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Background: Postnatal depression, which affects between 10 and 25% of women worldwide, is a major public health problem. However, studies have shown that patients with postnatal depression engage poorly with treatment. Objectives: This qualitative study aims to examine the help-seeking behaviours amongst women who were screened to be at risk of postnatal depression in a public maternity hospital. Methods: From April 2008 to January 2010, 214 women who returned to a public maternity hospital for their postnatal obstetric check-ups were screened to be at risk of postnatal depression, with scores of 13 and above on the Edinburgh Postnatal Depression Scale (EPDS). Of these, 48 women agreed to participate in an open-ended phone interview which explored facilitators and barriers to help-seeking. The interviews were audio-recorded, transcribed and analysed to identify recurrent themes. Results: Three overarching themes and corresponding sub-themes were identified: personal motivations for seeking treatment (wish to be a better mother, desire for emotional support, wish for diagnosis), external facilitators for seeking treatment (family support, referral by obstetrician, postnatal emotional health screening) and barriers to seeking treatment (practical concerns, stigma, lack of knowledge about postnatal depression). Conclusions: The barriers and facilitators reported by study participants were consistent with those in existing literature, though participants’ personal motivations for seeking treatment have not been widely reported. Potential interventions to encourage help-seeking in women at risk of postnatal depression should address barriers and facilitators of help-seeking, and women’s personal motivations for seeking treatment should be explored in greater detail.

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.

Abstract Pathological placental inflammation increases the risk for several adult disorders, but these mediators are also expressed under homeostatic conditions, where their contribution to adult health outcomes is unknown. Here we define an inflammation-related expression signature, primarily expressed in Hofbauer cells of the term placenta and use expression quantitative trait loci to create a polygenic score (PGS) predictive of its expression. Using this PGS in the UK Biobank we conduct a phenome-wide association study, followed by Mendelian randomization and identify protective, sex-dependent effects of the placental module on cardiovascular and depressive outcomes. Genes differentially regulated by intra-amniotic infection and preterm birth are over-represented within the module. We also identify aspirin as a putative modulator of this inflammation-related signature. Our data support a model where disruption of placental Hofbauer cell function, due to preterm birth or prenatal infection, contributes to the increased risk of depression and cardiovascular disease observed in these individuals.

BackgroundOntario stroke prevention clinics primarily held in-person visits before the COVID-19 pandemic and then had to shift to a home-based teleconsultation delivery model using telephone or video to provide services during the pandemic. This change may have affected service quality and patient experiences. ObjectiveThis study seeks to understand patient satisfaction with Ontario stroke prevention clinics’ rapid shift to a home-based teleconsultation delivery model used during the COVID-19 pandemic. The research question explores explanatory factors affecting patient satisfaction. MethodsUsing a cross-sectional service performance model, we surveyed patients who received telephone or video consultations at 2 Ontario stroke prevention clinics in 2021. This survey included closed- and open-ended questions. We used logistic regression and qualitative content analysis to understand factors affecting patient satisfaction with the quality of home-based teleconsultation services. ResultsThe overall response rate to the web survey was 37.2% (128/344). The quantitative analysis was based on 110 responses, whereas the qualitative analysis included 97 responses. Logistic regression results revealed that responsiveness (adjusted odds ratio [AOR] 0.034, 95% CI 0.006-0.188; P

Abstract Background The cultural normativeness theory posits that specific parenting behaviors can be interpreted as displays of appropriate parenting in contexts where they are deemed normative. Previous studies suggest high acceptance of physical discipline in Singapore, where strict parenting could be interpreted as care for the child. However, there is a lack of studies on the local prevalence and implications of physical discipline. This study aimed to investigate the prevalence of Singaporean children experiencing parental physical discipline, longitudinal changes in this prevalence, and how exposure to physical discipline relates to children’s evaluation of their parents’ parenting. Methods Participants were 710 children with parental reports of physical discipline at one or more assessments at ages 4.5, 6, 9, and 11 years in the Growing Up in Singapore Towards healthy Outcomes birth cohort study. Parental reports of physical discipline were obtained using the Parenting Styles and Dimensions Questionnaire or the Alabama Parenting Questionnaire across the four assessments. Child reports of their parents’ care and control were obtained using the Parental Bonding Instrument for Children at the age 9 assessment. Prevalence was specified as being exposed to at least one physical discipline at any frequency. A generalized linear mixed model was performed to examine whether children’s age predicted their exposure to physical discipline. Linear regression analyses were conducted to investigate whether children’s exposure to physical discipline predicted their evaluation of their parents’ parenting. Results The prevalence of children experiencing at least one physical discipline was above 80% at all ages. There was a decrease in this prevalence from age 4.5 to 11 years (B = − 0.14, SE = 0.01, OR = 0.87, p

Abstract 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 (β = 0.22, p

Postnatal depression is a critical public health issue with substantial impact on child development outcomes and family functioning. With the additional stressors that arose during the COVID-19 pandemic, the impact on global mental health has been marked. This study aims to examine the change in the prevalence of postnatal depression (PND) in Singaporean women before the onset of the pandemic and during the pandemic period. A single-center observational cross-sectional study was conducted at Kandang Kerbau Women’s and Children’s Hospital (KKH) where women were screened for postnatal depression using the Edinburgh Postnatal Depression Scale (EPDS). High scorers on EPDS (EPDS≥13) were considered probable cases of postnatal depression. The prevalence of high EPDS scorers increased from 4.9% in 2019 to 6.5% in 2021, which was statistically significant ( p = .028). The total number of women who received screening for postnatal depression at KKH increased by 42.6% in 2021 compared to 2019, whilst the numbers identified as probable cases increased by 91% over the same period. The prevalence of PND in Singapore significantly increased during the COVID-19 pandemic.

The cation-permeable TRPV2 channel is important for cardiac and immune cell function. Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique, we discover that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2-APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40°C) heat. Using cryo-EM, we uncover a new small-molecule binding site in the pore domain of rTRPV2 in addition to a nearby CBD site that had already been reported. The TRPV1 and TRPV3 channels are also activated by 2-APB and CBD and share multiple conserved features with TRPV2, but we find that strong sensitization by CBD is only observed in TRPV3, while sensitization for TRPV1 is much weaker. Mutations at non-conserved positions between rTRPV2 and rTRPV1 in either the pore domain or the CBD sites failed to confer strong sensitization by CBD in mutant rTRPV1 channels. Together, our results indicate that CBD-dependent sensitization of rTRPV2 channels engages multiple channel regions, and that the difference in sensitization strength between rTRPV2 and rTRPV1 channels does not originate from amino acid sequence differences at the CBD binding site or the pore domain. The remarkably robust effect of CBD on TRPV2 and TRPV3 channels offers a promising new tool to both understand and overcome one of the major roadblocks in the study of these channels – their resilience to activation.

Childhood-onset depression has adverse consequences that are sustained into adulthood, which increases the significance of detection in early childhood. The Children's Depression Inventory (CDI) is used globally in evaluating depressive symptom severity in adolescents, and its second version, the CDI-2, was developed by taking into account advances in childhood depression research. Prior research has reported inconsistencies in its factor structure across populations. In addition, the CDI-2 has not yet been empirically validated with Southeast Asian populations. This study sought to empirically validate the CDI-2's psychometric properties and evaluate its factorial structure with a Singaporean community sample of non-clinical respondents. A total sample of 730 Singaporean children aged between 8.5 and 10.5 years was used. Psychometric properties of the CDI-2, including internal consistency as well as convergent and discriminant validity, were assessed. Factor analyses were conducted to assess the developers' original two-factor structure for a Southeast Asian population. This two-factor structure was not supported in our sample. Instead, the data provided the best fit for a hierarchical two-factor structure with factors namely, socio-emotional problems and cognitive-behavioural problems. This finding suggests that socio-cultural and demographic elements influence interpretation of depressive symptoms and therefore the emerging factor structure of the construct under scrutiny. This study highlights the need to further examine the CDI-2 and ensure that its interpretation is culture-specific. More qualitative work could also bring to light the idiosyncratic understanding of depressive symptomatology, which would then guide culture-specific validation of the CDI-2.

Background: Childhood depression is a highly distinct and prevalent condition with an unknown neurobiological basis. We wish to explore the resting state fMRI data in children for potential associations between neural connectivity and childhood depressive symptoms. Methods: A longitudinal birth cohort study with neuroimaging data obtained at 4.5, 6.0 and 7.5 years of age and the Children Depression Inventory 2 (CDI) administered between 8.5 and 10.5 years was used. The CDI score was used as the dependent variable and tested for correlation, both simple Pearson and network based statistic, with the functional connectivity values obtained from the resting state fMRI. Cross-validated permutation testing with a general linear model was used to validate that the identified functional connections were indeed implicated in childhood depression. Results: Ten functional connections and four brain regions (Somatomotor Area B, Temporoparietal Junction, Orbitofrontal Cortex and Insula) were identified as significantly associated with childhood depressive symptoms for girls at 6.0 and 7.5 years. No significant functional connections were found in girls at 4.5 years or for boys at any timepoint. Network based statistic and permutation testing confirmed these findings. Conclusions: This study revealed significant sex-dependent associations of neural connectivity and childhood depressive symptoms. The regions identified are implicated in speech/language, social cognition and information integration and suggest unique pathways to childhood depressive symptoms.

Objectives: This study aimed to investigate public discourses and sentiments regarding the Freedom Convoy in Canada on Twitter.Methods: English tweets were retrieved from Twitter API from 15 January to 14 February 2022 when the Freedom Convoy occurred. Unsupervised topic modelling and sentiment analysis were applied to identify topics and sentiments for each topic.Results: Five topics resulted from the topic modelling, including convoy support, political arguments toward the current prime minister, lifting vaccine mandates, police activities, and convoy fundraising. Overall, sentiments for each topic began with more positive or negative sentiments but approached to neutral over time.Conclusion: The results show that sentiments towards the Freedom Convoy generally tended to be positive. Five topics were identified from the data collected, and these topics highly correlated with the events of the convoy. Our study also demonstrated that a mixed approach of unsupervised machine learning techniques and manual validation could generate timely evidence.

ABSTRACT Background and Aim Post‐marketing studies comparing low‐volume polyethylene glycol (PEG)‐based regimens are limited. This randomized study aimed to compare the efficacy and tolerability of a novel 1‐L low‐volume PEG‐based preparation: 1 L PEG+Asc (PEG3350, sodium ascorbate, sodium sulfate, ascorbic acid, sodium chloride, and potassium chloride) with PEG+SPMC (PEG3350, sodium chloride, potassium chloride and sodium sulfate, sodium picosulfate, magnesium oxide, citric acid, and aspartame), prior to routine colonoscopy at an Australian tertiary referral center. Methods Outpatients undergoing colonoscopy were randomized to receive either split‐dose 1 L PEG+Asc or split‐dose PEG+SPMC. Bowel preparation quality using the Boston Bowel Preparation Scale (BPPS), modified Aronchick scores, procedure time, cecal intubation, and adenoma detection rates were recorded. Patient compliance and tolerability were captured using a standardized questionnaire. Results A total of 173 patients were randomized, of whom 164 completed the study and were allocated to 1 L PEG+Asc (n = 82) or PEG+SPMC (n = 82). Non‐inferiority of 1 L PEG+Asc was demonstrated with 89% achieving successful preparation (total BPPS ≥6 and each sub‐score ≥2) compared with 85.4% in the PEG+SPMC group, resulting in an estimated difference of 3.7% (95% CI −6.6% to 13.9%). The median BBPS was non‐inferior in all colonic segments with 1 L PEG+Asc (BBPS 3 [interquartile range 2–3]) vs PEG+SPMC (BBPS 2 [interquartile range 2–3]). More 1 L PEG+Asc patients reported moderate to severe nausea (P = 0.028), but overall tolerability was similar. Conclusions The quality of bowel preparation achieved with 1 L PEG+Asc is non‐inferior to that with PEG+SPMC, with similar tolerability outcomes. Further studies are required in patients at risk of suboptimal bowel preparation.

Summary: Prenatal maternal mental health is a global health challenge with poorly defined biological mechanisms. We used maternal blood samples collected during the second trimester from a Singaporean longitudinal birth cohort study to examine the association between inter-individual genome-wide DNA methylation and prenatal maternal depressive symptoms. We found that (1) the maternal methylome was significantly associated with prenatal maternal depressive symptoms only in mothers with a female fetus; and (2) this sex-dependent association was observed in a comparable, UK-based birth cohort study. Qualitative analyses showed fetal sex-specific differences in genomic features of depression-related CpGs and genes mapped from these CpGs in mothers with female fetuses implicated in a depression-associated WNT/β-catenin signaling pathway. These same genes also showed enriched expression in brain regions linked to major depressive disorder. We also found similar female-specific associations with fetal-facing placenta methylome. Our fetal sex-specific findings provide evidence for maternal-fetal interactions as a mechanism for intergenerational transmission.

Abstract Background Female sexual dysfunction (FSD) is a prevalent problem, affecting up to 41% of reproductive aged women worldwide. However, the association between female sexual function (FSF) and fecundability in women attempting to conceive remains unclear. We aimed 1) to examine the association between FSF in reproductive-aged preconception Asian women and fecundability, as measured by time-to-pregnancy in menstrual cycles, and 2) to examine lifestyle and behavioral factors associated with FSF. Methods From the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) prospective cohort, we evaluated FSF using the 6-item Female Sexual Function Index (FSFI-6) and ascertained time-to-pregnancy within a year of baseline assessment. We estimated fecundability ratio (FR) and 95% confidence interval (CI) using the discrete-time proportional hazards model, accounting for left-truncation and right censoring. We used multivariable logistic and linear regression models to identify potential factors related to FSF. Results Among 513 participants, 58.9% had low FSF as defined by a total FSFI-6 score at or below the median value of 22. Compared to women with high FSF, those with low FSF had a 27% reduction in fecundability (FR 0.73; 95% CI 0.54, 0.99), with adjustment for age, ethnicity, education, parity and body mass index. Overall, the FRs generally reduced with decreasing FSFI-6 scores. Physical activity, obesity, absence of probable depression and anxiety were independently associated with reduced odds of low FSF and increased FSFI-6 scores, after adjusting for sociodemographic characteristics. Conclusions Low FSF is associated with a longer time-to-pregnancy. Early evaluation and optimization of FSF through increased physical activity and optimal mental health may help to improve female fecundity. The finding of obese women having improved FSF remains uncertain which warrants further investigations on plausibly mechanisms. In general, the current finding highlights the importance of addressing FSF in preconception care service for general women, which is currently lacking as part of the fertility promotion effort in the country.

Abstract The hypothalamus links the nervous system to the endocrine system and plays a crucial role in maintaining the human body's homeostasis. This study aims to investigate the resting state functional connectivity (rsFC) changes of the hypothalamus in fibromyalgia patients. 24 Fibromyalgia patients and 24 matched healthy controls (HCs) were recruited. Resting state fMRI data were collected from the fibromyalgia patients and HC’s. Fibromyalgia patients went through a second scan after 12 weeks of Tai Chi mind–body intervention. Data analysis showed that fibromyalgia patients displayed less medial hypothalamus (MH) rsFC with the thalamus and amygdala when compared to the functional connectivity in the HCs. After the Tai Chi mind–body intervention, fibromyalgia patients showed increased MH rsFC with the thalamus and amygdala accompanied by clinical improvement. Effective connectivity analysis showed disrupted MH and thalamus interaction in the fibromyalgia patients, which was altered by mind–body exercise. Our findings suggest that fibromyalgia is associated with altered functional connectivity within the diencephalon and limbic system. Elucidating the roles of the diencephalon and limbic system in the pathophysiology and development of fibromyalgia may facilitate the development of a new biomarker and effective treatment methods for this prevalent disorder. Trial Registration ClinicalTrials.gov, NCT02407665. Registered: 3 April 2015, https://clinicaltrials.gov/ct2/show/NCT02407665?term=NCT02407665&draw=2&rank=1

ObjectiveIncreasing evidence suggests that a subcortical pathway from the superior colliculus (SC) through the pulvinar to the amygdala plays a crucial role in mediating non-conscious processing in response to emotional visual stimuli. Given the atypical eye gaze and response patterns to visual affective stimuli in autism, we examined the functional and white matter structural difference of the pathway in boys with autism spectrum disorder (ASD) and typically developing (TD) boys.MethodsA total of 38 boys with ASD and 38 TD boys were included. We reconstructed the SC-pulvinar-amygdala pathway in boys with ASD and TD using tractography and analyzed tract-specific measurements to compare the white matter difference between the two groups. A region of interest-based functional analysis was also applied among the key nodes of the pathway to explore the functional connectivity network.ResultsDiffusion tensor imaging analysis showed decreased fractional anisotropy (FA) in pathways for boys with ASD compared to TD. The FA change was significantly associated with the atypical communication pattern in boys with ASD. In addition, compared to TD, we found that the ASD group was associated with increased functional connectivity between the right pulvinar and the left SC.ConclusionOur results indicated that the functional and white matter microstructure of the subcortical route to the amygdala might be altered in individuals with autism. This atypical structural change of the SC-pulvinar-amygdala pathway may be related to the abnormal communication patterns in boys with ASD.

Objective Poor sleep and depression are common problems during pregnancy, but there has been little investigation into the association between them. This prospective study aims to examine the relationship between sleep quality and depression during pregnancy. Methods Pregnant women under 14 weeks’ gestation attending routine outpatient antenatal care in Singapore’s largest maternity hospital were recruited between 2012 and 2014. Women with multiple pregnancies and deemed at high risk of miscarriage were excluded. Six hundred and forty participants completed the Pittsburgh Sleep Quality Index (PSQI) and Edinburgh Postnatal Depression Scale (EPDS) at the three trimesters during pregnancy. Results Mean PSQI score was highest in the third visit, suggesting poorer quality sleep in the late third trimester compared to other trimesters. 15.6% of participants at each time point fulfilled the criteria for antenatal depression according to the EPDS cut-off score > 14. PSQI scores were significantly correlated with EPDS scores, and also prospectively predicted EPDS scores in all three trimesters. Conclusion Sleep quality in Singaporean pregnant women was poorest in the third trimester, and was associated with the development of depressive symptoms. With more than 1 in 10 women having antenatal depression, interventions targeting sleep quality might be particularly beneficial.

Objective: This study aimed to explore topics and sentiments using tweets from Ontario, Canada, during the second wave of the COVID-19 pandemic.Methods: Tweets were collected from December 5, 2020, to March 6, 2021, excluding non-individual accounts. Dates of vaccine-related events and policy changes were collected from public health units in Ontario. The daily number of COVID-19 cases was retrieved from the Ontario provincial government’s public health database. Latent Dirichlet Allocation was used for unsupervised topic modelling. VADER was used to calculate daily and average sentiment compound scores for topics identified.Results: Vaccine, pandemic, business, lockdown, mask, and Ontario were six topics identified from the unsupervised topic modelling. The average sentiment compound score for each topic appeared to be slightly positive, yet the daily sentiment compound scores varied greatly between positive and negative emotions for each topic.Conclusion: Our study results have shown a slightly positive sentiment on average during the second wave of the COVID-19 pandemic in Ontario, along with six topics. Our research has also demonstrated a social listening approach to identify what the public sentiments and opinions are in a timely manner.

Purpose: Single agent PD-1 inhibitors have yielded durable responses in a minority of gastroesophageal cancers. Radiation therapy has been recognized to promote antitumor immune responses and may synergize with anti-PD-1 agents. We sought to evaluate if combining palliative radiation therapy with pembrolizumab can augment antitumor immune responses in gastroesophageal cancer. Methods and Materials: Patients had metastatic gastroesophageal cancer with indication for palliative radiation therapy with ≥2 disease sites outside of the radiation field assessable for abscopal response and biopsies for laboratory correlative analyses. Palliative radiation was delivered to a dose of 30 Gy over 10 fractions. Pembrolizumab, 200 mg, was administered concurrently intravenously every 3 weeks until disease progression, unacceptable toxicity, or study withdrawal, for up to 2 years. Endpoints included PD-L1 expression in pre- and posttreatment biopsies and abscopal objective response rate per Response Evaluation Criteria in Solid Tumors. Results: Of 14 enrolled patients, the objective response rate was 28.6% (95% confidence interval, 8.4%-58.1%), and the median duration of response was not reached (95% confidence interval, 6.9-NR months). Overall, 2 patients had treatment-related grade 3 to 4 adverse events with no grade 5 events. One patient discontinued therapy due to grade 4 colitis. We did not observe an association between radiation and abscopal changes in PD-L1 expression via assessment of an analogous PD-L1 Combined Positive Score, Tumor Proportion Score, Mononuclear Immune Cell Density Score, or proportion of PD-L1-expressing immune cells between pre- and posttreatment tumor biopsies. Conclusions: Combining palliative radiation therapy and pembrolizumab provided promising durable responses in this patient population but we were unable to definitively distinguish abscopal biologic changes. Biomarker analyses beyond PD-L1 expression are needed to better understand putative mechanisms and identify patients who will benefit from this approach.

Cell-based immunotherapies have had remarkable success in the clinic, specifically in the treatment of hematologic malignancies. However, these strategies have had limited efficacy in patients with solid tumors. To better understand the challenges involved, the National Cancer Institute (NCI) convened an initial workshop with immuno-oncology thought leaders in December 2018 and a follow-up workshop in December 2020. The goals of the NCI workshops on cell-based immunotherapy for solid tumors were to discuss the current state of the field of cell-based immunotherapy, obtain insights into critical knowledge gaps, and identify ways in which NCI could facilitate progress. At both meetings, subjects emphasized four main types of challenges in further developing cell-based immunotherapy for patients with solid tumors: scientific, technical, clinical, and regulatory. The scientific barriers include selecting appropriate targets, ensuring adequate trafficking of cell therapy products to tumor sites, overcoming the immunosuppressive tumor microenvironment, and identifying appropriate models for these investigations. While mouse models may provide some useful data, the majority of those that are commonly used are immunodeficient and unable to fully recapitulate the immune response in patients. There is therefore a need for enhanced support of small early-phase human clinical studies, preferably with adaptive trial designs, to provide proof of concept for novel cell therapy approaches. Furthermore, the requirements for manufacturing, shipping, and distributing cell-based therapies present technical challenges and regulatory questions, which many research institutions are not equipped to address. Overall, workshop subjects identified key areas where NCI support might help the research community in driving forward innovation and clinical utility: 1) provide focused research support on topics such as tumor target selection, immune cell fitness and persistence, cell trafficking, and the immunosuppressive tumor microenvironment; 2) support the rapid translation of preclinical findings into proof of concept clinical testing, harmonize clinical trial regimens, and facilitate early trial data sharing (including negative results); 3) expand manufacturing support for cell therapies, including vectors and reagents, and provide training programs for technical staff; and 4) develop and share standard operating procedures for cell handling and analytical assays, and work with the Food and Drug Administration to harmonize product characterization specifications.

With COVID-19 cases rising quickly at alarming rates across the U.S. and globally, the pandemic crisis has exposed the importance and accelerated the need for wireless telecommunication technology in the intensive care unit. Many of these critically ill COVID-19 patients in the ICU require mechanical ventilation. Moreover, due to their underlying diagnosis, these patients are required to be in isolated rooms and under contact precautions. Often times, immediate and emergency access to the mechanical ventilator are delayed or stalled by the hurdle to properly gown up with personal protective equipment before entering the room. Wireless telecommunication to access and control ventilator settings promptly from outside the isolation room, for example from a laptop computer, would overcome this barrier and time obstacle. Additionally, will save the already limited equipment and save money. Thus, the development of such technology is quite urgent as more and more critically ill COVID-19 patients are ending up on mechanical ventilation.

Recently, transcranial direct current stimulation (tDCS) has been applied to relieve symptoms in individuals with autism spectrum disorder (ASD). In this prospective, parallel, single-blinded, randomized study, we investigate the modulation effect of three-week tDCS treatment at the left dorsal lateral prefrontal cortex (DLPFC) in children with ASD. 47 children with ASD were enrolled, and 40 (20 in each group) completed the study. The primary outcomes are Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and the Repetitive Behavior Scale-Revised (RBS-R). We found that children with ASD can tolerate three-week tDCS treatment with no serious adverse events detected. A within-group comparison showed that real tDCS, but not sham tDCS, can significantly reduce the scores of CARS, Children’s Sleep Habits Questionnaire (CSHQ), and general impressions in CARS (15th item). Real tDCS produced significant score reduction in the CSHQ and in CARS general impressions when compared to the effects of sham tDCS. The pilot study suggests that three-week left DLPFC tDCS is well-tolerated and may hold potential in relieving some symptoms in children with ASD.

Background: Studies have identified lifestyle risk factors for perinatal depression, but none have examined the cumulative effect of these risk factors in pregnant women. Methods: We considered the following six factors during pregnancy: poor diet quality (Healthy eating index for Singapore pregnant women 5), physical inactivity (15) and at three months postpartum (≥13). Prevalence risk ratios were calculated with Poisson regressions while adjusting for potential confounders. Results: Of 535 pregnant women, 207 (39%) had zero or one risk factor, 146 (27%) had two, 119 (22%) had three, 48 (9%) had four, and 15 (3%) had ≥5 risk factors at 26–28 weeks' gestation. These six lifestyle habits contributed to 32% of the variance in depressive symptoms during pregnancy. The prevalence of being probably depressed was 6.4 (95% CI 2.1, 19.8; ptrend

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient–derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

BackgroundMaternal mental health problems often develop prenatally and predict post-partum mental health. However, the circumstances before and following childbirth differ considerably. We currently lack an understanding of dynamic variation in the profiles of depressive and anxiety symptoms over the perinatal period.MethodsDepressive and anxiety symptoms were self-reported by 980 women at 26-week pregnancy and 3 months post-partum. We used network analysis of depressive and anxiety symptoms to investigate if the symptoms network changed during and after pregnancy. The pre- and post-partum depressive-anxiety symptom networks were assessed for changes in structure, unique symptom-symptom interactions, central and bridging symptoms. We also assessed if central symptoms had stronger predictive effect on offspring’s developmental outcomes outcomes at birth and 24, 54, and 72 months old than non-central symptoms. Bridging symptoms between negative and positive mental health were also assessed.ResultsThough the depressive-anxiety network structures were stable during and after pregnancy, the post-partum network was more strongly connected. The central depressive-anxiety symptoms were also different between prenatal and post-partum networks. During pregnancy, central symptoms were mostly related to feeling worthless or useless; after pregnancy, central symptoms were mostly related to feeling overwhelmed or being punished. Central symptoms during pregnancy were associated with poorer developmental outcomes for the child. Anxiety symptoms were strongest bridging symptoms during and after pregnancy. The interactions between negative and positive mental health symptoms were also different during and after pregnancy.ConclusionsThe differences between pre- and post-partum networks suggest that the presentation of maternal mental health problems varies over the peripartum period. This variation is not captured by traditional symptom scale scores. The bridging symptoms also suggest that anxiety symptoms may precede the development of maternal depression. Interventions and public health policies should thus be tailored to specific pre- and post-partum symptom profiles.

Abstract Background Research on factors associated with dialysis withdrawal is scarce. This study examined the predictors that might influence rate of dialysis withdrawal. Existing literature is summarized, analyzed and synthesized to identify gaps in the literature with regard to the factors associated with dialysis withdrawal. Methods This scoping review used a systematic search to synthesize research findings related to dialysis withdrawal and identified gaps in the literature. The search strategy was developed and applied using PubMed, EMBASE and CINHAL databases. The selection criteria included articles written in English and published between 1997 and 2016 that examined dialysis withdrawal and associated factors in patients with any modality of renal dialysis.. Case reports and studies only including renal transplant patients were excluded. Fifteen articles were selected in accordance with these selection criteria. Results The literature review revealed a scarcity of research on dialysis withdrawal and associated factors. Furthermore, the study findings were inconsistent and inconclusive. Authors have defined dialysis withdrawal in terms of dialysis discontinuation, withholding, death, withdrawal, treatment refusal/cessation, or technique failure. Authors have selected homogeneous patient population on either hemodialysis (HD) or peritoneal dialysis (PD) patients, thus making comparisons of studies and generalization of findings difficult. Conclusion Future studies should explore the influence of both HD and PD on patient-elected dialysis withdrawal using a large a priori calculated sample size.

Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of Hmmr-knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development.

This qualitative study investigated the ways in which 84 parents from predominantly low-income communities described supporting their third graders’ reading skills, motivation, and habits. Thematic analysis of open-ended parent interviews indicated that parents actively and deliberately scaffolded their children’s progress toward developing independent reading skills. Parents explicitly communicated the value of reading in everyday conversations; actively listened to their children read, even if they did not understand the language in which the text was written; asked reading comprehension questions; created a home environment conducive to sustained reading; promoted reader autonomy through encouragement of strategy use; and incorporated reading practices into daily routines. Parents often described their own efforts as responsive to their children’s level of reading motivation and reading performance, thus highlighting the reciprocal nature of parent–child reading interactions. Findings reveal a variety of ways in which families support their children’s reading skills, motivation, and habits.

This study investigated the relationships between pre- and early post-natal maternal depression and their changes with frontal electroencephalogram (EEG) activity and functional connectivity in 6- and 18-month olds, as well as externalizing and internalizing behaviors in 24-month olds (n = 258). Neither prenatal nor postnatal maternal depressive symptoms independently predicted neither the frontal EEG activity nor functional connectivity in 6- and 18-month infants. However, increasing maternal depressive symptoms from the prenatal to postnatal period predicted greater right frontal activity and relative right frontal asymmetry amongst 6-month infants but these finding were not observed amongst 18-month infants after adjusted for post-conceptual age on the EEG visit day. Subsequently increasing maternal depressive symptoms from the prenatal to postnatal period predicted lower right frontal connectivity within 18-month infants but not among 6-month infants after controlling for post-conceptual age on the EEG visit day. These findings were observed in the full sample and the female sample but not in the male sample. Moreover, both prenatal and early postnatal maternal depressive symptoms independently predicted children's externalizing and internalizing behaviors at 24 months of age. This suggests that the altered frontal functional connectivity in infants born to mothers whose depressive symptomatology increases in the early postnatal period compared to that during pregnancy may reflect a neural basis for the familial transmission of phenotypes associated with mood disorders, particularly in girls.

While most secreted proteins contain defined signal peptides that direct their extracellular transport through the ER-Golgi pathway, nonclassical transport of leaderless peptides/proteins was first described 20 years ago and the mechanisms responsible for unconventional export of such proteins have been thoroughly reviewed. In addition to directed nonclassical secretion, a number of leaderless secreted proteins have been classified as damage-associated molecular-pattern (DAMP) molecules, which are nuclear or cytoplasmic proteins that, under necrotic or apoptotic conditions, are released outside the cell and function as proinflammatory signals. A strong association between persistent release of DAMPs, chronic inflammation, and the hypoxic tumor microenvironment has been proposed. Thus, protein localization and function can change fundamentally from intracellular to extracellular compartments, often under conditions of inflammation, cancer, and arthritis. If we are truly to understand, model, and treat such biological states, it will be important to investigate these multifunctional proteins and their contribution to degenerative diseases. Here, we will focus our discussion on intracellular proteins, both cytoplasmic and nuclear, that play critical extracellular roles. In particular, the multifunctional nature of HMMR/RHAMM and survivin will be highlighted and compared, as these molecules are the subject of extensive biological and therapeutic investigations within hematology and oncology fields. For these and other genes/proteins, we will highlight points of structural and functional intersection during cellular division and differentiation, as well as states associated with cancer, such as tumor-initiation and epithelial-to-mesenchymal transition (EMT). Finally, we will discuss the potential targeting of these proteins for improved therapeutic outcomes within these degenerative disorders. Our goal is to highlight a number of commonalities among these multifunctional proteins for better understanding of their putative roles in tumor initiation, inflammation, arthritis, and cancer.

Development of a vaccine for HIV-1 requires a detailed understanding of the neutralizing antibody responses that can be experimentally elicited to difficult-to-neutralize primary isolates. Rabbits were immunized with the gp120 subunit of HIV-1 JR-CSF envelope (Env) using a DNA-prime protein-boost regimen. We analyzed five sera that showed potent autologous neutralizing activity (IC50s at ∼10(3) to 10(4) serum dilution) against pseudoviruses containing Env from the primary isolate JR-CSF but not from the related isolate JR-FL. Pseudoviruses were created by exchanging each variable and constant domain of JR-CSF gp120 with that of JR-FL or with mutations in putative N-glycosylation sites. The sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions located on the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera are generally distinct from those of several well characterized mAbs (targeting conserved sites on Env) or other type-specific responses (targeting V1, V2, or V3 variable regions). The activity of one serum requires specific glycans that are also important for 2G12 neutralization and this serum blocked the binding of 2G12 to gp120. Our findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewing's sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewing's sarcoma to IGF1R inhibitor-based therapy.This pilot study assessed two patients with advanced Ewing's sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well.Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewing's sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewing's sarcoma merits further investigation as a guide to understanding response and resistance signatures.

A prophylactic vaccine is needed to slow the spread of HIV-1 infection. Optimization of the wild-type envelope glycoproteins to create immunogens that can elicit effective neutralizing antibodies is a high priority. Starting with ten genes encoding subtype B HIV-1 gp120 envelope glycoproteins and using in vitro homologous DNA recombination, we created chimeric gp120 variants that were screened for their ability to bind neutralizing monoclonal antibodies. Hundreds of variants were identified with novel antigenic phenotypes that exhibit considerable sequence diversity. Immunization of rabbits with these gp120 variants demonstrated that the majority can induce neutralizing antibodies to HIV-1. One novel variant, called ST-008, induced significantly improved neutralizing antibody responses when assayed against a large panel of primary HIV-1 isolates. Further study of various deletion constructs of ST-008 showed that the enhanced immunogenicity results from a combination of effective DNA priming, an enhanced V3-based response, and an improved response to the constant backbone sequences.

This qualitative study investigated the ways in which 84 parents from predominantly low-income communities described supporting their third graders' reading skills, motivation, and habits. Thematic analysis of open-ended parent interviews indicated that parents actively and deliberately scaffolded their children's progress toward developing independent reading skills. Parents explicitly communicated the value of reading in everyday conversations; actively listened to their children read, even if they did not understand the language in which the text was written; asked reading comprehension questions; created a home environment conducive to sustained reading; promoted reader autonomy through encouragement of strategy use; and incorporated reading practices into daily routines. Parents often described their own efforts as responsive to their children's level of reading motivation and reading performance, thus highlighting the reciprocal nature of parent--child reading interactions. Findings reveal a variety of ways in which families support their children's reading skills, motivation, and habits.

The authors conducted a cluster-randomized trial to examine the effectiveness of structured teacher adaptations to the implementation of an evidence-based summer literacy program that provided students with (a) books matched to their reading level and interests and (b) teacher scaffolding for summer reading in the form of end-of-year comprehension lessons and materials sent to students' homes in the summer months. In this study, 27 high-poverty elementary schools (75-100% eligibility for free or reduced-price lunch) were matched by prior reading achievement and poverty level and randomly assigned to one of two implementation conditions: a core treatment condition that directly replicated implementation procedures used in previous experiments, or a core treatment with structured teacher adaptations condition. In the adaptations condition, teachers were organized into grade-level teams around a practical improvement goal and given structured opportunities to use their knowledge, experience, and local data to extend or modify program components for their students and local contexts. Students in the adaptations condition performed 0.12 standard deviation higher on a reading comprehension posttest than students in the core treatment. An implementation analysis suggests that fidelity to core program components was high in both conditions and that teachers in the adaptations condition primarily made changes that extended or modified program procedures and activities in acceptable ways. Adaptations primarily served to increase the level of family engagement and student engagement with summer books. These results suggest that structured teacher adaptations may enhance rather than diminish the effectiveness of an evidence-based summer literacy program.