Predictors of pharmacotherapy outcomes for body dysmorphic disorder: a machine learning approach

Background Serotonin-reuptake inhibitors (SRIs) are first-line pharmacotherapy for the treatment of body dysmorphic disorder (BDD), a common and severe disorder. However, prior research has not focused on or identified definitive predictors of SRI treatment outcomes. Leveraging precision medicine techniques such as machine learning can facilitate the prediction of treatment outcomes. Methods The study used 10-fold cross-validation support vector machine (SVM) learning models to predict three treatment outcomes (i.e. response, partial remission, and full remission) for 97 patients with BDD receiving up to 14-weeks of open-label treatment with the SRI escitalopram. SVM models used baseline clinical and demographic variables as predictors. Feature importance analyses complemented traditional SVM modeling to identify which variables most successfully predicted treatment response. Results SVM models indicated acceptable classification performance for predicting treatment response with an area under the curve (AUC) of 0.77 (sensitivity = 0.77 and specificity = 0.63), partial remission with an AUC of 0.75 (sensitivity = 0.67 and specificity = 0.73), and full remission with an AUC of 0.79 (sensitivity = 0.70 and specificity = 0.79). Feature importance analyses supported constructs such as better quality of life and less severe depression, general psychopathology symptoms, and hopelessness as more predictive of better treatment outcome; demographic variables were least predictive. Conclusions The current study is the first to demonstrate that machine learning algorithms can successfully predict treatment outcomes for pharmacotherapy for BDD. Consistent with precision medicine initiatives in psychiatry, the current study provides a foundation for personalized pharmacotherapy strategies for patients with BDD.

Marked Increase of Gamma-Glutamyltransferase as an Indicator of Drug-Induced Liver Injury in Patients without Conventional Diagnostic Criteria of Acute Liver Injury

<b><i>Introduction:</i></b> Clinically significant drug-induced liver injury (DILI) is defined by elevations of alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), alkaline phosphatase (ALP) ≥2 × ULN, or ALT ≥3 × ULN and total bilirubin TBIL &#x3e;2 × ULN. However, DILI might also occur in patients who do not reach those thresholds and still may benefit from discontinuation of medication. <b><i>Methods:</i></b> Fifteen patients recruited for our prospective study on potentially hepatotoxic drugs were included. DILI diagnosis was based on RUCAM (Roussel Uclaf Causality Assessment Method) score and expert opinion and was supported by an in vitro test using monocyte-derived hepatocyte-like (MH) cells. <b><i>Results:</i></b> Median RUCAM score was 6 (range 4–8), indicating that DILI was possible or probable in all cases. The predominant types of liver injury were mixed (60%) and cholestatic (40%). While no elevation above 2 × ULN of ALP and TBIL was observed, gamma-glutamyltransferase (GGT) above 2 × ULN was identified in 8 of the patients. Six of the 15 patients did not achieve full remission and showed persistent elevation of GGT, which was significantly associated with peak GGT elevation above 2 × ULN (<i>p</i> = 0.005). <b><i>Conclusion:</i></b> Here we present a case series of patients with liver enzyme elevation below the conventional thresholds who developed DILI with a predominant GGT elevation leading to drug withdrawal and/or chronic elevation of liver parameters, in particular of GGT. Thus, we propose that DILI should be considered in particular in cases with marked increase of GGT even if conventional DILI threshold levels are not reached, resulting in discontinuation of the causative drug and/or close monitoring of the patients.

The Relationship Between the Gut Microbiome-Immune System-Brain Axis and Major Depressive Disorder

Major depressive disorder (MDD) is a prominent cause of disability worldwide. Current antidepressant drugs produce full remission in only about one-third of MDD patients and there are no biomarkers to guide physicians in selecting the best treatment for individuals. There is an urgency to learn more about the etiology of MDD and to identify new targets that will lead to improved therapy and hopefully aid in predicting and preventing MDD. There has been extensive interest in the roles of the immune system and the gut microbiome in MDD and in how these systems interact. Gut microbes can contribute to the nature of immune responses, and a chronic inflammatory state may lead to increased responsiveness to stress and to development of MDD. The gut microbiome-immune system-brain axis is bidirectional, is sensitive to stress and is important in development of stress-related disorders such as MDD. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota. Preclinical studies and preliminary clinical investigations have reported improved mood with administration of probiotics and prebiotics, but large, carefully controlled clinical trials are now necessary to evaluate their effectiveness in treating MDD. The roles that several gut microbe-derived molecules such as neurotransmitters, short chain fatty acids and tryptophan play in MDD are reviewed briefly. Challenges and potential future directions associated with studying this important axis as it relates to MDD are discussed.

Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience

Background: Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as “shunters”, are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. Objectives: To investigate and describe the use of thiopurine–XOI combination therapy in shunters with systemic autoimmune diseases. Methods: Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital’s laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. Results: Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. Conclusion: Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases. RÉSUMÉ Contexte : Les thiopurines sont des piliers de l’intervention thérapeutique contre les maladies auto-immunes. Cependant, 20 % à 30 % des patients surproduisent des métabolites méthylés (connus sous le nom 6-MMP), au détriment du métabolite actif, le nucléotide 6-thioguanine (6-TGN). Ces patients, communément appelés « courts-circuiteurs » sont prédisposés à résister à la thiopurine et à l’hépatotoxicité. Pour les patients ayant des maladies inflammatoires intestinales, on utilise la combinaison de thiopurine avec une xanthine oxydase inhibitrice (XOI) afin d’inverser ce métabolisme anormal et prévenir l’échec du traitement ou l’hépatotoxicité. Les données concernant l’adoption de cette stratégie pour les patients atteints d’autres maladies sont limitées. Objectifs : Étudier et décrire l’utilisation de la thérapie combinée de thiopurine et de XOI pour les « courts-circuiteurs » ayant des maladies auto-immunes systémiques. Méthodes : Les « courts-circuiteurs » traités dans l’hôpital où s’est déroulée l’étude entre le 1er janvier 2005 et le 31 décembre 2015 ont été identifiés à l’aide de la base de données du laboratoire de l’hôpital et les données cliniques ont été recueillies de manière rétrospective. L’évaluation des données cliniques et de laboratoire de chaque patient bénéficiant d’une optimisation de la thérapie par la thiopurine a porté sur six mois de traitement. Résultats : Trente-quatre patients ont été identifiés comme « courts-circuiteurs » et 14 d’entre eux ont bénéficié d’une optimisation de la thérapie par la thiopurine à l’aide d’une XOI. Ces derniers ont subi une thérapie de combinaison qui a fait passer la dose moyenne d’azathioprine de 1,95 à 0,78 mg/kg. De plus, le niveau moyen de 6-TGN est passé de 135 à 385 pmol/8 × 108 érythrocytes (p = 0,001). En outre, 11 des 14 patients ont vu le niveau de 6-TGN passer à plus de 235 pmol/8 ×108 érythrocytes. Inversement, le niveau moyen de 6-MMP est passé de 6267 à 271 pmol/8 × 108 érythrocytes (p = 0,001). À l’exception d’une augmentation de 12 % du volume corpusculaire moyen, aucun changement clinique important dans la numération globulaire n’a été noté. Trois patients ont développé des infections notables et l’un d’eux a dû arrêter le traitement à cause d’une cytopénie. Après six mois, la dose moyenne quotidienne de prednisone a été réduite de 74 %, pour passer de 16,7 mg à 4,4 mg (p = 0,005), et quatre patients ont été sevrés des corticostéroïdes. Sur les 14 patients, 11 (79 %) ont été déclarés en rémission totale et 2 (14 %) en rémission partielle. Conclusion : L’optimisation de la thérapie par la thiopurine associée à une XOI pourrait être sécuritaire et constituer une stratégie efficace pour les patients ayant une maladie auto-immune systémique.

Role of diagnostic imaging in psoriatic arthritis: how, when, and why

Psoriasis is a common skin disease. Up to 30% of patients with psoriasis develop psoriatic arthritis (PsA) resulting, by far, the most prevalent coexisting condition. Heterogeneity of clinical and radiological presentation is a major challenge to diagnosis of PsA. Initial reports about PsA emphasized a benign course in most patients, but it is now recognized that psoriatic arthritis often leads to impaired function and a reduced quality of life. PsA is a progressive disease characterized by diverse clinical features, often resulting in diagnostic delay and treatment that are associated with poor clinical and structural outcomes. New effective treatments may halt PsA progression, and consequently, treatment goals have evolved from simple reduction of pain to achieving full remission or minimal disease activity. This emerging treat-to-target strategy paradigm emphasize a need for early diagnosis; sensitive imaging techniques may be of value in this process. While radiography and CT depict structural damage, US and MRI have emerged as helpful tools to evaluate magnitude and severity of active inflammatory lesions. This review aims to describe the role of imaging modalities in diagnosis, follow-up and prognosis of PsA.

Efficacy and risk of sexual orientation change efforts: a retrospective analysis of 125 exposed men

Background: Voluntary therapeutic interventions to reduce unwanted same-sex sexuality are collectively known as sexual orientation change efforts (SOCE). Currently almost all evidence addressing the contested question whether SOCE is effective or safe consists of anecdotes or very small sample qualitative studies of persons who currently identify as sexual minority and thus by definition failed to change. We conducted this study to examine the efficacy and risk outcomes for a group of SOCE participants unbiased by current sexual orientation. Methods: We examined a convenience sample of 125 men who had undergone SOCE for homosexual-to-heterosexual change in sexual attraction, identity and behavior, and for positive and negative changes in psychosocial problem domains (depression, suicidality, self-harm, self-esteem, social function, and alcohol or substance abuse). Mean change was assessed by parametric (t-test) and nonparametric (Wilcoxon sign rank test) significance tests. Results: Exposure to SOCE was associated with significant declines in same-sex attraction (from 5.7 to 4.1 on the Kinsey scale, p <.000), identification (4.8 to 3.6, p < .000), and sexual activity (2.4 to 1.5 on a 4-point scale of frequency, p < .000). From 45% to 69% of SOCE participants achieved at least partial remission of unwanted same-sex sexuality; full remission was achieved by 14% for sexual attraction and identification, and 26% for sexual behavior. Rates were higher among married men, but 4-10% of participants experienced increased same-sex orientation after SOCE. From 0.8% to 4.8% of participants reported marked or severe negative psychosocial change following SOCE, but 12.1% to 61.3% reported marked or severe positive psychosocial change. Net change was significantly positive for all problem domains. Conclusion: SOCE was perceived as an effective and safe therapeutic practice by this sample of participants. We close by offering a unifying understanding of discrepant findings within this literature and caution against broad generalizations of our results.

Metabolomics-based discrimination of patients with remitted depression from healthy controls using 1H-NMR spectroscopy

The aim of the study was to investigate differences in metabolic profiles between patients with major depressive disorder (MDD) with full remission (FR) and healthy controls (HCs). A total of 119 age-matched MDD patients with FR (n = 47) and HCs (n = 72) were enrolled and randomly split into training and testing sets. A 1H-nuclear magnetic resonance (NMR) spectroscopy-based metabolomics approach was used to identify differences in expressions of plasma metabolite biomarkers. Eight metabolites, including histidine, succinic acid, proline, acetic acid, creatine, glutamine, glycine, and pyruvic acid, were significantly differentially-expressed in the MDD patients with FR in comparison with the HCs. Metabolic pathway analysis revealed that pyruvate metabolism via the tricarboxylic acid cycle linked to amino acid metabolism was significantly associated with the MDD patients with FR. An algorithm based on these metabolites employing a linear support vector machine differentiated the MDD patients with FR from the HCs with a predictive accuracy, sensitivity, and specificity of nearly 0.85. A metabolomics-based approach could effectively differentiate MDD patients with FR from HCs. Metabolomic signatures might exist long-term in MDD patients, with metabolic impacts on physical health even in patients with FR.

Mycovirus Containing Aspergillus flavus and Acute Lymphoblastic Leukemia: Carcinogenesis beyond Mycotoxin Production

Carcinogenic effects of Aspergillus spp. have been well established and generally attributed to a variety of mycotoxin productions, particularly aflatoxins. It is known that most carcinogenic mycotoxins, with the exception of fumonisins, are genotoxic and mutagenic, causing chromosomal aberrations, micronuclei, DNA single-strand breaks, sister chromatid exchange, unscheduled DNA synthesis etc. Some Aspergillus spp. are infected with mycoviruses which can result in loss of aflatoxin production. The effects of mycovirus containing Aspergillus on human health have not been fully evaluated. Recent studies in patients with acute lymphoblastic leukemia, in full remission, have revealed the existence of antibody to the products of a certain Aspergillus flavus isolate which harbored an unknown mycovirus. Exposure of blood mononuclear cells from these patients, but not controls, to the products of this organism had reproduced cell surface phenotypes and genetic markers, characteristic of acute lymphoblastic leukemia. Carcinogenic effects of Aspergillus spp. may not always be mycotoxin related and this requires further investigation.

Mevalonate kinase deficiency syndrome: Single center experience

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.