Identifying core global mental health professional competencies: A multi-sectoral perspective.

Concerned with sustainably alleviating mental distress and promoting the right to health worldwide, global mental health (GMH) is practised across various contexts spanning the humanitarian-development-peace nexus. The inherently intersectoral and multidisciplinary nature of GMH calls for competency frameworks and training programmes that embody diversity, decolonisation and multiprofessionalism. Existing competency frameworks have failed to capture the multi-sectoral, inter-professional nature of contemporary GMH practice. In response to these needs, a qualitative content analysis of relevant job advertisements was conducted to distil a comprehensive set of professional competencies in contemporary GMH practice. Approximately 200 distinct skills and competencies were extracted from 70 job advertisements and organised into four meta-dimensions: 'skills', 'sector', 'self' and 'subject'. The first known systematic attempt at a multi-sectoral GMH competency framework, it offers a springboard for exploring vital yet overlooked professional competencies such as resilience, self-reflection, political skills and entrepreneurialism. On this basis, recommendations for building a competent, agile and effective GMH workforce with diversified and future-proof skillsets are proposed. The framework can also inform inter-professional training and curriculum design, and capacity-building initiatives aimed at early-career professional development, particularly in low- and middle-income settings.

Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma.

Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Ductal, intraductal, and cribriform carcinoma of the prostate: Molecular characteristics and clinical management.

Prostatic acinar adenocarcinoma accounts for approximately 95% of prostate cancer (CaP) cases. The remaining 5% of histologic subtypes of CaP are known to be more aggressive and have recently garnered substantial attention. These histologic subtypes - namely, prostatic ductal adenocarcinoma (PDA), intraductal carcinoma of the prostate (IDC-P), and cribriform carcinoma of the prostate (CC-P) - typically exhibit distinct growth characteristics, genomic features, and unique oncologic outcomes. For example, PTEN mutations, which cause uncontrolled cell growth, are frequently present in IDC-P and CC-P. Germline mutations in homologous DNA recombination repair (HRR) genes (e.g., BRCA1, BRCA2, ATM, PALB2, and CHEK2) are discovered in 40% of patients with IDC-P, while only 9% of patients without ductal involvement had a germline mutation. CC-P is associated with deletions in common tumor suppressor genes, including PTEN, TP53, NKX3-1, MAP3K7, RB1, and CHD1. Evidence suggests abiraterone may be superior to docetaxel as a first-line treatment for patients with IDC-P. To address these and other critical pathological attributes, this review examines the molecular pathology, genetics, treatments, and oncologic outcomes associated with CC-P, PDA, and IDC-P with the objective of creating a comprehensive resource with a centralized repository of information on PDA, IDC-P, and CC-P.

Targeting the DNA damage response in hematological malignancies.

Deregulation of the DNA damage response (DDR) plays a critical role in the pathogenesis and progression of many cancers. The dependency of certain cancers on DDR pathways has enabled exploitation of such through synthetically lethal relationships e.g., Poly ADP-Ribose Polymerase (PARP) inhibitors for BRCA deficient ovarian cancers. Though lagging behind that of solid cancers, DDR inhibitors (DDRi) are being clinically developed for haematological cancers. Furthermore, a high proliferative index characterize many such cancers, suggesting a rationale for combinatorial strategies targeting DDR and replicative stress. In this review, we summarize pre-clinical and clinical data on DDR inhibition in haematological malignancies and highlight distinct haematological cancer subtypes with activity of DDR agents as single agents or in combination with chemotherapeutics and targeted agents. We aim to provide a framework to guide the design of future clinical trials involving haematological cancers for this important class of drugs.

Interferon-gamma release assay conversion after Mycobacterium tuberculosis exposure specifically associates with greater risk of progression to tuberculosis: A prospective cohort study in Leicester, UK.

OBJECTIVES: We investigated whether quantifying the serial QuantiFERON-TB Gold (QFT) response improves tuberculosis (TB) risk stratification in pulmonary TB (PTB) contacts. METHODS: A total of 297 untreated adult household PTB contacts, QFT tested at baseline and 3 months after index notification, were prospectively observed (median 1460 days). Normal variance of serial QFT responses was established in 46 extrapulmonary TB contacts. This informed categorisation of the response in QFT-positive PTB contacts as converters, persistently QFT-positive with significant increase (PPincrease), and without significant increase (PPno-increase). RESULTS: In total, eight co-prevalent TB (disease ≤3 months after index notification) and 12 incident TB (>3 months after index notification) cases were diagnosed. Genetic linkage to the index strain was confirmed in all culture-positive progressors. The cumulative 2-year incident TB risk in QFT-positive contacts was 8.4% (95% confidence interval, 3.0-13.6%); stratifying by serial QFT response, significantly higher risk was observed in QFT converters (28%), compared with PPno-increase (4.8%) and PPincrease (3.7%). Converters were characterised by exposure to index cases with a shorter interval from symptom onset to diagnosis (median reduction 50.0 days, P = 0.013). CONCLUSIONS: QFT conversion, rather than quantitative changes of a persistently positive serial QFT response, is associated with greater TB risk and exposure to rapidly progressive TB.

PET-CT-guided characterisation of progressive, preclinical tuberculosis infection and its association with low-level circulating Mycobacterium tuberculosis DNA in household contacts in Leicester, UK: a prospective cohort study.

BACKGROUND: Incipient tuberculosis, a progressive state of Mycobacterium tuberculosis infection with an increased risk of developing into tuberculosis disease, remains poorly characterised. Animal models suggest an association of progressive infection with bacteraemia. Circulating M tuberculosis DNA has previously been detected in pulmonary tuberculosis by use of Actiphage, a bacteriophage-based real-time PCR assay. We aimed to investigate whether serial [18F]fluorodeoxyglucose ([18F]FDG)-PET-CT could be used to characterise the state and progressive trajectory of incipient tuberculosis, and examine whether these PET-CT findings are associated with Actiphage-based detection of circulating M tuberculosis DNA. METHODS: We did a prospective 12-month cohort study in healthy, asymptomatic adults (aged ≥16 years) who were household contacts of patients with pulmonary tuberculosis, and who had a clinical phenotype of latent tuberculosis infection, in Leicester, UK. Actiphage testing of participants' blood samples was done at baseline, and [18F]FDG PET-CT at baseline and after 3 months. Baseline PET-CT features were classified as positive, indeterminate, or negative, on the basis of the quantitation (maximum standardised uptake value [SUVmax]) and distribution of [18F]FDG uptake. Microbiological sampling was done at amenable sites of [18F]FDG uptake. Changes in [18F]FDG uptake after 3 months were quantitatively categorised as progressive, stable, or resolving. Participants received treatment if features of incipient tuberculosis, defined as microbiological detection of M tuberculosis or progressive PET-CT change, were identified. FINDINGS: 20 contacts were recruited between Aug 5 and Nov 5, 2020; 16 of these participants had a positive result on IFNγ release assay (QuantiFERON-TB Gold Plus [QFT]) indicating tuberculosis infection. Baseline PET-CT scans were positive in ten contacts (all QFT positive), indeterminate in six contacts (three QFT positive), and negative in four contacts (three QFT positive). Four of eight PET-CT-positive contacts sampled had M tuberculosis identified (three through culture, one through Xpert MTB/RIF Ultra test) from intrathoracic lymph nodes or bronchial wash and received full antituberculosis treatment. Two further unsampled PET-CT-positive contacts were also treated: one with [18F]FDG uptake in the lung (SUVmax 9·4) received empirical antituberculosis treatment and one who showed progressive [18F]FDG uptake received preventive treatment. The ten untreated contacts with [18F]FDG uptake at baseline (seven QFT positive) had stable or resolving changes at follow-up and remained free of tuberculosis disease after 12 months. A positive baseline Actiphage test was associated with the presence of features of incipient tuberculosis requiring treatment (p=0·018). INTERPRETATION: Microbiological and inflammatory features of incipient tuberculosis can be visualised on PET-CT and are associated with M tuberculosis detection in the blood, supporting the development of pathogen-directed blood biomarkers of tuberculosis risk. FUNDING: MRC Confidence in Concept.

An integrated program to expand donor utilization in pediatric heart transplantation: Case report of successful transplant with multiple donor risk factors.

BACKGROUND: Pediatric heart transplantation (HT) continues to be limited by the shortage of donor organs, distance constraints, and the number of potential donor offers that are declined due to the presence of multiple risk factors. METHODS: We report a case of successful pediatric HT in which multiple risk factors were mitigated through a combination of innovative donor utilization improvement strategies. RESULTS: An 11-year-old, 25-kilogram child with cardiomyopathy and pulmonary hypertension, on chronic milrinone therapy and anticoagulated with apixaban, was transplanted with a heart from a Hepatitis C virus positive donor and an increased donor-to-recipient weight ratio. Due to extended geographic distance, an extracorporeal heart preservation system (TransMedics™ OCS Heart) was used for procurement. No significant bleeding was observed post-operatively, and she was discharged by post-operative day 15 with normal biventricular systolic function. Post-transplant Hepatitis C virus seroconversion was successfully treated. CONCLUSIONS: Heart transplantation in donors with multiple risk factor can be achieved with an integrative team approach and should be taken into consideration when evaluating marginal donors in order to expand the current limited donor pool in pediatric patients.

Establishment of CA19-9 reference intervals in an apparently healthy adult population in Singapore.

BACKGROUND: CA19-9 is elevated in pancreatic cancer and other malignancies, and commonly used in clinical practice. Unfortunately, CA19-9 immunoassays are not harmonized, and reference intervals may differ between assays. The aim of this study was to establish the reference interval of the ADVIA Centaur/Atellica IM CA19-9 assay in an apparently healthy Singapore adult population. METHODS: This is a retrospective cross-sectional study. De-identified data from Health Screening participants were extracted from our database. Subjects with biochemical results suggesting anaemia, diabetes mellitus, viral hepatitis or abnormal liver, and renal and tumour markers were excluded. Outlier and subclass analyses by age and sex were performed. CA19-9 reference limits and 90% confidence intervals were then determined for candidate subclasses. RESULTS: Data from 12,174 subjects (5846 males and 6328 females) were available after exclusion criteria were applied. CA19-9 results did not follow a normal distribution and were higher in females compared to males (P < .001). Although CA19-9 means were statistically different between certain age groups, the evaluable 99th percentile reference limits were not statistically different. The overall 99th percentile reference limits for the Centaur/Atellica CA19-9 assay was 37 U/mL for males 21-80 years, and 60 U/mL for females 21-80 years. CONCLUSIONS: Our results suggest that separate CA19-9 reference intervals should be applied for males and females.

Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis.

Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.

Differential Responses of Retinal Neurons and Glia Revealed via Proteomic Analysis on Primary and Secondary Retinal Ganglion Cell Degeneration.

To explore the temporal profile of retinal proteomes specific to primary and secondary retinal ganglion cell (RGC) loss. Unilateral partial optic nerve transection (pONT) was performed on the temporal side of the rat optic nerve. Temporal and nasal retinal samples were collected at 1, 4 and 8 weeks after pONT (n = 4 each) for non-biased profiling with a high-resolution hybrid quadrupole time-of-flight mass spectrometry running on label-free SWATHTM acquisition (SCIEX). An information-dependent acquisition ion library was generated using ProteinPilot 5.0 and OneOmics cloud bioinformatics. Combined proteome analysis detected 2531 proteins with a false discovery rate of <1%. Compared to the nasal retina, 10, 25 and 61 significantly regulated proteins were found in the temporal retina at 1, 4, and 8 weeks, respectively (p < 0.05, FC ≥ 1.4 or ≤0.7). Eight proteins (ALDH1A1, TRY10, GFAP, HBB-B1, ALB, CDC42, SNCG, NEFL) were differentially expressed for at least two time points. The expressions of ALDH1A1 and SNCG at nerve fibers were decreased along with axonal loss. Increased ALDH1A1 localization in the inner nuclear layer suggested stress response. Increased GFAP expression demonstrated regional reactivity of astrocytes and Muller cells. Meta-analysis of gene ontology showed a pronounced difference in endopeptidase and peptidase inhibitor activity. Temporal proteomic profiling demonstrates established and novel protein targets associated with RGC damage.

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.

Burn or Balm?: Exploring University Students' Experiences With Social Media During the COVID-19 Pandemic.

The impact on perceived burnout experiences among university students from the intensification of social media use during the earliest phase of the COVID-19 pandemic is not yet fully understood. In total, 516 university students (430 females) in a midsized city in Ontario, Canada completed one online survey that explored student characteristics (i.e., personality, life satisfaction, perceived stress, and basic psychological needs) as well as frequency and perceived purpose of social media use. Approximately 80% indicated an increase in their social media use with iMessage/Text messaging, Instagram, and Snapchat being the three most frequently accessed platforms. Social media use was associated with higher levels of perceived stress, extraversion, satisfaction and frustration of psychological relatedness needs, and frustration of competence need. Most students (87%) reported experiencing burnout. Greater burnout was associated with individuals who reported higher perceived stress, scored high in extroversion, and greater use of Instagram. Overall, intensified social media use during the pandemic yielded both positive and negative outcomes.

Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments.

Accumulation of filamentous aggregates of tau protein in the brain is a pathological hallmark of Alzheimer's disease (AD) and many other neurodegenerative tauopathies. The filaments adopt disease-specific cross-ß amyloid conformations that self-propagate and are implicated in neuronal loss. Development of molecular diagnostics and therapeutics is of critical importance. However, mechanisms of small molecule binding to the amyloid core is poorly understood. We used cryo-electron microscopy to determine a 2.7 Å structure of AD patient-derived tau paired-helical filaments bound to the PET ligand GTP-1. The compound is bound stoichiometrically at a single site along an exposed cleft of each protofilament in a stacked arrangement matching the fibril symmetry. Multiscale modeling reveals pi-pi aromatic interactions that pair favorably with the small molecule-protein contacts, supporting high specificity and affinity for the AD tau conformation. This binding mode offers critical insight into designing compounds to target different amyloid folds found across neurodegenerative diseases.

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma.

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. SIGNIFICANCE: Using single-cell-resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027.

Adolescents and oral health service utilization in Canterbury, New Zealand: A geospatial cross-sectional study.

OBJECTIVE: Non-utilization of dental care during adolescence can result in poorer oral health and subsequently higher expenditures on dental services. This study examined the geospatial and epidemiological factors associated with utilization of the publicly funded Adolescent Oral Health Services (AOHS) in Canterbury, Aotearoa New Zealand (NZ). METHODS: A secondary analysis of prospectively collected routine data from AOHS visits of adolescents in school Year 9 (13-14 years) for the financial year 2019-2020. Geographic information systems examined distance from home to dental practices. Multilevel mixed-effects Poisson regression models investigated associations between geospatial, demographic and clinical factors and non-utilization of dental services. Models were adjusted for sex, ethnicity, area-level deprivation, rural/urban classification, previous caries experience and the distance from home address to dental practice referred. RESULTS: Dental practices were concentrated in large urban areas and in the least deprived neighbourhoods, with several service area gaps identified. Rural areas and the most deprived areas of Christchurch City had the highest non-utilization rates. After adjustment, adolescents residing in the most deprived areas had a higher risk of non-utilization (adjusted risk ratio [aRR] = 1.38; 95% CI 1.26-1.51) compared to adolescents in the least deprived areas. Adolescents in remote areas also had an increased risk of non-utilization (aRR = 1.36; 95% CI 1.20-1.54) compared to adolescents in urban core areas. Finally, Maori (aRR = 1.37; 95% CI 1.29-1.46) and Pasifika (aRR = 1.46; 95% CI 1.35-1.59) adolescents had significantly higher risks of non-utilization compared to their NZ European counterparts. CONCLUSION: Inequitable utilization of dental services exists among adolescents in Canterbury, NZ, and is associated with Maori, Pasifika and those living in rural and most deprived areas. Adolescents at the greatest oral health risk are geographically underserved by current oral health services. The current health system should also explore the possibility of partnering with Maori and Pasifika communities to provide services within culturally appropriate settings.

Instructional materials that control cellular activity through synthetic Notch receptors.

The field of regenerative engineering relies primarily on the dual technical platforms of cell selection/conditioning and biomaterial fabrication to support directed cell differentiation. As the field has matured, an appreciation for the influence of biomaterials on cell behaviors has resulted in engineered matrices that meet biomechanical and biochemical demands of target pathologies. Yet, despite advances in methods to produce designer matrices, regenerative engineers remain unable to reliably orchestrate behaviors of therapeutic cells in situ. Here, we present a platform named MATRIX whereby cellular responses to biomaterials can be custom defined by combining engineered materials with cells expressing cognate synthetic biology control modules. Such privileged channels of material-to-cell communication can activate synthetic Notch receptors and govern activities as diverse as transcriptome engineering, inflammation attenuation, and pluripotent stem cell differentiation, all in response to materials decorated with otherwise bioinert ligands. Further, we show that engineered cellular behaviors are confined to programmed biomaterial surfaces, highlighting the potential to use this platform to spatially organize cellular responses to bulk, soluble factors. This integrated approach of co-engineering cells and biomaterials for orthogonal interactions opens new avenues for reproducible control of cell-based therapies and tissue replacements.

Multidisciplinary Stroke Pathway for Children Supported With Ventricular Assist Devices.

Mechanical circulatory support (MCS), including ventricular assist device (VAD) support, is a leading cause of stroke in children; however, existing pediatric stroke recommendations do not apply to many pediatric VAD patients. We sought to develop a multidisciplinary pathway to improve timely and effective acute stroke care and examine the early performance of the pathway in expediting stroke care. Stakeholders from pediatric heart failure, cardiac intensive care, neurology, interventional radiology, neuroradiology, neurosurgery, pharmacy, and adult VAD care convened at Stanford University in August 2017 to discuss the challenges of providing high-quality acute stroke care to children on VAD support, and to develop multidisciplinary acute stroke pathways. Stakeholders identified multiple barriers to providing timely acute stroke care to pediatric VAD patients. These include delayed recognition of stroke, and lack of clarity related to the optimal imaging technique, when to emergently reverse antithrombotic therapy (AT), pediatric indications for thrombectomy and cranial decompression, and strategies to avoid unnecessary serial CTS. Four stroke pathways were created including evaluation and management of the pediatric patient with (1) an acute neurologic change before an imaging diagnosis; (2) an arterial ischemic stroke (AIS); (3) an intracerebral hemorrhage (ICH); and (4) a subdural hematoma (SDH). With the implementation of the stroke pathway, the median time-to-first-CT image decreased by 43 minutes from 66 to 23 minutes ( P < 0.001) while the proportion with a CT within 30 minutes increased from 0% to 67% ( P < 0.001). Despite a variety of challenges, multidisciplinary consensus can be achieved on a rapid stroke management pathway for children on VAD support that addresses important barriers to timely stroke care. Although too few stoke events occurred to differentiate clinical outcomes, the time-to-first-CT image was significantly shorter after pathway implementation.