Search

Abstract BackgroundMobile devices for remote monitoring are inevitable tools to support treatment and patient care, especially in recurrent diseases such as major depressive disorder. The aim of this study was to learn if machine learning (ML) models based on longitudinal speech data are helpful in predicting momentary depression severity. Data analyses were based on a dataset including 30 inpatients during an acute depressive episode receiving sleep deprivation therapy in stationary care, an intervention inducing a rapid change in depressive symptoms in a relatively short period of time. Using an ambulatory assessment approach, we captured speech samples and assessed concomitant depression severity via self-report questionnaire over the course of 3 weeks (before, during, and after therapy). We extracted 89 speech features from the speech samples using the Extended Geneva Minimalistic Acoustic Parameter Set from the Open-Source Speech and Music Interpretation by Large-Space Extraction (audEERING) toolkit and the additional parameter speech rate. ObjectiveWe aimed to understand if a multiparameter ML approach would significantly improve the prediction compared to previous statistical analyses, and, in addition, which mechanism for splitting training and test data was most successful, especially focusing on the idea of personalized prediction. MethodsTo do so, we trained and evaluated a set of >500 ML pipelines including random forest, linear regression, support vector regression, and Extreme Gradient Boosting regression models and tested them on 5 different train-test split scenarios: a group 5-fold nested cross-validation at the subject level, a leave-one-subject-out approach, a chronological split, an odd-even split, and a random split. ResultsIn the 5-fold cross-validation, the leave-one-subject-out, and the chronological split approaches, none of the models were statistically different from random chance. The other two approaches produced significant results for at least one of the models tested, with similar performance. In total, the superior model was an Extreme Gradient Boosting in the odd-even split approach (RP ConclusionsOverall, our analyses highlight that ML fails to predict depression scores of unseen patients, but prediction performance increased strongly compared to our previous analyses with multilevel models. We conclude that future personalized ML models might improve prediction performance even more, leading to better patient management and care.

Abstract Pharmacogenomics aims to use the genetic information of an individual to personalize drug prescribing. There is evidence that pharmacogenomic testing before prescription may prevent adverse drug reactions, increase efficacy, and reduce cost of treatment. CYP2D6 is a key pharmacogene of relevance to multiple therapeutic areas. Indeed, there are prescribing guidelines available for medications based on CYP2D6 enzyme activity as deduced from CYP2D6 genetic data. The Agena MassARRAY system is a cost-effective method of detecting genetic variation that has been clinically applied to other genes. However, its clinical application to CYP2D6 has to date been limited by weaknesses such as the inability to determine which haplotype was present in more than one copy for individuals with more than two copies of the CYP2D6 gene. We report application of a new protocol for CYP2D6 haplotype phasing of data generated from the Agena MassARRAY system. For samples with more than two copies of the CYP2D6 gene for which the prior consensus data specified which one was present in more than one copy, our protocol was able to conduct CYP2D6 haplotype phasing resulting in 100% concordance with the prior data. In addition, for three reference samples known to have more than two copies of CYP2D6 but for which the exact number of CYP2D6 genes was unknown, our protocol was able to resolve the number for two out of the three of these, and estimate the likely number for the third. Finally, we demonstrate that our method is applicable to CYP2D6 hybrid tandem configurations.

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Abstract Background Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. Methods Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. Results Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). Conclusions Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments.

Abstract Objectives Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision‐making, and risk‐taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision‐making, and risk‐taking behavior in BD and MDD patients from bipolar multiplex families. Methods Eighty‐two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision‐making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. Results Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision‐making was associated with both mood disorders (BD and MDD). In risk‐taking behavior, no significant impairment was found in any group. Limitations As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. Conclusions Our findings show that alterations of cognitive domains—while present in both disorders—are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders.

BackgroundThe use of mobile devices to continuously monitor objectively extracted parameters of depressive symptomatology is seen as an important step in the understanding and prevention of upcoming depressive episodes. Speech features such as pitch variability, speech pauses, and speech rate are promising indicators, but empirical evidence is limited, given the variability of study designs. ObjectivePrevious research studies have found different speech patterns when comparing single speech recordings between patients and healthy controls, but only a few studies have used repeated assessments to compare depressive and nondepressive episodes within the same patient. To our knowledge, no study has used a series of measurements within patients with depression (eg, intensive longitudinal data) to model the dynamic ebb and flow of subjectively reported depression and concomitant speech samples. However, such data are indispensable for detecting and ultimately preventing upcoming episodes. MethodsIn this study, we captured voice samples and momentary affect ratings over the course of 3 weeks in a sample of patients (N=30) with an acute depressive episode receiving stationary care. Patients underwent sleep deprivation therapy, a chronotherapeutic intervention that can rapidly improve depression symptomatology. We hypothesized that within-person variability in depressive and affective momentary states would be reflected in the following 3 speech features: pitch variability, speech pauses, and speech rate. We parametrized them using the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) from open-source Speech and Music Interpretation by Large-Space Extraction (openSMILE; audEERING GmbH) and extracted them from a transcript. We analyzed the speech features along with self-reported momentary affect ratings, using multilevel linear regression analysis. We analyzed an average of 32 (SD 19.83) assessments per patient. ResultsAnalyses revealed that pitch variability, speech pauses, and speech rate were associated with depression severity, positive affect, valence, and energetic arousal; furthermore, speech pauses and speech rate were associated with negative affect, and speech pauses were additionally associated with calmness. Specifically, pitch variability was negatively associated with improved momentary states (ie, lower pitch variability was linked to lower depression severity as well as higher positive affect, valence, and energetic arousal). Speech pauses were negatively associated with improved momentary states, whereas speech rate was positively associated with improved momentary states. ConclusionsPitch variability, speech pauses, and speech rate are promising features for the development of clinical prediction technologies to improve patient care as well as timely diagnosis and monitoring of treatment response. Our research is a step forward on the path to developing an automated depression monitoring system, facilitating individually tailored treatments and increased patient empowerment.

Abstract Multiple sclerosis (MS) is the most common demyelinating autoimmune disease of the central nervous system (CNS). Immune-mediated myelin and axonal damage that is accompanied by chronic axonal loss causing destruction of the myelin sheaths are hallmarks of MS. While great strides have been made in understanding the molecular underpinnings of re-/myelination, currently no remyelination therapy is available for MS. As myelination is a complex process that is not fully understood, we sought to develop a systematic, reliable, automated and quantitative higher throughput screening method. We aimed to quantitate myelin sheaths in vitro with high sensitivity at the single cell level suitable for testing small compound libraries. To this end, we miniaturised in vitro retinal ganglion cell-oligodendrocyte precursor cell (RGC–OPC) co-cultures into a multi-well plate format. This allowed us to maintain the reciprocal interaction of live axons and oligodendrocytes (OLs) to ensure compact myelin formation. To quantify our co-cultures, we developed a novel computer vision algorithm to precisely measure myelination. We demonstrated efficacy of our system with known pro-differentiating compounds BQ3020 and XAV939 which exhibited robust, efficient, and dose dependent effects on myelination. Through this combination of experimental and technical advances, we have developed a method allowing systematic and reliable testing of remyelinating compound efficacy.

Abstract Aim The global pandemic of COVID-19 has led to extensive practice of online learning. Our main objective is to compare different online synchronous interactive learning activities to evaluate students’ perceptions. Moreover, we also aim to identify factors influencing their perceptions in these classes. Methods A cross-sectional, questionnaire-based study focusing on clinical year medical students’ perceptions and feedback was conducted between February 2021 –June 2021 at the University of Hong Kong. Online learning activities were divided into bedside teaching, practical skill session, problem-based learning (PBL) or tutorial, and lecture. A questionnaire based on the Dundee Ready Education Environment Measure (DREEM) was distributed to 716 clinical year students to document their perceptions. Results One hundred responses were received with a response rate of 15.4% (110/716, including 96 from bedside teaching, 67 from practical skill session, 104 from PBL/tutorial, and 101 from lecture). For the mean score of the DREEM-extracted questionnaire, online PBL/tutorial scored the highest (2.72 ± 0.54), while bedside scored the lowest (2.38 ± 0.68, p = 0.001). Meanwhile, there was no significant difference when we compared different school years (p = 0.39), age (p = 0.37), gender (p = 1.00), year of internet experience (

Collective optical Thomson scattering (TS) is a diagnostic commonly used to characterize plasma parameters. These parameters are typically extracted by a fitting algorithm that minimizes the difference between a measured scattered spectrum and an analytic spectrum calculated from the velocity distribution function (VDF) of the plasma. However, most existing TS analysis algorithms assume that the VDFs are Maxwellian, and applying an algorithm that makes this assumption does not accurately extract the plasma parameters of a non-Maxwellian plasma due to the effect of non-Maxwellian deviations on the TS spectra. We present new open-source numerical tools for forward modeling analytic spectra from arbitrary VDFs and show that these tools are able to more accurately extract plasma parameters from synthetic TS spectra generated by non-Maxwellian VDFs compared to standard TS algorithms. Estimated posterior probability distributions of fits to synthetic spectra for a variety of example non-Maxwellian VDFs are used to determine uncertainties in the extracted plasma parameters and show that correlations between parameters can significantly affect the accuracy of fits in plasmas with non-Maxwellian VDFs.

Abstract Major Depression and Bipolar Disorder Type I (BIP-I) and Type II (BIP-II), are characterized by depressed, manic, and hypomanic episodes in which specific changes of physical activity, circadian rhythm, and sleep are observed. It is known that genetic factors contribute to variation in mood disorders and biological rhythms, but unclear to what extent there is an overlap between their underlying genetics. In the present study, data from genome-wide association studies were used to examine the genetic relationship between mood disorders and biological rhythms. We tested the genetic correlation of depression, BIP-I, and BIP-II with physical activity (overall physical activity, moderate activity, sedentary behaviour), circadian rhythm (relative amplitude), and sleep features (sleep duration, daytime sleepiness). Genetic correlations of depression, BIP-I, and BIP-II with biological rhythms were compared to discover commonalities and differences. A gene-based analysis tested for associations of single genes and common circadian genes with mood disorders. Depression was negatively correlated with overall physical activity and positively with sedentary behaviour, while BIP-I showed associations in the opposite direction. Depression and BIP-II had negative correlations with relative amplitude. All mood disorders were positively correlated with daytime sleepiness. Overall, we observed both genetic commonalities and differences across mood disorders in their relationships with biological rhythms: depression and BIP-I differed the most, while BIP-II was in an intermediate position. Gene-based analysis suggested potential targets for further investigation. The present results suggest shared genetic underpinnings for the clinically observed associations between mood disorders and biological rhythms. Research considering possible joint mechanisms may offer avenues for improving disease detection and treatment.

Abstract Although the currently available antidepressants are well established in the treatment of the major depressive disorder (MDD), there is strong variability in the response of individual patients. Reliable predictors to guide treatment decisions before or in an early stage of treatment are needed. DNA-methylation has been proven a useful biomarker in different clinical conditions, but its importance for mechanisms of antidepressant response has not yet been determined. 80 MDD patients were selected out of >500 participants from the Early Medication Change (EMC) cohort with available genetic material based on their antidepressant response after four weeks and stratified into clear responders and age- and sex-matched non-responders (N = 40, each). Early improvement after two weeks was analyzed as a secondary outcome. DNA-methylation was determined using the Illumina EPIC BeadChip. Epigenome-wide association studies were performed and differentially methylated regions (DMRs) identified using the comb-p algorithm. Enrichment was tested for hallmark gene-sets and in genome-wide association studies of depression and antidepressant response. No epigenome-wide significant differentially methylated positions were found for treatment response or early improvement. Twenty DMRs were associated with response; the strongest in an enhancer region in SORBS2, which has been related to cardiovascular diseases and type II diabetes. Another DMR was located in CYP2C18, a gene previously linked to antidepressant response. Results pointed towards differential methylation in genes associated with cardiac function, neuroticism, and depression. Linking differential methylation to antidepressant treatment response is an emerging topic and represents a step towards personalized medicine, potentially facilitating the prediction of patients’ response before treatment.

Abstract Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Abstract Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality—the “Big Five”. In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2543) and GWAS on the Big Five (N = 76,551–122,886, Neuroticism N = 390,278). Polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status. Significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3*10−5) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all | rg | 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters “Depressed Affect” and “Worry”, and with a broad range of Neuroticism items (N = 348,219–376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk. The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the “Big Five” are needed to further explore the role of personality traits in the etiology of BPD.

IntroductionFamily history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment.MethodsAnalyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses.ResultsHigher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%–12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect.DiscussionThe present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent.

BackgroundCocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue.MethodsWe investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study (EWAS) and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology (GO) enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age.ResultsWhile no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified Neuropeptide FF Receptor 2 (NPFFR2) and Kalirin RhoGEF Kinase (KALRN) for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction (PPI) networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit (JUN). In BA9, we observed a trend toward epigenetic age acceleration (EAA) in individuals with CUD remaining stable even after adjustment for covariates.ConclusionResults from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7–10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020–October 2020; November 2020–February 2021). Associations of the children’s and mothers’ well-being with maternal perceived stress, of the children’s well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children’s but not the mothers’ emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children’s emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. OsteoplugTM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing osseous integration and vascular ingrowth. However, the cosmetic and safety outcomes of OsteoplugTM-C—the latest (2017) iteration, with a chamfered hole for subdural drains—remain unexplored. Data were collected from a single institution from April 2017 to March 2021. Patient-reported aesthetic outcomes (Aesthetic Numeric Analog (ANA)) and quality of life (EQ-5D-3L including Visual Analog Scale (VAS)) were assessed via telephone interviews. Clinical outcomes included SDH recurrence, postoperative infections, and drain complications. OsteoplugTM-C patients had significantly higher satisfaction and quality of life compared to those without a burrhole cover (ANA: 9 [7, 9] vs. 7 [5, 8], p = 0.019; VAS: 85 [75, 90] vs. 70 [50, 80], p = 0.021), and the absence of a burrhole cover was associated with poorer aesthetic outcomes after multivariable adjustment (adjusted OR: 4.55, 95% CI: 1.09–22.68, p = 0.047). No significant differences in other clinical outcomes were observed between OsteoplugTM-C, OsteoplugTM, or no burrhole cover. Our pilot study supports OsteoplugTM-C and its material polycaprolactone as suitable adjuncts to burrhole craniostomy, improving cosmetic outcomes while achieving comparable safety outcomes.

Introduction: Faced with a backdrop of an increasing chronic disease burden from an ageing global population compounded with rising healthcare costs, health systems are required to implement cost-effective, safe and equitable care through efficient service delivery models. One approach to achieving this is through Starfield's 4Cs of primary healthcare (PHC), which delineates the key attributes of a high-performing PHC system that upholds the pillars of care coordination, first contact of care, continuity of care and comprehensive care. Therefore, this study aims to explore and elucidate the key themes and subthemes related to and extending beyond Starfield's 4Cs of PHC by integrating findings from a comprehensive literature review and a qualitative study., Methods: In this case study analysis, case studies of PHC systems from 19 countries were purposefully selected to represent a range of income levels and diversity in health systems and PHC landscapes. A review of existing literature of peer-reviewed articles, policy documents and technical reports made publicly available data on PHC was complemented with data obtained from 61 in-depth interviews with health systems experts from a larger study. The research team thematically analysed the data and organised the key themes and subthemes into a conceptual framework that is anchored on Starfield's 4Cs of PHC., Results: Broadly, we developed a conceptual framework with the 4Cs, placing providers and patients at the centre. The key subthemes that manifested from Starfield's 4Cs included maximising the use of existing fiscal resources, leveraging technology, improving accessibility to health services and task sharing. Other relevant and overarching themes were the deployment of national frameworks, equity, healthcare provider retention, service integration, emergency preparedness and community engagement., Discussion: The subthemes derived point health systems in the right direction based on the trialled and tested PHC models of various countries. Their strong points were highlighted in our case studies to depict how Starfield's 4Cs are leveraged to strengthen PHC, and the themes we identified that went beyond the 4Cs are necessary considerations for modifying PHC policies going forward., Conclusion: As the world enters an era of ageing populations and acute system shocks, PHC needs to be fortified and integrated into the more extensive system to protect the health of the population and safeguard the well-being of providers. Our conceptual framework offers health systems a glimpse of how this can be achieved., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.)

The distribution of substitutional aluminum (Al) atoms in zeolites affects molecular adsorbate geometry, catalytic activity, and shape and size selectivity. Accurately determining Al positions has been challenging. We used synchrotron resonant soft x-ray diffraction (RSXRD) at multiple energies near the Al K-edge combined with molecular adsorption techniques to precisely locate "single Al" and "Al pairs" in a commercial H-ZSM-5 zeolite. This analysis depicts three distinct Al tetrahedral (T) sites: T8, T6, and T4. A combined suite of characterizations, including ammonia temperature-dependent desorption, neutron powder diffraction, solid-state nuclear magnetic resonance spectroscopy, and density functional theory calculations, reveal isolated ammonia adsorption on T8 as "single Al" in the straight channel and bridged ammonia adsorption on T6 and T4 as an "Al pair" (Al T6 -O-Si T5 -O-Al T4 ) in the straight-sinusoidal intersection.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Optical pooled screening (OPS) is a scalable method for linking image-based phenotypes with cellular perturbations. However, it has thus far been restricted to relatively low-plex phenotypic readouts in cancer cell lines in culture due to limitations associated with in situ sequencing of perturbation barcodes. Here, we develop PerturbView, an OPS technology that leverages in vitro transcription to amplify barcodes before in situ sequencing, enabling screens with highly multiplexed phenotypic readouts across diverse systems, including primary cells and tissues. We demonstrate PerturbView in induced pluripotent stem cell-derived neurons, primary immune cells and tumor tissue sections from animal models. In a screen of immune signaling pathways in primary bone marrow-derived macrophages, PerturbView uncovered both known and novel regulators of NF-κB signaling. Furthermore, we combine PerturbView with spatial transcriptomics in tissue sections from a mouse xenograft model, paving the way to in situ screens with rich optical and transcriptomic phenotypes. PerturbView broadens the scope of OPS to a wide range of models and applications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We describe real-world estimates of JYNNEOS vaccine effectiveness (VE) against symptomatic mpox in Los Angeles County (LAC). We conducted a retrospective cohort study of men aged ≥18 years residing in LAC who were at risk for mpox and eligible for the JYNNEOS vaccine from 5/19/2022 to 1/1/2023. Case demographics and route of JYNNEOS administration were obtained through vaccine administration data systems. HIV and sexually transmitted infection (STI) status was obtained through disease reporting systems for HIV and STI diagnoses in LAC. To estimate VE, we calculated weekly incidence of confirmed mpox for unvaccinated, partially vaccinated (episode date ≥14 days after first dose), and fully vaccinated (episode date ≥14 days after second dose) cohorts starting on 8/29/2022, when fully vaccinated coverage exceeded 3 %, and ending on 1/1/2023. Overall, 2,171 men had confirmed mpox, and 1,002 (46 %) of those were persons living with diagnosed HIV (PLWDH). 2,019 (93 %) mpox cases were unvaccinated, 114 (5 %) were partially vaccinated and 38 (2 %) were fully vaccinated. VE was 69 % (95 % CI 59-77) for partially vaccinated and 84 % (95 % CI 80-87) for fully vaccinated individuals. Among PLWDH, VE was 72 % (95 % CI 57-82) for fully vaccinated and 28 % (95 % CI -96 to 73) VE for partially vaccinated individuals. Among persons not living with diagnosed HIV, VE was 88 % (95 % CI 86-90) for fully vaccinated and 80 % (95 % CI 76-83) for partially vaccinated individuals. Of 111 individuals hospitalized with mpox, one was partially vaccinated, and the remaining were unvaccinated. Our results align with other published studies that reported that two doses of the JYNNEOS vaccine provided significant protection against symptomatic mpox., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In Singapore, an ageing population with increasing chronic disease burden and complex social circumstances have strained the healthcare system. For the health system to run more efficiently, patients should be appropriately sited according to their medical needs. In Singapore, community hospitals serve as an intermediate inpatient facility managing patients with sub-acute and rehabilitation care needs. Our policy brief uncovers the gaps in transforming community hospital care models and offers actionable steps to unlock the community hospital chokepoints in Singapore's health system. The future community hospitals can accommodate higher acuity but medically stable patients, while patients who do not require inpatient rehabilitation care can be appropriately sited to community partners, if policy, resourcing and technology factors are addressed. An evidence-based, stepwise approach involving all stakeholders will be required to pilot and evaluate new models before large-scale change., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Foo, Chia, Tan, Lai, Khoo, Tee, Lim and Teo.)

Background: We aimed to estimate the proportion of children hospitalized for influenza whose illness was complicated by bloodstream infection, describe their clinical course, and identify the factors associated with bloodstream infection., Methods: We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from the 2010-2011 to 2020-2021 influenza seasons. Factors associated with bloodstream infection were identified using multivariable logistic regression analyses., Results: Among 9179 laboratory-confirmed influenza hospital admissions, bloodstream infection occurred in 87 children (0.9%). Streptococcus pyogenes (22%), Staphylococcus aureus (18%) and Streptococcus pneumoniae (17%) were the most common bloodstream infection pathogens identified. Children with cancer [adjusted odds ratio (aOR): 2.78; 95% confidence interval (CI): 1.23-5.63], a laboratory-confirmed nonbloodstream bacterial infection (aOR: 14.1; 95% CI: 8.04-24.3) or radiographically-confirmed pneumonia (aOR: 1.87; 95% CI: 1.17-2.97) were more likely to experience a bloodstream infection, whereas children with chronic lung disorders were less likely (aOR: 0.41; 95% CI: 0.19-0.80). Disease severity markers such as intensive care unit admission (aOR: 2.11; 95% CI: 1.27-3.46), mechanical ventilation (aOR: 2.84; 95% CI: 1.63-4.80) and longer hospital length of stay (aOR: 1.02; 95% CI: 1.01-1.03) were associated with bloodstream infection. Bloodstream infection also increased the odds of death (aOR: 13.0; 95% CI: 4.84-29.1) after adjustment for age, influenza virus type and the presence of any at-risk chronic condition., Conclusions: Bloodstream infections, although infrequent, are associated with intensive care unit admission, mechanical ventilation, increased hospital length of stay and in-hospital mortality, thus requiring increased levels of care among pediatric influenza hospitalizations., Competing Interests: J.P. reports grants from MedImmune, grants and personal fees from Merck and personal fees from AstraZeneca, all outside the submitted work. M.S. is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC; he has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines with all funds paid to his institute, and he has not received any personal payments. S.A.H. has served on ad hoc advisory boards and has been an investigator on projects funded by Sanofi-Pasteur, GlaxoSmithKline, Merck, Pfizer, VBI, CanSino, Moderna and Seqirus. S.K.M. is a coinvestigator on an investigator-led grant from Pfizer, has served on ad hoc advisory boards for Pfizer, Sanofi Pasteur and Merck and has received speaker fees from GlaxoSmithKline and JNJ China, all unrelated to this study. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

How transient hyperglycemia contributes to cerebro-vascular disease has been a challenge to study under controlled physiological conditions. We use amplified, ultrashort laser-pulses to physically disrupt brain-venule endothelium at targeted locations. This vessel disruption is performed in conjunction with transient hyperglycemia from a single injection of metabolically active D -glucose into healthy mice. The observed real-time responses to laser-induced disruption include rapid serum extravasation, platelet aggregation, and neutrophil recruitment. Thrombo-inflammation is pharmacologically ameliorated by a platelet inhibitor, by a scavenger of reactive oxygen species, and by a nitric oxide donor. As a control, vessel thrombo-inflammation is significantly reduced in mice injected with metabolically inert L -glucose. Venules in mice with diabetes show a similar response to laser-induced disruption and damage is reduced by restoration of normo-glycemia. Our approach provides a controlled method to probe synergies between transient metabolic and physical vascular perturbations and can reveal new aspects of brain pathophysiology., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: Neurological involvement associated with SARS-CoV-2 infection is increasingly recognized. However, the specific characteristics and prevalence in pediatric patients remain unclear. The objective of this study was to describe the neurological involvement in a multinational cohort of hospitalized pediatric patients with SARS-CoV-2., Methods: This was a multicenter observational study of children <18 years of age with confirmed SARS-CoV-2 infection or multisystemic inflammatory syndrome (MIS-C) and laboratory evidence of SARS-CoV-2 infection in children, admitted to 15 tertiary hospitals/healthcare centers in Canada, Costa Rica, and Iran February 2020-May 2021. Descriptive statistical analyses were performed and logistic regression was used to identify factors associated with neurological involvement., Results: One-hundred forty-seven (21%) of 697 hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Headache ( n = 103), encephalopathy ( n = 28), and seizures ( n = 30) were the most reported. Neurological signs/symptoms were significantly associated with ICU admission (OR: 1.71, 95% CI: 1.15-2.55; p = 0.008), satisfaction of MIS-C criteria (OR: 3.71, 95% CI: 2.46-5.59; p < 0.001), fever during hospitalization (OR: 2.15, 95% CI: 1.46-3.15; p < 0.001), and gastrointestinal involvement (OR: 2.31, 95% CI: 1.58-3.40; p < 0.001). Non-headache neurological manifestations were significantly associated with ICU admission (OR: 1.92, 95% CI: 1.08-3.42; p = 0.026), underlying neurological disorders (OR: 2.98, 95% CI: 1.49-5.97, p = 0.002), and a history of fever prior to hospital admission (OR: 2.76, 95% CI: 1.58-4.82; p < 0.001)., Discussion: In this study, approximately 21% of hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Future studies should focus on pathogenesis and long-term outcomes in these children.

Voice banking involves recording an inventory of sentences produced via natural speech. The recordings are used to create a synthetic text-to-speech voice that can be installed on speech-generating devices. This study highlights a minimally researched, clinically relevant issue surrounding the development and evaluation of Singaporean-accented English synthetic voices that were created using readily available voice banking software and hardware. Processes used to create seven unique synthetic voices that produce Singaporean-accented English, and the development of a custom Singaporean Colloquial English (SCE) recording inventory, are reviewed. The perspectives of adults who spoke SCE and banked their voices for this project are summarized and were generally positive. Finally, 100 adults familiar with SCE participated in an experiment that evaluated the intelligibility and naturalness of the Singaporean-accented synthetic voices, as well as the effect of the SCE custom inventory on listener preferences. The addition of the custom SCE inventory did not affect intelligibility or naturalness of the synthetic speech, and listeners tended to prefer the voice created with the SCE inventory when the stimulus was an SCE passage. The procedures used in this project may be helpful for interventionists who wish to create synthetic voices with accents that are not commercially available.

Competing Interests: The authors declare no conflict of interests.

Objectives: To evaluate immunocompromising conditions and subgroups of immunocompromise as risk factors for severe outcomes among children admitted for influenza., Methods: We performed active surveillance for laboratory-confirmed influenza hospitalizations among children ≤16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, during 2010-2021. Logistic regression analyses were used to compare outcomes between immunocompromised and non-immunocompromised children, and for different subgroups of immunocompromise. The primary outcome was intensive care unit (ICU) admission; the secondary outcomes were mechanical ventilation and death., Results: Among 8982 children, 892 (9.9%) were immunocompromised; these patients were older (median, 5.6 (IQR, 3.1-10.0) vs. 2.4 (1-6) years; p < 0.001) than non-immunocompromised children, had a similar frequency of comorbidities, excluding immunocompromise and/or malignancy (38% (340/892) vs. 40% (3272/8090); p 0.2), but fewer respiratory symptoms, such as respiratory distress (20% (177/892) vs. 42% (3424/8090), p < 0.001). In multivariable analyses, immunocompromise (adjusted odds ratio (aOR), 0.19; 95% CI, 0.14-0.25) and its subcategories immunodeficiency (aOR, 0.16; 95% CI, 0.10-0.23), immunosuppression (aOR, 0.17; 95% CI, 0.12-0.23), chemotherapy (aOR, 0.07; 95% CI, 0.03-0.13), and solid organ transplantation (aOR, 0.17; 95% CI, 0.06-0.37) were associated with decreased probability of ICU admission in children admitted for influenza. Immunocompromise was also associated with a decreased probability of mechanical ventilation (aOR, 0.26; 95% CI, 0.16-0.38) or death (aOR, 0.22; 95% CI, 0.03-0.72)., Conclusion: Immunocompromised children are overrepresented among hospitalizations for influenza, but have a decreased probability of ICU admission, mechanical ventilation, and mortality following admission. Admission bias precludes generalizability beyond the hospital setting., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. All rights reserved.)

The COVID-19 pandemic had an inequitable and disproportionate impact on vulnerable populations, reversing decades of progress toward healthy populations and poverty alleviation. This study examines various programmatic tools and policy measures used by governments to support vulnerable populations during the pandemic. A comparative case study of 15 countries representing all World Health Organization's regions offers a comprehensive picture of countries with varying income statuses, health system arrangements and COVID-19 public health measures. Through a systematic desk review and key informant interviews, we report a spectrum of mitigation strategies deployed in these countries to address five major types of vulnerabilities (health, economic, social, institutional and communicative). We found a multitude of strategies that supported vulnerable populations such as migrant workers, sex workers, prisoners, older persons and school-going children. Prioritising vulnerable populations during the early phase of COVID-19 vaccination campaigns, direct financial subsidies and food assistance programmes were the most common measures reported. Additionally, framing public health information and implementing culturally sensitive health promotion interventions helped bridge the communication barriers in certain instances. However, these measures remain insufficient to protect vulnerable populations comprehensively. Our findings point to the need to expand fiscal space for health, enlarge healthcare coverage, incorporate equity principles in all policies, leverage technology, multi-stakeholder co-production of policies and tailored community engagement mechanisms., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The objective of this study was to describe the clinical course and outcomes in children with technology dependence (TD) hospitalized with SARS-CoV-2 infection., Methods: Seventeen pediatric hospitals (15 Canadian and one each in Iran and Costa Rica) included children up to 17 years of age admitted February 1, 2020, through May 31, 2021, with detection of SARS-CoV-2. For those with TD, data were collected on demographics, clinical course and outcome., Results: Of 691 children entered in the database, 42 (6%) had TD of which 22 had feeding tube dependence only, 9 were on supplemental oxygen only, 3 had feeding tube dependence and were on supplemental oxygen, 2 had a tracheostomy but were not ventilated, 4 were on non-invasive ventilation, and 2 were on mechanical ventilation prior to admission. Three of 42 had incidental SARS-CoV-2 infection. Two with end-stage underlying conditions were transitioned to comfort care and died. Sixteen (43%) of the remaining 37 cases required increased respiratory support from baseline due to COVID-19 while 21 (57%) did not. All survivors were discharged home., Conclusion: Children with TD appear to have an increased risk of COVID-19 hospitalization. However, in the absence of end-stage chronic conditions, all survived to discharge., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

In Los Angeles County, California, USA, public health surveillance identified 118 mpox cases among persons experiencing homelessness (PEH) during July-September 2022. Age and sex were similar for mpox case-patients among PEH and in the general population. Seventy-one (60%) PEH mpox case-patients were living with HIV, 35 (49%) of them virally suppressed. Hospitalization was required for 21% of case-patients because of severe disease. Sexual contact was likely the primary mode of transmission; 84% of patients reported sexual contact <3 weeks before symptom onset. PEH case-patients lived in shelters, encampments, cars, or on the street, or stayed briefly with friends or family (couch surfed). Some case-patients stayed at multiple locations during the 3-week incubation period. Public health follow-up and contact tracing detected no secondary mpox cases among PEH in congregate shelters or encampments. Equitable efforts should continue to identify, treat, and prevent mpox among PEH, who often experience severe disease.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) has recently caused a pandemic. Patients with COVID-19 presented with a wide spectrum of symptoms for the disease, from entirely asymptomatic disease to full-blown pneumonia and multiorgan failures. More evidence emerged, showing the production of interferons (IFNs) in the severe cases were significantly lower than their milder counterparts, suggesting linkage of COVID-19 to impaired innate immunity. This review presents a brief overview of how coronaviruses evade innate immunity, according to the current studies about SARS-CoV and middle-east respiratory syndrome-coronavirus (MERS-CoV). The coronaviruses manage to block, escape, or dampen the innate immune response by antagonizing double-stranded RNA (dsRNA) sensor, mitochondrial antiviral-signaling protein (MAVS) and stimulator of IFN genes (STING) pathways, epigenetic modification, posttranslational modifications, and host mRNA translation. We provide novel insights into a comprehensive therapy to combat SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A projected rise in patients with complex health needs and a rapidly ageing population will place an increased burden on the healthcare system. Care coordination can bridge potential gaps during care transitions and across the care continuum to facilitate care integration and the delivery of personalised care. Despite having a national strategic vision of improving care integration across different levels of care and community partners, there is no consolidation of evidence specifically on the salient dimensions of care coordination in the Singapore healthcare context. Hence, this scoping review aims to uncover the key themes that facilitate care coordination for patients with chronic conditions in Singapore to be managed in the community while illuminating under-researched areas in care coordination requiring further exploration. The databases searched were PubMed, CINAHL, Scopus, Embase, and Cochrane Library. Results from Google Scholar were also included. Two independent reviewers screened articles in a two-stage screening process based on the Cochrane scoping review guidelines. Recommendation for inclusion was indicated on a three-point scale and rating conflicts were resolved through discussion. Of the 5792 articles identified, 28 were included in the final review. Key cross-cutting themes such as having standards and guidelines for care programmes, forging stronger partnerships across providers, an interoperable information system across care interfaces, strong programme leadership, financial and technical resource availabilities and patient and provider-specific factors emerged. This review also recommends leveraging these themes to align with Singapore's national healthcare vision to contain rising healthcare costs.