julilili42/papers huggingface dataset:
Glucocorticoids vs glucocorticoids plus cyclophosphamide in eosinophilic granulomatosis with polyangiitis without poor-prognosis factors: a target trial emulation study
2025-05-24

Abstract Objectives Current recommendations suggest treating eosinophilic granulomatosis with polyangiitis (EGPA) without severe manifestations with glucocorticoids (GCs) and EGPA with severe manifestations with GCs plus cyclophosphamide (CYC) regardless of poor-prognostic factors. However, GCs plus CYC and GCs alone have never been compared in EGPA without poor-prognosis factors assessed by the 1996 Five Factor Score (FFS). We aimed to compare the efficacy of GCs plus CYC vs GCs alone for the treatment of EGPA without poor-prognosis, including among patients with severe manifestations. Methods We emulated a target trial using observational data from a European multicentre retrospective study. We included patients with (i) newly diagnosed EGPA, (ii) a FFS = 0 at diagnosis and (iii) treated with GCs or GCs plus CYC. Primary outcome was overall relapse at 12 months. Inverse probability of treatment weighting-based analysis was used to adjust for potential confounding factors. In a subgroup analysis, we focused on patients with severe manifestations not included in the FFS. Results A total of 250 patients were included: 177 treated with GCs alone and 73 with GCs plus CYC. After adjustment, no reduction in the risk of overall relapse was observed between the two treatment groups. Similar results were observed in the subgroup of patients with severe manifestations. Conclusion This study shows that the adjunction of CYC to GCs does not reduce the risk of relapse in patients with EGPA and no poor-prognosis factors. It supports current guidelines in patients without severe manifestations but challenges the need of CYC adjunction in patients with severe manifestations but no poor-prognosis factors.
Differential impact of sensory uncertainty in blocked versus trial-interleaved contexts when feedforward and feedback processes co-occur
2025-05-24

Theories of human motor learning commonly assume that the degree to which movement plans are adjusted in response to movement errors scales with the precision of sensory feedback received regarding their success. However, support for such models has mainly come from experiments that limit the amount of correction that can occur within an ongoing movement. In contrast, we have recently shown that when this restriction is relaxed, and both within-movement and between-movement corrections co-occur, movement plans undergo large and abrupt changes that are strongly correlated with the degree of sensory uncertainty present on the previous trial and are insensitive to the magnitude and direction of the experienced movement error. Here, we show that the presence of these abrupt and error-insensitive changes are only observed when different levels of sensory uncertainty are interleaved pseudo-randomly on a trial-by-trial basis, and are absent when sensory uncertainty levels vary across blocks of trials. These results suggest that the co-occurrence of within-movement and between-movement corrections is not the only important aspect of our earlier study that challenged traditional models of motor learning under uncertainty.
Advancing knowledge and public health: a scientific exploration of abortion safety
2025-05-24

Abortion is a fundamental component of reproductive healthcare, essential for managing unintended pregnancies and preserving the health and autonomy of individuals. Despite its medical necessity and established safety, abortion remains a topic of global controversy, shaped by sociopolitical, ethical, and legal factors rather than evidence-based practice. This editorial consolidates current scientific insights into abortion safety, mainly exploring its medical, but also legal, ethical, social, and public health dimensions. Globally, nearly 73 million abortions occur annually, highlighting the procedure's significance in healthcare systems. Abortion safety is highly dependent on the medical and systemic context. Medical abortion, involving mifepristone and misoprostol, boasts a success rate exceeding 95% for early gestation, with serious complications in less than 1% of cases. Surgical abortion, particularly vacuum aspiration, offers comparable safety with a major complication rate below 0.2%. When provided by trained professionals in supportive healthcare environments, abortion procedures are among the safest medical interventions. However, disparities persist globally. High-income countries with liberal abortion laws and robust healthcare infrastructures report near-universal access to safe abortions, with mortality rates approaching zero. In contrast, restrictive laws in low- and middle-income countries (LMICs) force individuals to seek unsafe procedures, contributing significantly to maternal morbidity and mortality. Unsafe abortion accounts for 13% of global maternal deaths, disproportionately affecting marginalized populations. Addressing these inequities requires comprehensive strategies, including legal reform, improved access to contraception, enhanced provider training, and destigmatization efforts. Integrating abortion care into broader reproductive health services can ensure safety and equity, advancing public health outcomes worldwide.
Safety, Feasibility, and Tolerability of Ten Days of At-Home, Remotely Supervised tDCS During Gamified Attention Training in Children with Acquired Brain Injury: An Open-Label, Dose-Controlled Pilot Trial
2025-05-24

Background/Objectives: Chronic attention problems occur in approximately 25% of children after acquired brain injury (ABI). When delivered daily, transcranial direct current stimulation (tDCS) may improve attention; however, access to daily in-clinic tDCS treatment can be limited by other commitments, including concurrent therapy, school commitments, and caregiver schedules. Treatment access can be improved through home-based interventions, though these require several practical and safety considerations in a pediatric ABI population. This study evaluated the safety, feasibility, and tolerability of remotely monitored at-home tDCS during online gamified attention training in pediatric ABI. Methods: We conducted a randomized, single-blind, dose-controlled clinical trial of at home tDCS in Brisbane, Australia (10 tDCS sessions; 20 min; 1 mA or 2 mA; bilateral dorsolateral prefrontal cortex). Participants attended our clinic at baseline for clinical assessments, fitting of the personalized tDCS headband, and training in how to use tDCS at home. All sessions were remotely supervised using live videoconferencing. We assessed the feasibility and tolerability of at-home tDCS and our customized, personalized at-home tDCS headband as primary outcomes. As secondary outcomes, we evaluated changes in functional connectivity (fc) and reaction time (RT). Results: Seventy-three participants were contacted over six months (January-June 2023) and ten were enrolled (5 males; mean age: 12.10 y [SD: 2.9]), satisfying a priori recruitment timelines (CONSORT reporting). All families successfully set up tDCS and completed attention training with excellent protocol adherence. There were no serious adverse events over the 100 total sessions. Nine participants completed all stimulation sessions (1 mA: n = 5, 2 mA: n = 4). Participants in the 2 mA group reported greater tingling, itching, and discomfort (all p &lt; 0.05). One participant in the 1 mA group was unable to complete all sessions due to tolerability challenges; however, these challenges were resolved in the second half of the intervention by gradually increasing the stimulation duration across the 10 days alongside additional coaching and support. Conclusions: Overall, daily remotely supervised at-home tDCS in patients with pediatric ABI is safe, feasible, and tolerable. Our results support larger, sham-controlled efficacy trials and provide a foundation for the development of safe and effective at-home stimulation therapeutics that may offer targeted improvement of neurocognitive symptoms in children.
CMRI-detected brain injuries and clinical key risk factors associated with adverse neurodevelopmental outcomes in very preterm infants
2025-05-25

Abstract Neurological impairment is high after preterm birth. This study evaluates the impact and interplay of cMRI-detected brain injuries (BI) and clinical risk factors on neurodevelopmental outcomes and extracts the most important key factors. A retrospective analysis was conducted on risk factors (perinatal/neonatal, cMRI-detected BI) for adverse motor (MO) and cognitive (CO) outcomes (Bayley Scales of Infant Development, 24 months corrected age) in a tertiary center cohort (2009–2018) of very preterm infants (&lt; 32 weeks of gestation) using uni-/multivariable regression models. We included 342 infants (mean gestational age:28.0 ± 2.3 weeks; male:49%). Significant clinical predictors for MO/CO included GA, birthweight, APGAR score, catecholamine treatment, ventilation, retinopathy of prematurity, transfusion of red blood cells (RBCs), bronchopulmonary dysplasia, surgery, and patent ductus arteriosus interventions (all p &lt; 0.01/ p &lt; 0.01), surfactant (MO: p = 0.037), and sepsis ( p &lt; 0.001/ p = 0.016). (Severe) cMRI-detected BIs (&gt; 1, all p &lt; 0.05) and not only severe intraventricular hemorrhage (IVH) III°/III°+PVHI and ventricular dilatation (VD) (all p &lt; 0.05), but also mild/moderate injuries like IVH II° ( p &lt; 0.001/ p &lt; 0.024), cerebellar hemorrhage (CO: p = 0.028), and moderate VD (MO: p = 0.005) significantly impacted outcomes. Independent key factors were &gt; 1 severe cMRI-detected BI (MO/CO:-11.27/-10.3 score points (sp), p = 0.021/0.043), APGAR score (10 min, MO/CO:+5.3/+4.45 sp/point, p &lt; 0.001/ p &lt; 0.001), surfactant administration (MO:+4.88 sp, p = 0.031), and transfusion of RBCs (MO/CO:-1.69/-1.96 sp/transfusion, p = 0.006/ p &lt; 0.001). In conclusion, combining imaging and clinical (key) risk factors is important for risk stratification of preterm infants. Even mild BI, like IVH II°, significantly contributes to adverse outcomes, underlining the importance of cMRI.
Speech-based digital cognitive assessments for detection of mild cognitive impairment: Validation against paper-based neurocognitive assessment scores
2025-05-25

Background Cognitive decline in Alzheimer's disease (AD) often includes speech impairments, where subtle changes may precede clinical dementia onset. As clinical trials focus on early identification of patients for disease-modifying treatments, digital speech-based assessments for scalable screening have become crucial. Objective This study aimed to validate a remote, speech-based digital cognitive assessment for mild cognitive impairment (MCI) detection through the comparison with gold-standard paper-based neurocognitive assessments. Methods Within the PROSPECT-AD project, speech and clinical data were obtained from the German DELCODE and DESCRIBE cohorts, including 21 healthy controls (HC), 110 participants with subjective cognitive decline (SCD), and 59 with MCI. Spearman rank and partial correlations were computed between speech-based scores and clinical measures. Kruskal-Wallis tests assessed group differences. We trained machine learning models to classify diagnostic groups comparing classification accuracies between gold-standard assessment scores and a speech-based digital cognitive assessment composite score (SB-C). Results Global cognition, as measured by SB-C, significantly differed between diagnostic groups ( H (2) = 30.93, p &lt; 0.001). Speech-based scores were significantly correlated with global anchor scores (MMSE, CDR, PACC5). Speech-based composites for memory, executive function and processing speed were also correlated with respective domain-specific paper-based assessments. In logistic regression classification, the model combining SB-C and neuropsychological tests at baseline achieved a high discriminatory power in differentiating HC/SCD from MCI patients (Area Under the Curve = 0.86). Conclusions Our findings support speech-based cognitive assessments as a promising avenue towards remote MCI screening, with implications for scalable screening in clinical trials and healthcare.
Chemical Switching: A Concept Inspired by Strategies from Biocatalysis and Organocatalysis
2025-05-26

In this perspective the character of aldehyde functional groups is outlined as central intermediates in DNA repair. As highly reactive entities, aldehydes exist in limited quantities and in contextualized scenarios only and are commonly masked as a Schiff base. Recent advances reveal that principles of organic chemistry can modulate the enzymatic cleavage of Schiff bases, a process termed chemical switching. This approach not only enhances the production of canonical DNA repair products, bolstering cellular function, but also generates novel reaction intermediates, potentially rewiring cellular pathways. However, such rewiring could increase the complexity and toxicity of DNA repair intermediates, influencing therapeutic outcomes. To shape novel classes of therapeutics, an exploitation of these fine‐tuned reaction principles requires expertise of enzymologists and scientists skilled in bio‐ and organocatalysis. Here, the current state of the art is outlined in chemically switching enzymatic function in cells with focus on DNA repair, highlighting challenges of this new type of protein modulation and discussing possible solutions. This paints a picture of the chemical switching concept as an emerging playing field with exciting translational prospects.
The subcellular distribution of phosphorylated Y‐box‐binding protein‐1 at S102 in colorectal cancer patients, stratified by KRAS mutational status and clinicopathological features
2025-05-26

Oncoprotein Y‐box‐binding protein‐1 (YB‐1) is involved in all cancer hallmarks. One of the most studied post‐translational modifications of YB‐1 is phosphorylation on Serine 102 (S102), which is involved in cancer progression. KRAS mutations are frequent, have been associated with poor prognosis and therapy resistance, and they are considered a major stimulator of S102 YB‐1 in vitro . In this study, a relationship between S102 YB‐1 phosphorylation in subcellular fractions and KRAS mutation was investigated in CRC tissues, and its association with clinicopathological parameters was analyzed. Immunohistochemistry on 36 patient samples and 5 normal tissue samples highlighted nuclear S102 YB‐1 was specific to cancer tissues. Nuclear S102 YB‐1 was expressed in 47.2% of tumor tissues, which was positively correlated with KRAS mutation ( P = 0.017). There was no significant association between cytoplasmic S102 YB‐1 with KRAS mutation status ( P = 0.391). Further studies in larger cohorts are needed to validate the observed results. The significant association between S102 YB‐1 in the nucleus and KRAS mutation may suggest YB‐1 as an effective target to improve survival of CRC patients with KRAS‐mutated tumors.
Added Therapeutic Benefits of Top‐Selling Drugs in Japan: A Cross‐Sectional Study Using Health Technology Assessment
2025-05-26

ABSTRACT It is unclear whether Japanese top‐selling drugs have meaningful added therapeutic benefits to justify their high sales. This question is relevant as Japan's healthcare costs are rising consistently, particularly due to increasing drug prices. This cross‐sectional study evaluated the added therapeutic benefits of Japan's top‐selling drugs in 2021 using ratings from established health technology assessment (HTA) agencies in Canada, France, and Germany. Drug characteristics and benefit ratings were obtained from public databases and HTA agencies, following the established method. Overall, added therapeutic benefit ratings were categorized as binary (high or low). Of 51 identified top‐selling drugs in Japan, 43 (86%) had at least one rating from three agencies. Notably, 20 (47%) received low added therapeutic benefit ratings even in our optimistic scenario. Low ratings were more common among small‐molecule drugs 15/20 (75%), while high ratings were predominant among biologics 14/23 (61%). Oncology drugs represented the largest category in both high 9/23 (39%) and low 5/20 (25%) groups. Interestingly, 9 drugs (9/16; 56%) approved between 2011 and 2021 received low ratings, compared to 41% (11/27) of those approved before 2011. Additionally, 70% of high‐benefit drugs received at least one expedited review, whereas this was 35% for low‐benefit drugs. Our findings revealed that many top‐selling drugs in Japan had low added therapeutic benefits. Utilizing HTA evaluation frameworks provides valuable insights, particularly in prioritizing drugs based on added therapeutic benefits. While full implementation of such a system in Japan requires further consideration, strengthening HTA processes could help ensure sustainable healthcare costs.
Multiplex LC–MS/MS assay for simultaneous quantification of artesunate and its active metabolite dihydroartemisinin with pyronaridine, proguanil, cycloguanil, and clindamycin in pharmacokinetic studies
2025-05-27

Abstract Background Malaria, especially caused by Plasmodium falciparum , remains a major global health concern, particularly in sub-Saharan Africa. To combat rising drug resistance, innovative treatment approaches like triple artemisinin-based combination therapy (TACT) and multi-drug antimalarial combination therapies (MDACTs) are being explored. Methods This study introduces a robust and validated multiplex LC–MS/MS assay for the simultaneous quantification of key antimalarial drugs and their metabolites, including artesunate, dihydroartemisinin, pyronaridine, proguanil, cycloguanil, and clindamycin. Developed in accordance with EMA guidelines, the assay ensures high accuracy, sensitivity, and stability. Serum samples were prepared through a process of protein precipitation with acetonitrile, followed by the evaporation of the supernatant. The resulting residues were then reconstituted in a 50/50 mixture of aqueous 20 mM ammonium formate buffer and methanol for the analysis. Results The assay achieves lower limits of quantifications of 1 ng/mL for proguanil, 0.2 ng/mL for cycloguanil, 1 ng/mL for artesunate, 4 ng/mL for dihydroartemisinin, 2 ng/mL for pyronaridine, and 5 ng/mL for clindamycin. The assay was successfully applied in a pharmacokinetic study conducted as part of a clinical trial in Gabon and Ghana, assessing novel drug combinations in both children and adults against a standard of care artemisinin-based combination therapy. Conclusions The developed assay can support the further clinical development of these TACTs and MDACTs, ultimately contributing to enhanced malaria treatment strategies.
Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan
2025-05-27

Abstract The recent development of brain charts for the human lifespan offers an ideal modelling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the Genetic FTD Initiative (GENFI) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study. We analysed 37 532 MRIs from control subjects covering the entire lifespan and a total of 1341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared with GRN or MAPT mutation carriers (25 and 18 regions, respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporo-insular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum. Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase. Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.
Cost Utility of Intensive Home Treatment Compared With Acute Psychiatric Inpatient Admission
2025-05-27

Importance Intensive home treatment (IHT) is regarded as a safe and effective alternative to psychiatric inpatient care during acute crises. Objective To estimate the cost-effectiveness of implementing IHT in comparison with inpatient treatment for persons with severe mental illness in acute crisis in the German health care system. Design, Setting, and Participants This health economic evaluation was performed as part of a quasiexperimental nonrandomized trial conducted at 10 sites in Germany from January 2021 to December 2022. It included 200 patients with severe mental illness treated by IHT for acute crisis matched by means of propensity scores with 200 patients with severe mental illness receiving inpatient treatment. Participants were observed for 12 months. All analyses were conducted from January 15 to October 30, 2024. Main Outcomes and Measures Incremental cost utility ratios (ICURs) were calculated for 12 months from the societal perspective and from the payer perspective of German statutory health insurance. ICUR uncertainty was estimated by nonparametric bootstrapping and estimated cost-effectiveness acceptability curves for maximum willingness to pay (MWTP) thresholds of €25 000 and €50 000. Results The mean (SD) age of all 400 eligible study participants was 45 (16) years, and 264 (66%) were female. Overall, 374 were considered in the analysis. The ICUR point estimates were €48 786.43 from the perspective of statutory health insurance and €38 433.81 from the societal perspective. Acceptability rates for IHT being a cost-effective alternative compared with inpatient treatment from the societal perspective were 67% at an MWTP threshold of €25 000 and 50% at an MWTP of €50 000 and were 60% at an MWTP of €25 000 and 44% at an MWTP of €50 000 from the perspective of the statutory health insurance. Conclusions and Relevance This economic analysis found that IHT for persons with severe mental illness in acute crisis is expected to be cost-effective compared with inpatient treatment, with a slightly higher acceptability probability for statutory health insurance than for the economy as a whole. Due to the high stochastic uncertainty, the study results suggest that more research is needed to assess the economic efficiency of IHT more clearly.