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Traumatic brain injury (TBI) is a biomechanical problem where the initiating event is dynamic loading (blunt, inertial, blast) to the head. To understand the relationship between the mechanical parameters of the injury and the deformation patterns in the brain, we have previously developed a surrogate head (SH) model capable of measuring spatial and temporal deformation in a surrogate brain under blunt impact. The objective of this work was to examine how material properties and anatomical features affect the motion of the brain and the development of injurious deformations. The SH head model was modified to study six variables independently under blunt impact: surrogate brain stiffness, surrogate skull stiffness, inclusion of cerebrospinal fluid (CSF), head/skull size, inclusion of vasculature, and neck stiffness. Each experimental SH was either crown or frontally impacted at 1.3 m/s (3 mph) using a drop tower system. Surrogate brain material, the Hybrid III neck stiffness, and skull stiffness were measured and compared to published properties. Results show that the most significant variables affecting changes in brain deformation are skull stiffness, inclusion of CSF and surrogate brain stiffness. Interestingly, neck stiffness and SH size significantly affected the strain rate only suggesting these parameters are less important in blunt trauma. While the inclusion of vasculature locally created strain concentrations at the interface of the artery and brain, overall deformation was reduced.

Background: Understanding the risk of cancer after the diagnosis of another condition can present opportunities for earlier diagnosis. We examined the risk of cancer diagnosis conditional on prior diagnosis of atrial fibrillation (AF)., Methods: Linked electronic health records were used to identify patients aged ≥18 with new-onset AF and age-sex-matched controls. Cumulative incidence of and mortality from cancer (overall and cancer-site specific) within three months, three months to five years and beyond five years from diagnosis of AF were examined. Findings were further validated using Mendelian randomisation (MR)., Results: The cohort included 117,173 patients with new-onset AF and 117,173 matched controls (median age 78). In the first three months, 2.2% of AF patients were diagnosed with cancer vs. 0.47% in controls (relative risk: 4.7 [95%CI 4.2-5.4] in men and 4.4 [95%CI 3.8-5.0] in women). Nearly 80% of cancers related to thoracic or abdominal organs. Differences in cumulative incidence were only evident in women between three months and five years (subdistribution hazard ratio=1.1 [95%CI 1.01-1.12]) and absent in all patients beyond five years. MR analysis did not support the presence of a causal association between AF and major cancer subtypes., Conclusion: There is a large short-term increase in cancer incidence and mortality following new-onset AF. The findings may reflect incidental identification of AF or paraneoplastic manifestation. New-onset AF confers high short-term risk of cancer diagnosis, at levels comparable with symptomatic risk threshold mandating urgent assessment for suspected cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally. GYHL is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871., (Copyright © 2024. Published by Elsevier Inc.)

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Accurate cancer risk assessment approaches could increase rates of early CRC diagnosis, improve health outcomes for patients and reduce pressure on diagnostic services. The faecal immunochemical test (FIT) for blood in stool is widely used in primary care to identify symptomatic patients with likely CRC. However, there is a 6-16% noncompliance rate with FIT in clinic and ~90% of patients over the symptomatic 10 µg/g test threshold do not have CRC. A polygenic risk score (PRS) quantifies an individual's genetic risk of a condition based on many common variants. Existing PRS for CRC have so far been used to stratify asymptomatic populations. We conducted a retrospective cohort study of 50,387 UK Biobank participants with a CRC symptom in their primary care record at age 40+. A PRS based on 201 variants, 5 genetic principal components and 22 other risk factors and markers for CRC were assessed for association with CRC diagnosis within 2 years of first symptom presentation using logistic regression. Associated variables were included in an integrated risk model and trained in 80% of the cohort to predict CRC diagnosis within 2 years. An integrated risk model combining PRS, age, sex, and patient-reported symptoms was predictive of CRC development in a testing cohort (receiver operating characteristic area under the curve, ROCAUC: 0.76, 95% confidence interval: 0.71-0.81). This model has the potential to improve early diagnosis of CRC, particularly in cases of patient noncompliance with FIT., Competing Interests: Competing interests The authors declare no competing interests. Ethical approval Data from the UK Biobank Resource were accessed under Application Number 74981. UK Biobank was approved as tissue bank resource by North West Multi-centre Research Ethics Committee. All UK Biobank participants gave written informed consent for use of their data for health research. Participants who withdrew consent during this study were excluded from analysis., (© 2024. The Author(s).)

Objective: To identify the prevalence and clinical features of leflunomide-associated peripheral neuropathy in patients with rheumatic disease over a 42-month observational period between January 1, 2016 and June 30, 2019., Methods: A retrospective observational study was conducted using regional prescription data identifying all patients treated with leflunomide for rheumatic diseases in the Southern District Health Board of New Zealand. Medical records were used to identify patients who developed peripheral neuropathy while receiving treatment with leflunomide. Demographic characteristics, co-therapies, and additional risk factors for peripheral neuropathy were also recorded., Results: A total of 482 patients were identified as receiving leflunomide for the treatment of rheumatic during the study period. In total, 23 patients developed leflunomide-induced peripheral neuropathy within the cohort giving a prevalence of 4.7%. Nerve conduction studies (NCS) performed in 18 (78.2%) of these patients confirmed a distal axonal, sensory, or sensorimotor peripheral neuropathy. The majority of patients (n = 22; 95.6%) either improved, stabilized, or resolved on cessation of the drug, with or without medication washout. Adverse symptoms were reported in association with peripheral neuropathy in 15 of the 23 patients (65.2%): these included pain, poor sleep, compromised skin integrity, poor balance, and a Charcot-like arthropathy. Additional treatment was required to manage symptoms of peripheral neuropathy including nine patients (39%) who received pain relief., Conclusions: This study supports the previously reported association between leflunomide treatment and the development of a peripheral neuropathy. However, our findings suggest that this is more common than the previous estimates. In patients with psoriatic arthritis and previous tarsitis, there appeared to be an association with a Charcot's-like arthropathy, a complication not previously noted in the literature., (© 2024 The Author(s). International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Rationale Findings from individual trials of physical rehabilitation interventions in critically ill adults have limited potential for meta-analysis and informing clinical decision-making due to heterogeneity in selection and reporting of outcomes used for evaluation. Objective The objective of this study was to determine a core outcome set (COS) for use in all future trials evaluating physical rehabilitation interventions delivered across the critical illness continuum of recovery. Methods An international, two-round, online, modified Delphi consensus process, following recommended standards, was conducted. Participants (N=329) comprised three stakeholder groups (Researchers, n=58 (18%); Clinicians, n=247 (75%); Patients and Caregivers, n=24 (7%)), and represented 26 countries and 9 healthcare professions. Participants rated the importance of a range of relevant outcomes. Outcomes included in the COS were those prioritised of "critical importance" by all three stakeholder groups. Results Survey response rates were 88% (Round 1) and 91% (Round 2). From a total of 32 initial outcomes, the following outcomes reached consensus for inclusion in the COS: Physical Function, Activities of Daily Living, Survival, Health-related Quality of Life, Exercise Capacity, Cognitive Function, Emotional and Mental Wellbeing, and Frailty. Conclusion This study developed a consensus-generated COS for future clinical research evaluating physical rehabilitation interventions in critically ill adults across the continuum of recovery. Ascertaining recommended measurement instruments for these core outcomes is now required to facilitate implementation of the COS. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Objectives: To investigate the role of comorbid chronic obstructive pulmonary disease (COPD) and symptom type on general practitioners' (GP's) symptom attribution and clinical decision-making in relation to lung cancer diagnosis., Design: Vignette survey with a 2×2 mixed factorial design., Setting: A nationwide online survey exploring clinical decision-making in primary care., Participants: 109 GPs based in the United Kingdom (UK) who were registered as responders on Dynata (an online survey platform)., Interventions: GPs were presented with four vignettes which described a patient aged 75 with a smoking history presenting with worsening symptoms (either general or respiratory) and with or without a pre-existing diagnosis of COPD., Primary and Secondary Outcome Measures: GPs indicated the three most likely diagnoses (free-text) and selected four management approaches (20 pre-coded options). Attribution of symptoms to lung cancer and referral for urgent chest X-ray were primary outcomes. Alternative diagnoses and management approaches were explored as secondary outcomes. Multivariable mixed-effects logistic regression was used, including random intercepts for individual GPs., Results: 422 vignettes were completed. There was no evidence for COPD status as a predictor of lung cancer attribution (OR=1.1, 95% CI=0.5-2.4, p=0.914). There was no evidence for COPD status as a predictor of urgent chest X-ray referral (OR=0.6, 95% CI=0.3-1.2, p=0.12) or as a predictor when in combination with symptom type (OR=0.9, 95% CI=0.5-1.8, p=0.767)., Conclusions: Lung cancer was identified as a possible diagnosis for persistent respiratory by only one out of five GPs, irrespective of the patients' COPD status. Increasing awareness among GPs of the link between COPD and lung cancer may increase the propensity for performing chest X-rays and referral for diagnostic testing for symptomatic patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background Presenting to primary care with fatigue is associated with a wide range of conditions, including cancer, although their relative likelihood is unknown. Aim To quantify associations between new-onset fatigue presentation and subsequent diagnosis of various diseases, including cancer. Design and setting Cohort study of patients presenting in English primary care with new-onset fatigue during 2007-2017 (fatigue presenters (FPs)), compared to non-fatigue presenters (NFPs), using Clinical Practice Research Datalink data linked to hospital episodes and national cancer registration data. Method We described excess short-term incidence of 237 diseases in FPs compared to NFPs. We modelled disease-specific 12-month risk by sex and calculated age-adjusted risk. Results We included 304,914 FPs and 423,671 NFPs. 127 of 237 diseases studied were more common in male FPs than in male NFPs, and 151 were more common in female FPs. Diseases that were most strongly associated with fatigue included: depression; insomnia & sleep disturbances, and hypo/hyperthyroidism (women only). By 80 years, cancer was the 3rd most common disease and had the 4th highest absolute excess risk in male FPs (FPs: 7.0%, CI = 6.6 to 7.5; NFPs: 3.4%, CI = 3.1 to 3.7; AER: 3.7%). In women, cancer remained relatively infrequent; by age 80 it had the 13th highest excess risk in FPs. Conclusion Our study ranks the likelihood of possible diagnoses in fatigue presenters, to inform diagnostic guidelines and doctors' decisions. Age-specific findings support recommendations to prioritise cancer investigation in older men with fatigue, but not women., (Copyright © 2024, The Authors.)

Background: Identifying patients presenting with nonspecific abdominal symptoms who have underlying cancer is a challenge. Common blood tests are widely used to investigate these symptoms in primary care, but their predictive value for detecting cancer in this context is unknown. We quantify the predictive value of 19 abnormal blood test results for detecting underlying cancer in patients presenting with 2 nonspecific abdominal symptoms., Methods and Findings: Using data from the UK Clinical Practice Research Datalink (CPRD) linked to the National Cancer Registry, Hospital Episode Statistics and Index of Multiple Deprivation, we conducted a population-based cohort study of patients aged ≥30 presenting to English general practice with abdominal pain or bloating between January 2007 and October 2016. Positive and negative predictive values (PPV and NPV), sensitivity, and specificity for cancer diagnosis (overall and by cancer site) were calculated for 19 abnormal blood test results co-occurring in primary care within 3 months of abdominal pain or bloating presentations. A total of 9,427/425,549 (2.2%) patients with abdominal pain and 1,148/52,321 (2.2%) with abdominal bloating were diagnosed with cancer within 12 months post-presentation. For both symptoms, in both males and females aged ≥60, the PPV for cancer exceeded the 3% risk threshold used by the UK National Institute for Health and Care Excellence for recommending urgent specialist cancer referral. Concurrent blood tests were performed in two thirds of all patients (64% with abdominal pain and 70% with bloating). In patients aged 30 to 59, several blood abnormalities updated a patient's cancer risk to above the 3% threshold: For example, in females aged 50 to 59 with abdominal bloating, pre-blood test cancer risk of 1.6% increased to: 10% with raised ferritin, 9% with low albumin, 8% with raised platelets, 6% with raised inflammatory markers, and 4% with anaemia. Compared to risk assessment solely based on presenting symptom, age and sex, for every 1,000 patients with abdominal bloating, assessment incorporating information from blood test results would result in 63 additional urgent suspected cancer referrals and would identify 3 extra cancer patients through this route (a 16% relative increase in cancer diagnosis yield). Study limitations include reliance on completeness of coding of symptoms in primary care records and possible variation in PPVs if extrapolated to healthcare settings with higher or lower rates of blood test use., Conclusions: In patients consulting with nonspecific abdominal symptoms, the assessment of cancer risk based on symptoms, age and sex alone can be substantially enhanced by considering additional information from common blood test results. Male and female patients aged ≥60 presenting to primary care with abdominal pain or bloating warrant consideration for urgent cancer referral or investigation. Further cancer assessment should also be considered in patients aged 30 to 59 with concurrent blood test abnormalities. This approach can detect additional patients with underlying cancer through expedited referral routes and can guide decisions on specialist referrals and investigation strategies for different cancer sites., Competing Interests: We declare no support from any organisation for the submitted work. BDN receives institutional research funding from GRAIL Inc unrelated to this study, MB receives personal fees from GRAIL Inc for Independent Data Monitoring Committee (IDMC) membership unrelated to this study and BW received personal funding from the British Liver Trust in 2023 for an unrelated data consultancy project, otherwise there are no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work., (Copyright: © 2024 Rafiq et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research., Methods: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement., Results: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration., Conclusions: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory., Competing Interests: Z. Wang is supported by a doctoral research grant from the Research Foundation—Flanders (FWO), Belgium (grant number: 1SF2922N). M. Barclay received consultancy fees from Douglas Pharmaceuticals and Janssen unrelated to submitted work. T. Mizuno served as a consultant of NDA Partners and received speaker honoraria from Astellas Pharma Inc. and Chugai Pharmaceutical Co. R. J. Keizer is an employee and stockholder of InsightRX, a company developing precision dosing software. S. G. Wicha received research grants from Boehringer Ingelheim and AqVida, consulting fees from Merck KGaA and Medicines from Malaria Venture, and speaker honoraria from GlaxoSmithKline. J. Lambert received unrestricted grants from AbbVie, Almirall, Celgene, Eli Lilly, Janssen-Cilag, LEO Pharma, Novartis, and UCB, served as a speaker for AbbVie, Almirall, Bristol-Myers Squibb, Janssen-Cilag, Pfizer, and UCB, and served as a consultant for AbbVie, argenx, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, LEO Pharma, Novartis, and UCB, with all fees and grants being paid to Ghent University (Hospital) scientific accounts and not to any personal account of Jo Lambert. S. Vermeire received grants from AbbVie, J&J, Pfizer, Galapagos, and Takeda, received consulting and/or speaker fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, and Zealand Pharma. K. Papamichael received lecture/speaker fees from Physicians Education Resource LLC and Grifols, scientific advisory board fees from ProciseDx Inc. and Scipher Medicine Corporation, and serves as a consultant from Prometheus Laboratories Inc. E. Dreesen received consultancy fees from Alimentiv, argenx, and Prometheus, lecture fees from Galapagos, and financial support from Janssen and Sandoz, outside the submitted work, with all honoraria/fees being paid to KU Leuven and not to any personal account of Erwin Dreesen. D. Alsoud, D. J. A. R. Moes, R. Soenen, Z. Layegh, I. K. Minichmayr, G. Wolbink, A. de Vries, and N. Padullés-Zamora declare that they have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Patients with multiple conditions present a growing challenge for healthcare provision. Measures of multimorbidity may support clinical management, healthcare resource allocation and accounting for the health of participants in purpose-designed cohorts. The recently developed Cambridge Multimorbidity scores (CMS) have the potential to achieve these aims using primary care records, however, they have not yet been validated outside of their development cohort., Methods: The CMS, developed in the Clinical Research Practice Dataset (CPRD), were validated in UK Biobank participants whose data is not available in CPRD (the cohort used for CMS development) with available primary care records (n = 111,898). This required mapping of the 37 pre-existing conditions used in the CMS to the coding frameworks used by UK Biobank data providers. We used calibration plots and measures of discrimination to validate the CMS for two of the three outcomes used in the development study (death and primary care consultation rate) and explored variation by age and sex. We also examined the predictive ability of the CMS for the outcome of cancer diagnosis. The results were compared to an unweighted count score of the 37 pre-existing conditions., Results: For all three outcomes considered, the CMS were poorly calibrated in UK Biobank. We observed a similar discriminative ability for the outcome of primary care consultation rate to that reported in the development study (C-index: 0.67 (95%CI:0.66-0.68) for both, 5-year follow-up); however, we report lower discrimination for the outcome of death than the development study (0.69 (0.68-0.70) and 0.89 (0.88-0.90) respectively). Discrimination for cancer diagnosis was adequate (0.64 (0.63-0.65)). The CMS performs favourably to the unweighted count score for death, but not for the outcomes of primary care consultation rate or cancer diagnosis., Conclusions: In the UK Biobank, CMS discriminates reasonably for the outcomes of death, primary care consultation rate and cancer diagnosis and may be a valuable resource for clinicians, public health professionals and data scientists. However, recalibration will be required to make accurate predictions when cohort composition and risk levels differ substantially from the development cohort. The generated resources (including codelists for the conditions and code for CMS implementation in UK Biobank) are available online., (© 2024. The Author(s).)