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Dear Editor, In the present study, we delineate the molecular pathways underlying atypical progressions of Gaucher disease (GD) that lead to unresponsiveness to enzyme replacement therapy (ERT). (B) Eight distinct protein clusters with different expression profiles in Pt1 GD1 T, Pt3 GD3 T and Pt 3 GD3 AT. Likewise, compared with that in untreated GD2/3 patients, the plasma level of TGF- was lower in GD3 patients who had been treated with high-dose ambroxol for 2 or more years10 (Figure 4C). (C) Heatmap and hierarchical clustering of the proteomic analysis data from Pt1 GD1 T, Pt3 GD3 T and Pt 3 GD3 AT. [Extracted from the article]

Background: The association between impaired social cognition and bipolar disorder (BD) is well established. However, to our knowledge, there has not been a recent systematic review that characterizes disparate dimensions of social cognition in BD. Herein, this systematic review and meta‐analysis aimed to synthesize the literature on core aspects of social cognition (i.e., Theory of Mind, emotion recognition, and social judgment) to identify potential areas of impairment. Methods: Online databases (i.e., PubMed, Cochrane Libraries, PsycINFO) and Google Scholar were searched from inception to May 2021. Studies with populations ages ≥16 with DSM‐IV or DSM‐5 defined BD (I or II) either in a euthymic or symptomatic state were included. The risk of bias was measured using the ROBINS‐1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively measured by synthesizing Hedge's g effect sizes through a random effects meta‐analytic approach. Results: A total of 29 studies were included in the final review (i.e., 12 studies on the Theory of Mind, 11 on emotion recognition, and 6 on social judgment). Overall, results demonstrated social cognition to be moderately impaired in individuals with BD (d = 0.59). The individual domains ranged in effect size (0.38 < d < 0.70), providing evidence for variation in impairment within social cognition. Discussion: Individuals with BD exhibit clinically significant deficits in social cognition during euthymic and symptomatic states. Social cognition impairments in individuals with BD are an important therapeutic target for treatment discovery and development. [ABSTRACT FROM AUTHOR]

Summary: Sleep disturbances are commonly reported in patients with treatment‐resistant depression (TRD). Available data have shown that intravenous (IV) ketamine is an effective treatment for patients with TRD and growing data suggest ketamine may improve overall sleep architecture. In the present study, we evaluated whether changes in sleep symptoms mediated the anti‐depressive and/or anti‐suicidal effects of IV ketamine and whether improvement in sleep correlated with a higher likelihood of achieving response or remission. Adults with TRD received four infusions of IV ketamine at a community‐based clinic. Total depressive symptom severity was measured with the Quick Inventory Depressive Symptoms Self‐Report 16‐Item (QIDS‐SR16) at baseline and was repeated across four infusions. Suicidal ideation (SI) and four sleep symptoms were measured using the SI item and the five sleep items on the QIDS‐SR16. A total of 323 patients with TRD received IV ketamine. Self‐reported improvements in insomnia, night‐time restlessness, hypersomnia, early morning waking, and total sleep were significant partial mediators to the improvements observed in depression severity. Similarly, insomnia, night‐time restlessness, early morning waking and total sleep improvements mediated the reduction of IV ketamine on SI. All sleep items, except for hypersomnia, were associated with an increased likelihood of achieving response or remission. Notably, each point improvement in total sleep score was significantly associated with achieving responder/remitter status (odds ratio 3.29, 95% confidence interval 2.00–5.41). Insomnia, sleep restlessness, early morning waking and total sleep improvements were significant mediators of antidepressant and anti‐suicidal improvements in patients with TRD receiving IV ketamine. [ABSTRACT FROM AUTHOR]

Summary: Most extremophilic anaerobes possess a sulfur formation (Suf) system for Fe–S cluster biogenesis. In addition to its essential role in redox chemistry and stress responses of Fe–S cluster proteins, the Suf system may play an important role in keratin degradation by Fervidobacterium islandicum AW‐1. Comparative genomics of the order Thermotogales revealed that the feather‐degrading F. islandicum AW‐1 has a complete Suf‐like machinery (SufCBDSU) that is highly expressed in cells grown on native feathers in the absence of elemental sulfur (S0). On the other hand, F. islandicum AW‐1 exhibited a significant retardation in the Suf system‐mediated keratin degradation in the presence of S0. Detailed differential expression analysis of sulfur assimilation machineries unveiled the mechanism by which an efficient sulfur delivery from persulfurated SufS to SufU is achieved during keratinolysis under sulfur starvation. Indeed, addition of SufS–SufU to cell extracts containing keratinolytic proteases accelerated keratin decomposition in vitro under reducing conditions. Remarkably, mass spectrometric analysis of extracellular and intracellular levels of amino acids suggested that redox homeostasis within cells coupled to extracellular cysteine and cystine recycling might be a prerequisite for keratinolysis. Taken together, these results suggest that the Suf‐like machinery including the SufS–SufU complex may contribute to sulfur availability for an extracellular reducing environment as well as intracellular redox homeostasis through cysteine released from keratin hydrolysate under starvation conditions. [ABSTRACT FROM AUTHOR]

EVIDENCE, an automated variant prioritization system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. DNA from 330 probands (age range, 0‐68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. EVIDENCE reported a total 228 variants in 200 (60.6%) of the 330 probands. The average number of organs involved per patient was 4.5 ± 5.0. After clinical reassessment and/or family member testing, 167 variants were identified in 141 probands (42.7%), including 105 novel variants. These variants were confirmed as being responsible for 121 genetic disorders. A total of 103 (61.7%) of the 167 variants in 95 patients were classified as pathogenic or probably to be pathogenic before, and 161 (96.4%) variants in 137 patients (41.5%) after, clinical assessment and/or family member testing. Factor associated with a variant being regarded as causative includes similar symptom scores of a gene variant to the phenotype of the patient. This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 42.7% diagnostic yield. [ABSTRACT FROM AUTHOR]

Objective: To determine the effectiveness of intravenous (IV) ketamine on anxiety, irritability, agitation, and suicidality, in adults with treatment‐resistant major depressive disorder (MDD) or bipolar disorder (BD). Method: Adults (N = 201) with treatment‐resistant MDD or BD received repeat‐dose IV ketamine treatment at a community‐based clinic. Mixed features were measured using symptoms of anxiety, irritability, and agitation (AIA), as measured by the Generalized Anxiety Disorder‐7 (GAD‐7) scale. The Quick Inventory for Depressive Symptomatology Self‐Report‐16 (QIDS‐SR16) was used to measure overall treatment response, and the QIDS‐SR16 suicidal ideation (SI) item was used to measure change in SI symptoms with ketamine treatment. The anxiety, irritability, and agitation items on the GAD‐7 were used to assess effectiveness of IV ketamine in treating symptoms of mixed features. Results: In this retrospective analysis, 113 participants met AIA criteria. Participants with AIA experienced a significantly greater reduction in overall depressive symptoms (F(1, 558) = 9.49, P =.002), SI (F(1, 558) = 3.103, P =.079), anxiety (F(1, 198) = 5.52, P =.007), irritability (F(1, 198) = 28.35, P <.001), and agitation as measured by "trouble relaxing" (F(1, 198) = 6.70, P =.010) from baseline compared to the non‐AIA group, regardless of number of treatments received. Conclusions: Our preliminary results suggest that IV ketamine is effective in rapidly treating AIA and SI in adults with treatment‐resistant mood disorders. This observation suggests that IV ketamine could be considered a treatment alternative for adults with MDD or BD presenting with mixed features. [ABSTRACT FROM AUTHOR]

Antidepressant medications are the first-line treatment option for moderate to severe major depressive disorder. However, most antidepressants have numerous documented adverse events, including cardiometabolic effects and weight gain, which are major public health concerns. Antidepressant agents provide varying risk of associated weight gain, including significant within-class differences. Some agents, such as mirtazapine, show significant levels of weight gain, while others, such as bupropion, demonstrate weight-loss effects. Current findings suggest the role of histamine and serotonin off-target appetite-promoting pathways in adverse weight-gain effects. Therefore, controlling for undesired weight effects is an important consideration for the selection of antidepressants. [ABSTRACT FROM AUTHOR]

Objectives: Metabolically based distinctions for disturbances in glucose and insulin may provide meaningful insights both clinically and mechanistically. Methods: Data were derived from 352 subjects of previously completed clinical studies with a mood disorder (MD) (bipolar disorder: n = 179, major depressive disorder: n = 173) and 218 healthy controls from the Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy. We conducted a factor analysis to replicate a priori dissociable factors informed by glucose and insulin levels and indices of insulin resistance and beta‐cell function: elevated insulin and insulin resistance ("insulin‐IR"), and increased fasting glucose and reduced insulin secretion ("glucotoxicity"). Cluster analyses were conducted, separately in men and women, to evaluate the clinical relevance of subtyping individuals with MDs using insulin‐IR and glucotoxicity (GT) factor scores. Results: Factors insulin‐IR and GT explained 92.64% and 92.09% of the variance in men and women respectively. Three clusters were replicated in men and women separately: metabolically healthy (MH), high GT, and insulin‐resistant (IR). After adjusting for age, gender, study cohort, MD diagnosis, and antipsychotics use, body mass index (BMI) and mean arterial pressure were higher in IR‐ vs GT‐ or MH‐clustered individuals; GT‐clustered individuals had more metabolic syndrome components and higher C‐reactive protein. Glucotoxic‐clustered subjects reported greater impairments in cognitive function and global functioning when compared to MH‐ or IR‐clustered subjects. Conclusions: Using simple, cost‐effective, and accessible measures, we identified stable, gender‐convergent, subgroups of individuals that significantly diverged on measures of cognitive dysfunction, self‐reported anhedonia, functional disability, BMI, and blood pressure. [ABSTRACT FROM AUTHOR]

Objective: The association between antipsychotic use and gastric cancer risk remains unclear. Therefore, this study aimed to determine the association between antipsychotic exposure and the incidence of gastric cancer. Methods: Using a nested case‐control design, a total of 34 470 gastric cancer patients and 163 430 nongastric cancer controls were identified from Taiwan's National Health Insurance Research Database between 1 January 1997 and 31 December 2013. We analyzed the data using a conditional logistic regression model to adjust for possible confounding variables. Results: Antipsychotic use was independently inversely associated with gastric cancer risk after controlling for potential confounding factors including income, urbanization, medications, physical and medical illness, aspirin use, nonsteroidal anti‐inflammatory drug use and triple therapy. In addition, dose‐dependent trends against gastric cancer risk were also shown with individual antipsychotic compounds including thioridazine, haloperidol, sulpiride, clozapine, olanzapine, quetiapine, amisulpride, and risperidone. A sensitivity analysis showed that second‐generation antipsychotics had significant dose‐dependent effects in reducing the risk of gastric cancer risk in patients with and without peptic ulcer disease. Conclusions: Antipsychotic use was inversely associated with gastric cancer risk, and dose‐dependent effects against gastric cancer were also seen with several individual antipsychotic compounds. [ABSTRACT FROM AUTHOR]

It has been encouraged to use large existing data like insurance claims data to investigate the new indications of old drugs. New strategies of research are warranted to identify feasible drugs. We conducted a dual research model with a population‐based case–control study using Taiwan's National Health Insurance Research Database and an in vitro study to investigate the association between atypical antipsychotic and Hepatocellular carcinoma (HCC) risk. The study herein consists of two components. The first is a population‐based case–control study using existing data from the Taiwan National Health Insurance Research Database. The second component was an in vitro study in which HCC cell lines (Huh7 and Hep G2) were treated with risperidone, quetiapine and clozapine. after treatment of the foregoing antipsychotics, the HCC cell lines were assessed for cell proliferation, invasion and apoptosis. Multivariate conditional logistic regression analysis revealed that antipsychotic use was independently and inversely associated with HCC risk (adjusted odds‐ratio [aOR]:0.85, 95% CI: 0.81–0.89). The protective effect was dose‐dependent: compared to the low cumulative defined daily dose (cDDD) group (0–29 cDDD), the 30–89 cDDD and ≥90 cDDD groups were associated with significantly reduced risk for HCC (aOR: 0.56, 95% CI: 0.41–0.76; aOR: 0.37, 95% CI: 0.27–0.50, respectively). In vitro study results indicated that risperidone, quetiapine and clozapine significantly inhibited cell proliferation, invasion and induced apoptosis in human HCC cell lines. Our results herein suggested that antipsychotic use might reduce the risk of HCC and may provide evidence for new uses of old drugs. What's new? The identification of novel applications for existing drugs potentially reduces costs associated with drug discovery and development. Data on candidate drugs and their potential uses in cancer therapy, however, are limited. Here, the authors analyzed data from the Taiwan National Health Insurance Research Database to investigate the repurposing of antipsychotic drugs against hepatocellular carcinoma (HCC). A subset of antipsychotics was negatively associated with HCC risk. In vitro, the candidate drugs risperidone, quetiapine, and clozapine inhibited proliferation and migration and induced apoptosis in HCC cells. The findings suggest that atypical antipsychotics may have a dual role as anti‐cancer drugs. [ABSTRACT FROM AUTHOR]

This study (registered with PROSPERO, CRD42018085967) compares the efficacy (i.e. pro‐cognitive effects) and acceptability of antidiabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials comparing antidiabetic agents with placebo and/or another active antidiabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4855) evaluating the effects of 6 different antidiabetic drugs (i.e. intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo. Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta‐analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro‐cognitive class effect of antidiabetic agents in AD/MCI. Other antidiabetic agents should also be investigated in future studies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: There is a need for a brief, reliable, valid, and sensitive assessment tool for screening cognitive deficits in patients with Major Depressive Disorders. This paper examines the psychometric characteristics of THINC‐it, a cognitive assessment tool composed of four objective measures of cognition and a self‐rated assessment, in subjects without mental disorders. Methods: N = 100 healthy controls with no current or past history of depression were tested on four sequential assessments to examine temporal stability, reliability, and convergent validity of the THINC‐it tests. We examined temporal reliability across 1 week and stability via three consecutive assessments. Consistency of assessment by the study rater (intrarater reliability) was calculated using the data from the second and third of these consecutive assessments. Results: Test–retest reliability correlations varied between Pearson's r = 0.75 and 0.8. Intrarater reliability between 0.7 and 0.93. Stability for the primary measure for each test yielded within‐subject standard deviation values between 5.9 and 11.23 for accuracy measures and 0.735 and 17.3 seconds for latency measures. Convergent validity for three tasks was in the acceptable range, but low for the Symbol Check task. Conclusions: Analysis shows high levels of reliability and stability. Levels of convergent validity were modest but acceptable in the case of all but one test. [ABSTRACT FROM AUTHOR]

Objectives: To compare frontal‐striatal brain volumes between offspring of individuals with bipolar disorder (BD) and healthy controls; to investigate the associations of body mass index (BMI) and age with brain volumes; and to assess the moderating effects of BMI and age on the relationship between risk status and structural brain differences. Methods: We cross‐sectionally assessed structural regional and global brain volumes using magnetic resonance imaging and BMI among 53 BD offspring subjects, stratified by risk status, and 23 non‐BD offspring controls (aged 8‐28 years). Analyses of variance and covariance and linear regression analyses were conducted to investigate the associations between BMI and measures of brain volume, as well as the interaction effects between age, BMI, and risk status on brain volumes. Results: After adjusting for age, sex, and intracranial volume, higher BD risk status was associated with lower bilateral cerebellar cortical and right pars orbitalis volumes. Higher BMI was significantly associated with greater brain volumes in frontal and subcortical structures. A significant interaction effect between BMI and risk status was observed in right middle frontal volume. The moderating effect of BMI on brain volume was most robustly observed among subjects aged 14‐19 years and less robustly observed among those aged 20‐28 years; BMI and brain volumes were negatively correlated among subjects aged 8‐13 years. Conclusions: Alterations in brain structures in individuals at risk for BD may be moderated by BMI. Obesity among individuals with a family history of BD may confer additional risk, particularly in mid‐adolescence. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the second leading cancer-related cause of mortality worldwide. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), are commonly used worldwide. Available evidence investigating the association between SSRIs use and HCC risk is limited.Objective: The present study aimed to investigate if the effect of all kinds of SSRIs on HCC was the same or not using population-based study.Methods: The nationwide population-based study herein using Taiwan's National Health Insurance Research Database included a total of 59 859 cases with HCC and 285 124 matched controls. Conditional logistic regression analyses were adjusted for confounding variables.Results: All common kinds of SSRIs including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine were associated with lower HCC risk, and the findings were dose-dependent (eg, fluoxetine: 1-28 DDD [defined daily dose]: adjusted odds ratio [aOR]: 0.81, 95% confidence interval [CI], 0.73-0.89; 29-365 DDD: aOR: 0.71, 95% CI, 0.64-0.79; and ≥366 DDD: aOR: 0.55, 95% CI, 0.45-0.67) (P for trend < .001).Conclusions: All kinds of SSRIs were associated with decreased risk of HCC. [ABSTRACT FROM AUTHOR]

Background The burden of illness associated with bipolar disorder ( BD) warrants early pre-emption/prevention. Prediction models limited to psychiatric phenomenology have insufficient predictive power. Herein, we aimed to evaluate whether the presence of overweight/obesity is associated with greater cognitive decline in individuals at high risk ( HR) or ultra high risk ( UHR) for BD. Methods We conducted a retrospective analysis to investigate the moderational role of body mass index ( BMI) on measures of cognitive function. Subjects between the ages of 8 and 28 years with a positive family history of BD were compared to age-matched controls with a negative family history of BD. Subjects with at least one biological parent with bipolar I/ II disorder were further stratified into UHR or HR status by the presence or absence, respectively, of subthreshold hypomanic, major depressive, attenuated psychotic, and/or attention-deficit/hyperactivity disorder symptoms. Results A total of 36 individuals at HR for BD, 33 individuals at UHR for BD, and 48 age-matched controls were included in the analysis. Higher BMI was significantly associated with lower performance on measures of processing speed (i.e. Brief Assessment of Cognition in Schizophrenia−symbol coding: r=−.186, P=.047) and attention/vigilance (i.e. Continuous Performance Test−Identical Pairs: r=−.257, P=.006). There were trends for negative correlations between BMI and measures of working memory (i.e. Wechsler Memory Scale- III Spatial Span: r=−0.177, P=.059) and overall cognitive function (i.e. Measurement and Treatment Research to Improve Cognition in Schizophrenia composite score: r=−.157, P=.097). Negative associations between BMI and cognitive performance were significantly stronger in the UHR group than in the HR group, when compared to controls. Conclusions Individuals at varying degrees of risk for BD exhibit greater cognitive impairment as a function of co-existing overweight/obesity. Prediction models for BD may be substantively informed by including information related to overweight/obesity and, perhaps, other general medical conditions that share pathology with BD. Our findings herein, as well as the salutary effects of bariatric surgery on measures of cognitive function in obese populations, provide the rationale for hypothesizing that mitigating excess weight in individuals at elevated risk for BD may forestall or prevent declaration of illness. [ABSTRACT FROM AUTHOR]

ABSTRACT In 2012, the 'Framework Act on Cooperatives' was legislated and about 7,500 co-operatives have been newly established in Korea. However, most of them are small, less competitive, and less skilled in management. In addition, they have difficulties in obtaining financial and management support from other organizations due to the lack of general awareness about co-operatives in Korea. To assist these co-operatives, secondary self-formed organizations composed of co-operatives have been created. This study explores the characteristics of these organizations and proposes possible models and strategies for cooperation among co-ops through these secondary organizations. In detail, we explore (1) the cooperation model to encourage collaboration among co-ops, (2) the roles and possibilities of secondary organizations to activate this cooperation model, and (3) the specific strategies and challenges for a more accessible cooperation model. To answer these questions, we conduct focus group and in-depth interviews with member and non-member co-ops in the Guro Community Association of Co-operatives, which is a self-organized secondary association in the Guro district in Seoul. Based on the interviews, we tried to find out their needs and the possibility for cooperation among co-ops at the level of the association. Also, we drew a conceptual cooperation model and its specific strategies through the association from theoretical review and interviews. [ABSTRACT FROM AUTHOR]