Allostatic load in children: The cost of empathic concern.

Early-life adversity affects long-term health outcomes but there is considerable interindividual variability in susceptibility to environmental influences. We proposed that positive psychological characteristics that reflect engagement with context, such as being concerned about people or performance on tasks (i.e., empathic concern), could moderate the interindividual variation in sensitivity to the quality of the early environment. We studied 526 children of various Asian nationalities in Singapore (46.6% female, 13.4% below the poverty line) with longitudinal data on perinatal and childhood experiences, maternal report on empathic concern of the child, and a comprehensive set of physiological measures reflecting pediatric allostatic load assessed at 6 y of age. The perinatal and childhood experiences included adversities and positive experiences. We found that cumulative adverse childhood experience was positively associated with allostatic load of children at 6 y of age at higher levels of empathic concern but not significantly associated at lower levels of empathic concern. This finding reveals evidence for the importance of empathic concern as a psychological characteristic that moderates the developmental impact of environmental influences, serving as a source for vulnerability to adversities in children.

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.

Modulation of Oxidative Stress and Neuroinflammation by Cannabidiol (CBD): Promising Targets for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia globally. Although the direct cause of AD remains under debate, neuroinflammation and oxidative stress are critical components in its pathogenesis and progression. As a result, compounds like cannabidiol (CBD) are being increasingly investigated for their ability to provide antioxidant and anti-inflammatory neuroprotection. CBD is the primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found to provide beneficial outcomes in a variety of medical conditions and is gaining increasing attention for its potential therapeutic application in AD. CBD is not psychoactive and its lipophilic nature allows its rapid distribution throughout the body, including across the blood-brain barrier (BBB). CBD also possesses anti-inflammatory, antioxidant, and neuroprotective properties, making it a viable candidate for AD treatment. This review outlines CBD's mechanism of action, the role of oxidative stress and neuroinflammation in AD, and the effectiveness and limitations of CBD in preclinical models of AD.

Fetal CCL2 signaling mediates offspring social behavior and recapitulates effects of prenatal stress.

Maternal stress during pregnancy is prevalent and associated with increased risk of neurodevelopmental disorders in the offspring. Maternal and offspring immune dysfunction has been implicated as a potential mechanism by which prenatal stress shapes offspring neurodevelopment; however, the impact of prenatal stress on the developing immune system has yet to be elucidated. Furthermore, there is evidence that the chemokine C-C motif chemokine ligand 2 (CCL2) plays a key role in mediating the behavioral sequelae of prenatal stress. Here, we use an established model of prenatal restraint stress in mice to investigate alterations in the fetal immune system, with a focus on CCL2. In the placenta, stress led to a reduction in CCL2 and Ccr2 expression with a concomitant decrease in leukocyte number. However, the fetal liver exhibited an inflammatory phenotype, with upregulation of Ccl2, Il6, and Lbp expression, along with an increase in pro-inflammatory Ly6CHi monocytes. Prenatal stress also disrupted chemokine signaling and increased the number of monocytes and microglia in the fetal brain. Furthermore, stress increased Il1b expression by fetal brain CD11b+ microglia and monocytes. Finally, intra-amniotic injections of recombinant mouse CCL2 partially recapitulated the social behavioral deficits in the adult offspring previously observed in the prenatal restraint stress model. Altogether, these data suggest that prenatal stress led to fetal inflammation, and that fetal CCL2 plays a role in shaping offspring social behavior.

Microglial function interacts with the environment to affect sex-specific depression risk.

There is a two-fold higher incidence of depression in females compared to men with recent studies suggesting a role for microglia in conferring this sex-dependent depression risk. In this study we investigated the nature of this relation. Using GWAS enrichment, gene-set enrichment analysis and Mendelian randomization, we found minimal evidence for a direct relation between genes functionally related to microglia and sex-dependent genetic risk for depression. We then used expression quantitative trait loci and single nucleus RNA-sequencing resources to generate polygenic scores (PGS) representative of individual variation in microglial function in the adult (UK Biobank; N = 54753-72682) and fetal (ALSPAC; N = 1452) periods. The adult microglial PGS moderated the association between BMI (UK Biobank; beta = 0.001, 95 %CI 0.0009 to 0.003, P = 7.74E-6) and financial insecurity (UK Biobank; beta = 0.001, 95 %CI 0.005 to 0.015, P = 2E-4) with depressive symptoms in females. The fetal microglia PGS moderated the association between maternal prenatal depressive symptoms and offspring depressive symptoms at 24 years in females (ALSPAC; beta = 0.04, 95 %CI 0.004 to 0.07, P = 0.03). We found no evidence for an interaction between the microglial PGS and depression risk factors in males. Our results illustrate a role for microglial function in the conferral of sex-dependent depression risk following exposure to a depression risk factor.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

BACKGROUND: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. METHODS: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. RESULTS: Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. CONCLUSIONS: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation.

Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GVL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the Experimental Therapeutics Clinical Trials Network 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T-cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T-cell populations and increased expression of markers of T-cell activation and costimulation such as PD-1, HLA-DR, and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T-cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T-cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GVL outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01822509.

Temporal Regulation of the Metabolome and Proteome in Photosynthetic and Photorespiratory Pathways Contributes to Maize Heterosis.

Heterosis or hybrid vigor is widespread in plants and animals. Although the molecular basis for heterosis has been extensively studied, metabolic and proteomic contributions to heterosis remain elusive. Here we report an integrative analysis of time-series metabolome and proteome data in maize (Zea mays) hybrids and their inbred parents. Many maize metabolites and proteins are diurnally regulated, and many of these show nonadditive abundance in the hybrids, including key enzymes and metabolites involved in carbon assimilation. Compared with robust trait heterosis, metabolic heterosis is relatively mild. Interestingly, most amino acids display negative mid-parent heterosis (MPH), i.e., having lower values than the average of the parents, while sugars, alcohols, and nucleoside metabolites show positive MPH. From the network perspective, metabolites in the photosynthetic pathway show positive MPH, whereas metabolites in the photorespiratory pathway show negative MPH, which corresponds to nonadditive protein abundance and enzyme activities of key enzymes in the respective pathways in the hybrids. Moreover, diurnally expressed proteins that are upregulated in the hybrids are enriched in photosynthesis-related gene-ontology terms. Hybrids may more effectively remove toxic metabolites generated during photorespiration, and thus maintain higher photosynthetic efficiency. These metabolic and proteomic resources provide unique insight into heterosis and its utilization for high yielding maize and other crop plants.

Effects of maternal childhood trauma on child emotional health: maternal mental health and frontoamygdala pathways.

BACKGROUND: Experiences of early life adversity pose significant psychological and physical health risks to exposed individuals. Emerging evidence suggests that these health risks can be transmitted across generations; however, the mechanisms underlying the intergenerational impacts of maternal early-life trauma on child health remain unknown. METHODS: The current study used a prospective longitudinal design to determine the unique and joint contributions of maternal childhood trauma (neglect and abuse) and maternal prenatal and postnatal mental health (anxiety and depressive symptoms) (N = 541) to children's resting frontoamygdala functional connectivity at 6 years (N = 89) and emotional health at 7-8 years, as indexed by parent-reported internalizing problems and child self-reported anxiety and depressive symptoms (N = 268-418). RESULTS: Greater maternal childhood neglect was indirectly associated with greater internalizing problems serially through a pathway of worse maternal prenatal and postnatal mental health (greater maternal anxiety and depressive symptoms). Worse maternal postnatal mental health was also uniquely associated with more negative child frontoamygdala resting-state functional connectivity, over and above maternal childhood trauma (both neglect and abuse) and prenatal mental health. More negative frontoamygdala functional connectivity was, in turn, associated with poorer child emotional health outcomes. CONCLUSIONS: Findings from the current study provide support for the existence of intergenerational influences of parental exposure to childhood trauma on childhood risk for psychopathology in the next generation and point to the importance of maternal factors proximal to the second generation (maternal prenatal and postnatal mental health) in determining the intergenerational impact of maternal early experiences.

Mid-pregnancy and postpartum maternal mental health and infant sleep in the first year of life.

Perinatal depression and anxiety are common and associated with sleep problems in the offspring. Depression and anxiety are commonly comorbid, yet often studied independently. Our study used an integrative measure of anxiety and depressive symptoms to examine the associations of maternal mental health (mid-pregnancy and postnatal) with infant sleep during the first year of life. A total of 797 mother-child dyads from the 'Growing Up in Singapore Towards healthy Outcome' cohort study provided infant sleep data at 3, 6, 9 and 12 months of age, using the caregiver reported Brief Infant Sleep Questionnaire. Maternal mental health was assessed at 26-28 weeks gestation and 3 months postpartum using the Edinburgh Postnatal Depression Scale, Beck Depression Inventory and State-Trait Anxiety Inventory. Bifactor modelling with the individual questionnaire items produced a general affect factor score that provided an integrated measure of anxiety and depressive symptoms. Linear mixed models were used to model the sleep outcomes, with adjustment for maternal age, education, parity, ethnicity, sex of the child and maternal sleep quality concurrent with maternal mental health assessment. We found that poorer mid-pregnancy, but not postpartum, maternal mental health was associated with longer wake after sleep onset duration across the first year of life (ß = 49, 95% confidence interval 13-85 min). Poor maternal mental health during mid-pregnancy is linked to longer period of night awakening in the offspring during infancy. Interventions that aim to improve maternal antenatal mental health should examine infant sleep outcomes.

Monkeypox: a review of epidemiological modelling studies and how modelling has led to mechanistic insight.

Human monkeypox (mpox) virus is a viral zoonosis that belongs to the Orthopoxvirus genus of the Poxviridae family, which presents with similar symptoms as those seen in human smallpox patients. Mpox is an increasing concern globally, with over 80,000 cases in non-endemic countries as of December 2022. In this review, we provide a brief history and ecology of mpox, its basic virology, and the key differences in mpox viral fitness traits before and after 2022. We summarize and critique current knowledge from epidemiological mathematical models, within-host models, and between-host transmission models using the One Health approach, where we distinguish between models that focus on immunity from vaccination, geography, climatic variables, as well as animal models. We report various epidemiological parameters, such as the reproduction number, R0, in a condensed format to facilitate comparison between studies. We focus on how mathematical modelling studies have led to novel mechanistic insight into mpox transmission and pathogenesis. As mpox is predicted to lead to further infection peaks in many historically non-endemic countries, mathematical modelling studies of mpox can provide rapid actionable insights into viral dynamics to guide public health measures and mitigation strategies.

Maternal distress and parenting during COVID-19: differential effects related to pre-pandemic distress?

BACKGROUND: Distinguishing whether and how pre-existing characteristics impact maternal responses to adversity is difficult: Does prior well-being decrease the likelihood of encountering stressful experiences? Does it protect against adversity's negative effects? We examine whether the interaction between relatively uniformly experienced adversity (due to COVID-19 experience) and individual variation in pre-existing (i.e., pre-pandemic onset) distress predicted mothers' pandemic levels of distress and insensitive caregiving within a country reporting low COVID-19 death rates, and strict nationwide regulations. METHOD: Fifty-one Singaporean mothers and their preschool-aged children provided data across two waves. Pre- pandemic onset maternal distress (i.e., psychological distress, anxiety, and parenting stress) was captured via self-reports and maternal sensitivity was coded from videos. Measures were repeated after the pandemic's onset along with questionnaires concerning perceived COVID-19 adversity (e.g., COVID-19's impact upon stress caring for children, housework, job demands, etc.) and pandemic-related objective experiences (e.g., income, COVID-19 diagnoses, etc.). Regression analyses (SPSS v28) considered pre-pandemic onset maternal distress, COVID-19 stress, and their interaction upon post-pandemic onset maternal distress. Models were re-run with appropriate covariates (e.g., objective experience) when significant findings were observed. To rule out alternative models, follow up analyses (PROCESS Model) considered whether COVID-19 stress mediated pre- and post-pandemic onset associations. Models involving maternal sensitivity followed a similar data analytic plan. RESULTS: Pre-pandemic maternal distress moderated the association between COVID-19 perceived stress and pandemic levels of maternal distress (ß = 0.22, p < 0.01) but not pandemic assessed maternal sensitivity. Perceived COVID-19 stress significantly contributed to post-pandemic onset maternal distress for mothers with pre-pandemic onset distress scores above (ß = 0.30, p = 0.05), but not below (ß = 0.25, p = 0.24), the median. Objective COVID-19 adversity did not account for findings. Post-hoc analyses did not suggest mediation via COVID-19 stress from pre-pandemic to pandemic maternal distress. CONCLUSIONS: Pre-existing risk may interact with subsequent perceptions of adversity to impact well-being. In combination with existing research, this small study suggests prevention programs should focus upon managing concurrent mental health and may highlight the importance of enhanced screening and proactive coping programs for people entering high stress fields and/or phases of life.

Preschoolers' emotion reactivity and regulation: Links with maternal psychological distress and child behavior problems.

Maladaptive offspring emotion regulation has been identified as one pathway linking maternal and child psychological well-being in school-aged children. Whether such a pathway is present earlier in life still remains unclear. The present study investigated the role of preschoolers' emotion reactivity and regulation in the association between maternal psychological distress and child internalizing and externalizing problems. Children's emotion reactivity and regulation were assessed through both observed behavior and physiology. At 42 months of age, children (n = 251; 128 girls) completed a fear induction task during which their heart-rate variability was assessed and their behavior was monitored, and maternal self-reports on depressive mood and anxiety were collected. At 48 months mothers and fathers reported on their children's internalizing and externalizing problems. Higher maternal depressive mood was associated with lower child fear-related reactivity and regulation, as indexed by heart-rate variability. The latter mediated the association between higher maternal depressive mood and higher preschoolers' externalizing problems. Overall, our findings support the role of preschoolers' emotion reactivity and regulation in the relationship between maternal psychological distress and children's socio-emotional difficulties. This role may also depend on the discrete emotion to which children react or seek to regulate as, here, we only assessed fear-related reactivity and regulation.

Tele-Balint under the microscope: What really happens in Tele-Balint groups?

OBJECTIVE: Balint groups provide a safe space for clinicians to discuss difficult cases, with the aim of deepening the clinician-patient relationship and providing space for self-introspection and personal development. During this COVID-19 period, mental health clinicians need a platform to undergo professional supervision and peer learning sessions, which can be provided for by Tele-Balint sessions. This study aims to understand the workings of Balint groups in a multi-disciplinary team, through exploring the experience and perceptions of mental health clinicians in a tertiary obstetrics- and paediatrics-focused hospital in Singapore towards Tele-Balint groups, and examining if these groups can address their professional needs. METHOD: A mixed-methods study was conducted. 26 mental health clinicians who had participated in Tele-Balint groups since March 2020 completed a semi-structured questionnaire, and 12 of them were interviewed. Qualitative analysis of interview transcripts was performed. RESULTS: Qualitative analysis revealed 5 themes. The first 4: professional and personal growth of clinicians, providing emotional support to clinicians, burnout in clinicians: what contributes and what helps, and psychological safety, address whether Tele-Balint groups meet clinicians' needs. The last theme, evolution of nature of Balint groups, addresses whether Tele-Balint groups meet clinicians' needs during the time of a pandemic. CONCLUSIONS: Tele-Balint group participation was found to be beneficial in facilitating personal and professional growth, providing emotional support and preventing burnout, despite some limitations. Members should maintain flexibility towards the Balint process, in order to accommodate others who have differing needs, especially in a multi-disciplinary group.

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy. METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete. FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy. INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. FUNDING: The US National Institutes of Health and the Dana-Farber Cancer Institute.

Glutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.

Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otcspf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia and reduced lethality. Knockdown of Gls2 but not Glud1 in Otcspf-ash mice exhibited reduced body weight loss and increased plasma glutamine concentration. These data suggest that Gls2 hepatic knockdown could potentially help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.

Service process factors affecting patients' and clinicians' experiences on rapid teleconsultation implementation in out-patient neurology services during COVID-19 pandemic: a scoping review.

BACKGROUND: The adoption of teleconsultation for outpatient neurology services was limited until the onset of the COVID-19 pandemic which forced many outpatient neurology services to rapidly switch to virtual models. However, it remains unclear how this change has impacted patients' and clinicians' perceptions of service quality. The purpose of this scoping review is to identify process factors that influence patients' and clinicians' experiences of outpatient teleconsultation services during COVID-19. METHODS: Arksey and O'Malley scoping review framework was used to search PubMed, Scopus, CINAHL, and PsycInfo for original peer-reviewed research studies that examined the experiences of synchronous teleconsultation between a clinician and patient in a home-setting since the World Health Organization announced the COVID-19 global pandemic. The service quality model SERVQUAL was used to conduct a deductive thematic analysis to identify the key factors that impacted the patients' and clinicians' perception of teleconsultation services. RESULTS: A total of nineteen studies published between January 1, 2020, and April 17, 2021, were identified. The most common service process factors affecting the patients' and clinicians' experiences of teleconsultation were technical issues, addressing logistical needs, communication, ability to perform clinical activities, appropriate triage, and administrative support. CONCLUSIONS: Our findings identified six key service process factors affecting the patients' and clinicians' teleconsultation experiences in outpatient neurology services. The need for improvement of triage process and standardizing administrative virtual care pathway are identified as important steps to improve patients and clinicians' teleconsultation experiences compared to pre-COVID era. More research is needed to assess outpatient neurology teleconsultation service quality from patients' and clinicians' perspectives.

An initial investigation of neonatal neuroanatomy, caregiving, and levels of disorganized behavior.

Attachment disorganization is a risk factor for difficulties in attention, social relationships, and mental health. Conceptually, attachment disorganization may indicate a breakdown in fear regulation resulting from repeated exposure to frightening maternal care. In addition, past research has examined the influence of stress-inducing contextual factors and/or child factors upon the development of disorganization. However, no past work has assessed whether infant neuroanatomy, important to stress regulation, moderates the association between maternal care and levels of disorganized behavior. Here, utilizing data from a subsample of 82 dyads taking part in the "Growing Up in Singapore towards Healthy Outcomes" (GUSTO) cohort, we assessed the prediction from maternal sensitive caregiving at 6 mo and levels of attachment disorganization at 1.5 y, as moderated by hippocampal and amygdala volume determined within the first 2 weeks of life. Results indicate a significant interaction between neonatal left hippocampal volume and maternal sensitivity upon levels of disorganized behavior. Although these results require substantiation in further research, if replicated, they may enable new strategies for the identification of processes important to child mental health and points for intervention. This is because neonatal neuroanatomy, as opposed to genetic variation and sociodemographic risk, may be more directly linked to stress responses within individuals.

Comparative Effectiveness of Transcutaneous Auricular Vagus Nerve Stimulation vs Citalopram for Major Depressive Disorder: A Randomized Trial.

OBJECTIVES: Major depressive disorder (MDD) is one of the most common mental illnesses. This study aims to investigate the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS) compared with the effectiveness of citalopram, a commonly used antidepressant, in patients with depression. MATERIAL AND METHODS: A total of 107 male and female patients with MDD (55 in the taVNS group and 52 in the citalopram group) were enrolled in a prospective 12-week, single-blind, comparative effectiveness trial. Participants were recruited from the outpatient departments of three hospitals in China. Participants were randomly assigned to either taVNS treatment (eight weeks, twice per day, with an additional four-week follow-up) or citalopram treatment (12 weeks, 40 mg/d). The primary outcome was the 17-item Hamilton Depression Rating Scale (HAM-D17) measured every two weeks by trained interviewers blinded to the treatment assignment. The secondary end points included the 14-item Hamilton Anxiety Scale and peripheral blood biochemical indexes. RESULTS: The HAM-D17 scores were reduced in both treatment groups; however, there was no significant group-by-time interaction (95% CI: -0.07 to 0.15, p = 0.79). Nevertheless, we found that taVNS produced a significantly higher remission rate at week four and week six than citalopram. Both treatments were associated with significant changes in the peripheral blood levels of 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and noradrenaline, but there was no significant difference between the two groups. CONCLUSION: taVNS resulted in symptom improvement similar to that of citalopram; thus, taVNS should be considered as a therapeutic option in the multidisciplinary management of MDD. Nevertheless, owing to the design of this study, it cannot be ruled out that the reduction in depression severity in both treatment groups could be a placebo effect.

Risk Management for Radiation-Induced Cardiovascular Disease (RICVD): The 2022 Consensus Statement of the Taiwan Society for Therapeutic Radiology and Oncology (TASTRO) and Taiwan Society of Cardiology (TSOC).

Advances in cancer management have significantly improved survival in patients with cancers. Cardiovascular complications of cancer treatment are becoming significant competing causes of death in these patients. Radiotherapy is an indispensable component of cancer treatment, and irradiation of the heart and vasculature during cancer radiotherapy is now recognized as a new risk factor for cardiovascular diseases. It is important to involve multidisciplinary expertise and provide practical recommendations to promote awareness, recognize risks, and provide adequate interventions without jeopardizing cancer control. In this consensus paper, experts from the Taiwan Society for Therapeutic Radiology and Oncology and Taiwan Society of Cardiology provide a focused update on the clinical practice for risk stratification and management of radiation-induced cardiovascular disease (RICVD). We believe that implementing RICVD care under a collaborative cardio-oncology program will significantly improve cancer treatment outcomes and will facilitate high quality clinical investigations.