Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

BACKGROUND: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. RESULTS: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. CONCLUSIONS: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase.

Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Isatin-indoloquinoxaline click adducts with a potential to overcome platinum-based drug-resistance in ovarian cancer.

Herein, a series of isatin tethered indolo[2,3-b]quinoxaline hybrids was synthesized by considering the pharmacophoric features of known DNA intercalators and topoisomerase II inhibitors. The anti-proliferative properties of the synthesized compounds were evaluated against ovarian cancer cell lines (SKOV-3 and Hey A8). Four of the compounds exhibited promising anti-proliferative activities, with one of them being 10-fold more potent than cisplatin against drug-resistant Hey A8 cells. Further investigations were carried out to determine the DNA intercalating affinities of the most active compounds as potential mechanisms for their anti-proliferative activities. ADMET in silico studies were performed to assess the physicochemical, pharmacokinetics, and toxicity parameters of active compounds. This study, to the best of our knowledge, is the first report on the potential of isatin-indoloquinoxaline hybrids as structural blueprints for the development of new DNA intercalators. Additionally, it explores their potential to circumvent platinum-based resistance in ovarian cancer.

Theoretical and Anti-Klebsiella pneumoniae Evaluations of Substituted 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide and Imidazopyridine Hydrazide Derivatives.

A series of multistep synthesis protocols was adopted to synthesize substituted imidazopyridines (IMPs) (SM-IMP-01 to SM-IMP-13, and DA-01-05). All substituted IMPs were then characterized using standard spectroscopic techniques such as 1H-NMR, 13C-NMR, elemental analyses, and mass spectrometry. Our both in vitro qualitative and quantitative results for antibacterial analysis, against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 6051 suggested that all compounds essentially exhibited activity against selected strains of bacteria. Our DFT analyses suggested that the compounds of the SM-IMP-01-SM-IMP-13 series have HOMO/LUMO gaps within 4.43-4.69 eV, whereas the compounds of the DA-01-DA-05 series have smaller values of the HOMO/LUMO gaps, 3.24-4.17 eV. The lowest value of the global hardness and the highest value of the global softness, 2.215 and 0.226 eV, respectively, characterize the compound SM-IMP-02; thus, it is the most reactive compound in the imidazopyridine carboxamide series (except hydrazide series). This compound also depicted lesser MIC values against Klebsiella pneumoniae ATCC 4352 and Bacillus subtilis ATCC 6051 as 4.8 µg/mL, each. In terms of another series, hydrazide DA-05 depicted strong antimicrobial actions (MIC: 4.8 µg/mL against both bacterial strains) and also had the lowest energy gap (3.24 eV), higher softness (0.309 eV), and lesser hardness (1.62 eV). Overall, when we compare qualitative and quantitative antimicrobial results, it is been very clear that compounds with dibromo substitutions on imidazopyridine (IMP) rings would act as better antimicrobial agents than those with -H at the eighth position on the IMP ring. Furthermore, substituents of higher electronegativities would tend to enhance the biological activities of dibromo-IMP compounds. DFT properties were also well comparable to this trend and overall, we can say that the electronic behavior of compounds under investigation has key roles in their bioactivities.

Chemical Composition, Preliminary Toxicity, and Antioxidant Potential of Piper marginatum Sensu Lato Essential Oils and Molecular Modeling Study.

The essential oils (OEs) of the leaves, stems, and spikes of P. marginatum were obtained by hydrodistillation, steam distillation, and simultaneous extraction. The chemical constituents were identified and quantified by GC/MS and GC-FID. The preliminary biological activity was determined by assessing the toxicity of the samples to Artemia salina Leach larvae and calculating the mortality rate and lethal concentration (LC50). The antioxidant activity of the EOs was determined by the DPPH radical scavenging method. Molecular modeling was performed using molecular docking and molecular dynamics, with acetylcholinesterase being the molecular target. The OES yields ranged from 1.49% to 1.83%. The EOs and aromatic constituents of P. marginatum are characterized by the high contents of (E)-isoosmorhizole (19.4-32.9%), 2-methoxy-4,5-methylenedioxypropiophenone (9.0-19.9%), isoosmorhizole (1.6-24.5%), and 2-methoxy-4,5-methylenedioxypropiophenone isomer (1.6-14.3%). The antioxidant potential was significant in the OE of the leaves and stems of P. marginatum extracted by SD in November (84.9 ± 4.0 mg TE·mL-1) and the OEs of the leaves extracted by HD in March (126.8 ± 12.3 mg TE·mL-1). Regarding the preliminary toxicity, the OEs of Pm-SD-L-St-Nov and Pm-HD-L-St-Nov had mortality higher than 80% in concentrations of 25 µg·mL-1. This in silico study on essential oils elucidated the potential mechanism of interaction of the main compounds, which may serve as a basis for advances in this line of research.

Use of Direct-to-Consumer Telemedicine to Access Mental Health Services.

BACKGROUND: The coronavirus disease 2019 pandemic has contributed to growing demand for mental health services, but patients face significant barriers to accessing care. Direct-to-consumer(DTC) telemedicine has been proposed as one way to increase access, yet little is known about its pre-pandemic use for mental healthcare. OBJECTIVE: To characterize patients, providers, and their use of a large nationwide DTC telemedicine platform for mental healthcare. DESIGN: Retrospective cross-sectional study. SETTING: Mental health encounters conducted on the American Well DTC telemedicine platform from 2016 to 2018. PARTICIPANTS: Patients and physicians. MAIN MEASURES: Patient measures included demographics, insurance report, and number of visits. Provider characteristics included specialty, region, and number of encounters. Encounter measures included wait time, visit length and timing, out-of-pocket payment, coupon use, prescription outcome, referral receipt, where care otherwise would have been sought, and patient satisfaction. Factors associated with five-star physician ratings and prescription receipt were assessed using logistic regression. KEY RESULTS: We analyzed 19,270 mental health encounters between 6708 patients and 1045 providers. Visits were most frequently for anxiety (39.1%) or depression (32.5%), with high satisfaction (4.9/5) across conditions. Patients had a median 2.0 visits for psychiatry (IQR 1.0-3.0) and therapy (IQR 1.0-5.0), compared to 1.0 visit (IQR 1.0-1.0) for urgent care. High satisfaction was positively correlated with prescription receipt (OR 1.89, 95% CI 1.54-2.32) and after-hours timing (aOR 1.18, 95% CI 1.02-1.36). Prescription rates ranged from 79.6% for depression to 32.2% for substance use disorders. Prescription receipt was associated with increased visit frequency (aOR 1.95, 95% CI 1.57-2.42 for ≥ 3 visits). CONCLUSIONS: As the burden of psychiatric disease grows, DTC telemedicine offers one solution for extending access to mental healthcare. While most encounters were one-off, evidence of some continuity in psychiatry and therapy visits-as well as overall high patient satisfaction-suggests potential for broader DTC telemental health use.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

Prospective evaluation of sleep disturbances in chronic pancreatitis and its impact on quality of life: a pilot study.

BACKGROUND: Patients with chronic pancreatitis (CP) have poor quality of life (QOL). Sleep disorders affect QOL when associated with chronic pain and opioid use. Hence patients with CP may have unrecognized sleep disturbances. AIMS: The aim of the study was to evaluate sleep disturbances in CP and its impact on QOL. METHODS: Established CP patients were prospectively enrolled after exclusion of patients with co-morbidities known to negatively affect sleep and QOL. Three questionnaires were used to identify sleep disturbances, PROMISv1SF8, Insomnia Severity Index, and Epworth Sleepiness Scale, and one for restless leg syndrome (RLS). PANQOLI and SF12 questionnaires were used to evaluate QOL. Two blinded sleep pulmonologists evaluated the responses. QOL assessments were then analyzed in patients with and without sleep disturbances. RESULTS: Of 89 patients, 48 met exclusion criteria, 41 were eligible, and 28 completed the study. Twenty patients (71%) had sleep disturbances with significantly worse scores across all 3 sleep questionnaires and also had lower scores on both PANQOLI (50 vs 76, p = 0.002) and SF-12 (physical component 29.3 vs 53.9, p < 0.001; mental component 36.4 vs 46.1, p = 0.03). Eleven patients (39%) had RLS and sleep disturbances. CONCLUSION: In patients with established CP there was a high prevalence of sleep disturbances and RLS with worse QOL representing a potential therapeutic target to improve QOL.

A qualitative assessment of perceptions and attitudes toward postoperative pain and opioid use in patients undergoing elective knee arthroscopy.

BACKGROUND: Orthopedic surgeons routinely prescribe opioids to manage post-operative pain. In the face of an opioid epidemic, a one-size-fits-all approach to pain management is no longer appropriate. Patient-centred prescribing practices should be used by surgeons; however, little is known about what influences patient attitudes toward postoperative pain and its management to inform such practices. We sought to explore patient attitudes toward postsurgical pain management, including opioids. METHODS: We conducted qualitative, semistructured interviews of 11 opioid-naive patients (age 16-46 yr) who were scheduled to undergo arthroscopic knee surgery. Transcripts were analyzed thematically using a framework analysis that involved familiarization, developing a thematic framework, indexing, charting and mapping, and interpretation. RESULTS: Participant attitudes toward postoperative pain and opioids were influenced by perceived tolerance to pain based on personal experience, perceived predisposition to addiction based on personal assumptions regarding addictive personality traits and risk factors, and perceptions of opioid use shaped by external influences, including family, friends and the media's depiction of the opioid epidemic. Every patient expressed that preoperative counselling and education regarding postoperative pain management would be beneficial in improving their knowledge base, easing anxieties and clarifying misunderstandings. CONCLUSION: Surgeons can address the patient-reported factors identified in this study to help optimize a patient's perioperative experience without relying solely on prescribed analgesia. By improving accessibility to education and promoting safe, patient-centred prescribing practices, we may reduce reliance on opioids in orthopedic surgery.

Mid-term outcomes of the Wagner Cone Prosthesis™ stem for developmental dysplasia of the hip: minimum two year follow-up.

PURPOSE: Treatment of symptomatic developmental dysplasia of the hip (DDH) requires a technically demanding total hip arthroplasty (THA) reconstruction. In patients with DDH, prostheses can be difficult to implant and often face the risk of fracture, mismatch, and loosening. The Wagner Cone Prosthesis™ is a tapered, conical stem which can improve treatment success in this population. We look at midterm survivorship and outcomes of THA for DDH using the Wagner Cone Prosthesis™. METHODS: We retrospectively analyzed 28 patients (33 hips) with DDH undergoing THA using the Wagner Cone Prosthesis™ between January 2008 and January 2020. Ten, nine, and fourteen included patients were classified as Hartofilakidis A, B, and C, respectively. Survivorship according to Kaplan-Meier analysis was the primary outcome, with re-operation and revision as endpoints. The Oxford hip score (OHS) was used to assess clinical outcome. We used multivariate analysis to determine predictors of poor outcomes. The average follow-up was 4.6 years, with a minimum of two years. RESULTS: Kaplan-Meier survivorship over the 13-year study period was 93.9 ± 4.2% for all-cause revision as an endpoint and 96.9 ± 3.1% for stem revisions only. The overall reoperation rate was 6.1%, with periprosthetic fracture and dislocation being reasons for re-operation. No patients were revised for aseptic loosening, and no patients were revised for subsidence. OHS improved from 19.3 ± 9.6 (4-39) pre-operatively to 37.6 ± 8.4 (19-48) at latest follow-up (p < 0.05). CONCLUSION: In patients with DDH, THA with the Wagner Cone Prosthesis™ demonstrates excellent clinical, radiographic, and patient-reported functional outcomes at midterm follow-up.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Identification and stratification of systemic lupus erythematosus patients into two transcriptionally distinct clusters based on IFN-I signature.

OBJECTIVE: Despite the significant advancement in the understanding of the pathophysiology of systemic lupus erythematosus (SLE) variable clinical response to newer therapies remain a major concern, especially for patients with lupus nephritis and neuropsychiatric systemic lupus erythematosus (NPSLE). We performed this study with an objective to comprehensively characterize Indian SLE patients with renal and neuropsychiatric manifestation with respect to their gene signature, cytokine profile and immune cell phenotypes. METHODS: We characterized 68 Indian SLE subjects with diverse clinical profiles and disease activity and tried to identify differentially expressed genes and enriched pathways. To understand the temporal profile, same patients were followed at 6 and 12-months intervals. Additionally, auto-antibody profile, levels of various chemokines, cytokines and the proportion of different immune cells and their activation status were captured in these subjects. RESULTS: Multiple IFN-related pathways were enriched with significant increase in IFN-I gene signature in SLE patients as compared to normal healthy volunteers (NHV). We identified two transcriptionally distinct clusters within the same cohort of SLE patients with differential immune cell activation status, auto-antibody as well as plasma chemokines and cytokines profile. CONCLUSIONS: Identification of two distinct clusters of patients based on IFN-I signature provided new insights into the heterogeneity of underlying disease pathogenesis of Indian SLE cohort. Importantly, patient within those clusters retain their distinct expression dynamics of IFN-I signature over the time course of one year despite change in disease activity. This study will guide clinicians and researchers while designing future clinical trials on Indian SLE cohort.

The Impact of Systematic Depression Screening in Primary Care on Depression Identification and Treatment in a Large Health Care System: A Cohort Study.

BACKGROUND: Unless implementation of systematic depression screening is associated with timely treatment, quality measures based on screening are unlikely to improve outcomes. OBJECTIVE: To assess the impact of integrating systematic depression screening with clinical decision support on depression identification and treatment. DESIGN: Retrospective pre-post study. PARTICIPANTS: Adults with a primary care visit within a large integrated health system in 2016 were included. Adults diagnosed with depression in 2015 or prior to their initial primary care visit in 2016 were excluded. INTERVENTION: Initiation of systematic screening using the Patient Health Questionnaire (PHQ) which began in mid-2016. MAIN MEASURES: Depression diagnosis was based on ICD codes. Treatment was defined as (1) antidepressant prescription, (2) referral, or (3) evaluation by a behavioral health specialist. We used an adjusted linear regression model to identify whether the percentage of visits with a depression diagnosis was different before versus after implementation of systematic screening. An adjusted multilevel regression model was used to evaluate the association between screening and odds of treatment. KEY RESULTS: Our study population included 259,411 patients. After implementation, 59% of patients underwent screening. Three percent scored as having moderate to severe depression. The rate of depression diagnosis increased by 1.2% immediately after systematic screening (from 1.7 to 2.9%). The percent of patients with diagnosed depression who received treatment within 90 days increased from 64% before to 69% after implementation (p < 0.01) and the adjusted odds of treatment increased by 20% after implementation (AOR 1.20, 95% CI 1.12-1.28, p < 0.01). CONCLUSIONS: Implementing systematic depression screening within a large health care system led to high rates of screening and increased rates of depression diagnosis and treatment.

Digital conversations about suicide among teenagers and adults with epilepsy: A big-data, machine learning analysis.

OBJECTIVE: Digital media conversations can provide important insight into the concerns and struggles of people with epilepsy (PWE) outside of formal clinical settings and help generate useful information for treatment planning. Our study aimed to explore the big data from open-source digital conversations among PWE with regard to suicidality, specifically comparing teenagers and adults, using machine learning technology. METHODS: Advanced machine-learning empowered methodology was used to mine and structure open-source digital conversations of self-identifying teenagers and adults who endorsed suffering from epilepsy and engaged in conversation about suicide. The search was limited to 12 months and included only conversations originating from US internet protocol (IP) addresses. Natural language processing and text analytics were employed to develop a thematic analysis. RESULTS: A total of 222 000 unique conversations about epilepsy, including 9000 (4%) related to suicide, were posted during the study period. The suicide-related conversations were posted by 7.8% of teenagers and 3.2% of adults in the study. Several critical differences were noted between teenagers and adults. A higher percentage of teenagers are: fearful of "the unknown" due to seizures (63% vs 12% adults), concerned about social consequences of seizures (30% vs 21%), and seek emotional support (29% vs 19%). In contrast, a significantly higher percentage of adults show a defeatist ("given up") attitude compared to teenagers (42% vs 4%). There were important differences in the author's determined sentiments behind the conversations among teenagers and adults. SIGNIFICANCE: In this first of its kind big data analysis of nearly a quarter-million digital conversations about epilepsy using machine learning, we found that teenagers engage in an online conversation about suicide more often than adults. There are some key differences in the attitudes and concerns, which may have implications for the treatment of younger patients with epilepsy.

Screening for suicidality and its relation to undiagnosed psychiatric comorbidities in children and youth with epilepsy.

INTRODUCTION: Depression and anxiety are the most common psychiatric comorbidities in children and youth with epilepsy (CYE) and known to contribute to suicidality among them. However, not much is known about suicidality in CYE without established psychiatric comorbidities. Our research aimed to fill this knowledge gap and correlate this latent suicidality with screening tests for depression and anxiety. METHOD: After Institutional Review Board (IRB) approval, CYE who attended the epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and lacked established psychiatric diagnosis were enrolled. They filled out self-reported, validated scales for screening of depression, anxiety, and suicidality (Center for Epidemiological Studies Depression Scale for Children [CES-DC], Screen for Child Anxiety Related Emotional Disorders [SCARED], and Ask Suicide-Screening Questions [ASQ], respectively). Univariate descriptive statistics along with χ2 test of association and independent Student's t-test were performed for statistical analysis. RESULTS: A total of 119 (54.6% females) CYE were included in the study. Close to a third (30.2%) of CYE were positive for anxiety on SCARED, and 41.2% were positive for depression based on CSE-DC scoring. A total of 13 (10.9%) CYE indicated suicidality by answering at least one positive response on ASQ. The SCARED had a low positive correlation with the ASQ (r = 0.32) but a moderate positive correlation with the CES-DC (r = 0.64). CONCLUSION: We found that a small but significant 11% of CYE without any established psychiatric diagnosis expressed suicidality on a self-reported questionnaire. This highlights the importance of using psychiatry screening tests in all CYE. Future research using a larger, diversified cohort is needed to confirm our findings.

Lithium monotherapy associated longitudinal effects on resting state brain networks in clinical treatment of bipolar disorder.

OBJECTIVES: Lithium is one of the most effective and specific treatments for bipolar disorder (BP), but the neural mechanisms by which lithium impacts symptoms remain unclear. Past research has been limited by a reliance on cross-sectional designs, which does not allow for identification of within-person changes due to lithium and has not examined communication between brain regions (ie, networks). In the present study, we prospectively investigated the lithium monotherapy associated effects in vivo on the brain connectome in medication-free BP patients. In particular, we examined the within-person impact of lithium treatment on connectome indices previously linked to mania and depression in bipolar disorder. METHODS: Thirty-nine medication-free subjects - 26 BP (13 (hypo)manic and 13 depressed) and 13 closely matched healthy controls (HC) - were included. fMRI data were obtained at 3 timepoints: baseline, after 2 weeks, and after 8 weeks (total of 117 scans: 78 BP and 39 HC scans). BP subjects were clinically treated with lithium for 8 weeks while HC were scanned at the same time points but not treated. Graph theory metrics and repeated measures GLM were used to analyze lithium treatment associated effects. RESULTS: Consistent with hypotheses, lithium treatment was associated with a normalizing effect on mania-related connectome indices. Furthermore, shifts in both mania- and depression-related connectome indices were proportional to symptom change. Finally, lithium treatment-associated impact on amygdala function differed depending on baseline mood. CONCLUSIONS: Present findings provide deeper insight into the therapeutic neural mechanisms associated with lithium treatment.

The piRNA pathway is developmentally regulated during spermatogenesis in Drosophila.

PIWI-interacting RNAs (piRNAs) are predominantly produced in animal gonads to suppress transposons during germline development. Our understanding about the piRNA biogenesis and function is predominantly from studies of the Drosophila female germline. piRNA pathway function in the male germline, however, remains poorly understood. To study overall and stage-specific features of piRNAs during spermatogenesis, we analyzed small RNAs extracted from entire wild-type testes and stage-specific arrest mutant testes enriched with spermatogonia or primary spermatocytes. We show that most active piRNA clusters in the female germline do not majorly contribute to piRNAs in testes, and abundance patterns of piRNAs mapping to different transposon families also differ between male and female germlines. piRNA production is regulated in a stage-specific manner during spermatogenesis. The piRNAs in spermatogonia-enriched testes are predominantly transposon-mapping piRNAs, and almost half of those exhibit a ping-pong signature. In contrast, the primary spermatocyte-enriched testes have a dramatically high amount of piRNAs targeting repeats like suppressor of stellate and AT-chX The transposon-mapping piRNAs in the primary spermatocyte stages lacking Argonaute3 expression also show a ping-pong signature, albeit to a lesser extent. Consistently, argonaute3 mutant testes also retain ping-pong signature-bearing piRNAs, suggesting that a noncanonical ping-pong cycle might act during spermatogenesis. Our study shows stage-specific regulation of piRNA biogenesis during spermatogenesis: An active ping-pong cycle produces abundant transposon-mapping piRNAs in spermatogonia, while in primary spermatocytes, piRNAs act to suppress the repeats and transposons.

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.