Availability of food determines the need for sleep in memory consolidation.

Sleep remains a major mystery of biology, with little understood about its basic function. One of the most commonly proposed functions of sleep is the consolidation of memory1-3. However, as conditions such as starvation require the organism to be awake and active4, the ability to switch to a memory consolidation mechanism that is not contingent on sleep may confer an evolutionary advantage. Here we identify an adaptive circuit-based mechanism that enables Drosophila to form sleep-dependent and sleep-independent memory. Flies fed after appetitive conditioning needed increased sleep for memory consolidation, but flies starved after training did not require sleep to form memories. Memory in fed flies is mediated by the anterior-posterior α'/ß' neurons of the mushroom body, while memory under starvation is mediated by medial α'/ß' neurons. Sleep-dependent and sleep-independent memory rely on distinct dopaminergic neurons and corresponding mushroom body output neurons. However, sleep and memory are coupled such that mushroom body neurons required for sleep-dependent memory also promote sleep. Flies lacking Neuropeptide F display sleep-dependent memory even when starved, suggesting that circuit selection is determined by hunger. This plasticity in memory circuits enables flies to retain essential information in changing environments.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Single cell RNA sequencing of human eosinophils from nasal polyps reveals eosinophil heterogeneity in chronic rhinosinusitis tissue.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed single cell RNA sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses), and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, Padj < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part by controlling inflammation and hyperproliferation of other cells.

Subtype-Specific Roles of Ellipsoid Body Ring Neurons in Sleep Regulation in Drosophila.

The ellipsoid body (EB) is a major structure of the central complex of the Drosophila melanogaster brain. Twenty-two subtypes of EB ring neurons have been identified based on anatomic and morphologic characteristics by light-level microscopy and EM connectomics. A few studies have associated ring neurons with the regulation of sleep homeostasis and structure. However, cell type-specific and population interactions in the regulation of sleep remain unclear. Using an unbiased thermogenetic screen of EB drivers using female flies, we found the following: (1) multiple ring neurons are involved in the modulation of amount of sleep and structure in a synergistic manner; (2) analysis of data for ΔP(doze)/ΔP(wake) using a mixed Gaussian model detected 5 clusters of GAL4 drivers which had similar effects on sleep pressure and/or depth: lines driving arousal contained R4m neurons, whereas lines that increased sleep pressure had R3m cells; (3) a GLM analysis correlating ring cell subtype and activity-dependent changes in sleep parameters across all lines identified several cell types significantly associated with specific sleep effects: R3p was daytime sleep-promoting, and R4m was nighttime wake-promoting; and (4) R3d cells present in 5HT7-GAL4 and in GAL4 lines, which exclusively affect sleep structure, were found to contribute to fragmentation of sleep during both day and night. Thus, multiple subtypes of ring neurons distinctively control sleep amount and/or structure. The unique highly interconnected structure of the EB suggests a local-network model worth future investigation; understanding EB subtype interactions may provide insight how sleep circuits in general are structured.SIGNIFICANCE STATEMENT How multiple brain regions, with many cell types, can coherently regulate sleep remains unclear, but identification of cell type-specific roles can generate opportunities for understanding the principles of integration and cooperation. The ellipsoid body (EB) of the fly brain exhibits a high level of connectivity and functional heterogeneity yet is able to tune multiple behaviors in real-time, including sleep. Leveraging the powerful genetic tools available in Drosophila and recent progress in the characterization of the morphology and connectivity of EB ring neurons, we identify several EB subtypes specifically associated with distinct aspects of sleep. Our findings will aid in revealing the rules of coding and integration in the brain.

How the Environmental Influences on Child Health Outcome (ECHO) cohort can spur discoveries in environmental epidemiology.

The Environmental Influences on Child Health Outcome (ECHO) program at the National Institutes of Health is an innovative, large, collaborative research initiative whose mission is to enhance the health of children for generations to come. The goal of the ECHO program is to examine effects of a broad array of early environmental exposures on child health and development. The information includes longitudinal data and biospecimens from more than 100 000 children and family members from diverse settings across the United States ECHO investigators have published collaborative analyses showing associations of environmental exposures-primarily in the developmentally sensitive pre-, peri-, and postnatal periods-with preterm birth and childhood asthma, obesity, neurodevelopment, and positive health. Investigators have addressed health disparities, joint effects of environmental and social determinants, and effects of mixtures of chemicals. The ECHO cohort is now entering its second 7-year cycle (2023-2030), which will add the preconception period to its current focus on prenatal through adolescence. Through a controlled access public-use database, ECHO makes its deidentified data available to the general scientific community. ECHO cohort data provide opportunities to fill major knowledge gaps in environmental epidemiology and to inform policies, practices, and programs to enhance child health. This article is part of a Special Collection on Environmental Epidemiology.

Myddosomes in Toll-like receptor signaling-one to bind and rule them all.

Toll-like receptors (TLRs) are innate immune sensors for the presence of pathogens and endogenous danger signals. TLR activation results in conserved intracellular signaling events that orchestrate inflammation and antimicrobial defense. While the identity and interplay of key TLR signaling components are well established, how these largely cytosolic proteins are physically connected is not well understood. For the activation of conserved intracellular signaling events, most TLRs engage the adapter MyD88 (myeloid differentiation primary response 88), which assembles into higher-order protein complexes, myddosomes. In their recent publication, Fisch et al. present evidence that oligomeric myddosomes detach from initiating TLRs and evolve into larger scaffolds that dynamically assemble not only proximal but also distal cytosolic elements required to execute the entire cascade of the TLR-MyD88 signaling pathway. Coinciding with decline in TLR signaling over time, myddosomes progressively recruit autophagy machinery that mediates myddosome clearance. These findings expand the current understanding of TLR signaling by positioning myddosomes as the central structural element that physically assembles the key executors and regulators of TLR-MyD88-dependent intracellular signaling cascades.

Emotional distress and future healthcare utilization in oncology populations: A systematic review.

OBJECTIVE: Emotional distress has been correlated with greater healthcare utilization and economic costs in cancer; however, the prospective relationship between positive distress screens and future healthcare utilization is less clear. Taken together, there is a critical need to synthesize studies examining the prospective relationship between emotional distress and future healthcare use to inform distress management protocols and motivate institutional resource allocation to distress management. The aim of the systematic review is to explore the relationship between emotional distress, measured via validated emotional distress questionnaires, and subsequent healthcare utilization in patients diagnosed with cancer. METHODS: A systematic search of seven databases was conducted on 29 March 2022 and updated 3 August 2023. Eligibility criteria were: (1) peer-reviewed, (2) quantitative or mixed methods, (3) adults (≥18 years) diagnosed with cancer, (4) cancer distress questionnaire(s) completed prior to healthcare utilization, and (5) written in English. Exclusion criteria included: (1) non-emotional aspects of distress (i.e., spiritual or physical distress), (2) healthcare utilization characterized via economic or monetary variables, and (3) caregiver or non-cancer populations. RESULTS: Nineteen peer-reviewed articles were included in the review. There was significant heterogeneity in emotional distress instruments and type of healthcare utilization used. Most studies examining general distress or anxiety found that increased distress was predictive of greater future healthcare utilization. CONCLUSION: The results suggest that individuals with higher levels of general distress and anxiety are at increased risk for future healthcare utilization.

Improving Neuromuscular Monitoring Through Education-Based Interventions and Studying Its Association With Adverse Postoperative Outcomes: A Retrospective Observational Study.

BACKGROUND: We assessed the association between education-based interventions, the frequency of train-of-four (TOF) monitoring, and postoperative outcomes. METHODS: We studied adults undergoing noncardiac surgery from February 1, 2020 through October 31, 2021. Our education-based interventions consisted of 3 phases. An interrupted time-series analysis, adjusting for patient- and procedure-related characteristics and secular trends over time, was used to assess the associations between education-based interventions and the frequency of TOF monitoring, postoperative pulmonary complications (PPCs), 90-day mortality, and sugammadex dosage. For each outcome and intervention phase, we tested whether the intervention at that phase was associated with an immediate change in the outcome or its trend (weekly rate of change) over time. In a sensitivity analysis, the association between education-based interventions and postoperative outcomes was adjusted for TOF monitoring. RESULTS: Of 19,422 cases, 11,636 (59.9%) had documented TOF monitoring. Monitoring frequency increased from 44.2% in the first week of preintervention stage to 83.4% in the final week of the postintervention phase. During the preintervention phase, the odds of TOF monitoring trended upward by 0.5% per week (odds ratio [OR], 1.005; 95% confidence interval [CI], 1.002-1.007). Phase 1 saw an immediate 54% increase (OR, 1.54; 95% CI, 1.33-1.79) in the odds, and the trend OR increased by 3% (OR, 1.03; 95% CI, 1.01-1.05) to 1.035, or 3.5% per week (joint Wald test, P < .001). Phase 2 was associated with a further immediate 29% increase (OR, 1.29; 95% CI, 1.02-1.64) but no significant association with trend (OR, 0.96; 95% CI, 0.93-1.01) of TOF monitoring (joint test, P = .04). Phase 3 and postintervention phase were not significantly associated with the frequency of TOF monitoring (joint test, P = .16 and P = .61). The study phases were not significantly associated with PPCs or sugammadex administration. The trend OR for 90-day mortality was larger by 24% (OR, 1.24; 95% CI, 1.06-1.45; joint test, P = .03) in phase 2 versus phase 1, from a weekly decrease of 8% to a weekly increase of 14%. However, this trend reversed again at the transition from phase 3 to the postintervention phase (OR, 0.82; 95% CI, 0.68-0.99; joint test, P = .05), from a 14% weekly increase to a 6.2% weekly decrease in the odds of 90-day mortality. In sensitivity analyses, adjusting for TOF monitoring, we found similar associations between study initiatives and postoperative outcomes. TOF monitoring was associated with lower odds of PPCs (OR, 0.69; 95% CI, 0.55-0.86) and 90-day mortality (OR, 0.79; 95% CI, 0.63-0.98), but not sugammadex dosing (mean difference, -0.02; 95% CI, -0.04 to 0.01). CONCLUSIONS: Our education-based interventions were associated with both TOF utilization and 90-day mortality but were not associated with either the odds of PPCs or sugammadex dosing. TOF monitoring was associated with reduced odds of PPCs and 90-day mortality.

Efficacy and safety of transcranial magnetic stimulation on cognition in mild cognitive impairment, Alzheimer's disease, Alzheimer's disease-related dementias, and other cognitive disorders: a systematic review and meta-analysis.

OBJECTIVE: We aim to analyze the efficacy and safety of TMS on cognition in mild cognitive impairment (MCI), Alzheimer's disease (AD), AD-related dementias, and nondementia conditions with comorbid cognitive impairment. DESIGN: Systematic review, Meta-Analysis. SETTING: We searched MEDLINE, Embase, Cochrane database, APA PsycINFO, Web of Science, and Scopus from January 1, 2000, to February 9, 2023. PARTICIPANTS AND INTERVENTIONS: RCTs, open-label, and case series studies reporting cognitive outcomes following TMS intervention were included. MEASUREMENT: Cognitive and safety outcomes were measured. Cochrane Risk of Bias for RCTs and MINORS (Methodological Index for Non-Randomized Studies) criteria were used to evaluate study quality. This study was registered with PROSPERO (CRD42022326423). RESULTS: The systematic review included 143 studies (n = 5,800 participants) worldwide, encompassing 94 RCTs, 43 open-label prospective, 3 open-label retrospective, and 3 case series. The meta-analysis included 25 RCTs in MCI and AD. Collectively, these studies provide evidence of improved global and specific cognitive measures with TMS across diagnostic groups. Only 2 studies (among 143) reported 4 adverse events of seizures: 3 were deemed TMS unrelated and another resolved with coil repositioning. Meta-analysis showed large effect sizes on global cognition (Mini-Mental State Examination (SMD = 0.80 [0.26, 1.33], p = 0.003), Montreal Cognitive Assessment (SMD = 0.85 [0.26, 1.44], p = 0.005), Alzheimer's Disease Assessment Scale-Cognitive Subscale (SMD = -0.96 [-1.32, -0.60], p < 0.001)) in MCI and AD, although with significant heterogeneity. CONCLUSION: The reviewed studies provide favorable evidence of improved cognition with TMS across all groups with cognitive impairment. TMS was safe and well tolerated with infrequent serious adverse events.

Wearable Technologies for Detecting Burnout and Well-Being in Health Care Professionals: Scoping Review.

BACKGROUND: The occupational burnout epidemic is a growing issue, and in the United States, up to 60% of medical students, residents, physicians, and registered nurses experience symptoms. Wearable technologies may provide an opportunity to predict the onset of burnout and other forms of distress using physiological markers. OBJECTIVE: This study aims to identify physiological biomarkers of burnout, and establish what gaps are currently present in the use of wearable technologies for burnout prediction among health care professionals (HCPs). METHODS: A comprehensive search of several databases was performed on June 7, 2022. No date limits were set for the search. The databases were Ovid: MEDLINE(R), Embase, Healthstar, APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science Core Collection via Clarivate Analytics, Scopus via Elsevier, EBSCOhost: Academic Search Premier, CINAHL with Full Text, and Business Source Premier. Studies observing anxiety, burnout, stress, and depression using a wearable device worn by an HCP were included, with HCP defined as medical students, residents, physicians, and nurses. Bias was assessed using the Newcastle Ottawa Quality Assessment Form for Cohort Studies. RESULTS: The initial search yielded 505 papers, from which 10 (1.95%) studies were included in this review. The majority (n=9) used wrist-worn biosensors and described observational cohort studies (n=8), with a low risk of bias. While no physiological measures were reliably associated with burnout or anxiety, step count and time in bed were associated with depressive symptoms, and heart rate and heart rate variability were associated with acute stress. Studies were limited with long-term observations (eg, ≥12 months) and large sample sizes, with limited integration of wearable data with system-level information (eg, acuity) to predict burnout. Reporting standards were also insufficient, particularly in device adherence and sampling frequency used for physiological measurements. CONCLUSIONS: With wearables offering promise for digital health assessments of human functioning, it is possible to see wearables as a frontier for predicting burnout. Future digital health studies exploring the utility of wearable technologies for burnout prediction should address the limitations of data standardization and strategies to improve adherence and inclusivity in study participation.

Evidence that oncostatin M synergizes with IL-4 signaling to induce TSLP expression in chronic rhinosinusitis with nasal polyps.

BACKGROUND: Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP). OBJECTIVE: We sought to study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NECs). METHODS: OSM receptors, IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NECs from patients with CRSwNP by quantitative PCR and immunofluorescence. Air-liquid interface-cultured NECs were stimulated with cytokines, including OSM, and quantitative PCR, ELISA, Western blot, and flow cytometry were used to assess the expression of OSM receptors, IL-4R, and TSLP. RESULTS: Increased levels of OSM receptor ß chain (OSMRß), IL-4Rα, and TSLP were observed in nasal polyp tissues and primary epithelial cells from nasal polyps of patients with CRSwNP compared with control tissues or cells from control subjects. The level of expression of OSMRß in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NECs increased the expression of OSMRß and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a signal transducer and activator of transcription 6 inhibitor. Stimulation of NECs with IL-4 plus OSM increased the expression of proprotein convertase subtilisin/kexin 3, an enzyme that truncates and activates TSLP. CONCLUSIONS: OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NECs. Because the combination of IL-4 and OSM also augmented the expression of proprotein convertase subtilisin/kexin 3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.

Student experiences with an interprofessional hope-based healthy aging research project.

Interprofessional education (IPE) and research enhances learning, team-based communication, and cross-disciplinary collaborations, which can result in higher quality care for older adults. Despite the importance of IPE, it remains underutilized in higher education, demonstrating the need for extracurricular IPE opportunities. This study describes an interprofessional research project that brought together faculty, undergraduate, and graduate students from several health and social science disciplines to design and deliver a 15-week healthy aging program for older adults living in the urban Circumpolar North. Five faculty and one graduate research assistant led the project while eight students team-taught weekly, 1-hour sessions in the community focusing on healthy lifestyles within a framework of Persuasive Hope Theory. This paper describes the project, the student training procedures, and reports the results of the student satisfaction survey regarding their involvement with the research. Using a student self-assessment survey, students report gains in thinking like a scientist, increased confidence conducting research tasks, benefits from teamwork, and greater consideration of the needs of older adults in their field of study. Despite a small sample size, this study also suggests that students may be more likely to consider a career working with older adults if given hands-on experiences.

Pairing-Dependent Plasticity in a Dissected Fly Brain Is Input-Specific and Requires Synaptic CaMKII Enrichment and Nighttime Sleep.

In Drosophila, in vivo functional imaging studies revealed that associative memory formation is coupled to a cascade of neural plasticity events in distinct compartments of the mushroom body (MB). In-depth investigation of the circuit dynamics, however, will require an ex vivo model that faithfully mirrors these events to allow direct manipulations of circuit elements that are inaccessible in the intact fly. The current ex vivo models have been able to reproduce the fundamental plasticity of aversive short-term memory, a potentiation of the MB intrinsic neuron (Kenyon cells [KCs]) responses after artificial learning ex vivo However, this potentiation showed different localization and encoding properties from those reported in vivo and failed to generate the previously reported suppression plasticity in the MB output neurons (MBONs). Here, we develop an ex vivo model using the female Drosophila brain that recapitulates behaviorally evoked plasticity in the KCs and MBONs. We demonstrate that this plasticity accurately localizes to the MB α'3 compartment and is encoded by a coincidence between KC activation and dopaminergic input. The formed plasticity is input-specific, requiring pairing of the conditioned stimulus and unconditioned stimulus pathways; hence, we name it pairing-dependent plasticity. Pairing-dependent plasticity formation requires an intact CaMKII gene and is blocked by previous-night sleep deprivation but is rescued by rebound sleep. In conclusion, we show that our ex vivo preparation recapitulates behavioral and imaging results from intact animals and can provide new insights into mechanisms of memory formation at the level of molecules, circuits, and brain state.SIGNIFICANCE STATEMENT The mammalian ex vivo LTP model enabled in-depth investigation of the hippocampal memory circuit. We develop a parallel model to study the Drosophila mushroom body (MB) memory circuit. Pairing activation of the conditioned stimulus and unconditioned stimulus pathways in dissected brains induces a potentiation pairing-dependent plasticity (PDP) in the axons of α'ß' Kenyon cells and a suppression PDP in the dendrites of their postsynaptic MB output neurons, localized in the MB α'3 compartment. This PDP is input-specific and requires the 3' untranslated region of CaMKII Interestingly, ex vivo PDP carries information about the animal's experience before dissection; brains from sleep-deprived animals fail to form PDP, whereas those from animals who recovered 2 h of their lost sleep form PDP.

Susceptibility Magnetic Resonance Imaging Correlates with Glial Density and Tau in the Substantia Nigra Pars Compacta.

BACKGROUND: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration. OBJECTIVE: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden. METHODS: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression. RESULTS: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden. CONCLUSIONS: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.

Borderline personality disorder symptom networks across adolescent and adult clinical samples: examining symptom centrality and replicability.

BACKGROUND: Numerous theories posit different core features to borderline personality disorder (BPD). Recent advances in network analysis provide a method of examining the relative centrality of BPD symptoms, as well as examine the replicability of findings across samples. Additionally, despite the increase in research supporting the validity of BPD in adolescents, clinicians are reluctant to diagnose BPD in adolescents. Establishing the replicability of the syndrome across adolescents and adults informs clinical practice and research. This study examined the stability of BPD symptom networks and centrality of symptoms across samples varying in age and clinical characteristics. METHODS: Cross-sectional analyses of BPD symptoms from semi-structured diagnostic interviews from the Collaborative Longitudinal Study of Personality Disorders (CLPS), the Methods to Improve Diagnostic Assessment and Service (MIDAS) study, and an adolescent clinical sample. Network attributes, including edge (partial association) strength and node (symptom) expected influence, were compared. RESULTS: The three networks were largely similar and strongly correlated. Affective instability and identity disturbance emerged as relatively central symptoms across the three samples, and relationship difficulties across adult networks. Differences in network attributes were more evident between networks varying both in age and in BPD symptom severity level. CONCLUSIONS: Findings highlight the relative importance of affective, identity, and relationship symptoms, consistent with several leading theories of BPD. The network structure of BPD symptoms appears generally replicable across multiple large samples including adolescents and adults, providing further support for the validity of the diagnosis across these developmental phases.

Efficacy and safety of lamotrigine in pediatric mood disorders: A systematic review.

AIM: To appraise the current evidence on the efficacy and safety of lamotrigine (LAM) in the treatment of pediatric mood disorders (PMD) (i.e., Major Depressive disorder [MDD], bipolar disorder [BD]). METHODS: Major databases were searched for randomized controlled trials (RCTs), open-label trials, and observational studies reporting on pediatric (age < 18 years) patients treated with LAM for mood disorders. RESULTS: A total of 3061 abstracts were screened and seven articles were selected for inclusion. Seven studies (319 BD and 43 MDD patients), including one RCT (n = 173), three prospective (n = 105), and three retrospective (n = 84) studies, met the study criteria with a study duration range from 8 to 60.9 weeks. The mean age of this pooled data is 14.6 ± 2.0 years. LAM daily dosage varied from 12.5 to 391.3 mg/day among the studies. In an important finding, the RCT reported favorable outcomes with LAM (HR = 0.46; p = 0.02) in 13- to 17-year-old age group as compared with 10- to 12-year-old age group (HR = 0.93; p = 0.88). In addition, time to occurrence of a bipolar event trended toward favoring LAM over placebo. All the studies identified LAM as an effective and safe drug in PMDs especially, BDs. Overall, LAM was well tolerated with no major significant side effects and no cases of Stevens-Johnson syndrome. CONCLUSIONS: Most studies suggested that LAM was safe and effective in pediatric patients with mood disorders. However, the data regarding the therapeutic range for LAM are lacking. Based on the data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM dosage for mood improvement in the pediatric population. Further studies including larger sample sizes are required to address this relevant clinical question.

Reproductive late effects after hematopoietic stem cell transplant in pediatric, adolescent, and young adult cancer survivors.

Reproductive late effects after hematopoietic stem cell transplant can have a significant impact on cancer survivors' quality of life. Potential late effects include gonadal insufficiency, genital graft-versus-host disease, uterine injury, psychosexual dysfunction, and an increased risk of breast and cervical cancer in patients treated with total body irradiation. Despite guidelines, screening and treatment are not standardized among at-risk patients. Provider barriers include lack of knowledge of at-risk therapies and evidenced-based guidelines. Patient barriers include a reluctance to report symptoms and lack of awareness of treatment options. System barriers include inefficient implementation of screening tools and poor dissemination of guidelines to providers who serve as the medical home for survivors. This review guides the clinician in identifying and managing reproductive late effects after hematopoietic stem cell transplant to improve outcomes.

Catheter ablation of atrial fibrillation in patients with and without hypertrophic cardiomyopathy: systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM). There is limited data regarding the outcomes of AF catheter ablation in HCM patients. In this study, we aimed to synthesize all available evidence on the effectiveness of ablation of AF in patients with HCM compared to those without HCM. METHODS AND RESULTS: We systematically reviewed bibliographic databases to identify studies published through February 2023. We included cohort studies with available quantitative information on rates of recurrent atrial arrhythmias, anti-arrhythmic drug (AAD) therapy, and repeat ablation procedures after initial AF ablation in patients with vs without HCM. Estimates were combined using random-effects meta-analysis models and reported as risk ratios (RR) and 95% confidence intervals (CI). Eight studies were included in quantitative synthesis (262 HCM and 642 non-HCM patients). During median follow-up 13-54 months across studies, AF recurrence rates ranged from 13.3% to 92.9% in HCM and 7.6% to 58.8% in non-HCM patients. The pooled RR for recurrent atrial arrhythmia after the first AF ablation in HCM patients compared to non-HCM controls was 1.498 (95% CI = 1.305-1.720; P < 0.001). During follow-up, HCM patients more often required AAD therapy (RR = 2.844; 95% CI = 1.713-4.856; P < 0.001) and repeat AF ablation (RR = 1.544; 95% CI = 1.070-2.228; P = 0.02). The pooled RR for recurrent atrial arrhythmias after the last AF ablation was higher in patients with HCM than those without HCM (RR = 1.607; 95% CI = 1.235-2.090; P < 0.001). CONCLUSIONS: Compared to non-HCM patients, those with HCM had higher rates of recurrent atrial arrhythmias, AAD use, and need for repeat AF ablation after initial ablation of AF.

Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Mortality Among COVID-19 Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are known to increase the expression of angiotensin converting enzyme 2 receptor, which has been shown to be the receptor for the acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). AREAS OF UNCERTAINTY: Based on these observations, speculations raised the concerns that ACEIs/ARBs users would be more susceptible to SARS-CoV-2 infection and would be at higher risk for severe COVID-19 disease and death. Therefore, we systematically reviewed the literature and performed a meta-analysis of the association between prior use of ACEIs and ARBs and mortality due to COVID-19 disease. DATA SOURCES: A comprehensive search of several databases from November 2019 to June 18, 2020 was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Medrxiv.org was also searched for unpublished data. THERAPEUTIC ADVANCES: Nine studies with a total of 18,833 patients infected with SARS-CoV-2 met our eligibility criteria. Prior use of ACEIs and/or ARBs was associated with reduced mortality among SARS-CoV-2-infected patients, with a pooled adjusted relative risk (aRR) from 6 studies of 0.63, 95% confidence interval (CI) (0.42-0.94) (I 2 = 65%). Three studies reported separately on ACEIs or ARBs and their association with survival among SARS-CoV-2-infected patients, with a pooled adjusted relative risk of 0.78, 95% CI (0.58-1.04) (I 2 = 0%) and 0.97, 95% CI (0.73-1.30) (I 2 = 0%) respectively. The results of sensitivity analyses were consistent with the main analysis. CONCLUSION: Our meta-analysis suggests that use of ACEIs/ARBs is associated with a decreased risk of death among SARS-CoV-2-infected patients. This finding provides a reassurance to the public not to stop prescribed ACEIs/ARBs because of fear of severe COVID-19.

Smoking Cessation Interventions in Indigenous North Americans: A Meta-Narrative Systematic Review.

INTRODUCTION: Indigenous North Americans have the highest cigarette smoking prevalence among all racial and ethnic groups in the United States. We seek to identify effective components of smoking cessation interventions in Indigenous people in the United States associated with favorable cessation outcomes. METHODS: A review of literature studying smoking cessation interventions in Indigenous North Americans (American Indians and Alaska Natives) from January 2010 through August 2021 was completed. The primary objective of this study was to identify components of interventions associated with positive smoking cessation outcomes in Indigenous people. The studies identified were synthesized in a meta-narrative approach. RESULTS: Ten studies out of 608 titles were included (6 randomized trials, 2 single-arm studies, 1 cohort study, and 1 prospective observational study). Five categories of smoking cessation interventions were identified; phone or web-based tools, culturally-tailored interventions, the inclusion of Indigenous study personnel, pharmaceutical cessation aids, and behavioral health interventions. Phone and web tools, cultural tailoring, and inclusion of Indigenous personnel conditions inconsistently influenced smoking cessation. Pharmaceutical aids were viewed favorably among participants. Individualized behavioral counseling sessions were effective at promoting smoking cessation, as was input from local communities in the planning and implementation phases of study. CONCLUSION: A successful smoking cessation intervention in Indigenous North Americans includes Tribal or community input in intervention design and implementation; should provide individualized counseling sessions for participants, and offer access to validated smoking cessation tools including pharmacotherapy. IMPLICATIONS: This study identifies a paucity of smoking interventions utilizing standard of care interventions in Indigenous North Americans. Standard of care interventions including individualized cessation counseling and pharmacotherapy were effective at promoting cessation. The use of novel culturally tailored cessation interventions was not more effective than existing evidence-based care with the exception of including Tribal and local community input in intervention implementation. Future smoking cessation interventions in Indigenous North Americans should prioritize the use of standard of care cessation interventions.