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Further characterisation of immortalised human lymphatic endothelial cells to explore their transcriptomic profile and VEGFC response
Get PDFIn vitro modelling relies on the availability of suitable cell types that accurately represent the organs under study. In lymphatic research, human dermal lymphatic endothelial cells represent the “gold standard”, even though they lose their identity and proliferative capacity over time. A recently established immortalised lymphatic endothelial cell line (imLEC) could become a promising new tool for lymphatic disease modelling. We further characterised this cell line by comparing imLECs and HDLECs in terms of the expression of proteins essential for correct lymphatic function, and the proliferation, migration and sprouting responses to vascular endothelial growth factor C (VEGFC). We show similarities in the expression of lymphatic markers and VEGFC-driven cellular responses, supporting imLECs can retain their VEGFC-driven lymphangiogenic capacity without losing their lymphatic identity. RNA sequencing, however, revealed certain transcriptional differences in genes regulating lymphatic function in health and disease, highlighting the need for further validation at single gene level or specific lymphatic-associated signalling pathways. We acknowledge these limitations should be considered in future applications. Nonetheless, we believe that imLECs represent a useful model for the development of gene editing techniques allowing better modelling of lymphatic disease-associated genetic variants, ensuring long-term culture and providing higher reproducibility in genotype–phenotype validation analyses
A Randomized Controlled Trial of a Healthy Lifestyle Intervention to Improve Mental Health among School-Going Adolescents
Get PDFObjective: Despite growing evidence on the influence of lifestyle on adolescent mental health, structured educational interventions addressing multiple health dimensions remain limited. The objective of this study was to assess the effectiveness of a healthy lifestyle educational intervention in improving mental health results among secondary school students.
Method: A randomized controlled trial based on the Information, Motivation, and Behavioral Skills (IMB) model was carried out with 347 adolescents (182 in the intervention group and 165 in the control group) from twelve secondary schools in Tehran. Participants completed a set of questionnaires assessing knowledge and attitudes concerning diet, physical activity, and stress management. Additionally, assessments included measures of eating behavior, daily physical activity, and psychological state using the Beck Depression Inventory-Short Form (BDI-S, BDI-13), and the Depression, Anxiety, and Stress Scale [DASS-21]). The innovation is addressing multiple dimensions of adolescent health in a comprehensive way and targeting mental health outcomes. It consisted of eleven one-hour sessions delivered to the intervention group in their schools. Data were then analyzed using descriptive statistics, Chi-square (association between categorical variables) and two-way repeated measure ANOVA (difference in the means score at follow-up).
Results: In the intervention group, significant improvements were observed in knowledge about lifestyle factors, including diet, stress management and physical activity and, from baseline to post-intervention (P < 0.05). Attitudes toward stress management also showed significant positive changes. Behaviorally, there was an increase in physical activity, participation in relaxation activities, and eating breakfast, while unhealthy practices such as eating out, drinking sweetened beverages, and consuming fast food decreased (P < 0.05). Additionally, depression symptoms decreased by 1.9 points (mean ± SD) at the 6-month follow-up (P < 0.05).
Conclusion: This study demonstrates that a six-month healthy lifestyle educational intervention can effectively enhance adolescents’ knowledge, attitudes, and behaviors related to healthy lifestyle factors, leading to improved mental health outcomes
Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia.
Get PDFBACKGROUND: Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce. METHODS: To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation. RESULTS: We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis. CONCLUSIONS: This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome
Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease.
Get PDFNeuropsychiatric symptoms are common and disabling in Parkinson's disease (PD), with troublesome anxiety occurring in one-third of patients. Management of anxiety in PD is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements, and largely ineffective treatments. In this study, we assessed the intracranial neurophysiological correlates of anxiety in PD patients treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta-alpha) activity would be associated with anxiety. We recorded local field potentials (LFP) from the subthalamic nucleus (STN) or the globus pallidus pars interna (GPi) DBS implants in three PD cohorts: 1) patients with recordings (STN) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON or OFF dopaminergic medication; 2) patients with recordings (STN or GPi) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic PerceptTM device), ON dopaminergic medication, with stimulation both on or off; 3) patients with recordings performed at home while engaging in a behavioral task via STN and GPi leads and electrocorticography paddles over premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on or off. Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4-8 Hz) and alpha (8-12 Hz) ranges were extracted from the LFP recordings, and their relation with anxiety ratings was assessed using linear mixed-effects models. In total, 33 PD patients (59 hemispheres) were included. Across three independent cohorts, with stimulation off, basal ganglia theta power was positively related to trait anxiety (all p<0.05). Also in a naturalistic setting, with individuals at home at rest with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (p<0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta-alpha power. There was no within-patient association between basal ganglia theta-alpha power and state anxiety. We showed that basal ganglia theta activity indexes trait anxiety in PD. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in PD, potentially suitable for guiding advanced DBS treatment tailored to the individual patient's needs, including non-motor symptoms
Progress towards a Group B streptococcal vaccine – where are we now?
Get PDFThe global burden of Group B streptococcal (GBS) disease remains high and an effective vaccine in pregnancy is an unmet public health need. GBS vaccines have been in development for decades, with earlier work providing evidence of immunogenicity and safety but not resulting in a licensed product. More recently, two vaccine candidates have reached advanced stages of clinical development. This article reviews the progress towards a GBS vaccine, the challenges that lie ahead and how they might be overcome
Interventions to prevent preterm birth following fetoscopic laser surgery for twin-to-twin transfusion syndrome: systematic review and meta-analysis
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To assess the impact of intervention with cervical cerclage, cervical pessary or vaginal progesterone on the risk of preterm birth (PTB) in monochorionic diamniotic (MCDA) twin pregnancies undergoing fetoscopic laser surgery (FLS) for twin-to-twin transfusion syndrome (TTTS).
Methods
The MEDLINE, Embase and Cochrane databases were searched from inception to November 2023. The inclusion criteria were studies on MCDA twin pregnancies undergoing FLS for TTTS, comparing those receiving with those not receiving an intervention to prevent PTB, including vaginal progesterone, cervical cerclage and cervical pessary. The primary outcome was gestational age (GA) at birth. The secondary outcomes included the interval between FLS and birth, PTB prior to 34, 32, 28 and 24 weeks' gestation, delivery within 2 and 4 weeks after FLS, preterm prelabor rupture of membranes, chorioamnionitis, double survival, survival of at least one twin, no survival, overall fetal or perinatal loss, and overall fetal or perinatal survival. All outcomes were explored in the overall population of MCDA twin pregnancies undergoing FLS for TTTS according to different cut-offs of cervical length (CL) for intervention. Random-effects meta-analysis was used to directly compare the risk of each outcome. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was used to assess the quality of the retrieved evidence.
Results
Ten studies (1159 MCDA pregnancies) were included in the systematic review, of which seven were included in the meta-analysis. There was no significant difference in mean gestational age at birth in MCDA twin pregnancies undergoing FLS for TTTS in women receiving vs not receiving cervical cerclage, with CL < 30, < 25, < 20 or < 15 mm. There was also no significant difference in the mean interval between FLS and delivery, and in the risk of fetal or perinatal loss between women receiving vs not receiving cervical cerclage. Similarly, intervention with cervical pessary was not associated with a higher gestational age at birth compared with no intervention. It was not possible to perform any comprehensive pooled data synthesis for women receiving progesterone. In women with CL < 30 mm, intervention with cervical pessary was not associated with a reduced risk of PTB < 32, < 28 or < 24 weeks' gestation, or with delivery within 2 or 4 weeks after FLS or perinatal loss. Finally, in women with CL < 25 mm, cervical pessary did not reduce the risk of PTB < 32 weeks or perinatal loss. On GRADE assessment, the quality of evidence was very low in showing that cervical cerclage and cervical pessary can affect gestational age at birth in MCDA twin pregnancies that underwent FLS for TTTS, irrespective of the degree of cervical shortening.
Conclusions
There is currently no evidence that intervention with cervical cerclage or pessary leads to a greater gestational age at birth or reduces the risk of PTB in MCDA twin pregnancies complicated by TTTS and undergoing FLS in women with a short CL, while the level of evidence for intervention with vaginal progesterone is insufficient for evaluation. However, the small sample sizes of the included studies, lack of comparison in the original publications and lack of stratification of the observed outcomes according to Quintero stage, gestational age at FLS and CL cut-off highlight the need for appropriately powered studies
Real-world effectiveness and safety of nirsevimab, RSV maternal vaccine and RSV vaccines for older adults: a living systematic review and meta-analysis
Get PDFBackground
The long-acting monoclonal antibody nirsevimab and respiratory syncytial virus (RSV) vaccines became available for prevention of severe RSV-associated disease in 2023. While clinical trials showed good efficacy and safety, their restrictive inclusion criteria, small sample sizes and short follow-up limit generalisability. We aimed to summarise real-world evidence on the effectiveness and safety of nirsevimab, RSV maternal vaccine and RSV vaccines for older adults.
Methods
A living systematic review and meta-analysis, with 5 monthly updated searches in three databases was performed. Eligible studies were published from 1 December 2022 to 10 March 2025. Meta-analyses for the effectiveness of nirsevimab and RSV vaccines were carried out using random-effects model. Safety data were summarised narratively.
Results
A total of 50 publications, covering approximately 7.6 million people, were included. Nirsevimab showed 80.7% effectiveness (95% CI: 75.7% to 85.7%; seven studies) against RSV-related emergency department visits, 80.7% (95% CI: 76.1% to 85.2%; 17 studies) against hospital admissions and 75.6% (95% CI: 63.3% to 87.9%; eight studies) against intensive care unit admissions. The effectiveness of RSV vaccines for older adults against RSV-related hospital admissions was 79.6% (95% CI: 73.8% to 85.3; three studies). No effectiveness data were available for RSV maternal vaccine. No severe adverse events were reported for nirsevimab, while RSV vaccines in older adults had fewer than 10 Guillain-Barré syndrome cases per million doses. No severe adverse events were reported for RSV maternal vaccine, although evidence was limited.
Conclusions
Our review demonstrated high effectiveness of nirsevimab in reducing RSV-related healthcare utilisation in infants and a favourable safety profile. More evidence is needed for evaluating RSV vaccines in pregnant people and older adults.
PROSPERO registration number
CRD42025643585
CRISPR typing and phage content of colonizing Group B Streptococci from healthy Egyptian women
Get PDFBackground
Streptococcus agalactiae or Group B Streptococcus (GBS) causes serious infections in neonates with a particularly high burden of disease in Africa. Maternal vaginal colonization is the primary source of neonatal transmission. Molecular surveillance of the maternal GBS population is crucial for informing maternal vaccine development and monitoring of the global circulation of GBS clones.
Methods
The current study analyzes the structure and diversity of the clustered regularly interspaced palindromic repeat (CRISPR)-associated (Cas) system and phage content in colonizing GBS isolates collected from healthy pregnant women from Ismailia, Egypt. The isolates were characterized by whole-genome sequencing within the global JUNO project.
Results
CRISPR arrays and phages were detected in a vast majority of GBS isolates. A strong congruence was observed between multilocus sequence typing (MLST), CRISPR profile, and phage content. Region-specific sequence types (STs) observed only in Africa were distinguishable from other lineages.
Conclusions
CRISPR typing is a promising low-cost tool for investigating the population structure of GBS clones, particularly in middle- and low-income countries
Validation of anthropometric and bioelectrical impedance equations for the prediction of fat mass amongst South African children
Get PDFBackground/Aims
While several prediction equations which combine anthropometric, demographic, and/or bioelectrical impedance (BIA) variables to estimate childhood fat mass (FM) are available, comprehensive comparisons of their performance are lacking. We validated FM estimates for children from a range of published equations against reference‐standard deuterium dilution observed FM.
Methods
This cross‐sectional study was based on 323 children (42% male) from South Africa of Black African ethnic origins aged 5 to 8 years with information on age, sex, ethnicity, height, weight, deuterium dilution observed FM, triceps and subscapular skinfold thickness, and BIA observed FM, resistance, and impedance. We extracted all equations from three systematic reviews of childhood FM prediction equations that used the above available predictors and were developed on more than 100 males and females. FM estimates from each equation were calculated and the performance of each, as well as FM reported from the BIA manufacturer software, was compared with deuterium dilution observed FM using statistics of R2, Calibration (slope and calibration‐in‐the‐large), and root mean square error (RMSE).
Results
Nineteen equations (1 based on basic anthropometry, 12 on skinfold thickness, 6 on BIA) were validated. R2 and RMSE values ranged between 58.3% (BIA manufacturer equation) and 89.0% (Britz et al. (2017) skinfold thickness equation), and between 1.1 kg (Wendel et al. (2016) skinfold thickness equation) and 3.4 kg (Horlick et al. (2002) BIA equation), respectively. Calibration varied considerably across the equations. From the basic anthropometry, skinfold thickness, and BIA categories, the best performing equations from each category were by: Hudda et al. (2019) (basic anthropometry), Wickramasinghe et al. (2008) (skinfold thickness), and Ramirez et al. (2012) (BIA).
Conclusions
The performance of published equations varied considerably upon external validation in this South African childhood population. Notably, the Hudda et al. (2019) equation, which relies solely on readily available information of weight, height, sex, age and ethnicity, produced one of the highest R2 values, was well calibrated, and produced a low RMSE value (1.4 kg). Alternative equations which also performed very well relied on additional measurements of skinfold thickness and/or BIA which require equipment, training, extra costs and additional time to obtain
Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics
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Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST‐related disorders and explore the underlying abnormal cellular mechanisms.
Methods
We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control.
Results
Individuals exhibited early‐onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole‐exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient‐derived fibroblasts, supporting the pathogenicity of the variants.
Interpretation
We provide the first evidence of biallelic inheritance in SPAST‐related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate‐to‐severe early‐onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST‐related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation
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