of individuals with Prader-Willi syndrome (PWS) through active communication with members by membership surveys and data registries. Thromboembolism and blood clots have emerged in clinical studies as significant risk factors for injury and death in PWS. A 66-item questionnaire was developed by a panel of PWS medical and scientific experts, with input from Prader-Willi Syndrome Association (USA) leadership, so as to probe their membership on the frequency, risk, and protective factors for venous thromboembolism, pulmonary embolism, and related findings. The characteristics of those with and without a reported history of blood clots and related health factors were tabulated and analyzed. Responses were obtained for 1067 individuals with PWS (554 females and 513 males), and 38 (23 females and 15 males) had a history of blood clots. The individuals with clots did not differ by gender, but were significantly older 32.8 ± 15 years vs 20.4 ± 13 years, and were more likely to have a reported history of obesity (76%), edema (59%), hypertension (24%), vasculitis (33%), and family history of blood clots (33%) than those without clots. Growth hormone treatment was more common in individuals without clots. The risk factors for thromboembolism in PWS overlap those commonly observed for the general population.

Relationship between body mass and clinical response to repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder.

Repetitive transcranial magnetic stimulation (rTMS) has been proven to be efficacious in the treatment of Major Depressive Disorder (MDD). We previously examined the effectiveness of rTMS for MDD in an applied clinical setting, AwakeningsKC Clinical Neuroscience Institute (CNI) and found high remission rates for patients diagnosed with MDD following rTMS treatment. An unexpected relationship with body composition and rTMS unit was discovered. This sub-study extends the previous investigation through a focused analysis of the effects of body composition on response to rTMS in the treatment of MDD. We utilized data collected from a retrospective review of medical records for patients diagnosed with MDD undergoing rTMS therapy at AwakeningsKC CNI. Patient Health Questionnaire 9 (PHQ-9) scores, time to remission status and body mass index (BMI) at baseline were considered while referencing two different rTMS instruments (MagVenture; NeuroStar). We found 23 (9%) of 247 participants met criteria for obese status (BMI≥30) with an average baseline PHQ-9 score of 22±4, classified as "severe depression". Obesity status was differentially impacted by the rTMS instrument used for treatment. Patients with obesity showed a shorter time to remission (mean 2.7±0.27 vs. mean 3.4±0.3 weeks) and proportionately greater remission rate (100% vs. 71%) when treated using the MagVenture relative to the NeuroStar instrument. Clinical response to rTMS therapy for MDD appears to be guided by individual factors including body composition and rTMS parameters such as the unit used for treatment. Further study of these influences could aid in the optimization of clinical response to rTMS.

Time to remission analysis for major depressive disorder after repetitive transcranial magnetic stimulation (rTMS).

We previously examined the efficacy of rTMS for major depressive disorder in an applied clinical practice. Clinical response was related to severity of depression as well as the rTMS instrument utilized suggesting a relationship to instrument or magnetic field parameters and individual factors. The effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder was further evaluated using Log-Rank statistics for time to remission outcomes. A follow-up retrospective medical records study was carried out on patients with major depressive disorder undergoing rTMS therapy at AwakeningsKC Clinical Neuroscience Institute (CNI), a suburban tertiary psychiatric clinic. Cox Proportional Hazard with Log-Rank statistics were applied and the time course to clinical remission was evaluated over a 6-week period with respect to age, gender, and depression severity. Clinical response was observed referencing two different rTMS instruments (MagVenture; NeuroStar). Time to remission studies of 247 case reports (N=98 males; N=149 females) showed consistently greater clinically defined remission rates after 6 weeks of rTMS treatment for patients using the MagVenture vs NeuroStar instrument. Patients previously admitted for inpatient psychiatric hospitalization exhibited higher response rates when treated with the MagVenture rTMS unit. Stepwise Cox Proportional Hazards Regression final model of time to remission included rTMS unit, inpatient psychiatric hospitalization and obese body habitus. Response to rTMS in applied clinical practice is related to severity of psychiatric illness and may require consideration of magnetic field parameters of the rTMS unit with respect to individual factors such as sex or body composition.

Repetitive transcranial magnetic stimulation (rTMS) using different TMS instruments for major depressive disorder at a suburban tertiary clinic.

Repetitive transcranial magnetic stimulation (rTMS) is a neurostimulatory technique used to modulate orbital frontal corticostriatal (OFC) activity and clinical symptomatology for psychiatric disorders involving OFC dysfunction. We examined the effectiveness of rTMS in the treatment of major depressive disorder in an applied clinical setting (Awakening KC CNI) to assess efficacy and optimize rTMS parameters within clinical practice. A retrospective review of medical records was carried out on patients with major depressive disorder undergoing rTMS therapy at Awakenings KC Clinical Neuroscience Institute (CNI), a suburban tertiary psychiatric clinic. A detailed de-identified data set of clinical outcomes was compiled. Patient Health Questionnaire 9 (PHQ-9) total score, clinical remission rate and week achieved were evaluated over 6 weeks of treatment to assess clinical response referencing two different rTMS instruments (MagVenture; NeuroStar). Our survey included 247 participants from males (N=98) and females (N=149) with average baseline PHQ-9 scores of 21.7±4, classified as severe depression. Clinically rated remission rates of 72% were achieved in 3.1±1.0 weeks and associated with prior history of psychiatric hospitalization, suicide attempts and substance use disorder. Average baseline PHQ- 9 scores decreased significantly over time with proportionately greater remission rates achieved for patients treated using the MagVenture over NeuroStar instrument. rTMS in applied clinical practice is efficacious over a wide range of settings and patients. Clinical response was related to severity of depression symptoms (e.g., prior hospitalization; suicide attempts) validating efficacy in critically ill groups. Clinical response may be impacted by rTMS instrument, magnetic field parameters or individual factors.

GeneAnalytics Pathways and Profiling of Shared Autism and Cancer Genes.

Recent research revealed that autism spectrum disorders (ASD) and cancer may share common genetic architecture, with evidence first reported with the PTEN gene. There are approximately 800 autism genes and 3500 genes associated with cancer. The VarElect phenotype program was chosen to identify genes jointly associated with both conditions based on genomic information stored in GeneCards. In total, 138 overlapping genes were then profiled with GeneAnalytics, an analysis pathway enrichment tool utilizing existing gene datasets to identify shared pathways, mechanisms, and phenotypes. Profiling the shared gene data identified seven significantly associated diseases of 2310 matched disease entities with factors implicated in shared pathology of ASD and cancer. These included 371 super-pathways of 455 matched entities reflecting major cell-signaling pathways and metabolic disturbances (e.g., CREB, AKT, GPCR); 153 gene ontology (GO) biological processes of 226 matched processes; 41 GO molecular functions of 78 matched functions; and 145 phenotypes of 232 matched phenotypes. The entries were scored and ranked using a matching algorithm that takes into consideration genomic expression, sequencing, and microarray datasets with cell or tissue specificity. Shared mechanisms may lead to the identification of a common pathology and a better understanding of causation with potential treatment options to lessen the severity of ASD-related symptoms in those affected.

Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study.

BACKGROUND: Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects. METHODS: High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age. RESULTS: We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200). CONCLUSIONS: We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.

A descriptive study on selected growth parameters and growth hormone receptor gene in healthy young adults from the American Midwest.

CONTEXT: The first study of growth hormone receptor (GHR) genotypes in healthy young adults in the United States attending a Midwestern university and impact on selected growth parameters. OBJECTIVE: To describe the frequency of GHR genotypes in a sample of healthy young adults from the United States attending a university in the Midwest and analyze the relationship between GHR genotypes and selected growth parameters. DESIGN: Saliva was collected from 459 healthy young adults (237 females, 222 males; age range = 18-25 y) and DNA isolated for genotyping of GHR alleles (fl/fl, fl/d3, or d3/d3). Selected growth parameters were collected and GHR genotype data examined for previously reported associations (e.g., height, weight or bone mass density) or novel findings (e.g., % body water and index finger length). RESULTS: We found 219 participants (48%) homozygous for fl/fl, 203 (44%), heterozygous fl/d3 and 37 (8%) homozygous d3/d3. The distribution of GHR genotypes in our participants was consistent with previous reports of non-US populations. Several anthropometric measures differed by sex. The distribution of GHR genotypes did not significantly differ by sex, weight, or other anthropometric measures. However, the fl/d3 genotype was more common among African-Americans. CONCLUSIONS: Our study of growth and anthropometric parameters in relationship to GHR genotypes found no association with height, weight, right index finger length, BMI, bone mass density, % body fat or % body water in healthy young adults. We did identify sex differences with increased body fat, decreased bone density, body water and index finger length in females.

Growth hormone receptor (GHR) gene polymorphism and scoliosis in Prader-Willi syndrome.

OBJECTIVE: A growth hormone receptor (GHR) gene polymorphism impacts sensitivity to endogenous and exogenous growth hormone (GH) to moderate growth and development. Increased sensitivity may accelerate spinal growth and contribute to scoliosis, particularly in GH-deficient and treated populations such as Prader-Willi syndrome (PWS). Therefore, we examined the relationship between GHR genotype and scoliosis (case and control) in PWS cohorts. DESIGN: We utilized a case-control design in a study of 73 subjects (34M; 39F) with genetically confirmed PWS in 32 individuals previously diagnosed with moderate to severe scoliosis (mean age=16.9±10.2years; age range of 1 to 41years) and 41 adults with no evidence of scoliosis (mean age=30.8±9.7years; age range of 18 to 56years). The GHR gene polymorphism was determined using PCR specific primers to capture the two recognized GHR gene fragment sizes [i.e., full length (fl) or exon 3 deletions (d3)]. RESULTS: Twenty-three (72%) of the 32 case subjects with scoliosis required surgical correction with an approximately equal balance for gender and PWS genetic subtype among cases and 41 control subjects without scoliosis. The GHR d3/d3 genotype was identified in N=2 of 8 (25%) cases with scoliosis and the d3/fl genotype was identified in N=11 of 25 (44%) cases with scoliosis but the distribution difference did not statistically differ. The GHR fl/fl genotype was correlated with a significantly faster rate and heavier weight gain among case subjects. CONCLUSION: Our examination of demographic and genetic markers associated with scoliosis and surgical repair in PWS found no evidence to support differences in gender, PWS genetic subtype or GHR d3 allele distributions among the case vs control groups. Those with fl/fl alleles were heavier than those with d3/d3 or d3/fl genotypes and warrant further study with a larger sample size and possibly to include other vulnerable populations requiring growth hormone treatment.

Survival trends from the Prader-Willi Syndrome Association (USA) 40-year mortality survey.

PurposePrader-Willi syndrome (PWS) is a complex genetic disorder characterized by hyperphagia and morbid obesity with increased cardiopulmonary and hyperphagia-related mortality. Survival trends in PWS were evaluated to assess the impact of modern interventions on mortality risk.MethodsThe Prader-Willi Syndrome Association (USA) 40-year mortality syndrome-specific database of 486 death reports was utilized to examine survival trends in PWS and cohort effects for recent deaths (years 2000-2015, N=331) relative to deaths prior to 2000 (N=94). Cox proportional hazards regression modeling was applied to generate log rank statistics and Kaplan-Meier curves examining sex, cause of death, and cohort.ResultsRisk for all-cause mortality in PWS was 1.5 (95% confidence interval (CI)=1.2-1.9) times higher for the Early than the Recent era cohort reflected in female cardiac failure (hazard ratio (HR)=1.8; 95% CI=1.3-2.6), pulmonary embolism (HR=6.1; 95% CI=1.7-22), and gastrointestinal-related (HR=3.2; 95% CI=1.1-7.4) causes. Accidental deaths in males increased in the Recent era cohort (HR=5.7; 95% CI=1.2-27.1), possibly due to enhanced weight management and mobility. Risk of death from respiratory failure was unchanged.ConclusionWe report measurable increases in survival effecting cardiovascular and gastrointestinal-related causes in PWS most likely attributable to earlier diagnosis and proactive interventions to prevent morbid obesity. More research is needed to address underlying vulnerability to respiratory failure, an unchanged mortality risk in PWS.

Functional analysis of schizophrenia genes using GeneAnalytics program and integrated databases.

Schizophrenia (SCZ) is a chronic debilitating neuropsychiatric disorder with multiple risk factors involving numerous complex genetic influences. We examined and updated a master list of clinically relevant and susceptibility genes associated with SCZ reported in the literature and genomic databases dedicated to gene discovery for characterization of SCZ genes. We used the commercially available GeneAnalytics computer-based gene analysis program and integrated genomic databases to create a molecular profile of the updated list of 608 SCZ genes to model their impact in select categories (tissues and cells, diseases, pathways, biological processes, molecular functions, phenotypes and compounds) using specialized GeneAnalytics algorithms. Genes for schizophrenia were predominantly expressed in the cerebellum, cerebral cortex, medulla oblongata, thalamus and hypothalamus. Psychiatric/behavioral disorders incorporating SCZ genes included ADHD, bipolar disorder, autism spectrum disorder and alcohol dependence as well as cancer, Alzheimer's and Parkinson's disease, sleep disturbances and inflammation. Function based analysis of major biological pathways and mechanisms associated with SCZ genes identified glutaminergic receptors (e.g., GRIA1, GRIN2, GRIK4, GRM5), serotonergic receptors (e.g., HTR2A, HTR2C), GABAergic receptors (e.g., GABRA1, GABRB2), dopaminergic receptors (e.g., DRD1, DRD2), calcium-related channels (e.g., CACNA1H, CACNA1B), solute transporters (e.g., SLC1A1, SLC6A2) and for neurodevelopment (e.g., ADCY1, MEF2C, NOTCH2, SHANK3). Biological mechanisms involving synaptic transmission, regulation of membrane potential and transmembrane ion transport were identified as leading molecular functions associated with SCZ genes. Our approach to interrogate SCZ genes and their interactions at various levels has increased our knowledge and insight into the disease process possibly opening new avenues for therapeutic intervention.

Exploring genetic susceptibility to obesity through genome functional pathway analysis.

OBJECTIVE: Obesity has been reaching epidemic levels in recent decades, with a growing body of research identifying predisposing genetic components. To explore the relationship of genetic factors contributing to obesity, an analytical computer-based gene-profiling approach utilizing an updated list of clinically relevant and known obesity-related genes was undertaken. METHODS: An updated list of 494 genes reportedly associated with obesity was compiled, and the GeneAnalytics profiling software was utilized to interrogate genomic databases from GeneCards® to cross-reference obesity gene sets against tissues and cells, diseases, genetic pathways, gene ontology (GO)-biological processes and GO-molecular functions, phenotypes, and compounds. RESULTS: Obesity-related fields identified by GeneAnalytics algorithms included 8 diseases, 46 pathways, 62 biological processes, 22 molecular functions, 148 phenotypes, and 286 compounds impacting adipogenesis, signal transduction by G-protein coupled receptors, and lipid metabolism involving insulin-related genes (IGF1, INS, IRS1). GO-biological processes identified feeding behavior, cholesterol metabolic process, and glucose and cholesterol homeostasis pathways, while GO-molecular processes pertained to receptor binding, affecting glucose homeostasis, body weight, and circulating insulin and triglyceride levels. CONCLUSIONS: The gene-profiling model suggests that pathogenesis of obesity relates to the coordination of biological responses to glucose and intracellular lipids possibly through a disruption of biochemical cascades and cellular signaling arising from affected receptors.

GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia.

Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction.

Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. METHODS: The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards. RESULTS: A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. CONCLUSIONS: These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.