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Family-focused intervention programme to foster adolescent mental health and well-being: protocol for a multicountry cluster randomised factorial trial (FLOURISH Phase 2).
INTRODUCTION: Adolescent mental health problems represent a significant global health issue, particularly in low- and middle-income countries, such as the Republic of North Macedonia and the Republic of Moldova. Effective and scalable interventions are urgently needed to address these challenges. METHODS AND ANALYSIS: This protocol outlines a multicountry cluster randomised factorial trial, implemented according to the multiphase optimisation strategy (Phase 2), which evaluates the effectiveness and costs of three add-on components for the Parenting for Lifelong Health for Parents and Teens programme: adolescent mental health tools based on UNICEFs Helping Adolescents Thrive comics, adolescent peer support based on UNICEFs 'I Support My Friends' intervention and engagement booster designed to enhance attendance and programme completion through incentives. The study will recruit 720 families and involve 64 clusters in North Macedonia and Moldova. Primary outcomes will include adolescent internalising problems and social support, family functioning and attendance during the programme. Secondary outcomes will assess broader aspects of mental health among caregivers and adolescents, as well as implementation and cost outcomes. Data will be collected at baseline and postintervention, approximately, 8 weeks later. Statistical analyses will include regression models to assess the main and interaction effects of the intervention components and cost analyses. ETHICS AND DISSEMINATION: The study received ethical approval from the University of Klagenfurt in Austria (approval number: 2023-013), the Medical Faculty at St. Cyril and Methodius University in North Macedonia (approval number: 03-2144/4) and the National Committee of Ethical Expertise for Clinical Trials in Moldova (approval number: 1476). The results will be disseminated through peer-reviewed journals, conferences, webinars in multiple languages, regional forums, stakeholder meetings with policymakers and practitioners, public communication through media engagement and open access platforms, including data sharing and early release of findings. TRIAL REGISTRATION DETAILS: Trial registration: NCT06562244; Project page: https://www.flourish-study.org/about.html.
Corrigendum: Motor learning in developmental coordination disorder: behavioral and neuroimaging study.
[This corrects the article DOI: 10.3389/fnins.2023.1187790.].
White Matter
Diffusion weighted imaging has further pushed the boundaries of neuroscience by allowing us to peer farther into the white matter microstructure of the living human brain. By doing so, it has provided answers to fundamental neuroscientific questions, launching a new field of research that had been largely inaccessible. We will briefly summarize key questions, that have historically been raised in neuroscience, concerning the brain's white matter. We will then expand on the benefits of diffusion weighted imaging and its contribution to the fields of brain anatomy, functional models and plasticity. In doing so, this article will highlight the invaluable contribution of diffusion weighted imaging in neuroscience, present its limitations and put forth new challenges for the future generations who may wish to exploit this powerful technology to gain novel insights.
Biomarkers.
BACKGROUND: Cerebrovascular reactivity (CVR) is implicated in the progression of dementia, though the underlying mechanisms is not understood. This study examines the relationships between CVR and brain structure and cognitive decline, moderated by mid-life dementia risk. METHOD: 163 participants from the Whitehall-II cohort underwent neuropsychological testing and MRI, including T1-weighted, FLAIR, and DTI sequences, at two phases (Phase-I: mean age=68.2±4.4; Phase-II: mean age=76.9±4.5). CVR was quantified via BOLD response to 5% CO2 only at Phase-II. Linear regression tested the Phase-II and Phase-I to Phase-II associations between CVR and brain and cognitive outcomes (Table 1), alongside its interaction with dementia risks. Post-hoc analysis clarified the extent of these associations among different risk groups. RESULT: Tables 2 and 3 list significant cross-sectional and longitudinal results, respectively. At Phase-II, global CVR was positively associated with volume of left nucleus accumbens, and temporoparietal junction (p<0.03). Parietal CVR was positively associated with left hippocampus volume (p=0.03). These associations were more pronounced in the low-risk group. Temporal CVR was related to thalamus volume (p<0.05) across all participants, with associations of the right thalamus exclusive to the high-risk group (p=0.03). Longitudinally, lower global and regional CVR at Phase-II was linked to greater reduction in temporoparietal junction volume (p<0.04). In high-risk individuals, lower frontal, parietal, or global CVR was linked to larger volume declines in total grey matter or right thalamus respectively (p<0.05). Across all participants, lower parietal CVR at follow-up was linked to greater FA reductions and RD increases between examinations in the corpus callosum (p=0.02) and to greater declines in FA and increases in MD, RD, and L1 in the cingulum bundle (p<0.04), with these effects being more pronounced in the low-risk group. At Phase-II, lower parietal and temporal CVR was associated with worse fluency and intelligence, respectively, in high-risk individuals (p<0.05). Lower frontal CVR was linked to more executive function decline in the low-risk group over-time (p=0.03). CONCLUSION: This study highlights the differential impacts of global and regional CVR on brain structure and cognitive changes dependent on mid-life dementia risks, which provides evidence for CVR as a potential biomarker for dementia and age-related cognitive change.
A Meta-analysis Exploring the Efficacy of Neuropathic Pain Medication for Low Back Pain or Spine-Related Leg Pain: Is Efficacy Dependent on the Presence of Neuropathic Pain?
BACKGROUND AND OBJECTIVE: Highly variable pain mechanisms in people with low back pain or spine-related leg pain might contribute to inefficacy of neuropathic pain medication. This meta-analysis aimed to determine how neuropathic pain is identified in clinical trials for people taking neuropathic pain medication for low back pain or spine-related leg pain and whether subgrouping based on the presence of neuropathic pain influences efficacy. METHODS: EMBASE, MEDLINE, Cochrane Central, CINAHL [EBSCO], APA PsycINFO, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry were searched from inception to 14 May, 2024. Randomized and crossover trials comparing first-line neuropathic pain medication for people with low back pain or spine-related leg pain to placebo or usual care were included. Two independent authors extracted data. Random-effects meta-analyses of all studies combined, and pre-planned subgroup meta-analyses based on the certainty of neuropathic pain (according to the neuropathic pain Special Interest Group [NeuPSIG] neuropathic pain grading criteria) were completed. Certainty of evidence was judged using the grading of recommendations assessment development and evaluation [GRADE] framework. RESULTS: Twenty-seven included studies reported on 3619 participants. Overall, 33% of studies were judged unlikely to include people with neuropathic pain, 26% remained unclear. Only 41% identified people with possible, probable, or definite neuropathic pain. For pain, general analyses revealed only small effects at short term (mean difference [MD] - 9.30 [95% confidence interval [CI] - 13.71, - 4.88], I2 = 87%) and medium term (MD - 5.49 [95% CI - 7.24, - 3.74], I2 = 0%). Subgrouping at short term revealed studies including people with definite or probable neuropathic pain showed larger effects on pain (definite; MD - 16.65 [95% CI - 35.95, 2.65], I2 = 84%; probable; MD - 10.45 [95% CI - 14.79, - 6.12], I2 = 20%) than studies including people with possible (MD - 5.50 [95% CI - 20.52, 9.52], I2 = 78%), unlikely (MD - 6.67 [95% CI - 10.58, 2.76], I2 = 0%), or unclear neuropathic pain (MD - 8.93 [95% CI - 20.57, 2.71], I2 = 96%). Similarly, general analyses revealed negligible effects on disability at short term (MD - 3.35 [95% CI - 9.00, 2.29], I2 = 93%) and medium term (MD - 4.06 [95% CI - 5.63, - 2.48], I2 = 0%). Sub-grouping at short term revealed larger effects in studies including people with definite/probable neuropathic pain (MD - 9.25 [95% CI - 12.59, - 5.90], I2 = 2%) compared with those with possible/unclear/unlikely neuropathic pain (MD -1.57 [95% CI - 8.96, 5.82] I2 = 95%). Medium-term outcomes showed a similar trend, but were limited by low numbers of studies. Certainty of evidence was low to very low for all outcomes. CONCLUSIONS: Most studies using neuropathic pain medication for low back pain or spine-related leg pain fail to adequately consider the presence of neuropathic pain. Meta-analyses suggest neuropathic pain medication may be most effective in people with low back pain or spine-related leg pain with a definite/probable neuropathic pain component. However, the low to very low certainty of evidence and poor identification of neuropathic pain in most studies prevent firm recommendations.
The local molecular signature of human peripheral neuropathic pain.
Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature ( MARCO, CD163, STAB1 ) , indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163 + MARCO + macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO + subset implicated.
Integrating the environmental and genetic architectures of aging and mortality.
Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3-26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5-49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.
Discovery of reversing enzymes for RNA ADP-ribosylation reveals a possible defence module against toxic attack.
Nucleic acid ADP-ribosylation and its associated enzymes involved in catalysis and hydrolysis are widespread among all kingdoms of life. Yet, its roles in mammalian and bacterial physiology including inter-/intraspecies conflicts are currently underexplored. Recently, several examples of enzymatic systems for RNA ADP-ribosylation have been identified, showing that all major types of RNA species, including messenger RNA, ribosomal RNA, and transfer RNA, can be targeted by ADP-ribosyltransferases (ARTs) which attach ADP-ribose modifications either to nucleobases, the backbone ribose, or phosphate ends. Yet little is known about the reversibility of RNA ADP-ribosylation by ADP-ribosylhydrolases belonging to the macrodomain, ARH, or NADAR superfamilies. Here, we characterize the hydrolytic activity of ADP-ribosylhydrolases on RNA species ADP-ribosylated by mammalian and bacterial ARTs. We demonstrate that NADAR ADP-ribosylhydrolases are the only hydrolase family able to reverse guanosine RNA base ADP-ribosylation while they are inactive on phosphate-end RNA ADP-ribosylation. Furthermore, we reveal that macrodomain-containing PARG enzymes are the only hydrolase type with the ability for specific and efficient reversal of 2'-hydroxyl group RNA ADP-ribosylation catalysed by Pseudomonas aeruginosa effector toxin RhsP2. Moreover, using the RhsP2/bacterial PARG system as an example, we demonstrate that PARG enzymes can act as protective immunity enzymes against antibacterial RNA-targeting ART toxins.
Bilingual Toddlers' Vocabulary Growth Interacts with Existing Knowledge and Cross-Linguistic Similarity.
We explored whether bilingual toddlers make use of semantic and phonological overlap between their languages to learn new words. We analysed cross-sectional and longitudinal CDI data on the words understood and produced by 1.0 to 3.0-year-old bilingual toddlers with English and one additional language. Cognates were more likely to be understood and produced compared to non-cognates. Cognate effects were modulated by whether the toddler knew the translation equivalent in the other language, highlighting that young learners are sensitive to the similarities across their languages. Additionally, exploratory analyses suggest that children with smaller vocabularies rely more on translation equivalents to support the acquisition of difficult words. Children with larger vocabulary sizes exhibited no preference for translation equivalents in comprehension, and a preference for new concepts in production. The rapid acceleration of vocabulary growth in the second year of life may explain this developmental change in translation equivalent preference.
Aspirin after completion of standard adjuvant therapy for colorectal cancer (ASCOLT): an international, multicentre, phase 3, randomised, double-blind, placebo-controlled trial.
BACKGROUND: Aspirin is a simple, globally available medication that has been shown to reduce the incidence of colorectal cancer. We aimed to evaluate the safety and efficacy of aspirin in the secondary prevention of colorectal cancer. METHODS: This phase 3, randomised, double-blind, placebo-controlled trial was conducted at 66 centres across 11 countries and territories (ten in Asia-Pacific; one in the Middle East). The trial included patients aged 18 years and older with Dukes' C or high-risk Dukes' B colon cancer or Dukes' B or C rectal cancer who had undergone resection and had completed standard adjuvant therapy (at least 3 months of chemotherapy). Patients with contraindications to aspirin, familial syndromes of colorectal cancer, recent other cancers, and clinically significant history of cardiovascular disease or stroke were excluded. Patients were randomly assigned (1:1) to aspirin 200 mg daily or placebo for 3 years, and were followed up for 5 years. Randomisation was stratified by study centre, tumour site and stage, and inclusion of oxaliplatin in adjuvant chemotherapy. The patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival. The primary analysis used a stratified Cox model in those commencing study treatment (modified intention-to-treat population), analysing all events to March 31, 2023. Safety was analysed in the same population. This trial is registered at ClinicalTrials.gov (NCT00565708). The primary analysis has been completed, but translational studies of putative aspirin sensitivity biomarkers are ongoing. FINDINGS: Between Feb 25, 2009, and June 30, 2021, 1587 patients underwent randomisation, of whom 1550 were included in the modified intention-to-treat analysis: 791 (51%) in the aspirin group and 759 (49%) in the placebo group. Of these patients, the median age was 57 years (IQR 48-65); 897 (58%) were male and 653 (42%) female; 271 (17%) had Dukes' B colon cancer, 770 (50%) Dukes' C colon cancer, and 509 (33%) rectal cancer. Median follow-up at data cutoff was 59·2 months (IQR 36·7-60·0). 5-year disease-free survival was 77·0% (95% CI 73·6-80·0) in the aspirin group and 74·8% (71·3-77·9) in the placebo group (hazard ratio of 0·91 [95% CI 0·73-1·13]; p=0·38). Any-grade adverse events were reported in 390 (49%) of 791 patients in the aspirin group versus 386 (51%) of 759 in the placebo group. Serious adverse events were reported in 95 (12%) patients in the aspirin group versus 107 (14%) in the placebo group. There were no treatment-related deaths in either group. Among adverse events of special interest, there were no cases of acute myocardial infarction in the aspirin group versus two in the placebo group; no ischaemic cerebrovascular events in the aspirin group versus two in the placebo group; and three major gastrointestinal bleeds in the aspirin group versus one in the placebo group. INTERPRETATION: In patients with colorectal cancer, aspirin 200 mg daily for 3 years after completion of standard adjuvant therapy was well tolerated but did not significantly improve disease-free survival. FUNDING: SingHealth Foundation, National Medical Research Council Singapore, National Cancer Centre Research Fund, Rising Tide Foundation, Lee Foundation, Lee Kim Tah Foundation, Duke-NUS Khoo Bridge Funding Award, Terry-Fox Run, Silent Foundation, Cancer Australia, Bowel Cancer Australia, and Cancer Council NSW.
Machine learning to attribute the source of Campylobacter infections in the United States: A retrospective analysis of national surveillance data.
OBJECTIVES: Integrating pathogen genomic surveillance with bioinformatics can enhance public health responses by identifying risk and guiding interventions. This study focusses on the two predominant Campylobacter species, which are commonly found in the gut of birds and mammals and often infect humans via contaminated food. Rising incidence and antimicrobial resistance (AMR) are a global concern, and there is an urgent need to quantify the main routes to human infection. METHODS: During routine US national surveillance (2009-2019), 8856 Campylobacter genomes from human infections and 16,703 from possible sources were sequenced. Using machine learning and probabilistic models, we target genetic variation associated with host adaptation to attribute the source of human infections and estimate the importance of different disease reservoirs. RESULTS: Poultry was identified as the primary source of human infections, responsible for an estimated 68% of cases, followed by cattle (28%), and only a small contribution from wild birds (3%) and pork sources (1%). There was also evidence of an increase in multidrug resistance, particularly among isolates attributed to chickens. CONCLUSIONS: National surveillance and source attribution can guide policy, and our study suggests that interventions targeting poultry will yield the greatest reductions in campylobacteriosis and spread of AMR in the US. DATA AVAILABILITY: All sequence reads were uploaded and shared on NCBI's Sequence Read Archive (SRA) associated with BioProjects; PRJNA239251 (CDC / PulseNet surveillance), PRJNA287430 (FSIS surveillance), PRJNA292668 & PRJNA292664 (NARMS) and PRJNA258022 (FDA surveillance). Publicly available genomes, including reference genomes and isolates sampled worldwide from wild birds are associated with BioProject accessions: PRJNA176480, PRJNA177352, PRJNA342755, PRJNA345429, PRJNA312235, PRJNA415188, PRJNA524300, PRJNA528879, PRJNA529798, PRJNA575343, PRJNA524315 and PRJNA689604. Contiguous assemblies of all genome sequences compared are available at Mendeley data (assembled C. coli genomes doi: 10.17632/gxswjvxyh3.1; assembled C. jejuni genomes doi: 10.17632/6ngsz3dtbd.1) and individual project and accession numbers can be found in Supplementary tables S1 and S2, which also includes pubMLST identifiers for assembled genomes. Figshare (10.6084/m9.figshare.20279928). Interactive phylogenies are hosted on microreact separately for C. jejuni (https://microreact.org/project/pascoe-us-cjejuni) and C. coli (https://microreact.org/project/pascoe-us-ccoli).
Whole-genome sequencing of non-typeable Haemophilus influenzae isolated from a tertiary care hospital in Surabaya, Indonesia.
BACKGROUND: Haemophilus influenzae causes life-threatening invasive diseases such as septicaemia and meningitis. Reports on circulating H. influenzae causing invasive disease in lower-middle income settings, including Indonesia, are lacking. This study describes the serotype distributions and whole-genome sequence (WGS) data of H. influenzae isolated from hospitalized patients at Soetomo Hospital, Surabaya, Indonesia. METHODS: H. influenzae isolates were isolated from blood and pleural fluid specimens and identified using culture-based and molecular methods, followed by serotyping and WGS using RT‒PCR and Illumina MiSeq, respectively. Sequencing reads were assembled, and further analyses were undertaken to determine the genomic content and reconstruct the phylogeny. A second dataset consisting of publicly available H. influenzae genomes was curated to conduct phylogenetic analyses of isolates in this study in the context of globally circulating isolates. RESULTS: Ten H. influenzae isolates from hospitalized patients were collected, and septicaemia was the most common diagnosis (n=8). RT‒PCR and WGS were performed to determine whether all the isolates were nontypeable H. influenzae (NTHi). There were four newly identified STs distributed across the two main clusters. A total of 91 out of 126 virulence factor (VF)-related genes in Haemophilus sp. were detected in at least one isolate. Further evaluation incorporating a global collection of H. influenzae genomes confirmed the diverse population structure of NTHi in this study. CONCLUSION: This study showed that all H. influenzae recovered from invasive disease patients were nonvaccine-preventable NTHi isolates. The inclusion of WGS revealed four novel STs and the possession of key VF-associated genes.
Longitudinal study of meningococcal carriage in adolescents and young adults in South Australia 2017-2020.
BACKGROUND: This analysis investigated longitudinal changes in meningococcal carriage in adolescents in South Australia over 4 years. METHODS: Data from the "B Part of It" study, which included a state-wide cluster randomized controlled trial in secondary-school students (n = 34,489 in 2017 and 2018) and serial cross-sectional studies in school leavers aged 17-25 years (n = 4028 in 2019-2020). Individuals had oropharyngeal swabs collected annually. This study included two unique cohorts: (1) individuals enrolled in 2019, with three consecutive annual swabs taken in 2017, 2018 and 2019; and (2) individuals enrolled in 2020, with swabs taken in 2017, 2018, and 2020. Disease-associated N. meningitidis genogroups were identified using PCR and whole genome sequencing. Univariate analysis identified risk factors for recurrent carriage (≥2). RESULTS: Among school leavers, 50 (1.7%, total n = 2980) had carriage detected at successive visits. In participants with meningococcal carriage at successive visits, 38/50 (76.0%) had the same genogroup detected by porA PCR. Of those, 19 had the same MLST type and demonstrated minimal variation, indicating they most likely had sustained carriage of the same isolate (range 226 to 490 days, mean duration 352 [SD 51] days). In the 2019 school leaver cohort, 6.7% acquired carriage in their first year out of school compared to 3.3% in their final school year. Compared to single carriage detection, recurrent carriage was potentially more likely in older adolescents (16 compared to ≤15 years; OR = 1.97 (95%CI 1.0, 3.86); p = 0.048). CONCLUSION: Whilst carriage is typically transient, some adolescents/young adults may have persistent carriage and are likely to be an important group in the transmission of meningococci.
Visual Analytics Exploration of PubMLST Meningitis Genomic Data
Bacterial meningitis is an infectious disease of the brain that occurs worldwide and is a major public health challenge. A leading cause of this often-fatal disease is the bacterium Neisseria meningitidis, also called meningococcus. Genomics is having a transformational impact on medicine. It enables advances in accurate diagnosis, analysis and prediction of anti-microbial resistance, development and assessment of vaccines etc. PubMLST.org, developed and run by the authors, is a major open-access genomics reference database. It is an integrated collection of databases consisting of phenotype metadata linked to nucleotide sequence data including genome assemblies, for molecular typing of many bacterial species. This paper discusses visual analytics and visualization work conducted to explore and analyse Neisseria meningitidis data from PubMLST.