Citations

Abstract Despite the growing evidence supporting the existence of CNS involvement in acute and chronic graft-versus-host disease (CNS-GvHD), the characteristics and course of the disease are still largely unknown. In this multicentre retrospective study, we analysed the clinical, biological, radiological and histopathological characteristics, as well as the clinical course of 66 patients diagnosed with possible CNS-GvHD (pCNS-GvHD), selected by predetermined diagnostic criteria. Results were then contrasted depending on whether pCNS-GvHD onset occurred before or after Day 100 following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The median time between allo-HSCT and pCNS-GvHD onset was 149 days (interquartile range25–75 48–321), and pCNS-GvHD onset occurred before Day 100 following transplantation in 44% of patients. The most frequent findings at presentation were cognitive impairment (41%), paresis (21%), altered consciousness (20%), sensory impairment (18%) and headache (15%). Clinical presentation did not significantly differ between patients with pCNS-GvHD occurring before or after Day 100 following transplantation. Brain MRI found abnormalities compatible with the clinical picture in 57% of patients, while CT detected abnormalities in only 7%. Seven patients had documented spinal cord MRI abnormalities, all of them with pCNS-GvHD occurring after Day 100 following transplantation. In the CSF, the white blood cell count was increased in 56% of the population (median 18 cells/μl). Histopathological analyses were performed on 12 specimens and were suggestive of pCNS-GvHD in 10. All compatible specimens showed parenchymal and perivascular infiltration by CD3+ and CD163+ cells. Immunosuppressive therapy was prescribed in 97% of patients, achieving complete clinical response in 27%, partial improvement in 47% and stable disease in 6%. Response to immunosuppressive therapy did not differ significantly between patients with pCNS-GvHD occurring before or after Day 100 following transplantation. Clinical relapse was observed in 31% of patients who initially responded to treatment. One-year overall survival following pCNS-GvHD onset was 41%. Onset before Day 100 following haematopoietic stem cell transplantation [hazard ratio with 95% confidence interval: 2.1 (1.0–4.5); P = 0.041] and altered consciousness at initial presentation [3.0 (1.3–6.7); P = 0.0077] were associated with a reduced 1-year overall survival probability. Among surviving patients, 61% had neurological sequelae. This study supports that immune-mediated CNS manifestations may occur following allo-HSCT. These can be associated with both acute and chronic GvHD and carry a grim prognosis. The clinical presentation as well as the radiological and biological findings appear variable.

Abstract Lead (Pb) poisoning is a significant threat to Aotearoa New Zealand's endangered kea ( Nestor notabilis ), an avian species important to Māori. Historically, exposure was thought to be from lead‐containing building materials; however, recent field observations suggest lead‐based ammunition as an additional source. We used stable lead isotopes to investigate the sources of lead to kea. Comparing 207 Pb/ 206 Pb ratios in kea blood ( n = 91) to both ammunition and building materials, we found approximately one‐third of exposed kea (blood lead > 10 µg/dL) had lead isotope ratios consistent with exposure to lead‐based ammunition. As lead ammunition is still used, including in government‐sponsored culling programs, our data indicate an urgent need to shift toward non‐lead ammunition use to prevent further poisoning and aid conservation efforts. Collaborating with tangata whenua /Māori guardians, we advocate for immediate policy changes to eliminate lead‐based ammunition in kea habitat to safeguard this endangered culturally treasured species from extinction.

Abstract There are limited treatment options for individuals with drug‐resistant idiopathic generalized epilepsy (IGE). Small, limited case series suggest that centromedian thalamus deep brain stimulation (CM‐DBS) may be an effective treatment option. The optimal CM‐DBS target for IGE is underexamined. Here, we present a retrospective analysis of CM‐DBS targeting and efficacy for five patients with drug‐resistant IGE. Volume of tissue activated (VTA) overlap with CM nucleus was performed using an open‐source toolbox. Median follow‐up time was 13 months. Median convulsive seizure frequency reduction was 66%. One patient had only absence seizures, with >99% reduction in absence seizure frequency. Four patients had electrode contacts positioned within the CM nucleus target, all of whom had >50% reduction in primary semiology seizure, with 85% median seizure reduction ( p = .004, paired‐sample t test). Volumetric “sweet‐spot” mapping revealed that best outcomes were correlated with stimulation of the middle ventral CM nucleus. Connectivity strength between the sweet‐spot region and central peri‐Rolandic cortex was increased significantly relative to other cortical regions ( p = 8.6 × 10 −4 , Mann–Whitney U test). Our findings indicate that CM‐DBS can be an effective treatment for patients with IGE, highlight the importance of accurate targeting and targeting analysis, and within the context of prior work, suggest that ideal CM‐DBS targets may be syndrome specific.

Background The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. Objective To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department. Design Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone. Setting United Kingdom Major Trauma Centres. Participants Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta. Interventions Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta. Main outcome measures Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon. Data sources Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data). Results Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%). Limitations The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates. Conclusions This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful. Future work The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.

AbstractObjectivesTo report lessons from integrating the methods and perspectives of clinical informatics (CI) and implementation science (IS) in the context of Improving the Management of symPtoms during and following Cancer Treatment (IMPACT) Consortium pragmatic trials.Materials and MethodsIMPACT informaticists, trialists, and implementation scientists met to identify challenges and solutions by examining robust case examples from 3 Research Centers that are deploying systematic symptom assessment and management interventions via electronic health records (EHRs). Investigators discussed data collection and CI challenges, implementation strategies, and lessons learned.ResultsCI implementation strategies and EHRs systems were utilized to collect and act upon symptoms and impairments in functioning via electronic patient-reported outcomes (ePRO) captured in ambulatory oncology settings. Limited EHR functionality and data collection capabilities constrained the ability to address IS questions. Collecting ePRO data required significant planning and organizational champions adept at navigating ambiguity.DiscussionBringing together CI and IS perspectives offers critical opportunities for monitoring and managing cancer symptoms via ePROs. Discussions between CI and IS researchers identified and addressed gaps between applied informatics implementation and theory-based IS trial and evaluation methods. The use of common terminology may foster shared mental models between CI and IS communities to enhance EHR design to more effectively facilitate ePRO implementation and clinical responses.ConclusionImplementation of ePROs in ambulatory oncology clinics benefits from common understanding of the concepts, lexicon, and incentives between CI implementers and IS researchers to facilitate and measure the results of implementation efforts.

ImportanceExposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role.ObjectiveTo investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration.Design, Setting, and ParticipantsThis cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses.ExposurePrior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts).Main Outcomes and MeasuresIndividual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume.ResultsAnalyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10−8 [95% CI, 0.50 × 10−8 to 4.93 × 10−8]; P = .03) and CHII-G (β = 2.24 × 10−6 [95% CI, 0.35 × 10−6 to 4.13 × 10−6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = −0.74 [95% CI, −1.35 to −0.13]; P = .04).Conclusions and RelevanceThese findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.

Objective We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

Objective We provide evidence‐based recommendations regarding the treatment of interstitial lung disease (ILD) in adults with systemic autoimmune rheumatic diseases (SARDs). Methods We developed clinically relevant population, intervention, comparator, and outcomes questions. A systematic literature review was then performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A panel of clinicians and patients reached consensus on the direction and strength of the recommendations. Results Thirty‐five recommendations were generated (including two strong recommendations) for first‐line SARD‐ILD treatment, treatment of SARD‐ILD progression despite first‐line ILD therapy, and treatment of rapidly progressive ILD. The strong recommendations were against using glucocorticoids in systemic sclerosis–ILD as a first‐line ILD therapy and after ILD progression. Otherwise, glucocorticoids are conditionally recommended for first‐line ILD treatment in all other SARDs. Conclusion This clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the treatment of ILD in people with SARDs.

ObjectiveWe provide evidence‐based recommendations regarding screening for interstitial lung disease (ILD) and the monitoring for ILD progression in people with systemic autoimmune rheumatic diseases (SARDs), specifically rheumatoid arthritis, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue disease, and Sjögren disease.MethodsWe developed clinically relevant population, intervention, comparator, and outcomes questions related to screening and monitoring for ILD in patients with SARDs. A systematic literature review was performed, and the available evidence was rated using the Grading of Recommendations, Assessment, Development, and Evaluation methodology. A Voting Panel of interdisciplinary clinician experts and patients achieved consensus on the direction and strength of each recommendation.ResultsFifteen recommendations were developed. For screening people with these SARDs at risk for ILD, we conditionally recommend pulmonary function tests (PFTs) and high‐resolution computed tomography of the chest (HRCT chest); conditionally recommend against screening with 6‐minute walk test distance (6MWD), chest radiography, ambulatory desaturation testing, or bronchoscopy; and strongly recommend against screening with surgical lung biopsy. We conditionally recommend monitoring ILD with PFTs, HRCT chest, and ambulatory desaturation testing and conditionally recommend against monitoring with 6MWD, chest radiography, or bronchoscopy. We provide guidance on ILD risk factors and suggestions on frequency of testing to evaluate for the development of ILD in people with SARDs.ConclusionThis clinical practice guideline presents the first recommendations endorsed by the American College of Rheumatology and American College of Chest Physicians for the screening and monitoring of ILD in people with SARDs.