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Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localization is associated with clinical outcomes. We investigated cortical thickness in 1778 cognitively unimpaired (CU) older adults with amyloid-β (Aβ) PET from the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) and LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) studies, with a subset (N = 445) with tau PET. We estimated the networks disrupted by each individual's cortical thinning using a large normative connectome database (N = 1000), and tested whether this preclinical AD atrophy network is associated with clinical manifestations and longitudinal cognitive (PACC) and functional (CDR) trajectories. Distinct networks connected to atrophy patterns were associated with Aβ and regional tau in CU older adults. These networks were similar to a previously published atrophy network for AD dementia (Aβ: r = 0.817, P = 0.006; tau: r = 0.712, P = 0.046). Atrophy connectivity to this preclinical AD network was associated with higher Aβ and tau, independent of total cortical atrophy, and cross-sectionally with lower cognition, greater subjective cognitive decline, and increased anxiety; longitudinally, it predicted faster cognitive and functional decline over ~5 years. After tau adjustment, the functional-decline effect was preserved while the cognitive-slope effect was largely attenuated. Atrophy in preclinical AD localizes to a network resembling AD dementia, and is independently associated with AD pathologies, clinical outcomes, and longitudinal decline. Network-level neurodegeneration is detectable and clinically informative in preclinical AD, supporting future network-based research and therapeutic development.
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are severe psychiatric disorders with distinct and overlapping clinical and neurobiological features. Despite extensive evidence of brain structural abnormalities, the transdiagnostic neuropathological mechanisms remain poorly understood. A comprehensive literature search was performed for voxel-based morphometry (VBM) studies reporting altered gray matter volume (GMV) in MDD, BD or SZ. A transdiagnostic meta-analysis was conducted to identify common and disorder-specific GMV alterations using the Seed-based d Mapping toolbox. Disease epicenter and buffering mapping were further investigated using a normative functional connectome to understand the network-constrained GM atrophy patterns. A total of 221 studies (MDD: n = 66; BD: n = 59; SZ: n = 96) encompassing 10,485 patients and 12,128 healthy controls were included. Transdiagnostic GMV reductions were identified in the medial prefrontal cortex and superior temporal gyrus. Less atrophy in the limbic/paralimbic regions and temporoparietal junction were observed for MDD, whereas SZ patients exhibited more pronounced GMV reductions in these areas. The ventrolateral prefrontal cortex emerged as a shared disease epicenter and the precuneus as a common buffer across these affective and psychotic disorders. The visual and dorsal attention networks exhibited the most pronounced buffering effects, while epicenter effects were primarily concentrated within the limbic, frontoparietal, subcortical and default mode networks. These findings suggested that affective and psychotic disorders are characterized by both shared and unique network-constrained GM atrophy patterns, which might advance precision diagnostics and inform targeted therapeutic strategies in the future.
Theory of mind (ToM), the ability to infer others' beliefs (cognitive ToM) and emotions (affective ToM), is compromised in behavioural variant frontotemporal dementia (bvFTD). However, its diagnostic and prognostic value in other frontotemporal dementia (FTD) variants remains underexplored due to limited understanding of the underlying neural mechanisms. This study investigated whether ToM deficits are shared across the frontotemporal dementia spectrum and explored the functional connectivity alterations underlying these disturbances using resting-state functional magnetic resonance imaging. Sixty-seven FTD patients [14 non-fluent variant primary progressive aphasia (nfvPPA), 17 semantic variant primary progressive aphasia (svPPA), 23 bvFTD, 13 right temporal variant frontotemporal dementia (rtvFTD); 34 women; mean age 66.5 ± 7.7 years] and two control groups (48 age-matched healthy controls; 50 young healthy controls) underwent clinical, neuropsychological and brain magnetic resonance imaging assessments. ToM was evaluated in patients using the Story-Based Empathy Task (SET), which includes the Story-Based Empathy Task affective subtest (SET-EA) and the Story-Based Empathy Task cognitive subtest (SET-IA). Resting-state functional connectivity networks were obtained in young healthy controls using seed-based analysis centred on the left medial prefrontal cortex for affective ToM and the right supramarginal gyrus for cognitive ToM. In addition, four large-scale functional networks were reconstructed to reflect disease-specific vulnerability. Functional brain connectivity within all networks was quantified using graph analysis and connectomics, and between-group comparisons were performed on both global and seed-based regional metrics. All patient groups showed similar impairments in affective and cognitive ToM performance. Network analyses revealed two dissociable but interconnected ToM systems. Global metrics of network topology indicated increased path length and reduced nodal strength in both ToM networks, particularly in bvFTD and nfvPPA patients (P < 0.05). Direct seed-based connectivity analyses confirmed widespread functional connectivity reductions from key nodes (e.g. left inferior frontal gyrus, anterior cingulate cortex) in these groups. In contrast, svPPA and rtvFTD cases exhibited relatively preserved functional connectivity within ToM circuits. Correlation analyses revealed associations between cognitive ToM network metrics and global ToM performance, and between functional connectivity in the salience network and behavioural dysfunction. Affective and cognitive ToM abilities are comparably impaired across FTD variants, suggesting that socio-cognitive impairments may represent a core and early feature across the FTD spectrum. Such deficits are mirrored by patterns of functional disconnection within dedicated large-scale networks, with bvFTD and nfvPPA showing the most pronounced disruptions. This study underscores the diagnostic relevance of socio-cognitive markers and highlights their potential as clinical and biomarker targets in future therapeutic interventions.
Crohn's disease is an inflammatory bowel disease (IBD) that can extend to any part of the gut. Many people with Crohn's disease fail to reach and maintain remission using conventional therapies. Biologic therapies with different mechanisms have advanced rapidly over recent decades. Comparative data for efficacy and safety are needed to clarify the relative position of these agents and guide decision-making. To assess the effects of biologic and advanced treatments for induction and maintenance of remission in Crohn's disease. A secondary objective was to rank the included interventions. In June 2025, we searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP. Randomised controlled trials (RCTs) comparing biologics with any other active comparator, placebo or no treatment for induction or maintenance of remission in adults with Crohn's disease. Our critical outcome was clinical remission/relapse. Important outcomes were clinical response/loss of response, endoscopic remission/relapse, withdrawals due to adverse events, serious adverse events and total adverse events. We assessed the risk of bias using the Cochrane tool (RoB 1). We expressed outcomes as risk ratios (RR) with 95% confidence intervals (CI). We conducted network meta-analyses for a network of induction studies and a network of maintenance studies. We assessed the certainty of the evidence using GRADE. We included 94 RCTs, of which 66 were on induction (n = 20,653) and 22 on maintenance (n = 6823) of remission. Induction For clinical remission, there is high-certainty evidence that ustekinumab is more effective (RR 2.01, 95% CI 1.67 to 2.43, number needed to treat for an additional beneficial outcome (NNTB) = 6, small effect size) and moderate-certainty evidence that adalimumab combined with purine analogues (RR 2.6, 95% CI 1.71 to 3.96, NNTB = 3, moderate effect size), guselkumab (RR 2.49, 95% CI 1.95 to 3.18, NNTB = 4, moderate effect size), adalimumab (RR 2.36, 95% CI 1.75 to 3.18, NNTB = 4, moderate effect size), upadacitinib (RR 1.76, 95% CI 1.34 to 2.3, NNTB = 7, small effect size), vedolizumab (RR 1.57, 95% CI 1.15 to 2.13, NNTB = 10, trivial effect size) and natalizumab (RR 1.37, 95% CI 1.08 to 1.73, NNTB = 15, trivial effect size) are probably more effective than placebo. There is low-certainty evidence that risankizumab (RR 2.26, 95% CI 1.8 to 2.84, moderate effect), BI695501 (adalimumab biosimilar) (RR 2.09, 95% CI 1.31 to 3.33, small effect), a combination of infliximab with purine analogues (RR 2.04, 95% CI 1.14 to 3.64, small effect) and filgotinib (RR 1.55, 95% CI 1.18 to 2.04, trivial effect) may be more effective. The evidence for humicade, a combination of natalizumab with infliximab and purine analogues, CTP13 (infliximab biosimilar) with purine analogues, infliximab, mirikizumab, etrolizumab, certolizumab, tesnatilimab, onercept, andecaliximab and etanercept was of very low certainty and no conclusions can be drawn. There is moderate-certainty evidence that vedolizumab (RR 0.71, 95% CI 0.41 to 1.23), ustekinumab (RR 0.72, 95% CI 0.52 to 0.99) and upadacitinib (RR 0.8, 95% CI 0.46 to 1.39) probably lead to a similar number of withdrawals due to adverse events. There is low-certainty evidence that risankizumab may lead to fewer withdrawals due to adverse events (RR 0.36, 95% CI 0.22 to 0.59, small effect size) and low-certainty evidence that humicade (RR 0.81, 95% CI 0.39 to 1.68), natalizumab (RR 0.79, 95% CI 0.47 to 1.33), apilimod mesylate (RR 0.84, 95% CI 0.36 to 1.95), certolizumab (RR 0.98, 95% CI 0.65 to 1.49), filgotinib (RR 1.06, 95% CI 0.64 to 1.78) and tesnatilimab (RR 1.51, 95% CI 0.82 to 2.8) may lead to a similar number of withdrawals due to adverse events. Maintenance For preventing clinical relapse, there is moderate-certainty evidence that adalimumab (RR 0.69, 95% CI 0.58 to 0.82, NNTB = 2, moderate effect size) is probably more effective than placebo. There is low-certainty evidence that CTP13 (RR 0.55, 95% CI 0.43 to 0.71, large effect size), infliximab (RR 0.68, 95% CI 0.57 to 0.81, moderate effect size) and upadacitinib (RR 0.72, 95% CI 0.56 to 0.94, small effect size) may be more effective than placebo. Vedolizumab (RR 0.78, 95% CI 0.6 to 1.01), ustekinumab (RR 0.83, 95% CI0.67 to 1.03), etrolizumab (RR 0.89, 95% CI 0.67 to 1.17) and tofacitinib (RR 0.9, 95% CI 0.67 to 1.21) may be similar to placebo. The certainty of the evidence ranged between high and very low, with the main limitations being imprecision and risk of bias. There is moderate-certainty evidence that vedolizumab probably leads to a similar number of withdrawals due to adverse events during maintenance (RR 0.84, 95% CI 0.63 to 1.11). There is low-certainty evidence that tofacitinib (RR 0.78, 95% CI 0.47 to 1.31), ustekinumab (RR 0.74, 95% CI 0.4 to 1.38), etrolizumab (RR 1.42, 95% CI 0.73 to 2.77) and upadacitinib (RR 1.51, 95% CI 0.73 to 3.11) may be no different to placebo in withdrawals due to adverse events. The evidence for certolizumab, natalizumab, filgotinib, risankizumab, infliximab combined with purine analogues, and vedolizumab combined with purine analogues was of very low certainty and no conclusions can be drawn. This review has supported evidence generation, but head-to-head comparative trials for key interventional subclasses or specific agents may be needed, as guided by key stakeholders; for example, on the use of biosimilar versions of medications out of patent. The role of concomitant purine analogues is a key confounding factor and future studies may not only want to investigate specifically the role of combinations, but also consider stratifying populations or purposefully excluding participants based on this key class of therapy to avoid such heterogeneity. Given the majority of evidence focusses on the outcomes of clinical remission and relapse, future studies may want to further consider other outcomes of clear interest to clinicians and patients, particularly endoscopic remission. Finally, long-term safety data are limited throughout the networks. Whilst future studies with longer follow-ups could provide increased data, it may be that study designs outside of randomised trials are employed for such outcomes. This project is funded by an NIHR Evidence Synthesis Programme Grant (NIHR132748). A protocol for this review was published in 2017: doi.org/10.1002/14651858.CD012751.
To examine the efficacy of conservative (non-surgical) treatments, usual care, and no treatment for chronic radicular and non-specific back pain. Time course network meta-analysis. Six electronic databases (Medline, SPORTDiscus, CINAHL, PsycINFO, Embase, and CENTRAL), searched from inception to 24 July 2020, and 302 previous systematic reviews. Full peer reviewed publications in English or German of randomised controlled trials, randomised clinical trials, randomised controlled cluster trials, or randomised crossover trials in adults (aged ≥18 years) receiving common conservative treatments for non-specific and radicular chronic low back pain. Treatments examined were acupuncture, education or advice, electrotherapy (including heat and ice electrotherapeutic modalities applied non-invasively), exercise training, manual treatments or manipulation, massage, the McKenzie method, pharmacotherapy, psychological treatments, traction, physical therapy (otherwise not falling into specific treatment combinations), placebo, multidisciplinary pain management, usual care (eg, management by a doctor), and no treatment (true control). Back pain intensity, leg pain intensity, disability, and mental health outcomes were reported immediately (<1 day), and at short term (≥1 day and ≤3 months), intermediate term (>3 and <12 months), and long term (≥12 months) time points. 581 reports of 551 studies (71 126 patients) were included. 510 trials included people with non-specific chronic low back pain and 41 trials included those with radicular chronic low back pain. For back pain (0-100 scale), acupuncture (mean difference -20.91, 95% credible interval -24.00 to -11.95), electrotherapy (-18.98, -21.84 to-10.95), exercise (-15.59, -17.51 to -10.05), manual treatment (-19.48, -22.17 to -11.74), massage (-25.61, -30.42 to -10.91), and multidisciplinary pain management (-18.96, -22.26 to -9.58) exceeded the minimal clinically important difference (set at 0.5 standard deviation) in the short term. For disability (0-100 scale), acupuncture (mean difference -10.52, 95% credible intervals -11.84 to -6.59), massage (-9.95, -11.45 to -5.50), and multidisciplinary pain management (-12.56, -13.91 to -8.55) were clinically effective in the short term. In the immediate and intermediate term only, the McKenzie method and massage, respectively, exceeded the minimal clinically important difference. In the long term, although two of the 14 treatments for back pain and nine of 14 treatments for disability had statistically significant benefits compared with no treatment, the effects were not clinically significant. The certainty of the evidence based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework was low (1.4%) to very low (98.6%) across interventions and time points. Findings for massage and the McKenzie method were not stable in the sensitivity analyses. Treatment effects for radicular chronic low back pain did not seem to differ from those for non-specific chronic low back pain. Some treatments were effective for pain and function in non-specific chronic low back pain, but improvements did not persist long term. Most of the evidence was for non-specific chronic low back pain; the evidence base for radicular chronic low back pain was limited. Although sensitivity analyses did not provide evidence for a different response in radicular chronic low back pain, an evidence gap remains for this subpopulation. Future work should explore strategies to establish the long term efficacy of modifications to lifestyle and behaviour. PROSPERO CRD42020182039.
Unmanned aerial vehicles (UAVs) are emerging as critical enablers of next generation Internet of Things (IoT) infrastructures, supporting real-time data collection, wireless relaying, and agile operations in dynamic environments. However, achieving safe and energy efficient multi UAV navigation under sixth generation (6G) communication constraints remains a significant challenge due to dynamic obstacles, limited on board energy, and the high cost of centralized coordination. This study introduces a multi agent soft actor-critic (MASAC) framework for UAV path planning and energy aware coordination in a fixed RIS assisted IoT grid. MASAC integrates entropy regularized actor-critic learning with reconfigurable intelligent surface (RIS) aware reward shaping to support energy aware navigation, RIS assisted recharging, and connectivity guided trajectory optimization. A lightweight convolutional policy network is used to encode spatial information from the grid environment, including obstacle locations, dynamic obstacle states, exploration memory, and UAV position, enabling efficient policy learning under constrained navigation settings. Extensive simulations in RIS assisted, 6G enabled IoT environments demonstrate that MASAC achieves a 100% mission success rate, where mission success is defined as reaching the fixed goal cell before energy depletion and within the maximum episode horizon of 500 steps. Compared with the strongest baseline success rate of 75%, this corresponds to a 25%-point absolute improvement and a 33.3% relative improvement under the same evaluation protocol and identical environmental settings. Within the adopted grid level energy abstraction, MASAC also achieves approximately 33% higher RIS recharge utilization. It also provides 6% greater grid level 6G connectivity and 23% higher cumulative reward. Meanwhile, it maintains a low simulation time evaluation latency of approximately 38 ms per UAV. Statistical analysis confirms these gains as significant ([Formula: see text]). The proposed framework offers a simulation level benchmark for energy efficient UAV navigation in RIS assisted IoT environments. It also supports future deployment oriented research under realistic operational constraints.
Preconception health improvement is vital for maternal and child health, yet societal perceptions about who holds responsibility for this remain underexplored. We conducted a hybrid workshop at the 2024 UK Preconception Early-Mid Career Researcher (EMCR) Network conference, attended by academics, health professionals and members of the public (N = 60). Small-group discussions on responsibility for preconception health improvement were audio-recorded and transcribed alongside notes from online whiteboards and paper-based flipcharts. Using framework analysis, we applied a deductive coding framework derived from the workshop questions. Attendees felt a disproportionate burden of responsibility for preconception health improvement was placed on women, reflecting deeply entrenched gendered norms within research, healthcare and broader societal structures. Attendees' recommendations centred around (i) society, community and culture, (ii) education and early awareness, (iii) considerations for future research, and (iv) systems-level and policy solutions. These findings provide valuable insights for developing equitable public health strategies and research agendas relating to preconception health. Being healthy before pregnancy and parenthood is important. It affects pregnancy outcomes and lifelong wellbeing. But there are mixed views on who should be responsible for improving health before pregnancy. We held a workshop with 60 people, including health workers, researchers, and members of the public. We asked who is responsible for health before pregnancy and how this shows up in different contexts. We also asked for suggestions for how to make sure this responsibility is shared evenly.Attendees felt that women carry most of the burden. This happens in health care, research, and everyday life. Men are often left out of conversations about health around pregnancy. Current approaches to improving health before pregnancy focus on women’s choices and actions such as diet and smoking rather than wider issues like poverty, education, and health care access.Attendees felt that health before pregnancy should be a shared responsibility between partners, health workers, government, and society. They suggested including men equally in health care, research, and campaigns around health before pregnancy. They also said that education about this should start early, in schools. They called for changes in communities to support health before pregnancy, so that people don’t need to do this alone.These suggestions can help create fairer approaches to improving health before pregnancy and parenthood that support everyone. They reflect that this requires support from the whole of society.
Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017 in response to the publication of the 2015 American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: (1) creation of a national multidisciplinary professional network and regular forum, (2) delivery of training and education, (3) establishment of a consensus approach to the fundamentals of variant interpretation in CSGs, (4) development and ratification of gene-specific frameworks for variant interpretation for CSGs, (5) development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community and (6) facilitation of UK contribution to international variant interpretation endeavours. A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. The utility of the CanVIG-UK consensus recommendations for variant interpretation in CSGs was highly rated, with 89/145 (61.4%) of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128 (96.9%) rating it as extremely/very useful. The usage frequency and perceived utility reported for the gene-specific guidance by survey respondents were similar. Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community.
Objective.Energetic optimality has long been used to explain vascular design, but many analyses treat hydraulic costs in isolation and neglect oxygen delivery. The objective of this study is to examine whether local cerebral bifurcation geometry can be interpreted through an energetic principle that explicitly accounts for oxygen delivery.Approach.We study an idealised, geometrically constrained arterial bifurcation using an objective that combines viscous dissipation, volume maintenance, and oxygen extraction via a simple wall mass-transfer description. The model is optimised over branching angle and child radius asymmetry under a generalised Murray-type relationship.Main results.The optimal angle shows a broad, shallow minimum around 30-45°, consistent with classical equal-radius benchmarks near 37.5° and indicating limited sensitivity to angle within this range. Across the parameter regime examined, oxygen extraction in the parent segment is near complete, so geometry primarily influences the energetic cost. Moderately asymmetric bifurcations can remain energetically efficient, whereas highly asymmetric configurations tend to push solutions toward boundary designs, reflecting increased viscous losses for very small child vessels.Significance. The results suggest that local bifurcation geometry can be interpreted through an energetic principle that explicitly accounts for oxygen delivery and may provide useful priors for larger network models incorporating transit-time-basedmetrics.
Network meta-analysis (NMA) is a common approach to synthesizing efficacy and safety data from randomized controlled trials (RCTs). Within the last 5 years, there has been an increase in the number of published NMAs in the clinical literature. One potential risk of this trend is the acceptance of NMA findings with translation into therapeutic decisions for daily clinical practice without first critically assessing the validity of the method's core assumptions, including trial exchangeability and homogeneity. We use the recent surge in NMAs of advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC) as a case study to illustrate the risks of overly permissive interpretation practices toward NMA methods and findings. We first highlight the potential violations of core NMA assumptions posed by known sources of heterogeneity across trials in CD and UC, and then outline several methodological strategies, ranging from data handling techniques to meta-regression, that can help to address or mitigate these violations. We put forward a checklist for users of NMAs to aid the interpretation of their results in the context of both methods and study inclusion/exclusion. While NMAs offer important insights into the relative treatment effects of different therapies and useful guidance to healthcare decision-makers, it is important that readers and users of NMA publications carefully review and critically evaluate the methods and results to ensure potential biases introduced by cross-trial heterogeneity are sufficiently mitigated and transparently documented, and that the results of any given NMA are interpreted within the context of the wider literature.
Therapeutic management of systemic sclerosis (SSc) has evolved considerably in recent years. However, contemporary treatment patterns and prescribing determinants remain poorly characterized. Data from the German Network for SSc (DNSS) cohort containing 6,583 patients were analyzed to describe trends in vasoactive, immunomodulatory, and antifibrotic therapy; assess variation between centers and specialties; delineate co-prescription patterns; and identify clinical predictors of treatment. Use of endothelin receptor antagonists and prostanoids / prostacyclin receptor agonists increased from 3.0% [95% confidence interval (CI): 1.5%-5.3%] in 2005 to 28.4% [25.5%-31.3%] in 2025, whereas prescription of calcium channel blockers and phosphodiesterase-5 inhibitors remained stable. Immunomodulatory therapy shifted away from cyclophosphamide towards mycophenolate mofetil, rituximab, and nintedanib, accompanied by a marked decline in glucocorticoid use (50.0% [31.9%-68.1%] in 2000 to 18.1% [11.8%-25.9%] in 2025). University or rheumatology centers prescribed immunomodulators and antifibrotics more frequently than non-university or dermatology centers. Co-prescription patterns showed common combination therapy with tocilizumab or rituximab and methotrexate. Nintedanib was commonly co-administered with mycophenolate, but also with cyclophosphamide or methotrexate. Rituximab was most commonly combined with mycophenolate and tocilizumab with methotrexate. Multivariable mixed models identified modified Rodnan skin score, interstitial lung disease, heart involvement, and care in a university, particularly rheumatology, center as major determinants of immunomodulatory and antifibrotic therapy. SSc treatment has evolved over the past 25 years, with prescribing patterns increasingly reflecting evidence and guideline recommendations. However, differences between specialties and care settings highlight the need for broader implementation of multidisciplinary, guideline-based care.
The International Children's Palliative Care Network (ICPCN) held its 4th international conference in Manila, Philippines (12th-15th November 2025), in partnership with The Ruth Foundation. The conference, 'Milestones & Horizons,' marked ICPCN's 20th anniversary and convened 419 delegates from 49 countries across all World Health Organisation regions to celebrate the progress of children's palliative care (CPC), while identifying priorities for equitable access for the 21 million children with life-threatening and life-limiting conditions. Hosted in the Philippines, it showcased local developments, including the National Children's Hospital Pediatric Palliative Care Unit and community models, catalysing CPC's formal recognition as a specialty by the Philippine Pediatric Society. The conference featured 155 accepted abstracts (63 oral, 26 rapid-fire and 46 posters), 10 keynotes, 5 plenary panels, 7 'Meet the Expert' sessions and 9 workshops on leadership, research, advocacy, spiritual care, touch therapy and equity. Sessions highlighted milestones in system building, service integration, interdisciplinary collaboration and family-informed research, alongside horizons in digital innovation, humanitarian reach and children's voices. Several sessions highlighted significant CPC 'Milestones', focusing on health system strengthening, service integration and diverse multidisciplinary research. Around the theme of 'Horizons', key conference sessions explored future directions such as digital innovation, care in humanitarian settings, interprofessional leadership and amplifying children's voices through co-design and creative therapies. Conference evaluations emphasised the high value of the in-person event with the opportunity for increasing personal motivation, peer support and new collaborations. The 2025 ICPCN conference demonstrated CPC's maturation through interdisciplinary collaboration while catalysing local progress in the Philippines. Critically, the conference demonstrated the irreplaceable value of in-person convening for relationship-building across diverse organisations, creating momentum toward shared goals of universal access and health system integration. Evaluations confirmed this collaborative energy as uniquely motivating, fostering cross-border partnerships and actionable commitments amid constrained resources, climate challenges and humanitarian needs.
Lecanemab approval in the European Union (EU) was granted after a delay. This delay resulted in concerns from many stakeholders, but attitudes of patients with early symptomatic Alzheimer's disease receiving specialist memory-clinic care remained insufficiently assessed. Therefore, we evaluated attitudes of specialist memory-clinic patients with early symptomatic Alzheimer's disease towards lecanemab in Europe. In this anonymous, international, multicentre, cross-sectional survey conducted from October 14, 2024 to February 18, 2025, a standardized, expert-developed questionnaire assessed attitudes towards lecanemab treatment and EU approval. Before answering four binary questions, participants received brief explanatory information on expected clinical benefit, amyloid-related imaging abnormalities (ARIA), and the increased ARIA risk associated with APOE ε4 homozygosity. The survey was conducted in specialist memory clinics within the European Alzheimer's Disease Consortium (EADC), the German memory clinic network (DNG), and Austrian memory centers. Available recruitment-flow data were limited to completed questionnaires because the survey was anonymous and distributed locally. 281 patients with early symptomatic Alzheimer's disease completed the survey. Network-level sample sizes were EADC n = 202, DNG n = 60, and Austria n = 19; country-specific sample sizes within the EADC and response rates were not available. Endorsement was high for both individual treatment with lecanemab (81.9%, 95% confidence interval [CI] 76.8-86.2) and general EU approval (91.8%, 95% CI 87.9-94.7). Endorsement remained substantial, but was lower, in the context of APOE ε4 homozygosity (treatment: 61.2%, 95% CI 55.2-66.9; approval: 76.5%, 95% CI 71.1-81.3). Approval-related questions received higher endorsement than treatment-related questions (84% vs. 72%; p < 0.001). Support for approval for APOE ε4 homozygotes declined after regulatory recommendations excluded this group (from 87% to 73%; p = 0.025); this comparison reflects independent respondents completing the anonymous survey before versus after November 14, 2024. Network-level comparisons were descriptive and underpowered for geographic inference. High endorsement within this specialist memory-clinic sample suggests perceived value of access to lecanemab. Greater endorsement for approval than for individual treatment may reflect support for treatment access beyond personal treatment choice, but alternative explanations such as social desirability, acquiescence, misunderstanding, or effects of the survey information cannot be excluded. The findings should not be generalized beyond specialist memory-clinic patients and should be interpreted in view of potential selection and response biases, absent response-rate data, and the brief, non-validated binary questionnaire.
Systemic mastocytosis (SM) is a spectrum of hematologic disorders characterized by accumulation of atypical mast cells (MCs) in extracutaneous organs. SM with an associated hematologic neoplasm (SM-AHN), the most frequent subtype of advanced SM, is predominantly associated with myeloid neoplasms, consistent with shared clonal architecture. Because of its rarity and heterogeneity, robust outcome data aligned with contemporary classifications are needed to inform risk stratification. We analyzed the 10th data wave of the European Competence Network on Mastocytosis registry (34 European centers and 1 US center). SM and AHN diagnoses followed the 2022 World Health Organization classification. Baseline characteristics and overall survival (OS) were compared between patients with myeloid SM-AHN and SM without AHN (SM-no-AHN). Within SM-AHN, outcomes were analyzed by SM component (advanced: aggressive SM [ASM] or MC leukemia [MCL] vs. non-advanced: bone marrow mastocytosis, indolent SM, or smoldering SM) and AHN subtype. Among 3,925 patients with SM, 467 (11.9%) had myeloid SM-AHN. Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) were the most frequent AHN category (41.1%), with chronic myelomonocytic leukemia as the most common subtype (29.6%). Compared with SM-no-AHN, SM-AHN patients were older, more often male, and less frequently had skin involvement. The SM component was advanced in 55.0% of SM-AHN versus 5.8% of SM-no-AHN (p < 0.001). OS was shorter in SM-AHN than SM-no-AHN (median 36.1 vs. 340.9 months; p < 0.001) and was reduced across SM subtypes, including ASM (31.0 vs. 81.1 months) and MCL (7.1 vs. 23.2 months). Within SM-AHN, advanced SM-AHN had shorter OS than non-advanced SM-AHN (28.3 vs. 70.9 months; p < 0.001). Median OS differed by AHN subtype (57.0 months in SM-MPN, 35.7 in SM-MDS, 34.2 in SM-MDS/MPN, and 14.7 in SM associated with acute myeloid leukemia; p < 0.001). In multivariable analysis, non-advanced SM (vs. advanced) remained independently associated with improved OS (hazard ratio = 0.44; p < 0.001). SM-AHN is associated with reduced survival compared with SM without AHN across SM subtypes. Outcomes in SM-AHN are driven primarily by the aggressiveness of the mastocytosis component, supporting recognition and classification of SM in patients with concomitant myeloid neoplasms, given approved KIT-targeted tyrosine kinase inhibitors for advanced SM.
Patients with metastatic hormone-sensitive prostate cancer (mHSPC) require long-term treatment to delay progression and improve survival, while minimizing adverse events or negative impact on symptoms (e.g. pain) and health-related quality of life (HRQoL). In ARASENS (NCT02799602), darolutamide plus androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (primary endpoint) versus placebo plus ADT and docetaxel. We report clinically relevant endpoints and HRQoL in ARASENS. Patients with mHSPC were randomized to darolutamide 600 mg orally twice daily or placebo, with ADT and docetaxel. Outcomes of interest were times to metastatic castration-resistant prostate cancer (mCRPC), pain progression, worsening of Brief Pain Inventory-Short Form pain interference/severity, and worsening of National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy Prostate Cancer Symptom Index 17-item questionnaire (NFPSI-17) scores. In 1305 patients analyzed (darolutamide 651, placebo 654), darolutamide significantly delayed time to mCRPC (hazard ratio 0.36 [95 % confidence interval 0.30-0.42]) and time to pain progression (0.79 [0.66-0.95]) versus placebo. Times to worsening of pain interference/severity and NFPSI-17 scores were similar between treatment groups. Incidences of treatment-emergent adverse events (TEAEs) commonly associated with androgen receptor pathway inhibition were generally low and similar between groups (median follow-up: > 3.5 years). Darolutamide plus ADT and docetaxel provided significant benefits in clinically relevant endpoints versus ADT and docetaxel, with similar control of pain, maintenance of HRQoL, and no cumulative TEAEs over long-term treatment. These data reinforce darolutamide triplet therapy as a standard-of-care treatment option in patients with mHSPC.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. However, ICIs are associated with potentially life-threatening immune-related adverse events (irAEs). Janus kinase inhibitors (JAKi) are a promising steroid-sparing agent for treating corticosteroid-refractory severe irAEs. However, little is known about their safety in the ICI population, limiting clinical adoption due to concerns of reduced anticancer immunity and ICI response. In this retrospective multi-institutional cohort study, we aim to evaluate the safety of JAKi in the management of refractory irAEs requiring escalation beyond the standard of care with systemic corticosteroid therapy. Patients who received both ICI and JAKi at Mass General Brigham Healthcare System and the Dana-Farber Cancer Institute between 2018 and 2025 were manually reviewed for irAE presence, severity, treatment response, and survival (n=33). A comparator cohort of patients with irAEs treated with systemic corticosteroids (n=99). JAKi-treated patients were matched 1:4 to controls using nearest-neighbor matching with a 0.4 caliper based on age, cancer type, number of organs affected by ICI toxicity, and ICI regimen, yielding a matched cohort of 27 cases and 83 controls. Associations between JAKi use, progression-free survival, and overall survival were evaluated with multivariable Cox regression with landmark analyses to account for immortal time bias. To address limited power for survival analyses, we performed an external validation using the TriNetX research network, generating a 1:1 matched multi-institutional cohort of 297 JAKi-treated and 297 non-JAKi-treated irAE patients. Kaplan-Meier analysis showed no statistically significant difference in overall survival (median 34 vs 45 months) or progression-free survival (median 5.6 vs 9.6 months) in JAKi-treated versus control groups. These findings remained consistent with multivariable Cox proportional hazard models. Across all landmark times, the association between JAKi use and survival outcomes remained similar between the two treatment groups. Similarly, in the larger TriNetX cohort, JAKi therapy was not associated with inferior overall survival compared with matched non-JAKi-treated patients. In these complementary multi-institutional cohorts, no large adverse signal was observed with JAKi versus standard-of-care systemic corticosteroid therapy for severe irAEs in this real-world cohort. These results merit further investigation in prospective studies.
Congenital melanocytic naevi (CMN) and arteriovenous malformations (AVM) are rare, severe and incurable birthmark conditions associated with lifelong visible difference and complex medical needs. Despite the importance of early health care experiences for parental and child adjustment in general, these remain unexplored in this context. This study aimed to explore parental experiences of raising a child with rare severe birthmarks, the role of specialist care in parental adjustment, and to develop recommendations for clinical care. Reflective thematic analysis (RTA) was used to analyse semi-structured narrative-style interviews conducted with 23 parents of children aged ≤12 years recruited sequentially from a specialized NHSE Rare Disease Collaborative Network (RDCN) outpatient clinic in London, UK. Interviews were conducted virtually via telephone or Zoom and analysed using RTA using NVivo software (version 13). Reflexivity was achieved through the keeping of a reflexive journal and debriefing with the research team. Through RTA, three themes were generated which highlight the challenges faced by parents of children with rare birthmarks. Firstly, parents' experiences before coming to the first appointment, secondly 'learning to belong' in the health care system and thirdly 'making room' for the condition. These themes and respective subthemes provide new insights into the importance of specialist centres in relation to parental adjustment to rare birthmarks. Findings underscore the pivotal role of specialist care in parental adjustment to rare, appearance-altering conditions. Practical care recommendations are presented to support families across care pathways.
Pleural mesothelioma (PM) is often presaged by benign asbestos-associated pleural inflammation (AAPI), offering a unique window of opportunity for translational research. The PREDICT-Meso International Accelerator Network is leveraging this natural history to perform target identification and develop novel therapies for early-stage or pre-invasive disease. This requires assembly of a unique bioresource of longitudinal human tissue samples spanning the terminal stages of PM evolution, development of preclinical models for drug screening and reliable tools for risk prediction in patients presenting with AAPI. Mesothelioma Observational study of Risk prediction and Generation of paired benign-meso tissue samples, Including a Nested MRI Substudy (Meso-ORIGINS) is a prospective, multicentre observational study, comprising two arms (A and B), with a nested MRI substudy in arm A. Arm A will recruit 300 AAPI patients and perform 6-monthly surveillance for 2 years. Suspicion of PM evolution will prompt repeat biopsy and banking, delivering a primary objective of ≥38 longitudinal AAPI-PM tissue pairs. This target reflects a projected PM evolution rate of 14% (95% CI 10.5 to 19.2) derived from a prior multicentre feasibility trial. Multiomic risk profiling will be performed in arm A, using blood proteomics, exhaled breath metabolomics and perfusion MRI. Arm B will recruit 300 patients with suspected PM, permitting collection of multiregion pleural biopsies in patients spanning AAPI and PM timepoints for evaluation of anatomical heterogeneity. Where possible, patients in arm B diagnosed with AAPI will be recruited to arm A for 2-year surveillance +/- repeat biopsy in subsequent PM evolution cases. Pleural fluid will be collected in arm B for cell-line generation and diagnostic biomarker evaluation. Exhaled breath will be collected in arm B for diagnostic biomarker evaluation. The study has ethical approval (REC Ref 21/WS/0120). Results will be disseminated via peer-reviewed journals and national/international scientific conferences. Tissues, data and derived omics will be shared via the PREDICT-Meso Research Tissue Bank (REC Ref 21/WS/0011). ISRCTN22929761.
Advances in ultrasensitive assay techniques have enabled precise quantification of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP), highlighting their potential as dynamic biomarkers for detecting neuroaxonal injury, disease activity and progression in multiple sclerosis (MS). In the NeuroFilMS study, sNfL is being investigated prospectively as a prognostic biomarker for clinical and radiological disease activity in relapsing MS, while sGFAP is retrospectively explored as a marker of disease progression. The aim is to assess whether longitudinal monitoring of sNfL can inform diagnostic and therapeutic decisions in the treatment of people with MS (pwMS) and whether retrospective sGFAP measurements provide additional insights into disease progression. The study additionally aims to evaluate the comparability of different assay methods. NeuroFilMS is a prospective, multicentre study that will be conducted across multiple MS study centres throughout Germany, in collaboration with the German Multiple Sclerosis Registry set up by the German National Multiple Sclerosis Society (Deutsche Multiple Sklerose Gesellschaft). The study aims to enrol 1500 pwMS diagnosed with relapsing MS. Participants will be randomised in a 2:1 ratio (n=1000 vs n=500) to either immediate sNfL reporting or delayed sNfL reporting to treating physicians, in order to evaluate how sNfL availability influences therapeutic decision-making in routine healthcare regarding diagnostics and therapy decisions. Over a 2-year follow-up period, pwMS will attend three study visits integrated into routine care, including blood sampling for sNfL, clinical evaluations and routine MRI assessments; sGFAP will be measured retrospectively in batches, as it is not currently available for routine diagnostic use. The study follows the standardised protocols for biosample collection, performed both within clinical routine laboratory procedures and through research collaboration. Statistical analyses will involve both descriptive and inferential methods to evaluate biomarker performance and clinical associations. The study has received ethical approval from the Clinical Ethics Committee of Charité-Universitätsmedizin Berlin (EA4/136/24) and will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Findings will be disseminated through peer-reviewed publications, conference presentations and engagement with patient organisations and clinical networks. DRKS00034337.
Lung cancer remains the most significant cause of cancer-related death worldwide due to the critical challenges in diagnosis. Despite the promising efforts, the existing models faced challenges in capturing the complex patterns in medical imaging data while minimizing the computational complexity. In this research, the lung cancer detection using Computed Tomography (CT) images is performed using the Reverse Task attention-enabled Distributed Elman convolutional neural Network (RTsDEN) model that helps in mitigating the challenges in existing methods and improving the detection performance for real-time applications. The proposed model, combining the Reverse Task attention-(RTsAt) module and the distributed Elman concept, significantly contributes to capturing the intricate disease patterns from the complex backgrounds and varying environmental conditions. In addition, the proposed method exploits the adaptive lobe and multigranular nodule segmentation stage to facilitate better understanding and interpretation for accurate diagnosis. Experimental results reveal that the proposed RTsDEN outperforms other existing models by attaining 97.12% accuracy, 98.03% precision 96.22% recall using LUNA 16 dataset and 97.72% accuracy, 98.31% precision, 97.14% recall using the LIDC-IDRI dataset. The research introduces an efficient DL model with an ensemble approach, which significantly influences effective lung cancer detection.