King's College Hospital NHS Foundation Trust

Background In African populations, estimated glomerular filtration rate by cystatin C (eGFRcys) is better aligned with gold-standard GFR measurements than eGFR by creatinine (eGFRcr). Moreover, eGFRcys is unaffected by the effects of antiretroviral therapy (ART) on tubular secretion and may thus provide better estimates of GFR in people with HIV on ART. Setting Observational cohort study of people of African ancestry living with suppressed HIV RNA on ART in London, United Kingdom. Methods Cross-sectional analysis of 360 paired serum creatinine and cystatin C measurements. Participants whose eGFRcys substantially (>10%) exceeded eGFRcr were identified, and factors associated with this outcome were identified in logistic regression analysis. Results The median age of participants was 52 years, 56% were women, and 82% born in Africa or the Caribbean. The eGFRcys substantially exceeded eGFRcr in 42% of participants in the overall cohort, and in 68% of those with eGFRcr 45–75 mL/min/1.73 m². In multivariable analysis, a higher eGFRcr was associated with lower odds (0.59 [0.50, 0.68] per 10 mL/min/1.73 m² increase) of eGFRcys substantially exceeding eGFRcr; a higher BMI was also associated with this outcome, while ART regimens inhibiting tubular secretion of creatinine were not predictive. Of the 22 participants with eGFRcr 45–60 mL/min/1.73 m², 16 (73%) had eGFRcys >60 mL/min/1.73 m². Conclusions We report substantially higher eGFRcys than eGFRcr in a subset of people of African ancestry with suppressed HIV, particularly among those with eGFRcr 45–75 mL/min/1.73 m². In this population, eGFRcys provides clinically useful information irrespective of ART regimen.

Histone mutations (H3 K27M, H3 G34R/V) are molecular features defining subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises in exceptional cases, these mutations co-occur. We report one such case of a 2-year-old female presenting with neurological symptoms; MRI imaging identified a brainstem lesion which was biopsied. Histology showed diffusely infiltrating pleomorphic astrocytes, multinucleated cells, and conspicuous mitotic activity; the diagnosis was DMG, H3 K27-altered (immunohistochemistry: H3K27me3 loss, H3K27M positivity). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package)) classified the tumour as ‘DMG, H3 K27-altered’ (calibrated score = 0.99). Further molecular studies (whole exome, whole genome sequencing) revealed concurrent H3.1 K27M and G34R mutations (clonal, in the same reads) of H3C3, FGF11 and PIK3CA somatic variants, and a pathogenic germline NBN variant. The RNAseq profile clustered with H3K27M-mutant tumours. A patient-derived cell culture was established enabling unbiased in vitro drug screening; no selective sensitivities were identified. Chromatin immunoprecipitation assays with sequencing (ChIP-seq; H3K27ac, H3K27me3, H3K36me3, RNApol2 marks) showed features in keeping with DMG H3 K27M-mutant tumours (H3K27ac loci including OLIG2, IRX1/2, PKDCC). The patient was treated with adjuvant radiotherapy, but progressed and passed away 13 months post-diagnosis. This case is an exceptionally rare, complex variant of histone-mutant paediatric HGG, illustrating that the H3.1 K27M mutation demonstrates a dominance over the molecular and clinical profiles compared to G34R, and highlights the importance of broad molecular profiling to identify such examples for further study. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-024-01899-5.

Background The cognitive and behavioural changes that occur in around 50% of people with amyotrophic lateral sclerosis (ALS) may significantly affect people around them, contributing to heightened burden, anxiety, and depression. Despite existing evidence linking behavioural impairment to caregiver distress, the role of cognitive impairment remains less clear, with mixed findings on its impact. Methods This study assessed the influence of cognitive and behavioural impairments in people with ALS on the distress of their nominated informants. The data were collected face-to-face and remotely due to the COVID-19 pandemic. The cognitive and behavioural impairments were measured using established screening tools. Informants’ distress was evaluated through composite measures of burden, anxiety, and depression. Regression analyses were employed to determine the predictive value of cognitive and behavioural impairment on informant distress. Results A total of 98 ALS patients and 84 informants participated. Behavioural impairment predicted informant distress across various tools. In contrast, cognitive impairment was a less consistent predictor of informant distress across screening measures and did not significantly interact with behavioural impairment in predicting distress. Administration mode did not affect predictive relationships. Conclusions Behavioural impairment in ALS significantly predicts informant distress, with varying predictive power across different screening tools. Cognitive impairment also affects informant distress, but its impact is less substantial compared to behavioural factors. The interaction between cognitive and behavioural impairments did not significantly predict informant distress.

Background Vestibular dysfunction causing imbalance affects c. 80% of acute hospitalized traumatic brain injury (TBI) cases. Poor balance recovery is linked to worse return-to-work rates and reduced longevity. We previously showed that white matter network disruption, particularly of right inferior longitudinal fasciculus, mediates the overlap between imbalance and impaired vestibular perception of self-motion (i.e., vestibular agnosia) in acute hospitalized TBI. However, there are no prior reports tracking the acute-longitudinal trajectory of objectively measured vestibular function for hospitalized TBI patients. We hypothesized that recovery of vestibular agnosia and imbalance is linked and mediated by overlapping brain networks. Methods We screened 918 acute major trauma in-patients, assessed 146, recruited 39 acutely, and retested 34 at 6 months. Inclusion criteria were 18–65-year-old adults hospitalized for TBI with laboratory-confirmed preserved peripheral vestibular function. Benign paroxysmal positional vertigo and migraine were treated prior to testing. Vestibular agnosia was quantified by participants’ ability to perceive whole-body yaw plane rotations via an automated rotating-chair algorithm. Subjective symptoms of imbalance (via questionnaires) and objective imbalance (via posturography) were also assessed. Results Acute vestibular agnosia predicted poor balance recovery at 6 months. Recovery of vestibular agnosia and linked imbalance was mediated by bihemispheric fronto-posterior cortical circuits. Recovery of subjective symptoms of imbalance and objective imbalance were not correlated. Conclusion Vestibular agnosia mediates balance recovery post-TBI. The link between subjective dizziness and brain injury recovery, although important, is unclear. Therapeutic trials of vestibular recovery post-TBI should target enhancing bi-hemispheric connectivity and linked objective clinical measures (e.g., posturography).

Fluctuation-related pain (FRP) affects more than one third of people with Parkinson’s disease (PwP, PD) and has a harmful effect on health-related quality of life (HRQoL), but often remains under-reported by patients and neglected by clinicians. The National Institute for Health and Care Excellence (NICE) recommends The Parkinson KinetiGraphTM (the PKGTM) for remote monitoring of motor symptoms. We investigated potential links between the PKGTM-obtained parameters and clinical rating scores for FRP in PwP in an exploratory, cross-sectional analysis of two prospective studies: “The Non-motor International Longitudinal, Real-Life Study in PD—NILS” and “An observational-based registry of baseline PKG™ in PD—PKGReg”. 63 PwP (41.3% female; age: 64.24±9.88 years; disease duration, DD: 6.83±5.63 years; Hoehn and Yahr Stage, H&Y: 2 (1–4); Levodopa Equivalent Daily Dose 535 (0–3230) mg) were included. PwP with FRP (n = 23) had longer DD (8.88 (1.29–19.05) vs. 3.16 (0.34–28.92), p = 0.001), higher severity of motor symptoms (H&Y 3 (1–4) vs. 2 (1–4), p = 0.015; SCOPA Motor total score 21.35±10.19 vs. 13.65±8.99, p = 0.003), more dyskinesia (SCOPA Motor Item 18 ≥1 60.9% vs. 7.5%, p<0.001), and worse HRQoL (PDQ-8 Total Score 10.74±5.98 vs. 6.78±5.13, p = 0.007) then PwP without FRP (n = 40). In the multivariate logistic regression, after the adjustment for DD, H&Y and SCOPA-Motor total score, the presence of FRP was significantly associated with the PKGTM-derived Fluctuation-dyskinesia score (Exp (B) = 1.305, 95% CI for Exp (B) 1.012–1.683, p = 0.040) and the Bradykinesia score (Exp (B) = 0.917, 95% CI for Exp (B) 0.842–0.999, p = 0.048). The PKGTM system may potentially advance the way we screen for, assess, and treat FRP in clinical practice.

Translational network neuroscience aims to integrate advanced neuroimaging and data analysis techniques into clinical practice to better understand and treat neurological disorders. Despite the promise of technologies such as functional MRI and diffusion MRI combined with network analysis tools, the field faces several challenges that hinder its swift clinical translation. We have identified 9 key roadblocks that impede this process: (1) Theoretical and basic science foundations; (2) Network construction, data interpretation, and validation; (3) MRI access, data variability, and protocol standardization; (4) Data sharing; (5) Computational resources and expertise; (6) Interdisciplinary collaboration; (7) Industry collaboration and commercialization; (8) Operational efficiency, integration and training; and (9) Ethical and legal considerations. To address these challenges, we propose several possible solution strategies. By aligning scientific goals with clinical realities and establishing a sound ethical framework, translational network neuroscience can achieve meaningful advances in personalized medicine and ultimately improve patient care. We advocate for an interdisciplinary commitment to overcoming translational hurdles in network neuroscience and integrating advanced technologies into routine clinical practice.

Introduction Pancreatic ductal adenocarcinoma (PDAC) of the body/tail is notably different than PDAC in the head of the pancreas. Surgery plus chemotherapy is known to improve outcomes for all PDAC. The sequence of this therapy is well studied in head cancers yet has never been evaluated systematically in relation to distal pancreatectomy (DP). Methods Patients receiving DP for PDAC and who received chemotherapy were included. Patients were compared receiving neoadjuvant systemic therapy (NAST) only, adjuvant (AST) only, both NAST + AST, and who received total neoadjuvant therapy (TNT), defined as > 24 weeks NAST before DP. PSM was performed 1:1 between AST and each other group creating quadruplets of patients for analysis. Matching factors were determined by multivariate cox‐regression analysis of factors independently affecting survival. Survival was considered from diagnosis and from surgery to account for potential biases. Results In total, 4677 patients were selected with 400 (8.6%) receiving TNT, 536 (11.5%) NAST, 3235 (69.2%) AST, and 506 (10.8%) NAST + AST. A total of 341 quadruplets were selected after PSM. There were no differences in comorbidities, T/N‐stage, retrieved or positive lymph nodes, and margin status after matching. Kaplan–Meier analysis showed no difference in median OS between the matched treatment groups (33.71 ± 2.07 vs. 35.22 ± 1.62 vs. 32.53 ± 3.31 vs. 37.88 ± 1.90, respectively; log‐rank p = 0.464). Five‐year OS was not different between the groups (21% vs. 18% vs. 20% vs. 25%, respectively; p = 0.501). Conclusion The sequence of chemotherapy and surgery did not impact survival in distal PDAC. Providers should tailor an individualized approach designed to maximize the chance of completing both treatments.

Context Improved continence outcomes are reliant on identification of unmet need, education delivery, and shared decision‐making. The evidence base on which to derive innovative approaches in these areas was unclear. Methods A debate held at the International Consultation on Incontinence‐Research Society meeting, held in Bristol in June 2024, considered ways to improve research requirements to advance these areas. Results and Conclusion Artificial intelligence solutions and digital approaches to healthcare are emerging at pace and offer possibilities to improve these three key areas but this must be driven by person‐centered approaches. Care must be taken to avoid increasing inequality through digital exclusion and language barriers. Research questions are highlighted to derive innovation in these three key areas.

Background Depression and anxiety are commonly experienced by people with chronic kidney disease (CKD). This study aimed to evaluate person- and service-level factors associated with depression and anxiety symptoms. We sought to also understand utilisation of mental health treatments and preferences for future psychological support. Methods An online survey recruited participants from six UK kidney services with varying levels of psychosocial provision. The survey was also advertised on social media. Participants completed screening questionnaires for depression and anxiety, alongside questions about mental health history, self-efficacy, treatment and support. The study included adults (18 years or older) living with CKD (stages 3b and above) or those receiving any form of Kidney Replacement Therapy (KRT), including individuals with a functioning kidney transplant. Eligible participants had to complete study measures and be proficient in reading and writing in either English or Welsh, as the survey was administered in these languages. This survey was developed with our Patient and Public Involvement group and was administered from January 2023 until 31st January, 2024 using Qualtrics and RedCap. Results Four hundred fifty-eight people completed the survey. Moderate-severe symptoms of depression and anxiety were 37.7% and 26.5%, respectively. Over 50% reported a history of diagnosed depression. In addition to depression, sleep problems and fatigue were identified as future support needs, with over a third indicating a preference for in-centre provision. In case-mix adjusted analysis, there was no variability in depression and anxiety symptoms across centres. Centre location and size were unrelated to symptoms. Age, female gender, current mental health treatments, self-efficacy and perceptions regarding opportunity for support, were associated with symptoms of depression and anxiety. In sub-analysis, there was a negative association between psychosocial staffing levels and depression symptoms. Conclusion Patient-related factors and behavioural characteristics were related to variation of these symptoms. There was little evidence of symptom variability across centres, although in a small sub-analysis, psychosocial provision showed a weak negative correlation with depression symptoms. Our findings highlight preferences of future needs which could be helpful for designing future research and service provision. Graphical abstract

Background Lymphatic leaks are associated with significant mortality and morbidity. Intranodal lymphangiography (ILAG) involves the direct injection of ethiodised lipid into the hilum of lymph nodes. It is diagnostic procedure that can have therapeutic effects secondary to a local sclerosant effect. The aim of the study is to describe the technical and clinical success of ILAG and adjunctive lymphatic interventions performed as first line interventional techniques for lymphatic leaks refractory to conservative and medical management in a multicentre cohort of patients with symptomatic large volume lymphatic leaks. Methods Multicentre retrospective study of all lymphatic interventions performed between 2017–2023 in patients with large volume lymphatic leaks (> 500 ml a day). Intranodal lymphangiography was performed initially with technical success defined as opacification of the lymphatics at the aortic bifurcation and demonstration of lymphatic leak on the index ILAG procedure or immediate post procedural CT was recorded. Lymphatic embolisation was performed with a combination of direct puncture or transvenous cannulation with glue and or coil embolisation of the thoracic duct or leak point and in cases with refractory leak. Clinical success was defined as reduction in drain output to less than 20 mL per 24 h, or no further insensible lymph leak. Time to clinical success after ILAG and adjunctive embolisation was recorded. Results ILAG alone lead to clinical success in 14 of 32 (44%) patients after a median of 14 days. Subsequent embolisation was performed in 12 refractory cases; this was successful in 8 (67%) at median of 8 days. Overall clinical success of all lymphatic interventions was 69% (22 of 32 patients) at a median of 11 days (IQR 5–34). No statistically significant correlation between the site of leakage, aetiology or embolisation technique correlated with clinical success. Decision to proceed to repeat ILAG or an adjunct procedure was made on a clinical basis, following multidisciplinary discussion. Conclusions ILAG can be employed a first line interventional therapeutic technique to treat clinically significant lymphatic leaks that are refractory to conservative and medical management. Adjunctive procedures, including embolisation, can be considered as part of clinical decision making after a period of 1–2 weeks’ watchful waiting in continuingly refractory cases.

Background and objectives: The Chordate System administers kinetic oscillation stimulation (K.O.S) into the nasal cavity thereby potentially modulating the activity of trigemino-autonomic reflex. Modulation of this reflex has been proposed as a potential therapeutic target in migraine. The aim of this clinical trial was to evaluate the efficacy of K.O.S for the preventive treatment of chronic migraine (CM). Methods: In this randomized, double-blind, sham-controlled, multicenter clinical trial, patients with CM were treated with K.O.S once per week over a period of 6 weeks. The primary performance endpoint was the mean change in monthly headache days with moderate to severe intensity (MHDs) from the 28-day pretreatment baseline period to the performance assessment period (days 14-42 of treatment). Mean change from baseline in monthly migraine days (MMDs), proportion of participants with 30% and 50% or greater reduction in moderate to severe headache days compared with baseline, and change in the use of abortive medications from baseline were also assessed during the performance assessment period. Headache-related disability and quality-of-life measures were evaluated up to 70-day posttreatment. Results: The primary endpoint showed a significantly larger reduction of MHD across the performance assessment period with active treatment (-3.5 days, n = 67) compared with sham (-1.2 days, n = 65) (p = 0.0132). Compared with sham, active treatment consistently also led to significant reduction of MHD during the follow-up period (-2.7 [-4.3; -1.0, p = 0.0014]) as well as of mean MMDs during the assessment (-2.4 [-4.1; -0.7, p = 0.0048]) and follow-up (-2.9 [-4.5; -1.2, p = 0.0008]) periods. 61.8% of participants reported treatment-emergent adverse events (TEAEs) with similar incidences among treatment groups (63.2% [active], 60.3% [sham]), with nasopharyngitis (8.3%), dizziness (6.3%), and epistaxis (6.3%) being the most common TEAEs. Treatment-related serious adverse events were not observed. Discussion: The Chordate System provides significant benefits to patients with CM by reducing the number of MHDs. The nonpharmacologic nature of the treatment option positions K.O.S as a valuable addition to the current therapeutic portfolio for the management of CM. Trial registration information: The trial was registered on ClinicalTrials.gov (NCT03400059) on January 17, 2018. The first patient was enrolled on March 22, 2018, and the last patient completed the study on October 1, 2022. The trial registration initially described the timing of the secondary endpoints incorrectly due to clerical error, and this was corrected to match the protocol and analysis plan once discovered. Classification of evidence: This study provides Class I evidence that weekly intranasal K.O.S is associated with a reduced number of headache days per month in patients with CM.

Objectives This study aims to explore patients' and clinicians' understanding and experiences of refractory disease (RD) and persistent physical and emotional symptoms (PPES) in patients with inflammatory arthritis (IA), namely rheumatoid arthritis or polyarticular juvenile idiopathic arthritis from their perspectives through interviews and/or focus groups. Design A qualitative study was conducted, following a pragmatic epistemology approach with framework analysis employed. Methods Semi‐structured interviews or focus groups with IA patients ( n = 25) and multi‐disciplinary rheumatology HCPs ( n = 32) were conducted at one time point to obtain participants respective understanding and experiences of managing RD/PPES, and its impact on the patient‐professional relationship. Results Three key themes were identified from both patients and professionals' experiences of RD/PPES: (1) relevant treatment experiences, (2) symptoms (with or without inflammation) and (3) impact: physical, psychological and social. These themes included 28 specific categories that would be considered as components characterizing RD/PPES, most common to both patients and HCPs with six being patient‐specific and only one HCP‐specific. The specific biopsychosocial symptoms and impacts of RD/PPES pertain to pain, fatigue, stiffness, joint involvement and physical, psychological and social functioning and quality of life, covering disease‐related distress, mobility and independence. Wider influential factors such as comorbidities, non‐adherence, health/medication beliefs and behaviours and social support were also identified. Conclusion Common persistent symptoms that have both mental and physical impact characterize RD/PPES in IA and therefore a more integrated holistic approach to treatment is needed from multi‐disciplinary HCPs, including health psychologists.

Research on biomarkers in BA promises to predict and change outcomes in BA. This goal is still unrealized at the moment. The study by Kamp et al attempts to understand the drivers of fibrosis and elucidate the role of amyloid-related genes in the pathophysiology of BA. Based on this, they attempt to predict outcomes in BA using biomarkers by analysing plasma samples for amyloid precursor protein. There is a need to evaluate if shifting the focus from pre-KPE biomarkers to post-KPE biomarkers, serial evaluations and the use of composite scores could help in better prognostication.