Background: Intermediate phenotypes, such as characteristic neuroimaging patterns, offer unique insights into the genetic and stress-related underpinnings of neuropsychiatric disorders like depression. This study aimed to identify neuroimaging intermediate phenotypes associated with depression, bridging etiological factors to behavioral manifestations and connecting insights from animal models to diverse clinical populations.
Methods: We analyzed datasets from both rodents and humans. The rodent studies included a genetic model (P11 knockout) and an environmental stress model (chronic unpredictable mild stress), while the human data comprised 748 participants from three cohorts. Using the amplitude of low-frequency fluctuations, we identified neuroimaging patterns in rodent models. We then applied a machine-learning approach to cluster neuroimaging subtypes of depression. To assess the genetic predispositions and stress-related changes associated with these subtypes, we analyzed genotype and metabolite data. Linear regression was employed to determine which neuroimaging features predicted core depression symptoms across species.
Results: The genetic and environmental stress models exhibited distinct neuroimaging patterns in subcortical and sensorimotor regions. Consistent patterns emerged in two neuroimaging subtypes identified across three independent depressed cohorts. The subtype resembling P11 knockout demonstrated higher genetic susceptibility, with enriched expression of risk genes in brain tissues and abnormal metabolites linked to tryptophan metabolism. In contrast, the stress animal-like subtype did not show changes in genetic risk scores but exhibited enriched risk gene expression in somatic and endocrine tissues, along with mitochondrial dysfunction in the antioxidant stress system. Notably, these distinct subcortical-sensorimotor neuroimaging patterns predicted anhedonia, a core symptom of depression, in both rodent models and depressed subtypes.
Conclusions: This cross-species validation suggests that these neuroimaging patterns may serve as robust intermediate phenotypes, linking etiology to anhedonia and facilitating the translation of findings from animal models to humans with depression and other psychiatric disorders.
Background: The clinical phenotypes of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have been found to overlap with several other diseases. The new criteria proposed in 2023 were designed to better identify the disease but require validation across various populations to ascertain its clinical utility. We aimed to investigate the diagnostic performance in phenotypically diverse patients.
Methods: This multicenter study retrospectively included adult and pediatric patients who were hospitalized for a first suspected demyelinating event and tested positive for MOG immunoglobulin G (IgG) during the acute phase. The 2023 Lancet Neurology criteria were assessed against the benchmark of empirical clinical diagnosis, and the 2018 JAMA Neurology and Journal of Neuroinflammation criteria were also evaluated for comparative analysis.
Results: Among the 291 eligible patients (82 adults, 209 children), 282 (96.9%) were clinically diagnosed as definite MOGAD (77 adults, 205 children), while 262 (90.0%) fulfilled the 2023 diagnostic criteria (78 adults, 184 children). A total of 265 patients met the criteria for core clinical demyelinating events, and 76 (26.1%) had serum clear positive MOG-IgG (≥ 1:100). The sensitivity of the 2023 criteria was 0.91 (adults vs. children = 0.97 vs. 0.89), the specificity was 0.56 (adults vs. children = 0.40 vs. 0.75), positive likelihood ratio was 2.06 (adults vs. children = 1.62 vs. 3.57), and negative likelihood ratio (NLR) was 0.15 (adults vs. children = 0.06 vs. 0.14). Additionally, 264 and 256 cases were classified as definite MOGAD by the 2018 JAMA Neurology and Journal of Neuroinflammation criteria, respectively. Compared to the 2023 diagnostic criteria, the 2018 JAMA Neurology criteria demonstrated similar diagnostic performance. However, the 2018 Journal of Neuroinflammation criteria exhibited comparable sensitivity (0.92, adults vs. children = 0.96 vs. 0.89), higher specificity (1.00, adults vs. children = 1.00 vs. 1.00) and better NLR (0.09, adults vs. children = 0.04 vs. 0.11).
Conclusions: The 2023 criteria demonstrated good sensitivity in adult and pediatric patients in China yet modest specificity. Close follow-up is needed for patients with atypical phenotypes but high-titer MOG-IgG to avoid underdiagnosis.
Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced stage due to the lack of non-invasive early detection tools, which significantly impacts patient prognosis. Given that glycosylation alterations especially high sialylation and fucosylation, frequently occur during cellular malignant transformation, but their roles are not elucidated. We examined alterations in disease-specific glycosylated extracellular vesicles (EVs)-derived miRNAs in the serum of ESCC patients, evaluating their utility as diagnostic biomarkers.
Methods: A total of 371 ESCC and 303 healthy controls (HCs) were recruited in this multi-stage, multicentre case-control study. Fucosylated (Fuc-) and sialylated (Sia-) EVs were isolated utilizing Lentil lectin (LCA) and wheat germ lectin (WGA)-coated magnetic beads, respectively. The glycosylated EVs-derived miRNAs-based signature (RiskscoreFuc-&Sia-) was established through logistic regression in a training cohort and subsequently validated in an internal and an external multicentre cohort.
Results: The RiskscoreFuc-&Sia- effectively identified ESCC across all stages, demonstrating high AUC values in training (0.980), internal validation (0.957), and external multicentre validation (0.973) cohorts, markedly higher than carcinoembryonic antigen (CEA) (AUC = 0.769, training cohort; AUC = 0.749, internal validation cohort; AUC = 0.765, external validation cohort). Notably, this score exhibited robust accuracy in detecting CEA (-) ESCC cases (CEA < 5 ng/ml) (AUC = 0.974, training & internal cohort; AUC = 0.973, external multicentre validation cohort). Additionally, it displayed strong efficacy in differentiating early-stage ESCC patients (AUC = 0.982, training cohort; AUC = 0.977, external multicentre validation cohort).
Conclusions: Our study illustrates the effectiveness of glycosylated EVs capture strategy for isolating tumour-specific EVs. The unique glycosylated EVs-derived miRNAs-based signature shows the optimal potential as a biomarker for early detection of ESCC.
Background: A new circulating biomarker superior to carbohydrate antigen 19-9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs.
Methods: This multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t-distributed stochastic neighbor embedding (t-SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells.
Results: In total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t-SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth.
Conclusions: The serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard.
Background: Cervical cancer is a significant health issue, especially in low- and middle-income countries like India, where it ranks fourth among women. The Human papillomavirus (HPV) vaccination, a vital preventive measure, has suboptimal uptake among nursing students. We aimed to assess the level of knowledge, attitudes, willingness, and reasons for non-uptake of HPV vaccination among nursing students.
Methods: A descriptive cross-sectional study was conducted from April to June 2023, using a total enumeration method. Data were collected from 313 nursing students using a validated questionnaire covering sociodemographic information, knowledge, attitudes, and reasons for non-uptake of HPV vaccination. Statistical analysis was performed using SPSS version 26.0. Descriptive statistics summarized the data, while binary and multivariable logistic regression analyses identified factors associated with knowledge, attitude, and willingness for HPV vaccination.
Results: The mean age of the students was 20.98 ± 2.38 years, with the majority being females (81.2%) and unmarried (93.0%). About half of the participants demonstrated moderate knowledge (52.4%) and negative attitudes (50.1%) towards HPV vaccination, with none having received the vaccine. Female students had 4.24 times the odds of having good knowledge (AOR = 4.24, 95% CI = 1.66-10.80), while those pursuing a bachelor's degree exhibited 2.70 times the odds of good knowledge (AOR = 2.70, 95% CI = 1.40-5.21). In contrast, first-year students had 0.30 times the odds of having good knowledge (AOR = 0.30, 95% CI = 0.11-0.79) but displayed 4.69 times the odds of having a positive attitude (AOR = 4.69, 95% CI = 1.92-11.41). Additionally, Hindu students had 2.44 times the odds of being willing to receive the vaccine (AOR = 2.44, 95% CI = 1.15-5.20). Most participants expressed willingness to receive the vaccine (62.0%), citing reasons such as not being sexually active (35.8%) and needing more information (18.2%) for non-uptake of the vaccine.
Conclusions: The study highlights gaps in knowledge and negative attitudes towards HPV vaccination among nursing students. Targeted educational interventions and policy initiatives are essential to improve awareness, promote positive attitudes, and increase HPV vaccination uptake among nursing students.
Background: Maternal stress during pregnancy may impact offspring development via changes in the intrauterine environment. However, genetic and environmental factors shared between mothers and children might skew our understanding of this pathway. This study assesses whether prenatal maternal stress has causal links to offspring outcomes: birthweight, gestational age, or emotional and behavioral difficulties, triangulating across methods that account for various measured and unmeasured confounders.
Methods: We used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), including maternal reports on prenatal stress at work, at home, and via stressful life events as exposures. Outcomes were children's birthweight and gestational age, from the Medical Birth Registry of Norway, and maternal reports on early offspring emotional and behavioral difficulties. We assessed associations using four approaches: sibling control analyses, gene-environment interaction analyses, intergenerational Mendelian randomization (MR), and negative control (i.e., postnatal stress) analyses.
Results: Maternal prenatal stress was observationally associated with offspring lower birthweight (e.g., βwork = - 0.01 [95%CI: - 0.02, - 0.01]), earlier birth (e.g., βwork = - 0.04 [95%CI: - 0.04, - 0.03])), and more emotional (e.g., βevents = 0.08 [95%CI: 0.07, 0.09]) and behavioral difficulties (e.g., βrelationship = 0.08 [95%CI: 0.07, 0.09]) in the full sample (N = 112,784). However, sibling control analyses (N = 36,511) revealed substantial attenuation of all associations after accounting for familial factors. Gene-environment interaction models (N = 76,288) showed no clear evidence of moderation of associations by mothers' polygenic scores for traits linked to stress sensitivity. Intergenerational MR analyses (N = 29,288) showed no clear evidence of causal effects of maternal plasma cortisol on any offspring outcomes. Negative control exposure analyses revealed similar effect sizes whether exposures were measured prenatally or postnatally.
Conclusions: Our results indicate that links between prenatal maternal stress and variation in early offspring outcomes are more likely to be confounded than causal. While no observational study can rule out causality, the consistency of our findings across different approaches is striking. Other sources of prenatal stress or more extreme levels may represent intrauterine causal risk factors for offspring development. Nonetheless, our research contributes to identifying boundary conditions of the fetal programming and developmental origins of health and disease hypotheses, which may not be as universal as sometimes assumed.
Background: Recent evidence from both randomized controlled trials and cohort studies in adults suggests that plasma remnant cholesterol (RC) levels predict cardiovascular disease. In children, studies are scarce, although high levels of RC might represent a marker of early atherosclerotic damage. Thus, the aim of this study was to explore the cardiometabolic risk associated with RC, which extends beyond low-density lipoprotein cholesterol (LDL-c) in children.
Methods: Cardiometabolic risk factors (plasma insulin levels, homeostatic model assessment for insulin resistance, mean arterial blood pressure (MAP), waist circumference (WC), and cardiorespiratory fitness (CRF)) were examined in 3417 Spanish schoolchildren aged 8-11 years. The children were categorized into four subgroups (low vs. high) based on the cutoff of ≥ 110 mg/dL for LDL-c and of ≥ 15 mg/dL for RC to define higher levels, and ANCOVA models were applied to assess the role of both lipid parameters in cardiometabolic risk. Additionally, multilevel mixed-effects generalized linear regression models were used to assess the associations of RC or LDL-c with cardiometabolic risk factors and to examine whether the associations between RC and these factors varied in children with low or high LDL-c levels.
Results: Children in the high-RC subgroups, specifically those with low LDL-c/high RC and high LDL-c/high RC, presented significantly greater insulin levels and WC than did their peers in the low-RC subgroups. RC was more strongly associated with cardiometabolic risk factors than LDL-c (insulin β = 2.073/ - 0.026; HOMA-IR β = 0.451/ - 0.002; MAP β = 1.214/0.300; WC β = 2.842/1.058; and CRF β = - 0.316/ - 0.194 for RC and LDL-c, respectively). Furthermore, RC exhibited associations even in children with low LDL-c levels: insulin (β = 2.305; p < 0.001), HOMA-IR (β = 0.499; p < 0.001), MAP (β = 1.397, p < 0.001), WC (β = 2.842; p < 0.001), and CRF (β = - 0.367; p < 0.001).
Conclusions: The associations between RC and cardiometabolic risk factors were stronger than those between LDL-c and cardiometabolic risk, extending its significance even in children with low LDL-c levels. These findings may be clinically useful for cardiovascular risk stratification and for guiding future interventions in children, although they should be confirmed by longitudinal studies.
Background: Current research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF.
Methods: We employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions.
Results: Multiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300-1.961; Pval = 8.290 × 10 - 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses.
Conclusions: BRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes.
Background: The NHS App launched in 2019 as the 'digital front door' to the National Health Service in England with core features including General Practitioner (GP) appointment booking, repeat prescriptions, patient access to records and, later on, COVID-19 vaccination certification. Similar patient portals have been adopted in different formats and with variable levels of success. In this longitudinal study (2021-2023) we examined how the NHS App became implemented in the pandemic context and beyond.
Methods: We recruited 88 participants in 62 qualitative interviews and four focus groups. Participants included patients, carers, members of the public, clinical/non-clinical NHS staff from five GP practices (where we also conducted over 60 h of observations) across England, as well as other industry, policy and civil rights stakeholders. Document analysis also contributed to participant recruitment and data interpretation. Data collection and analysis was informed by the Non-Adoption, Abandonment, Scale-up, Spread and Sustainability (NASSS) framework.
Results: Our study identified the various ways in which complexity manifested as part of the implementation, use and roll-out of the NHS App. Patients had diverse (positive and negative) user experiences as the app evolved, with some of its features described as more useful than others (e.g. prescription ordering, COVID Pass). As the app primarily provided a gateway to general practice systems and infrastructures, not all features were available by default or consistently to all users, with information often appearing fragmented or system-facing (e.g. coded). NHS staff viewed the app as constituting core NHS infrastructure in the long term which made it appealing, even though initially there was less recognition of its immediate value. There was variable organisational capacity to enable implementation and to put in place processes and staff roles required to support patient adoption. Shifting emphasis towards in-person care, challenges with digital inclusion and controversies related to features such as patient access to own records further complicated roll-out.
Conclusions: As the NHS App remains a complex innovation in a shifting landscape, it is clear ongoing work is needed to ensure its potential can be sustained to meet patient, service and policy needs.
Clinical study registration: ISRCTN72729780.
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