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Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n=66) received four sub-anesthetic doses of IV ketamine (0.5-0.75mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety and functioning were assessed with validated self-report measures.Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SRReal world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.

Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic-inflammatory disease associated with poor outcomes and decreased quality of life. NAFLD is overrepresented in patients with psychiatric disorders like depression, bipolar disorder, and schizophrenia; however, a comprehensive review on NAFLD and psychiatric disorders remains to be delineated. This review endeavors to investigate the association of NAFLD with psychiatric disorders, including shared pathogenesis and future clinical derivatives. Extant literature suggests that patients with psychiatric disorders (in particular, mood disorders) are more susceptible to the development of NAFLD due to multiple reasons, including but not limited to hypothalamic–pituitary–adrenal axis dysregulation, metabolic syndrome, and chronic perceived stress. Moreover, the clinical manifestations of mood disorders (e.g., anhedonia, psychomotor retardation, lifestyle modification, etc.), and potentially long-term treatment with weight-gaining agents, differentially affect these patients, making them more prone to NAFLD. Considering the increased morbidity associated with both mood disorders and NAFLD, our review recommends regular screenings for NAFLD in select patients with mood disorders exhibiting signs of increased risk (i.e., obesity, metabolic syndrome, diabetes, or family history of NAFLD) for better diagnosis and holistic care of both potentially interrelated conditions.

Background The aim of this study was to determine the validity of using social media for depression screening. Method Article searches on PubMed and PsycINFO from database inception to August 20, 2019 were completed with a search string and filters. Results 15 articles made the inclusion criteria. Facebook, Twitter, and Instagram profiles of depressed people were distinguishable from nondepressed people shown by social media markers. Facebook studies showed that having fewer Facebook friends and mutual friends, posting frequently, and using fewer location tags positively correlated with depressive symptoms. Also, Facebook posts with explicit expression of depressive symptoms, use of personal pronouns, and words related to pain, depressive symptoms, aggressive emotions, and rumination predicted depression. Twitter studies showed that the use of “past focus” words, negative emotions and anger words, and fewer words per Tweet positively correlated with depression. Finally, Instagram studies showed that differences in follower patterns, photo posting and editing, and linguistic features between depressed people and nondepressed people could serve as a marker. Limitations The primary articles analyzed had different methods, which constricts the amount of comparisons that can be made. Further, only four social media platforms were explored. Conclusion Social media markers like number and content of Facebook messages, linguistic variability in tweets and tweet word count on Twitter, and number of followers, frequency of Instagram use and the content of messages on Instagram differed between depressed people and nondepressed people. Therefore, screening social media profiles on these platforms could be a valid way to detect depression.

Background: Ketamine is an emerging treatment for treatment-resistant depression (TRD) associated with rapid and robust improvements in depressive symptoms and suicidality. However, the efficacy and safety of ketamine in transitional age youth (TAY; age 18–25) populations remains understudied. Methods: In this retrospective analysis, TAY patients ( n = 52) receiving ketamine for TRD were matched for sex, primary diagnosis, baseline depression severity, and treatment resistance with a general adult (GA) sample (age 30–60). Patients received four ketamine infusions over 2 weeks (0.5–0.75 mg/kg over 40 min). The primary outcome was the change in Quick Inventory of Depressive Symptomatology Self-Report 16-item (QIDS-SR16) over time. Secondary outcomes were changes in QIDS-SR16 suicidal ideation (SI) item, anxiety (Generalized Anxiety Disorder 7-item (GAD-7)), and adverse effects (ClinicalTrials.gov: NCT04209296). Results: A significant main effect of infusions on reduction of total QIDS-SR16 ( p Conclusion: Ketamine was associated with comparable clinical benefits, safety, and tolerability in a TAY sample as compared to a matched GA TRD sample.

Acute lymphoblastic leukemia (ALL) cases with e13a3 fusion transcripts are extremely rare. We report a 24-year-old male with Ph-positive (Ph+) ALL with an aberrant e13a3 fusion transcript treated with CD19-specific chimeric antigen receptor T-cell (CAR-T) therapy. He developed refractory disease post-chemotherapy induction, andreceived allogeneic hematopoietic stem cell transplantation (allo-HSCT) after salvage with imatinib in combination with chemotherapy regimen. Unfortunately, the patient relapsed after +90 days post-transplant. He was consented to CAR-T therapy trial and achieved complete remission, highlighting the efficacy of CAR-T treatment in relapsed-refractory B-ALL irrespective of the underlying genetic drivers in leukemia cells .

Highlights • The coronavirus disease 2019 (COVID-19) pandemic has resulted in unprecedented hazards to mental health globally. • Relatively high rates of anxiety, depression, post-traumatic stress disorder, psychological distress, and stress were reported in the general population during the COVID-19 pandemic in eight countries. • Common risk factors associated with mental distress during the COVID-19 pandemic include female gender, younger age group (≤40 years), presence of chronic/psychiatric illnesses, unemployment, student status, and frequent exposure to social media/news concerning COVID-19. • Mitigation of COVID-19 induced psychological distress requires government intervention and individual efforts., Background As a major virus outbreak in the 21st century, the Coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented hazards to mental health globally. While psychological support is being provided to patients and healthcare workers, the general public's mental health requires significant attention as well. This systematic review aims to synthesize extant literature that reports on the effects of COVID-19 on psychological outcomes of the general population and its associated risk factors. Methods A systematic search was conducted on PubMed, Embase, Medline, Web of Science, and Scopus from inception to 17 May 2020 following the PRISMA guidelines. A manual search on Google Scholar was performed to identify additional relevant studies. Articles were selected based on the predetermined eligibility criteria. Results: Relatively high rates of symptoms of anxiety (6.33% to 50.9%), depression (14.6% to 48.3%), post-traumatic stress disorder (7% to 53.8%), psychological distress (34.43% to 38%), and stress (8.1% to 81.9%) are reported in the general population during the COVID-19 pandemic in China, Spain, Italy, Iran, the US, Turkey, Nepal, and Denmark. Risk factors associated with distress measures include female gender, younger age group (≤40 years), presence of chronic/psychiatric illnesses, unemployment, student status, and frequent exposure to social media/news concerning COVID-19. Limitations A significant degree of heterogeneity was noted across studies. Conclusions The COVID-19 pandemic is associated with highly significant levels of psychological distress that, in many cases, would meet the threshold for clinical relevance. Mitigating the hazardous effects of COVID-19 on mental health is an international public health priority.

Semantic processing impairments are present in a proportion of individuals with autism spectrum disorder (ASD). Despite the numerous imaging studies investigating this language domain in ASD, there is a lack of consensus regarding the brain structures showing abnormal pattern of activity. This meta-analysis aimed to identify neural activation patterns present during semantic processing in ASD. Findings reveal activation of areas associated with semantic processing and executive functions in ASD. However, the activation was less concise in comparison to controls and there was less activation in the right hemisphere and in areas associated with executive functions. This provides strong support for impaired semantic processing in ASD that is consistently associated with abnormal patterns of neural activity in the semantic network.

Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of different formulations and routes of delivery invites the need for evaluating relative effect sizes.Effect size with respect to depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2-6 days, 7-20 days, 21-28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal and oral routes of administration. Analysis was also conducted evaluating the effect size of racemic ketamine to esketamine.The pooled effect size for intranasal ketamine/esketamine at 24 h was g = 1.247 (n = 5, 95% CI: 0.591-1.903, p 0.01). At 2-6 days, the pooled effect size for intravenous ketamine/esketamine was g = 0.949 (n = 14, 95% CI: -0.308-2.206, p = 0.139). At 7-20 days, intranasal ketamine had a pooled effect size of g = 1.018 (n = 4, 95% CI: 0.499-1.538, p 0.01). At 21-28 days, oral ketamine had a pooled effect size of g = 0.633 (n = 2, 95% CI: 0.368-0.898, p 0.01).Additional comparative studies are needed with regards to the efficacy of different formulations and routes of delivery.The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. Interpreting the efficacy of oral ketamine was limited by the need for studies with larger samples across independent sites. No conclusions regarding comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct comparative studies are needed to further inform treatment options for TRD.

Background Major Depressive Disorder (MDD) is a common and debilitating mood disorder. Individuals with MDD are often misdiagnosed or diagnosed in an untimely manner, exacerbating existing functional impairments. Ecological momentary assessment (EMA) involves the repeated sampling of an individual's symptoms within their natural environment and has been demonstrated to assist in illness assessment and characterization. Capturing data in this way would set the stage for improved treatment outcomes and serve as a complementary resource in the management and treatment of depressive symptoms. Methods Online databases PubMed/MedLine and PsycINFO were searched using PRISMA guidelines and combinations of the following keywords: EMA, depression, smartphone app, diagnosing, symptoms, phone, app, ecological momentary assessment, momentary assessment, data mining, unobtrusive, passive data, GPS, sensor. Results A total of nineteen original articles were identified using our search parameters and ten articles met the inclusion criteria for full-text review. Among the ten relevant studies, three studies evaluated feasibility, seven evaluated detection, and three evaluated treatment of MDD. Limitations Limitations include that the design of all of the studies included in this review are non-randomized. It should be noted that most of the studies included were pilot studies and/or exploratory trials lacking a control group. Conclusions Available evidence suggests that the use of passive smartphone-based applications may lead to improved management of depressive symptoms. This review aids the creation of new EMA applications, highlights the potential of EMA usage in clinical settings and drug development, emphasizes the importance for regulation of applications in the mental health field, and provides insight into future directions.

Background Replicated evidence has documented elevated levels of pro-inflammatory cytokines in populations with major depressive disorder (MDD). However, childhood trauma, a risk factor for MDD, has been separately shown to also impact inflammatory systems; its potential moderating effect on inflammation in MDD has been less frequently investigated. Methods We systematically searched the PubMed, Google Scholar, Scopus, Web of Science, and PsycINFO databases between database inception to June 19th, 2019 using the search string: (Childhood trauma or Adverse childhood experiences or childhood abuse or childhood rape or physical abuse or emotional abuse) AND (Inflammation or inflammatory cytokines or interleukin-6 or tumor necrosis factor-alpha or c-reactive protein) AND (Major Depressive Disorder or Depression). Results We identified nine articles that evaluated inflammatory biomarkers in MDD populations with adverse childhood experiences (ACE). Eight articles evaluated IL-6, three articles evaluated CRP, and five articles evaluated TNF-α. The strongest effects were observed for IL-6; six studies reported significantly elevated levels of IL-6 in MDD and ACE patients compared to healthy controls and/or MDD-only populations. Meanwhile, only three studies found TNF-α to be significantly elevated in the MDD and ACE cohort. In contrast, MDD-ACE populations did not exhibit significantly elevated CRP. Limitations The methodological heterogeneity amongst studies was very high. Conclusion The current review suggests that MDD and ACE subpopulations present elevated levels of IL-6 compared to MDD-only and healthy control populations. Therefore, research should consider whether elevated inflammation in MDD is just an epiphenomenon of previous ACE and whether MDD-ACE subgroups are more likely to respond to immune-inflammatory targeted intervention.

While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and the enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse compared to (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders.

Psychiatric and metabolic disorders are highly comorbid and the relationship between these disorders is bidirectional. The mechanisms underlying the association between psychiatric and metabolic disorders are presently unclear, which warrants investigation into the dynamics of the interplay between metabolism, substrate utilization, and energy expenditure in psychiatric populations, and how these constructs compare to those in healthy controls. Indirect calorimetry (IC) methods are a reliable, minimally invasive means for assessing metabolic rate and substrate utilization in humans. This review synthesizes the extant literature on the use of IC on resting metabolism in psychiatric populations to investigate the interaction between psychiatric and metabolic functioning. Consistently, resting energy expenditures and/or substrate utilization values were significantly different between psychiatric and healthy populations in the studies contained in this review. Furthermore, resting energy expenditure values were systematically overestimated when derived from predictive equations, compared to when measured by IC, in psychiatric populations. High heterogeneity between study populations (e.g., differing diagnoses and drug regimens) and methodologies (e.g., differing posture, time of day, and fasting status at measurement) impeded the synthesis of results. Standardized IC protocols would benefit this line of research by enabling meta-analyses, revealing trends within and between different psychiatric disorders.

Available studies have evaluated cognition in the unaffected relatives of bipolar disorder patients; however, to our knowledge, there has been no quantitative analysis evaluating the foregoing association. Herein, this meta-analysis aims to provide a quantitative synthesis of the extant literature reporting on the association between performance in cognitive domains (i.e., executive function, attention, learning and memory or global cognition) amongst unaffected individuals of probands with bipolar disorders.Online databases (i.e., PubMed, PsycINFO) and Google Scholar were searched from inception to 20 September 2021. Studies with unaffected, first-degree relatives of individuals with DSM-IV or DSM-5 defined bipolar disorders were included. The risk of bias was assessed using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively synthesized using Cohen's d effect sizes via a random-effects meta-analytic approach on JASP.A total of 15 studies were included in the final review. Overall, results indicate that cognitive performance across all domains is moderately impaired in unaffected relatives of individuals with bipolar disorders (d = 0.488). Sub-analysis suggests there is a higher level of impairment in executive functioning (d = 0.612).The identification of cognitive deficits in unaffected relatives of probands with bipolar disorders indicates that cognitive impairment is endophenotypic and a core disturbance in persons with bipolar disorders; future studies should endeavour to target cognition as a potential pre-emptive and prevention strategy of bipolar disorders.

HighlightsNew practice models are in demand for prevention and reduction in rates of catheter thrombosis that can be devastating to the health care system and patients Risk factors for catheter thrombosis were analyzed retrospectively for their impact Site of insertion and overall use of anticoagulation at the time of catheter placement did not show any significant impact on incidence of thrombosis Several variables (i.e., triple lumen, critically ill) were used to create a clinical prediction score model

The large percentage of adults with major depressive disorder (MDD) insufficiently responding and/or tolerating conventional monoamine-based antidepressants invites the need for mechanistically novel treatments. Convergent evidence implicates glutamatergic signaling as a potential therapeutic target in MDD.The synthesis herein of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and exhibits clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with MDD. DXM efficacy has been preliminarily reported in adults with bipolar depression. The combination of DXM and bupropion represents a pharmacokinetic and pharmacodynamic synergy which may account for the rapidity of action in MDD.The combination of DXM and bupropion is a safe, well tolerated and efficacious treatment option in adults with MDD. Priority questions are whether DXM/bupropion is uniquely effective across discrete domains of psychopathology (e.g. anhedonia, reward processing, general cognitive systems) and/or whether it is able to significantly improve patient-reported outcomes (e.g. quality of life, psychosocial functioning). The availability of ketamine/esketamine and DXM/bupropion instantiates the relevance of glutamate as a treatment target in MDD. Studies in bipolar depression with DXM/bupropion are warranted as well as in MDD with suicidality.

Background: There is much advancement in treatment of chronic myeloid leukemia (CML) since the approval of first tyrosine kinase inhibitor (TKI), imatinib, by US FDA in 2001. One of them is definitely the concept of stopping TKI, starting at the CML patients who have achieved deep molecular response (MR) of MR4.5 for a reasonable long period of at least two years, pioneered by the researchers from French and Australia. Meanwhile, interferon, the standard treatment of CML before the era of TKI, showed that interferon-responded patients may indeed retain the response once interferon was withdrawn via interferon-induced immunity towards the leukemic clone. This is further supported by stop trial in Japan, in which after stopping TKI, interferon was given for 2 years and it showed a higher drug-free rate compared to stop trial from French and Australia. Hence, it is logical to postulate the use of interferon after TKI was stopped when patients have attained deep MR for more than two years will increase the percentage of patients remain TKI-free on follow-up. Materials and Methods: This is a multi-center randomized controlled trial. Adult CML patients, diagnosed in chronic phase, treated with ongoing TKI for at least 3 years without previous history of TKI failure and have achieved stable deep MR on International Scale for ≥2 years with at least 2 readings of MR4.5 (including the latest before study entry), were randomized into 2 arms: (1) peginterferon-α-2a, subcutaneous weekly, starting at 180 mcg, or (2) observation. Disease is monitored by PCR (centralized in Ampang Hospital) at monthly for the first year, 2 monthly for the second year and 3 monthly for the third year. Relapse is defined as either (i) one reading of loss of major MR, i.e. reading of >0.1% IS and confirmed by second analysis taken 1 month later if the first analysis point reading is ≤1% IS, or (ii) positivity of BCR-ABL1 transcripts, as confirmed by a second analysis point, indicating the increase (at least 1 log) in relation to the first analysis point at two successive assessments. Quality of Life is assessed using EORTC QLO-C30. Results: At the time of writing, total of 8 patients were randomized, 5 into peginterferon arm, 3 into observation arm, all were on imatinib, M:F = 4:4, Malay: Chinese:Indian = 3:4:1, median age 49.5 (range 25-58), median follow-up 4 months (range 1-6) and none of them relapse. Two patients developed imatinib withdrawal syndrome, both female on observation arm, one was mild and resolved after 2 months but one was severe and needed termination after 2 months and restarted on imatinib. Two patients in peginterferon arm developed mild hepatitis with liver enzymes

Anhedonia is a trans-diagnostic, multidimensional phenotype that mediates patient outcomes and suicidality. Convergent evidence suggests that ketamine may be effective in targeting measures of anhedonia in adults with treatment resistant depression (TRD).This retrospective, post-hoc analysis included 203 (x̄ = 45 ± 14.6 years of age) patients receiving four infusions of intravenous (IV) ketamine at a community-based clinic. The primary outcome measure was change in anhedonia severity, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Secondary measures sought to determine if improvement on the SHAPS mediated the effect of repeated IV ketamine infusions on symptoms of depression and suicidal ideations, as measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SRAfter adjusting for age, sex, primary diagnosis, concomitant medication, body mass index, and baseline depression severity, there was a statistically significant reduction in symptoms of anhedonia with IV ketamine treatment (F (2, 235.6) = 31.6, p0.001). Improvements in depressive symptoms, suicidal ideation, and anxiety symptoms with repeated-dose IV ketamine were significantly partially mediated by reduction in anhedonic severity. Moreover, the combination of number of infusions received and change in anhedonic severity accounted for 26% of the variance in depressive score improvements.This is a post-hoc analysis of retrospective data and lacks a control group.Ketamine was effective in improving measures of anhedonia in this large, well-characterized community-based sample of adults with TRD. Improvements in anhedonia also partially mediated the significant improvement in depressive symptoms, suicidality, and anxiety.

Background The effectiveness, tolerability, and safety of intravenous (IV) ketamine in adults with treatment resistant depression (TRD) receiving care in real-word settings is insufficiently characterized. Herein, results from a naturalistic, retrospective study are presented from a Canadian outpatient IV ketamine clinic. Methods Adults (N = 213; Mage = 45) with Major Depressive Disorder or Bipolar Disorder, with a minimum of Stage 2 antidepressant resistance, received IV ketamine at a community-based multi-disciplinary clinic. The primary outcome measure was change from baseline to post-infusion 4 on the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16; n = 190). Secondary measures included QIDS-SR16-measured response and remission rates, changes from baseline to endpoint in Generalized Anxiety Disorder-7 Scale (GAD-7; n = 188) and the Sheehan Disability Scale (SDS; n = 168). Results Significant improvement in total depressive symptoms severity (p Limitations This was a naturalistic, retrospective study, without a control group. Conclusions IV ketamine was safe, well-tolerated, and effective at improving depressive, anxiety, and functional impairment symptoms in a well-characterized cohort of adults with TRD.

As interest has grown in the potential psychiatric applications of ketamine, the number of registered clinical trials has grown substantially. Herein, we summarize and analyze clinical trials registered with ClinicalTrials.gov that assess the treatment of any psychiatric disorder with ketamine or ketamine enantiomers (e.g., S-ketamine, R-ketamine), with a focus on ongoing clinical trials. A ClinicalTrials.gov search on February 21, 2020 returned 140 registered trials. Frequency data was analyzed to determine the distribution of study designs. The majority of trials (70%) investigated the therapeutic effect of ketamine in mood disorders (unipolar: 60%, bipolar: 0.7%, both: 5.7%). Suicidal ideation (13.1%), post-traumatic stress disorder (5.4%), and obsessive-compulsive disorder (3.6%) were also investigated. Intravenous (IV) administration was the most common route with 87% of the studies using IV ketamine. Single-dose studies represented 50% of IV ketamine studies. Few studies were assessing maintenance treatment. Most studies were phase I or II with few definitive phase III trials registered. Given the large number of ongoing studies assessing psychiatric application of ketamine, researchers and relevant stakeholders should consider not only completed, published studies, but also ongoing registered studies in adjudicating the most relevant research questions. More definitive phase III trials and maintenance studies of IV ketamine for mood disorders are required, as numerous completed and ongoing studies have already assessed and demonstrated the proof-of-concept of acute antidepressant effects in phase I and II trials.

The objective of the current study was to assess the association between adverse childhood experiences (ACEs) and irritable bowel syndrome (IBS) in mood disorder patients. Self-report data from the International Mood Disorders Collaborative Project were cross-sectionally analyzed to compare rates of IBS in participants with confirmed diagnoses of major depressive disorder (MDD; n = 279) or bipolar disorder (BD; n = 219). Data was sub-grouped and compared based on history of ACEs. In total, 69 of the 498 participants reported a diagnosis of IBS (13.8%). BD was associated with significantly elevated rates of IBS compared to MDD (18.5% versus 10.1% respectively). After adjusting for age and sex, history of childhood sexual abuse was associated with increased rates of IBS in mood disorder participants [adjusted odds ratio (aOR) = 1.95]. In the MDD subgroup, ACEs (all categories and individual categories) were not associated with increased rates of IBS. In the BD subgroup, history of childhood sexual abuse was associated with significantly increased rates of IBS (38% versus 14%; aOR = 3.7). In summary, BD was associated with a higher prevalence of IBS compared to MDD. Additionally, history of sexual abuse was associated with an increased prevalence of IBS in BD, but not in MDD.

Background: It is well established that deficits in motivation, reward, and cognition are common during and in between syndromal episodes of depression as part of Major Depressive Disorder (MDD). Informed by evidence indicating functional and structural interconnectivity between cognitive and reward brain circuits, we preliminarily evaluate the association between measures of cognitive performance and reward/motivation. Methods: This is a post-hoc analysis of a primary study (i.e. the THINC-it sensitivity to change study). Adults (18–65 years of age) meeting DSM-5 criteria for MDD, single-episode or recurrent confirmed by M.I.N.I. with moderate severity or greater (i.e. Montgomery Asberg Depression Rating Scale ≥20). All eligible subjects received vortioxetine 10–20 mg open-label for 8 weeks. The Effort Expenditure Reward Task (EEfRT) was the principal measure of motivation and reward. We directly compare the effects of cognitive measures and depressive symptoms on effort-based decision-making using the THINC-it composite score and MADRS total score. Results: Twenty-one participants with MDD (Mean age = 38.47, SD = 12.85) and 20 healthy volunteers (Mean age = 41.50, SD = 14.21) completed the optional EEfRT task. Amongst individuals with MDD, performance in processing speed, executive function (i.e. Trails B) and overall composite cognitive score was positively associated with the proportion of hard-task choices in the high reward condition (i.e. greater reward valuation). Across both groups, a greater probability (χ2 = 1.137) and magnitude of reward (χ2 = 0.045) was associated with increased effort (i.e. choosing the hard task more frequently). Using fully factored GEE models, we observed a positive association between performance on the Trails test (β = 2.223, SE = 0.928, p = 0.017) as well as the composite score (β = 0.978, SE = 0.0.459, p = 0.033), and greater effort for high rewards. In addition, it was observed that a positive association (i.e. greater effort for reward in higher probability) was observed with depressive symptoms and overall cognitive measures. Conclusion: Herein, we observed that an association exists between overall cognitive function, notably processing speed and executive function and reward function. Specifically, a greater effort for hard task rewards (using the EEfRT task) was manifested in individuals exhibiting higher levels of cognitive performance in a well-characterized sample of MDD treated with Vortioxetine. Keywords: Motivation, Reward, Anhedonia, MDD, Major depressive disorder, Vortioxetine

Numerous pharmacological treatments for mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased neurotrophic factors all contribute to mood disorder pathophysiology and are therefore treatment targets of interest. Pentoxifylline (PTX) is a phosphodiesterase inhibitor with potent anti-inflammatory and antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in brain derived neurotrophic factor (BDNF) levels. The direct effect of non-specific phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for antidepressant and procognitive effects, however, have yet to be replicated in larger mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in major depressive disorder (MDD), showing clinically and statistically significant antidepressant effects compared to placebo. No studies have assessed PTX in bipolar disorder (BD), where inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement, antidepressant, procognitive and mood stabilizing effects.

Objective— Increased von Willebrand factor (VWF) levels in lungs are associated with diseases such as pulmonary hypertension. The objective of our study was to determine the mechanism of increased VWF levels in conditions, such as hypoxia, which contribute to pulmonary hypertension. Approach and Results— We have previously reported generation of transgenic mice that express LacZ transgene under the regulation of lung- and brain-specific transcriptional regulatory elements of the VWF gene. Hypoxia exposure of these transgenic mice resulted in increased VWF and LacZ mRNA levels as well as redistribution of their expression from primarily larger vessels in the lungs to microvessels. Exposure of cultured lung microvascular endothelial cells to hypoxia demonstrated that VWF upregulation was accompanied by increased platelet binding. Transcription upregulation was mediated through inhibition of the repressor nuclear factor-IB association with the VWF promoter, and increased nuclear translocation of the transcription factor YY1 and association with its cognate binding site on the VWF gene. Knockdown of YY1 expression abolished the hypoxia-induced upregulation and reduced basal level of VWF. Conclusions— These analyses demonstrate that hypoxia induces a phenotypic shift, accompanied by modulation of nuclear factor-IB and YY1 activities, in microvascular endothelial cells of the lungs to support VWF promoter activation.

The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response.

The acute phase response is traditionally characterized by hepatic synthesis of proteins as an inflammatory response to injury, with interleukin-6 (IL-6) being the key mediator. In contrast, microarray studies in human renal transplant implantation biopsies indicate a strong acute phase response in the deceased donor kidney, associated with a significant upregulation of oncostatin M receptor β (OSMR). The aim of this study was to determine whether the kidney can generate a strong acute phase response, mediated by the OSM/OSMR gateway. Genes associated with the IL-6 cytokine family and acute phase reactants were analyzed by real-time RT-PCR in four groups of human biopsies spanning a spectrum of renal injury. OSM, OSMR, and fibrinogen β (FGB) were progressively more highly expressed from prenephrectomy, living donor, deceased donor, to discarded donor kidneys, suggesting correlation with severity of injury and local renal synthesis. Acute phase response gene expression was analyzed in human proximal tubular cells in culture in response to OSM. OSM induced a significant increase in expression of FGB, OSMR, serpin peptidase inhibitor A1, IL-6, and lipopolysaccharide binding protein, and a decrease in IL-6R. These changes were largely attenuated by coincubation with an OSMR blocking antibody, indicating the OSM effect was mediated through OSMR. OSM also resulted in a significantly altered expression of acute phase genes compared with IL-6 or leukemia inhibitory factor, suggesting that OSM is the predominant cytokine mediating the renal tubular acute phase response. In conclusion, the renal parenchyma is capable of generating a strong acute phase response, likely mediated via OSM/OSMR.

The Philadelphia (Ph) chromosome, or t(9;22), is the hallmark of chronic myelogenous leukemia (CML). It results in juxtaposition of the 5' part of the BCR gene on chromosome 22 to the 3' part of the ABL1 gene (previously ABL) on chromosome 9. CML is clinically characterized by three distinct phases: chronic, accelerated, and blast phase. Blast crisis is characterized by the rapid expansion of a population of differentiation arrested blast cells (myeloid or lymphoid cells population), with secondary chromosomal abnormalities present. We report a case of myeloid blast crisis of CML resistant to imatinib mesylate and chemotherapy. By use of cytogenetic, fluorescence in situ hybridization, and comparative genomic hybridization methods, we identified a cluster of BCR-ABL amplification on inverted duplication of the Ph chromosome with t(3;21)(q26;q22) and increased genomic levels of the RUNX1 gene (previously AML1). The t(3;21)(q26;q22) is a recurrent chromosomal abnormality in some cases of CML blast phase and in treatment-related myelodysplastic syndrome and acute myeloid leukemia. Amplification or copy number increase of RUNX1 has been reported in childhood acute lymphoblastic leukemia. Our study indicated that the progenitor of CML was BCR-ABL dependent through the amplification of Ph chromosome as a mechanism of resistance to imatinib therapy. The coexistence of BCR-ABL and t(3;21)(q26;q22) with RUNX1 rearrangement might play a pivotal role in the CML blast transformation.

Recurrent vulvovaginal candidiasis affects women worldwide and the resistance to azole drugs may be an important factor. The extent of strain-to-strain variation within a species and its relationship to the ability of the organism to colonize the vulvovaginal mucosa is not well established. The aims of this study were to compare: (i) the genotypes of Candida strains in sequential infections in patients with recurrent vaginitis, (ii) the genotypes of strains in patients with only one episode of infection in a period of 1 year and (iii) determine the in vitro antifungal susceptibilities of strains that cause recurrent vaginitis. Fifty-one cultured specimens from six distinct Candida species were genotyped via random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) method using the ERIC1 and ERIC2 primers (ERIC, enterobacterial repetitive intergenic consensus). Statistical analyses allowed three different scenarios to be discerned for recurrent cases: (i) strain maintenance without genetic variation, (ii) strain maintenance with minor genetic variation and (iii) outright strain replacement. The genetic relatedness between strains from patients with recurrent vaginitis and patients with single episode of vaginitis were demonstrated by the dendogramme and the mean pairwise similarity coefficient S(AB) for the intergroup comparison was 0.223. However, intragroup genetic relatedness was slightly higher than intergroup comparison, with mean S(AB) of 0.261 and 0.331 for Groups I and II, respectively. A high proportion of Group I isolates (87.5%) causing recurrent infections were resistant to ketoconazole, whereas 41.7% of these isolates were cross-resistant to both clotrimazole and ketoconazole as shown by the in vitro antifungal susceptibility test, especially for C. glabrata isolates. Pregnancy status of patients displayed a highly significant association with C. albicans species whereas non-albicans species had a markedly higher prevalence in non-pregnant patients (p