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Newborn screening (NBS) for inborn errors of metabolism is challenged by high false-positive rates, which may lead to parental anxiety and increased healthcare costs associated with diagnostic follow-up. False-positive results often arise from changes in metabolite concentrations that mimic metabolic disorders as a consequence of differences in perinatal factors or nutritional status. To address this, Collaborative Laboratory Integrative Reports (CLIR) and the associated post-analytical tools (PATs) using multivariate interpretation and covariate-adjusted reference intervals may be used to improve specificity of NBS algorithms. In the current study, we examined whether CLIR can be applied to optimize the Dutch NBS program by reducing the false-positive rates. We developed and validated a CLIR-based PAT for CPT1 deficiency, GA-I, IVA and MSUD within the Dutch NBS program. Single-condition tools (SCTs) and multivariate approaches, including marker ratios and covariate adjustments, were evaluated for their ability to discriminate true- and false-positive referrals. For CPT1 deficiency, age-adjusted SCT combined with birthweight, location correction, and the C18:1/methionine ratio substantially reduced false positives. For GA-I, C3DC-based ratios improved specificity while preserving true-positive detection, potentially reflecting postnatal renal immaturity in some cases. For IVA, the dual scatter plot fully separated true- and false-positive referrals, highlighting the limitations of single-marker screening. For MSUD, differences between false-positive and true-positive cases were more pronounced, yet a similar number of false positives were still referred; valine-related markers contributed to false positives, while leucine and the Xle/Phe ratio better identified true positives. CLIR-based post-analytical tools enhanced NBS specificity through covariate-aware, multivariate interpretation. This provides important input for decision makers in both the Dutch NBS, as well as the NBS community worldwide.

Since October 2019, screening for methylmalonic acidemia (MMA) has been implemented in the Dutch Newborn Screening (NBS) program. Since implementation, most referrals for MMA have been the result of (maternal) vitamin B12 deficiency. Although vitamin B12 deficiency is an important condition and early detection can confer health benefits, its identification was not the original objective of the screening. We therefore examined whether genetic forms of MMA can be distinguished from acquired forms. Early distinction between these forms is essential for guiding clinical management, informing prognosis, and enabling appropriate genetic counseling. Specifically, we tested whether the use of Collaborative Laboratory Integrated Reports (CLIR) to complement NBS results improved specificity of the test for genetic MMAs. We found that with the use of CLIR, genetic conditions including methylmalonyl-CoA mutase (mut) deficiency and cobalamin (cbl) A, B, C and D deficiency can be partially differentiated from acquired causes. This results in a significant reduction in the number of second-tier tests required. However, this approach may also exclude certain other genetic causes. Based on all findings, we provide considerations and implications for MMA screening that may inform decision-makers in (other) NBS programs.

Background: Prostaglandin E2 (PGE2) suppresses perinatal breathing. Reducing antenatal PGE2 concentrations with paracetamol could stimulate spontaneous breathing in premature infants at birth. We aimed to assess feasibility and potential effects of antenatal paracetamol. Methods: In this randomised, placebo-controlled, triple-blind feasibility trial, pregnant women <31 weeks’ gestation were randomised to receive either intravenous paracetamol (intervention) or placebo (control). Multiple pregnancies were also eligible, and the number of infants could exceed the number of enrolled women. The primary outcome was feasibility of administering study medication within 30–120 min prior to birth. Secondary exploratory outcomes included measures of breathing and other physiological parameters of infants during the first 1–10 min after birth and were compared between infants from mothers who received paracetamol and infants from mothers who received a placebo irrespective of timing of administration. Planned enrolment was 40 women. Results: The trial enrolled 23 women before termination due to low recruitment. Five women did not receive study medication, while 18 did (9 per group). Overall, 11 of the 23 enrolled women (48%) received study medication within the specified timeframe. The nine women in the intervention group gave birth to 13 infants, while the nine women in the control group gave birth to 12 infants. Among infants, average minute volume did not differ significantly between groups (intervention (n = 13) vs. control (n = 12); mean ± SEM; 147 ± 12 vs. 114 ± 14 mL/kg/min, p = 0.093). However, the intervention group had a significantly higher area under the curve for minute volume, greater inspiratory drive, and a higher heart rate (1120 ± 410 vs. 707 ± 346 mL/kg, p = 0.020; 11.8 ± 1.0 vs. 8.4 ± 1.3 mL/kg/breath/s, p = 0.046; 137 ± 5 vs. 121 ± 5 beats/min, p = 0.037). Conclusions: Antenatal paracetamol administration 30–120 min prior to birth was feasible in only half of the women, below the pre-specified threshold of 80%, but the exploratory findings suggest that it may improve the breathing effort of premature infants.

Abstract Grey matter network topology is altered in Alzheimer’s disease and these alterations are related to cognitive decline. Understanding the biological underpinnings of loss of brain connectivity may provide insights into mechanisms related to developing Alzheimer’s dementia (i.e. dementia A+). We investigated which biological processes as measured in CSF proteomics were associated with loss of brain connections across the Alzheimer’s disease continuum. We included 347 individuals with abnormal CSF amyloid [mean age ± standard deviation (SD) 66 ± 8; 98 cognitively unimpaired—A+, 88 mild cognitive impairment—A+, 161 dementia A+] and 146 cognitively unimpaired individuals with normal CSF amyloid (mean age ± SD 62 ± 8) and available T1w MRI-scans and CSF proteomic data (3097 proteins using tandem mass tag spectrometry) from the Amsterdam Dementia Cohort. We used an automated pipeline to construct grey matter networks from 3D-T1 sequences and for each network, calculated the small-worldness coefficient, which we previously found to be robustly related to cognitive decline. Linear models were applied to test associations between CSF protein levels and connectivity measures using an interaction term for clinical stage while controlling for connectivity density, age and sex. We validated our results in data from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Pathway enrichment analysis was performed for proteins associated with loss of brain connectivity (P &lt; 0.05) using the Gene Ontology database. Individuals across the Alzheimer’s disease continuum had lower small-worldness coefficients compared with controls (ANOVA P &lt; 0.001). In amyloid positive individuals, higher levels of 222 proteins and lower levels of 482 proteins were associated with lower small-worldness coefficients and were enriched for innate immune system and neuroplasticity pathways, respectively. Stratified for disease stage, most protein associations with lower small-worldness coefficients were found in mild cognitive impairment A+ (n = 527 proteins) and dementia A+ (n = 799 proteins) with considerable overlap (n = 239 proteins). Proteins in these stages were enriched for complement activation and synaptic integrity. In cognitive unimpairment A+, we found proteins enriched for processes involved in apoptosis. We did not find any enriched biological processes in controls. Repeating analyses in ADNI indicated that similar biological processes were associated with altered grey matter network connectivity. Higher CSF levels of proteins involved in immune responses and lower levels of proteins related to neuroplasticity were associated with lower small-worldness coefficients across the Alzheimer’s disease continuum. This suggests that preserving cognitive function in the presence of amyloid and prevention of dementia A+ may require therapies that strengthen synapses and targets the innate immune system in addition to amyloid and tau.

Abstract Complete response (CR) is an important treatment goal in follicular lymphoma (FL). In relapsed or refractory (R/R) FL, CR rates decline, and disease progression accelerates with each treatment line, with particularly poor outcomes in patients with high‐risk features. Odronextamab, a CD20 × CD3 bispecific antibody, demonstrated deep, durable responses and generally manageable safety in R/R FL in the Phase 2 ELM‐2 study (NCT03888105); we present an exploratory analysis in patients who attained a CR. Patients received intravenous odronextamab with step‐up dosing in Cycle 1, 80 mg weekly in Cycles 2–4, then 160 mg once every 2 weeks until disease progression or other protocol‐defined reason for discontinuation. Patients with CR lasting ≥9 months switched to dosing once every 4 weeks. Overall, 73.4% (94/128) of patients attained CR, 93.6% (88/94) by first response assessment (~Week 12). Median time to CR was 2.7 months (range 2.3–7.9). Median duration of CR was 25.1 months (95% confidence interval [CI] 20.5–not evaluable [NE]) overall and 23.7 months (18.2–NE) in patients with high‐risk features. Overall, 79.5% (35/44) of patients who switched to Q4W dosing maintained CR at last assessment. Patients with low/undetectable CD20 expression by immunohistochemistry (<10% CD20 + cells) or RNA sequencing (messenger RNA < 500 transcripts per million) could achieve CR. Median progression‐free survival was 27.8 months (95% CI 23.0–NE) in patients with CR and not reached in those with undetectable circulating tumor DNA at Week 12. Treatment‐emergent adverse events (TEAEs) led to treatment discontinuation in 16.0% of patients with CR; the most common TEAE was cytokine release syndrome (56.4%). This generally manageable safety profile and the sustainability of CRs support odronextamab as a potential long‐term treatment for heavily pretreated R/R FL.

Background Psychiatric disorders are increasingly contributing to global disability. Despite advances in conservative management, the prevalence of treatment-resistant cases remains high. Meanwhile, neurosurgery for psychiatric disorders (NPD) remains underused, largely due to strict regulations and historical concerns, particularly those related to neuropsychological side effects (NPSE). Objective To address this issue, we conducted a systematic review with meta-analysis to compare NPSE associated with radiofrequency ablative NPD to those observed in neuro-oncological, neurovascular and epilepsy surgeries. Methods PubMed, Embase and LILACS databases were searched in April 2024 for articles published in English/Spanish from 1990 to 2022, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results A total of 48 articles with 2678 participants were included. The frequency of transient and permanent NPSE in the NPD group ranged from 0.94% to 11.50% and 0.94% to 2.03%, respectively, comparable to the other surgical groups (epilepsy: 0.31–11.70%; vascular: 0.52–22.90%; oncology: 0.94–17.60% for transient NPSE; epilepsy: 0.31–12%; vascular: 0.40–1.96% and oncology: 0.84–1.48% for permanent NPSE). Regarding permanent NPSE, arguably the most critical consideration, the NPD group showed better outcomes in memory, language and social cognition than the epilepsy group, but worse outcomes in executive and perceptual-motor functions. Compared with the vascular group, the NPD group had better executive function but worse complex attention. Finally, the NPD group had fewer permanent deficits than the oncology group in executive function, complex attention and perceptual-motor domains, although language performance was lower. Conclusions Contemporary NPD apparently carries a similar risk of NPSE as other conventional neurosurgical procedures, challenging misconceptions and this unjustified barrier to its broader use.

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

Abstract Introduction Odronextamab, a CD20×CD3 bispecific antibody, demonstrated compelling efficacy with a generally manageable safety profile in heavily pretreated patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). Pts in ELM-2 received odronextamab monotherapy until disease progression or unacceptable toxicity, with dosing frequency reduced to every 4 weeks (Q4W) in those with sustained complete response (CR) for at least 9 months. Here, we report longer term outcomes in the global FL population of ELM-2, including efficacy and safety in pts who switched to Q4W dosing. Methods Details of the ELM-2 study for the R/R FL cohort have been reported previously. Odronextamab monotherapy was administered intravenously, with step-up dosing in Cycle (C) 1 to help mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg in C2–4, then 160 mg every 2 weeks (Q2W) maintenance. Pts with a CR for ≥9 months switched from 160 mg Q2W to Q4W. Pts with the opportunity for response assessment at 12 weeks were included in this analysis. Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Key secondary endpoints included CR rate, duration of response (DOR), and progression-free survival (PFS) by ICR, overall survival (OS), and safety. Results As of May 5, 2025 data cutoff, 128 pts with R/R FL Grade (Gr) 1–3a were evaluable for efficacy and safety analysis (overall global population). Median duration of odronextamab exposure was 42.9 weeks (range 0.4–264.0) and median follow-up was 34.1 months (95% CI 33.8–37.9). Eligible pts (n=48) switched to Q4W dosing, with median duration of follow-up from time of switching to Q4W dosing of 19.7 months (95% CI 16.2–31.9). Baseline characteristics were generally similar between the overall population and the subgroup of pts who switched to Q4W dosing. The ORR by ICR in the overall population was 80.5% and CR rate was 74.2%, with a median DOR of 26.0 months and median duration of CR of 32.2 months. In pts with sustained CR for ≥9 months who transitioned to Q4W maintenance, the median DOR from time of switching was 31.5 months. In the overall population, the median PFS was 24.1 months and median OS was not reached (estimated 24- and 36-month OS rates: 70.1% and 64.3%, respectively). In pts with CR, median PFS was 38.0 months and median OS was not reached (24- and 36-month OS rates: 80.1% and 75.2%). All 128 pts had treatment-emergent adverse events (TEAEs), with Gr ≥3 TEAEs reported in 112 pts (87.5%). Discontinuation due to TEAEs occurred in 29 pts (22.7%), and 5 pts died due to treatment-related TEAEs. With the 0.7/4/20 mg step-up regimen, CRS was reported in 55.0% (33/60; Gr 3 in 1 pt) of pts, with no new CRS events observed after switching to Q4W. Infections occurred in 81.3% (Gr ≥3, 46.1%) of pts, with COVID-19 (any Gr, 39.8%) the most frequent. After switching to Q4W dosing, the rate of any grade infection was 81.3% (Gr ≥3, 39.6%). Opportunistic infections (narrow SMQ defined) were reported in 18% (Gr ≥3, 8.6%) of pts in the overall population, with 22.9% (Gr ≥3, 8.3%) of pts having an opportunistic infection after switching to Q4W. Conclusions In the ELM-2 study with ~3-year follow-up in heavily pretreated pts with R/R FL, odronextamab continued to demonstrate deep and durable responses, as well as encouraging PFS and OS, particularly in the majority of pts who achieved CR. Responses remain durable in those who switched to Q4W dosing, lasting for a median additional 31.5 months from the time of switching, demonstrating the long-term, continued therapeutic benefit of odronextamab in pts with R/R FL. The safety profile remained generally manageable, with no new safety signals observed, and no evidence of increased infection risk in pts who switched to Q4W maintenance. Updated data will be presented.