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De novo protein-coding gene variants in developmental stuttering
No full textDevelopmental stuttering is a common childhood condition characterized by disfluencies in speech, such as blocks, prolongations, and repetitions. While most children who stutter do so only transiently, there are some for whom stuttering persists into adulthood. Rare-variant screens in families including multiple relatives with persistent stuttering have so far identified six genes carrying putative pathogenic variants hypothesized to act in a monogenic fashion. Here, we applied a complementary study design, searching instead for de novo variants in exomes of 85 independent parent-child trios, each with a child with transient or persistent stuttering. Exome sequencing analysis yielded a pathogenic variant in SPTBN1 as well as likely pathogenic variants in PRPF8, TRIO, and ZBTB7A - four genes previously implicated in neurodevelopmental disorders with or without speech problems. Our results also highlighted two further genes of interest for stuttering: FLT3 and IREB2. We used extensive bioinformatic approaches to investigate overlaps in brain-related processes among the twelve genes associated with monogenic forms of stuttering. Analyses of gene-expression datasets of the developing and adult human brain, and data from a genome-wide association study of human brain structural connectivity, did not find links of monogenic stuttering to specific brain processes. Overall, our results provide the first direct genetic link between stuttering and other neurodevelopmental disorders, including speech delay and aphasia. In addition, we systematically demonstrate a dissimilarity in biological pathways associated with the genes thus far implicated in monogenic forms of stuttering, indicating heterogeneity in the etiological basis of this condition.</p
Attentional bias in people with moderate-to-severe cannabis use disorder
No full textBACKGROUND: Attentional bias to cannabis images is posited to drive loss of control over cannabis use and relapse in cannabis use disorder (CUD), but the literature is mixed and limited by inconsistent measurement of CUD and of confounders, including alcohol and nicotine use. This study examined attentional bias in moderate-to-severe CUD (n = 66) compared to controls (n = 42), and its relationship with cannabis/nicotine use, accounting for alcohol use.METHODS: We measured attentional bias using the visual probe task, as the difference in reaction times (RTs) for cannabis versus neutral images, in order to account for individual variability. Linear mixed effect models examined how RTs were affected by (i) group (CUD, control), image type (cannabis, neutral), group-by-image type, and group-by-image type-by-Stimulus Onset Asynchrony (SOA, 200/500 milliseconds) in the whole sample; and (ii) by image type, SOA, and moderators in the CUD group only (i.e., Cannabis Use Disorder Identification Test-Revised [CUDIT-R], subjective craving, arousal/valence ratings of the task's cannabis/neutral images, and nicotine). All models were adjusted for alcohol use.RESULTS: There were no significant group differences in attentional bias. In the CUD group, image type-by-CUDIT-R subgroups differed on RTs (β = -0.748, p = .014), whereby the high-CUDIT-R versus lower CUDIT-R subgroups had significantly faster RTs to cannabis versus neutral images (p = .034, d = -0.10), but this effect did not survive Bonferroni correction for multiple comparisons. No other results were significant.CONCLUSION: Attentional bias might not be a robust feature of CUD, though this notion requires validation in a larger sample using more direct measures of attentional bias.</p
Physical exercise training improves muscle strength and self- esteem in children with intestinal failure
No full textObjectives: Pediatric intestinal failure (IF) patients are less physically active compared to healthy peers, exhibit an altered body composition and low bone mineral density, which can be improved through physical activity. We assessed the effects of a tailored exercise intervention on physical fitness, nutritional status, and psychological functioning in children with IF. Methods: Pediatric IF patients, still on and weaned off parenteral nutrition aged 6–18 years were eligible. Physical fitness ([sub]maximal exercise capacity, amount of physical activity, motor performance, strength, and core stability), nutritional status (body composition, energy expenditure, and laboratory parameters) and psychological functioning (fear, quality of life, fatigue, gastrointestinal symptoms, and self-esteem) were assessed before and after an initial control period and after a 12-week tailored exercise intervention. Results: Sixteen participants (median age 12.2 years [10.5–14.6]) underwent baseline assessments, and eight were weaned off parenteral nutrition. Exercise capacity was normal, but the majority (63%) did not meet physical activity guidelines. Motor skills and muscle strength were impaired. Postintervention, exercise capacity in VO2peak did not improve significantly, but workload in watt (p < 0.01), muscle strength in various muscle groups (p < 0.05), core stability (p < 0.05), and self-esteem (p < 0.05) improved. Nutritional status remained unchanged. Baseline motor skills and change in VO2peak were positively correlated (R = 0.66, p < 0.05). Conclusions: Our tailored exercise intervention improved muscle strength, core stability, and self-esteem. Most participants do not meet physical activity recommendations and exhibit impaired muscle strength and motor skills, while exercise capacity is normal. Notably, participants with better baseline motor skills showed greater improvements in exercise capacity. Clinical Trial Registration: Registration ID: NL8181, https://onderzoekmetmensen.nl/nl/trial/27466.</p
Clozapine-Associated Pulmonary Embolism:Continuation of Clozapine Therapy With Concurrent Anticoagulation
No full textClozapine, a gold standard for treatment-resistant schizophrenia, is associated with a range of adverse effects, including the rare but serious risk of pulmonary embolism (PE). The management of such complications, particularly in the absence of clear guidelines for preventive anticoagulation, poses significant challenges. We present a case of a male (in his late 30s) with schizophrenia who developed recurrent thromboembolic events during clozapine therapy. Despite the occurrence of a second PE, clozapine therapy was continued successfully with concurrent anticoagulation. This case highlights the need for individualized treatment strategies and underscores the critical gap in evidence regarding preventive anticoagulation in patients with clozapine.</p
Are Social Media Platforms a Threat to Democracy?: An Ecosystem Governance Perspective
No full textCastello, Colleoni, Scherer, and Trittin contend that social media platforms threaten democratic processes by facilitating the spread of misinformation and fostering polarized debates – dynamics that ultimately serve to monetize user attention. We acknowledge the problem but challenge their proposed solution of conceptualizing social media as political spaces. Instead, drawing on ecosystem theory, we propose an ‘ecosystem failure’ analysis as a more robust analytical framework. Within this perspective, we see these information-related problems as negative externalities that weaken the entire platform ecosystem. These externalities are structurally distinct due to algorithmic curation that selectively amplifies content in ways that reinforce user biases, strong network effects with almost zero replication costs, and engagement-based monetization that decouples production from editorial standards. We therefore advance a reflexive ecosystem governance approach that accounts for broader ecosystem value, shifting the focus beyond short-term economic performance to encompass overall ecosystem health. This approach transforms the management of negative externalities into a core strategic interest for the platform and aligns the incentives of individual actors ex ante, by design, prioritizing risk-adjusted reach and demotion of low-integrity content over ex post moderation. We analyse the mechanisms that align private incentives with democratic resilience and highlight the inherent trade-offs involved.</p
Pollution risk exposure assessment for Portugal and the Baltic Sea with an emphasis on shadow fleets
No full textRecent geopolitical developments influence trade flows and risk exposure of shipping. This comprehensive study based on 45.2 million estimates of the global fleet quantifies the change in pollution risk exposure in the Baltic Sea Area and Portugal with an emphasis on the emerging shadow fleets. Risk exposure is expressed as potential incident costs calculated at the ship level. We construct a shadow fleet watchlist based on designated lists and supplemented by a prediction model based on balanced random forests. We evaluate the prediction power of operational and behavioral aspects of vessels. The results confirm that safety qualities are strongly correlated with sanction compliance and that trade flows and safety qualities of vessel trading out of the Baltic Area have changed. Pollution risk exposure increased by over 100% in the Gulf of Finland and from 2023 to 2024 and over 54% of pollution risk exposure is associated with vessel on our watchlist compared to a global average of 16.4%. Furthermore, we predict a monthly projected increase of 2.7% for this region. As of December 2024, an estimated total risk exposure from all ship types of USD 68.8 million USD (9.9% of the regional total) is potentially not covered by insurance in the Baltic Area. To improve intelligence applications for coastal states, ship specific risk predictions can be with live AIS data to enhance domain awareness. The results help maritime stakeholders better understand the magnitude and change in risk exposure in general and due to the emerging shadow fleet.</p
The moment of youth:learning from youth-led research on sexual and reproductive health and rights (SRHR) in Malawian and Zambian settings
No full textBackground: Research about young people in lower- and middle-income countries is seldom done by young people themselves. Engaging youth in designing and conducting research that concerns their well-being can improve their skills and make the findings more relevant to young people’s needs. This commentary outlines five lessons learned in the process of conducting a youth-led research study in Malawi and Zambia on youth sexual and reproductive health and rights for the Break Free! programme. Reflections on the challenges and successes encountered by the research team during this study were documented via notes. A reference group of youth advocates was set up to guide the study, and an evaluation was conducted with them about their experience. Data from both these sources were thematically organised and discussed between the research team. Lessons learned: The commentary outlined that meaningfully involving youth in the study methods, not only as participants but also with a youth-led research team and a youth reference group enhanced the quality of study findings. The combination of seasoned youth researchers working with emerging youth researchers from prior collaborations laid a good foundation to implement the study and was identified as a success factor. Fostering a positive working culture that centred peer-to-peer support and the expertise of researchers in and from the ‘Global South’ was a key success in having a fair partnership that shifted power. However, time taken for mentoring, and knowledge exchange, between youth researchers and with the youth reference group was under-estimated and under-budgeted and an adaptable approach to time and resources allowed the research team to address these challenges. Lastly, the support of an established institution was instrumental in the conceptualization and execution of the study and functioned as a pre-condition for success. Conclusion: The lessons outlined in the commentary highlights the added value of engaging youth in all stages of the research cycle and can offer food for thought for future researchers looking to adopt this approach. While youth-led research may not be suited to every context, its principles of equity and participation can transform both the young participants and the research process.<p/
Automated CT-derived body composition predicts pathologic response to neoadjuvant immunotherapy in non–small cell lung cancer
No full textTumor-intrinsic biomarkers alone insufficiently predict pathological complete response (pCR) to neoadjuvant immunochemotherapy (NICT) in non-small cell lung cancer (NSCLC). Artificial intelligence (AI)-based three-dimensional CT-derived body composition may provide complementary predictive value. We evaluated its association with pCR following NICT in NSCLC. This multicenter retrospective study of NSCLC patients treated with NICT in China between July 2019 and July 2024. Pre- and post-treatment CT scans were used for automated T1–T12 localization and volumetric body composition segmentation. Metrics included skeletal muscle, intermuscular, visceral, and subcutaneous adipose volume index (SAVI), and their percentage changes between scans. Among 657 patients (mean age, 61.3 years; 87.4 % men), pCR rates were 39.7 % (training), 38.4 % (internal validation), and 34.9 % (external validation). In multivariable analysis, high baseline skeletal muscle volume index (SMVI) was independently associated with pCR (OR = 2.22). During NICT, each 1 % relative increase in SMVI was associated with a 16 % higher likelihood of pCR (OR = 1.16), whereas every 10 % relative increase in SAVI improved pCR probability (OR = 1.56). A machine learning model integrating clinical variables, baseline SMVI, %ΔSMVI, and %ΔSAVI demonstrated significantly better discrimination than models using clinical variables alone ( p < 0.05) in all cohorts. The performance was observed in the internal and external validation cohorts, with sensitivities of 62.1 % and 52.8 %, and specificities of 66.7 % and 74.7 %, respectively. AI-based CT–derived body composition quantification, particularly baseline SMVI and dynamic changes in SMVI and SAVI during NICT, are independently associated with pCR in NSCLC. Incorporating these modifiable biomarkers into predictive models improves performance beyond clinical variables alone.</p
Genetic risk factors for MASLD/MASH and cardiovascular disease in elderly individuals
No full textIntroduction and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, MASH, are closely related to obesity and lifestyle. From previous studies, MASLD is also known for its strong genetic background. This study aimed to investigate the association between previously reported genetic polymorphisms of MASLD/MASH and clinical outcomes in an elderly Western European population.Patients and Methods:We performed an analysis of 5,244 participants (mean age 75.3 years) from the PROSPER cohort study who were followed for 3.2 years. FIB-4 scores were calculated using age, AST, ALT, and platelet count, applying age-specific cutoffs. Thirty MASLD/MASH-associated SNPs, previously identified in GWAS analyses, were evaluated for their association with FIB4 scores. For SNPs showing significant differences in FIB-4 score across genotypes, associations with clinical outcomes and all-cause mortality were assessed using Cox proportional hazards regression models, adjusted for relevant clinical covariates. Results:Five SNPs were significantly associated with FIB-4 scores. PNPLA3_rs738409 and SAMM50_rs3761472 showed higher FIB-4 scores in mutant homozygotes, while SLC39A8_rs13107325, TRIB1_rs2954021, and ANPEP_rs7168849 showed the opposite trend. Despite statistical significance, absolute FIB-4 scores remained within ranges typically associated with low fibrosis risk. TRIB1_rs2954021 was linked to stroke, SLC39A8_rs13107325 to myocardial infarction and ANPEP_rs7168849 to all-cause and cancer-related mortality. No significant associations were observed for PNPLA3_rs738409 or SAMM50_rs3761472 with cardiovascular and mortality outcomes. Conclusions:Our findings reveal that specific MASLD/MASH-associated genetic variants influence FIB-4 scores and are linked to cardiovascular and mortality outcomes in an elderly population. These results suggest that liver fibrosis may reflect not only hepatic injury, but also broader systemic vulnerability driven by genetic predisposition. Incorporating genetic risk profiles may improve stratification for both liver and cardiometabolic disease.<p/
An extension of the validation cohort of the Dutch Early-Stage Melanoma (D-ESMEL) study for stage-specific analyses
No full textThere is a high need for accurate prognostic models among stage II melanoma to determine who may benefit from (neo)adjuvant systemic therapy. The Dutch Early- Stage Melanoma (D-ESMEL) study was designed to identify new prognostic features in a population-based sample of stage I/II melanoma patients in addition to American Joint Committee of Cancer (AJCC) staging. The validation cohort of the D-ESMEL study employs a nested case-control design. Initially, controls were randomly sampled to develop prognostic that included both known and new prognostic factors to assess the additive value of new prognostic factors. As a consequence, most controls had a very thin melanoma (<1.0 mm) while most cases had a thicker melanoma (>2.0 mm). This resulted in insufficient variability and high weights for stage II controls when applying weighted analyses in absolute risk prediction models. Therefore, randomly sampled controls were re-matched on AJCC stage (stage IA, IB, IIA, IIB, IIC), and new stage-matched controls were collected for cases who could not be rematched. The original D-ESMEL validation cohort included 5,815 stage I/II melanoma patients, of whom 154 developed distant metastasis (cases). 98/154 Cases were stage II and only 24 stage II controls were included, while the stage-matched design now includes 153 stage-matched case-control sets of which 97 stage II cases and 97 stage II controls derived from a population-based cohort of 5,785 stage I/II patients. The updated design increased the biological variability among stage II controls, balanced weights in weighted analyses and thereby facilitating reliable subgroup analyses in this clinically important subgroup.</p