Altered DTI scalars in the hippocampus are associated with morphological and structural changes after traumatic brain injury.

Blunt and diffuse injury is a highly prevalent form of traumatic brain injury (TBI) which can result in microstructural alterations in the brain. The blunt impact on the brain can affect the immediate contact region but can also affect the vulnerable regions like hippocampus, leading to functional impairment and long-lasting cognitive deficits. The hippocampus of the moderate weight drop injured male rats was longitudinally assessed for microstructural changes using in vivo MR imaging from 4 h to Day 30 post-injury (PI). The DTI analysis found a prominent decline in the apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) values after injury. The perturbed DTI scalars accompanied histological changes in the hippocampus, wherein both the microglia and astrocytes showed changes in the morphometric parameters at all timepoints. Along with this, the hippocampus showed presence of Aß positive fibrils and neurite plaques after injury. Therefore, this study concludes that TBI can lead to a complex morphological, cellular, and structural alteration in the hippocampus which can be diagnosed using in vivo MR imaging techniques to prevent long-term functional deficits.

Cortical Gray Matter Thickness and Volume Changes and Their Association with Memory Functions in Hyperthyroid Patients.

INTRODUCTION: Hyperthyroidism, characterized by excessive thyroid hormone production, is a common endocrine disorder that affects various physiological processes, including brain function. Recent advancements in neuroimaging techniques have enabled researchers to investigate structural alterations in the brain associated with hyperthyroidism. This study aimed to examine regional cortical thickness and cortical volume differences across the brain between hyperthyroid patients and control subjects. METHODS: We examined localized cortical thicknesses and volumes in 34 hyperthyroid patients and 35 control subjects with high-resolution T1-weighted images using FreeSurfer software and assessed group differences with analysis of covariance (covariates: age, sex, education, and total intracranial volume). Spearman and partial correlations were performed between clinical variables and cortical thicknesses/volumes and between neuropsychological scores and cortical thicknesses/volumes, respectively. RESULTS: Hyperthyroid patients exhibited significantly increased cortical thickness in bilateral superior temporal and superior frontal gyri, along with higher cortical volumes in various regions, including the right superior temporal gyrus, right superior parietal gyrus, right rostral and caudal middle frontal gyrus, and left superior frontal gyrus. Notably, thyroid hormones (fT3, fT4) correlated positively with cortical thicknesses and volumes in the superior temporal gyrus and superior frontal gyrus. Additionally, recognition memory scores negatively correlated with the right superior temporal gyrus and right superior frontal gyrus cortical thickness. CONCLUSION: The observed cortical thickening and increased cortical volume in specific brain areas provide new insights into the pathophysiological mechanism associated with brain impairment in hyperthyroidism.

Camouflage Detection and Its Association with Cognitive Style: A Functional Connectivity Study.

Background: Individual differences exist in performance in tasks that require visual search, such as camouflage detection (CD). Field dependence/independence (FD/I), as assessed using the Group Embedded Figures Test (GEFT), is an extensively studied dimension of cognitive style that classifies participants based on their visual perceptual styles. Materials and Methods: In the present study, we utilized fMRI on 46 healthy participants to investigate the underlying neural mechanisms specific to the cognitive styles of FD/FI while performing a CD task using both activation magnitude and an exploratory functional connectivity (FC) analysis. Group differences between high and low performers on the two extremes of the accuracy continuum of GEFT were studied. Results: No statistically significant group differences were observed using whole-brain voxel-wise comparison. However, the exploratory FC analysis revealed an enhanced communication between various regions subserving the cognitive traits required for visual search by FI participants over and above their FD counterparts. Conclusion: These enhanced connectivities suggest additional recruitment of cognitive functions to provide computational support that might facilitate superior performance in CD task by the participants who display a field-independent cognitive style.

Treated periodontitis and recurrent events after first-time myocardial infarction: A Danish nationwide cohort study.

AIM: To investigate the association between previous periodontal treatment and recurrent events after first-time myocardial infarction (MI). MATERIALS AND METHODS: From the Danish nationwide registries, patients with first-time MI between 2000 and 2015 were divided into three groups according to oral health care within 1 year prior to first-time MI. A multiple logistic regression model provided adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to assess the 3-year risk of major adverse cardiovascular events (MACE). RESULTS: A total of 103,949 patients were included. Patients with treated periodontitis (PD) prior to first-time MI had an adjusted 3-year risk of MACE similar to patients presumed periodontally healthy (OR 0.97 [95% CI 0.92-1.03]). Patients with no prior dental visits were significantly older, had more comorbidities and showed significantly increased adjusted 3-year risks of MACE (OR 1.47 [95% CI 1.42-1.52]), cardiovascular death (OR 1.71 [95% CI 1.64-1.78]) and heart failure (OR 1.13 [95% CI 1.07-1.20]) compared with patients presumed periodontally healthy. CONCLUSIONS: Patients with treated PD 1 year prior to first-time MI had a similar risk of recurrent cardiovascular events as patients presumed periodontally healthy. No dental visit prior to first-time MI was an independent risk factor for recurrent events.

Importance of familial predisposition to heart failure to the risk of anthracycline-related cardiotoxicity: A nationwide study.

BACKGROUND: Anthracycline-based chemotherapy has improved the prognosis of various malignancies, but increases the long-term risk of heart failure (HF). Identification of patients at risk prior to treatment initiation is warranted. Therefore, the aim of this study was to evaluate if a familial predisposition to HF increases the risk of anthracycline related HF. METHODS: Using nationwide Danish registries, all patients treated with anthracycline from 2004 to 16 were identified. The primary outcome was long-term HF risk. First-degree relatives were identified in the Danish Family Registry and exposure was defined as a first-degree biological relative with prior HF. Risk of HF was evaluated in a cumulative incidence function and the association in a multivariable Cox regression model. RESULTS: A total of 11,651 patients (median age 49.1 years (IQR: 43.6-53.7), 12.2% male) were included after exclusion of 46 with preanthracycline HF. Median follow-up was 3.8 years (IQR 1.9-6.4). In the group with a first-degree relative with HF (n = 1,608) 35 patients (2.2%) were diagnosed with HF vs 133 (1.3%) in the group without a first-degree relative with HF (n = 10,043), corresponding to incidence rates per 1,000 patient-years of 5.2 (CI:3.8-7.3) vs 3.0 (CI:2.5-3.5). The cumulative incidence of HF after 10 years was higher in the first-degree relative group (3.2% vs 2.0%, P = .004); adjusted hazard ratio 1.53 (CI:1.05-2.23, P = .03). CONCLUSION: In this nationwide register-based study having a first-degree relative with HF was associated with increased risk of anthracycline related HF, suggesting that attention towards family predisposition may be warranted when estimating the risk of anthracycline related cardiotoxicity.

Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.

INTRODUCTION: Blast induced Traumatic brain injury (BI-TBI) is common among military personnels as well as war affected civilians. In the war zone, people can also encounter repeated exposure of blast wave, which may affect their cognition and metabolic alterations. OBJECTIVE: In this study we assess the metabolic and histological changes in the hippocampus of rats at 24 h post injury. METHOD: Rats were divided into four groups: (i) Sham; (ii) Mild TBI (mi); (iii) Moderate TBI (mo); and (iv) Repetitive mild TBI (rm TBI) and then subjected to different intensities of blast exposure. Hippocampal tissues were collected after 24 h of injury for proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) and immunohistochemical (IHC) analysis. RESULTS: The metabolic alterations were found in the hippocampal tissue samples and these alterations showed significant change in glutamate, N-Acetylaspartic acid (NAA), acetate, creatine, phosphoethanolamine (PE), ethanolamine and PC/choline concentrations in rmTBI rats only. IHC studies revealed that AH3 (Acetyl histone) positive cells were decreased in rm TBI tissue samples in comparison to other TBI groups and sham rats. This might reflect an epigenetic alteration due to repeated blast exposure at 24 h post injury. Additionally, astrogliosis was observed in miTBI and moTBI hippocampal tissue while no change was observed in rmTBI tissues. CONCLUSION: The present study reports altered acetylation in the presence of altered metabolism in hippocampal tissue of blast induced rmTBI at 24 h post injury. Mechanistic understanding of these intertwined processes may help in the development of better therapeutic pathways and agents for blast induced TBI in near future.

Clinical cardiovascular phenotypes and the pattern of future events in patients with type 2 diabetes.

IMPORTANCE: Updated guidelines on diabetes recommend targeting sodium-glucose cotransporter-2 inhibitors (SGLT2i) at patients at risk of heart failure (HF) and glucagon-like peptide-1 receptor agonists (GLP1-RA) at those at greater risk of atherothrombotic events. OBJECTIVE: We estimated the risk of different cardiovascular events in patients with type 2 diabetes (T2D) and newly established cardiovascular disease. DESIGN, SETTING AND PARTICIPANTS: Patients with T2D and newly established cardiovascular disease from 1998 to 2016 were identified using Danish healthcare registers and divided into one of four phenotype groups: (1) HF, (2) ischemic heart disease (IHD), (3) transient ischemic stroke (TIA)/ischemic stroke, and (4) peripheral artery disease (PAD). The absolute 5-year risk of the first HF- or atherothrombotic event occurring after inclusion was calculated, along with the risk of death. MAIN OUTCOMES AND MEASURES: The main outcome was the first event of either HF or an atherothrombotic event (IHD, TIA/ischemic stroke or PAD) in patients with T2D and  new-onset cardiovascular disease. RESULTS: Of the 37,850 patients included, 40% were female and the median age was 70 years. Patients with HF were at higher 5-year risk of a subsequent HF event (17.9%; 95% confidence interval (CI) 17.1-18.8%) than an atherothrombotic event (15.8%; 15.0-16.6%). Patients with IHD were at higher risk of a subsequent atherothrombotic event (24.6%; 23.9-25.3%) than developing HF, although the risk of HF was still substantial (10.6%; 10.2-11.1%). Conversely, patients with PAD were at low risk of developing HF (4.4%; 3.8-5.1%) but at high risk of developing an atherothrombotic event (15.9%; 14.9-17.1%). Patients with TIA/ischemic stroke had the lowest risk of HF (3.2%; 2.9-3.6%) and the highest risk of an atherothrombotic event (20.6%; 19.8-21.4). CONCLUSIONS: In T2D, a patient's cardiovascular phenotype can help predict the pattern of future cardiovascular events.

Prevalence of allergic sensitization with vernal keratoconjunctivitis: A systematic review with meta-analyses.

To determine the prevalence of allergic sensitization in patients with vernal keratoconjunctivitis (VKC) and to provide an overview of published studies on this topic. We systematically searched 11 literature databases on 24 May 2021, for studies with cross-sectional data on the prevalence of positive allergy tests in patients with VKC. Our main outcome of interest was the prevalence of allergic sensitization and the allergens involved. Prevalence meta-analyses were made to provide summary estimates. We identified 33 eligible studies for qualitative review with 2122 patients with VKC. Studies were predominantly based on patients seen in ophthalmology clinics. Overall, studies reported that the most prevalent positive allergen tests were the inhaled allergens house dust mites and pollen. Twenty-nine studies were eligible for the quantitative analysis. Here, we calculated the prevalence of allergen-positive patients to 57.7% (95% confidence interval: 52.5%-62.8%). Subgroup analyses of pooled estimates on sensitization based on specific testing methods found prevalence estimates of 51.4% for conjunctival provocation test, 68.7% for total tear IgE, 58.9% for specific tear IgE, and 58.2% for skin prick test. The prevalence of allergic sensitization in patients with VKC is 57.7%, and mostly towards inhaled allergens. The most frequent positive allergens are house dust mites and pollen. Identifying possible clinically relevant allergens provide information that may aid in managing VKC, such as environmental allergy-avoidance or allergy-specific treatment.

Prognosis of acute coronary syndrome stratified by cancer type and status - a nationwide cohort study.

BACKGROUND: To investigated the prognosis of the most prevalent cancers (breast-, gastrointestinal-, and lung cancer), according to cancer status (i.e., active-, non-active-, history of-, and no cancer), following first-time of acute coronary syndrome (ACS). METHODS: Danish nationwide registers were used to identify patients with first-time ACS from 2000-2018. Patients were stratified according to cancer type and status. Hazard ratios (HR) estimated by adjusted Cox regression models for 1year all-cause mortality reported. Further absolute risks of 1year cardiovascular versus non-cardiovascular death and 30-day cumulative incidence of coronary angiograms (CAG) was estimated, using the Aalen-Johansen non-parametric method, with competing risk of death. RESULTS: We identified 150,478 (95.7%) with no cancer, 2,370 (1.5%) with history of cancer, 2,712 (1.7%) with non-active cancer and 1,704 (1.1%) with active cancer. Cancer patients were older with more comorbidities than patients with no cancer. When compared with no cancer, we found HRs (95% confidence intervals) of 1.71 (1.44-2.02), 2.47 (2.23-2.73) and 4.22 (3.87-4.60) correspondingly for active breast-, gastrointestinal-, and lung cancer. Increased HRs were also found for non-active cancers, but not for history of cancer. Cardiovascular disease was the leading cause of death in all patients. Among patients with active breast-, gastrointestinal-, and lung cancer 43%, 43%, and 31% underwent CAG, correspondingly, compared with 77% of patients without cancer. CONCLUSIONS: Active- and non-active cancers were associated with an increased 1-year all-cause mortality compared with patients with history of cancer and no cancer. Cardiovascular disease was the leading cause of death; notably CAG was less frequently performed in cancer patients.

18F-FDG 18F-FDG Positron Emission Tomography Imaging of Cortical Reorganization in Spinal Trauma.

Objective: Spinal cord injury (SCI) extensively impacts the sensorimotor reorganization in the brain. The effects can be both anatomical and functional. To date, not many studies using 18F-Fluoro-2-Deoxyglucose positron emission tomography (18F-FDG PET) to evaluate metabolic changes in the brain are done. Understanding such changes is crucial for developing clinical management and evidence-based rehabilitation strategies for these patients. Subjects and Methods: In this study, we compared 18F-FDG PET imaging of 6 SCI patients with complete paraplegia and 19 controls. Statistical parametric mapping software was utilized to compare the images on a voxel to voxel basis (significance level P < 0.05 and clusters having >50 voxels). Results: The study showed raised metabolism in supplementary motor areas, comprehension centers, some areas in the parietal and temporal lobe, putamen and cerebellum while reduced metabolic uptake in areas like anterior cingulate gyrus, hippocampus and sensory cortical areas when SCI patients were compared against healthy controls. The frontal lobe showed varied results where certain regions showed higher metabolism while the others showed lower in patients compared with controls. Conclusion: Cerebral deafferentation or disuse atrophy can be linked with reduced metabolism while raised uptake can be associated with initiation and planning of movement and cognitive changes in the brain posttrauma.

Incidence rates of dilated cardiomyopathy in adult first-degree relatives versus matched controls.

Background: The incidence rates and importance of traditional risk factors in dilated cardiomyopathy among first-degree relatives are unknown. Methods and Results: We identified all probands with dilated cardiomyopathy (n = 13,714, mean age at diagnosis 63 years) from the Danish nationwide registries between 1994 and 2017. Incidence rates among first-degree relatives (n = 29,671, mean age 38 years) and for up to 10 age- and sex-matched controls were calculated. Totally 233 (0.8%) first-degree relatives and 285 (0.1%) controls developed dilated cardiomyopathy during a median follow-up of 8.2 (Q1-Q3 4.4-13.3) years. Incidence rates (per 100,000 person-years) were 86.4 (95% confidence interval 73.9-101.0) and 111.1 (79.4-128.7) for first-degree relatives aged < 50 and ≥ 50 years, respectively, versus 7.5 (6.4-8.9) and 19.7 (16.8-23.2) for controls. Atrial fibrillation, diabetes, ischemic heart disease, and hypertension were associated with increased risks of developing dilated cardiomyopathy both in first-degree relatives and controls. Population attributable fractions for the 4 risk factors were 27.7% for first-degree relatives and 37.3% for controls aged < 50 years, and 46.4% versus 58.4% for first-degree relatives and controls among people aged ≥ 50 years, respectively. Conclusions: The absolute incidence rates of dilated cardiomyopathy in first-degree relatives to patients with dilated cardiomyopathy were low, but significantly higher than in matched controls and elevated by the presence of additional risk factors, especially atrial fibrillation. Additional investigations are warranted to assess whether aggressive treatment of risk factors translates into a reduction of dilated cardiomyopathy in first-degree relatives.

Does the initial chest radiograph severity in COVID-19 impact the short- and long-term outcome? - a perspective from India.

PURPOSE: The chest radiograph (CXR) is among the most widely used investigations in coronavirus disease 2019 (COVID-19) patients. Little is known about its predictive role on the long-term outcome. The purpose of this study was to explore its association with the short and long-term outcome in COVID-19 patients. METHODS: A total of 1530 patients were assessed for the presence, radiographic pattern and distribution of lung lesions observed on baseline chest radiographs obtained at admission. The Brixia scoring system was applied for semiquantitative assessment of lesion severity. Short-term outcome was determined by clinical severity, duration of hospitalization and mortality. The 1415 survivors in this group were assessed after 5-6 months for the presence of residual symptoms. RESULTS: About 67% patients had an abnormal baseline CXR. Bilateral involvement with a basal preponderance was observed and ground-glass opacification was the most frequent finding. The Brixia score ranged from 0 to 16, median 2, interquartile range (IQR) [0-6]. About 36% patients were symptomatic on 5-6-month follow-up, with fatigability being the commonest symptom. A good correlation was observed between the CXR score and disease severity as well as duration of hospitalization. On multivariate analysis, the CXR score was found to be a significant independent predictor of in-patient mortality as well as presence of long-term residual symptoms in survivors. CONCLUSIONS: Disease severity as seen on the chest radiograph appears to play an important role in driving the short and long-term consequences of COVID-19 and could serve as a prognostic indicator, which influences short-term management and long-term follow-up.

Brain functional connectivity in patients with hyperthyroidism after anti-thyroid treatment.

Thyroid disease is known to affect brain metabolism and cognitive function, although the recovery of thyroid-induced brain functional changes after treatment remains unclear. We aimed to investigate the alteration in brain functional connectivity and its correlation with neuropsychological variables in hyperthyroid patients before and after anti-thyroid treatment using a resting-state functional magnetic resonance imaging (rsfMRI) technique. This is a follow-up rsfMRI study of previous work that showed impaired brain functional connectivity in hyperthyroid patients compared to healthy controls. We included rsfMRI and neuropsychological data from 21 hyperthyroid patients out of an original cohort of 28 patients, before and after anti-thyroid treatment for 30 weeks. Functional connectivity analysis and neuropsychological scores were compared using paired t tests in patients at baseline and at follow-up. Patients showed an improvement in some of the memory (p < .05) and executive, visuospatial and motor (p < .001) functions after treatment, and also showed increased functional connectivity in the regions of the right fronto-parietal network, left fronto-parietal network, and default mode network (DMN) (p < .05). At follow-up, the functional connectivity of the right fronto-parietal network showed a significantly positive correlation with the recognition of objects memory score. The overall findings suggest that anti-thyroid treatment with carbimazole improves the functional connectivity within some of the resting state networks in the hyperthyroid patients, whereas the remaining networks still show impairment.

Neurometabolite Changes in Hyperthyroid Patients Before and After Antithyroid Treatment: An in vivo 1H MRS Study.

Purpose: Patients with hyperthyroidism have frequent neuropsychiatric symptoms such as lack of attention, concentration, poor memory, impaired executive functions, depression, and anxiety. These neurocognitive impairments such as memory, attention, and executive functions appear to be associated with dysfunction in brain regions. This study was conducted to investigate the metabolic changes in the brain subcortical regions, i.e., posterior parietal cortex and dorsolateral prefrontal cortex (DLPFC), in patients with hyperthyroidism before and after antithyroid treatment using proton magnetic resonance spectroscopy (1H MRS). Materials and Methods: We collected neuropsychological and 1H MRS data from posterior parietal cortex and DLPFC, in both control (N = 30) and hyperthyroid (N = 30) patients. In addition, follow-up data were available for 19 patients treated with carbimazole for 30 weeks. The relative ratios of the neurometabolites were calculated using the Linear Combination Model (LCModel). Analysis of co-variance using Bonferroni correction was performed between healthy controls and hyperthyroid patients, and a paired t-test was applied in patients at baseline and follow-up. Spearman's rank-order correlation was used to analyze bivariate associations between thyroid hormone levels and metabolite ratios, and the partial correlation analysis was performed between neuropsychological scores and metabolite ratios, with age and sex as covariates, in the patients before and after treatment. Results: Our results revealed a significant decrease in choline/creatine [glycerophosphocholine (GPC) + phosphocholine (PCh)/creatine (tCr)] in both the posterior parietal cortex and DLPFC in hyperthyroid patients, and these changes were reversible after antithyroid treatment. The posterior parietal cortex also showed significantly reduced glutamate/creatine (Glu/tCr), (glutamate + glutamine)/creatine (Glx/tCr), and increased glutathione/creatine (GSH/tCr) ratios in the hyperthyroid patients over control subjects. In DLPFC, only (N-acetyl aspartate + N-acetyl aspartyl-glutamate)/creatine (NAA + NAAG)/tCr was increased in the hyperthyroid patients. After antithyroid treatment, (GPC + PCh)/tCr increased, and Glx/tCr decreased in both brain regions in the patients at follow-up. Gln/tCr in the posterior parietal cortex was decreased in patients at follow-up. Interestingly, (GPC + PCh)/tCr in DLPFC showed a significantly inverse correlation with free tri-iodothyronine (fT3) in hyperthyroid patients at baseline, whereas NAA/tCr showed positive correlations with fT3 and free thyroxine (fT4) in hyperthyroid patients before and after antithyroid treatment, in the posterior parietal cortex. In DLPFC, only (NAA + NAAG)/tCr showed positive correlations with fT3 and fT4 in the patients before treatment. Conclusion: The overall findings suggest that all the brain metabolite changes were not completely reversed in the hyperthyroid patients after antithyroid treatment, even after achieving euthyroidism.

Rate of Heart Failure Following Atrial Fibrillation According to Presence of Family History of Dilated Cardiomyopathy or Heart Failure: A Nationwide Study.

Background It is poorly understood why some patients with atrial fibrillation develop heart failure (HF) and others do not. We examined the rate of developing HF in patients with atrial fibrillation with and without first-degree family members with HF or dilated cardiomyopathy (DCM). Methods and Results Using Danish nationwide registries, patients born after 1942 diagnosed with atrial fibrillation in the period 2005 to 2015 were identified and followed for up to 5 years. Patients with pre-existing HF, DCM, and/or ischemic heart disease diagnoses were excluded. Exposure was defined as a first-degree relative with HF or DCM. The rate of developing the composite end point of HF or death, and the components, was estimated with multivariable Cox proportional hazard regression models. We included 10 605 patients. A total of 17% had a family member with DCM/HF. Having a family member with HF/DCM was associated with an increased 5-year risk of the composite of HF/death (cumulative incidence, 9.2% [95% CI, 7.8-10.7] versus 5.6% [95% CI, 5.0-6.1]; adjusted hazard ratio [HR] 1.36 [95% CI, 1.13-1.64]). (HF 8.4% [95% CI, 7.0-9.8] versus 4.5% [95% CI, 4.1-5.0]); (adjusted HR, 1.49 [95% CI, 1.22-1.82]). However, familial HF/DCM was not significantly associated with an increased 5-year risk and rate of death (0.8% [95% CI, 0.4-1.2] versus 1.1% [95% CI, 0.8-1.3]); (adjusted HR, 0.80 [95% CI, 0.46-1.39]). Conclusions In patients with incident atrial fibrillation without prior ischemic heart disease or HF diagnoses, 1 of 6 had a first-degree relative with HF, and having such a family history of HF/DCM was associated with an 87% increase in 5-year incidence of HF compared with those without.

A Methodology to Compare Biomechanical Simulations With Clinical Brain Imaging Analysis Utilizing Two Blunt Impact Cases.

According to the US Defense and Veterans Brain Injury Center (DVBIC) and Centers for Disease Control and Prevention (CDC), mild traumatic brain injury (mTBI) is a common form of head injury. Medical imaging data provides clinical insight into tissue damage/injury and injury severity, and helps medical diagnosis. Computational modeling and simulation can predict the biomechanical characteristics of such injury, and are useful for development of protective equipment. Integration of techniques from computational biomechanics with medical data assessment modalities (e.g., magnetic resonance imaging or MRI) has not yet been used to predict injury, support early medical diagnosis, or assess effectiveness of personal protective equipment. This paper presents a methodology to map computational simulations with clinical data for interpreting blunt impact TBI utilizing two clinically different head injury case studies. MRI modalities, such as T1, T2, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC), were used for simulation comparisons. The two clinical cases have been reconstructed using finite element analysis to predict head biomechanics based on medical reports documented by a clinician. The findings are mapped to simulation results using image-based clinical analyses of head impact injuries, and modalities that could capture simulation results have been identified. In case 1, the MRI results showed lesions in the brain with skull indentation, while case 2 had lesions in both coup and contrecoup sides with no skull deformation. Simulation data analyses show that different biomechanical measures and thresholds are needed to explain different blunt impact injury modalities; specifically, strain rate threshold corresponds well with brain injury with skull indentation, while minimum pressure threshold corresponds well with coup-contrecoup injury; and DWI has been found to be the most appropriate modality for MRI data interpretation. As the findings from these two cases are substantiated with additional clinical studies, this methodology can be broadly applied as a tool to support injury assessment in head trauma events and to improve countermeasures (e.g., diagnostics and protective equipment design) to mitigate these injuries.

Risk for Myocardial Infarction Following 5-Fluorouracil Treatment in Patients With Gastrointestinal Cancer: A Nationwide Registry-Based Study.

BACKGROUND: Myocardial infarction is a cardiac adverse event associated with 5-fluorouracil (5-FU). There are limited data on the incidence, risk, and prognosis of 5-FU-associated myocardial infarction. OBJECTIVES: The aim of this study was to examine the risk for myocardial infarction in patients with gastrointestinal (GI) cancer treated with 5-FU compared with age- and sex-matched population control subjects without cancer (1:2 ratio). METHODS: Patients with GI cancer treated with 5-FU between 2004 and 2016 were identified within the Danish National Patient Registry. Prevalent ischemic heart disease in both groups was excluded. Cumulative incidences were calculated, and multivariable regression and competing risk analyses were performed. RESULTS: A total of 30,870 patients were included in the final analysis, of whom 10,290 had GI cancer and were treated with 5-FU and 20,580 were population control subjects without cancer. Differences in comorbid conditions and select antianginal medications were nonsignificant (P > 0.05 for all). The 6-month cumulative incidence of myocardial infarction was significantly higher for 5-FU patients at 0.7% (95% CI: 0.5%-0.9%) versus 0.3% (95% CI: 0.3%-0.4%) in population control subjects, with a competing risk for death of 12.1% versus 0.6%. The 1-year cumulative incidence of myocardial infarction for 5-FU patients was 0.9% (95% CI: 0.7%-1.0%) versus 0.6% (95% CI: 0.5%-0.7%) among population control subjects, with a competing risk for death of 26.5% versus 1.4%. When accounting for competing risks, the corresponding subdistribution hazard ratios suggested an increased risk for myocardial infarction in 5-FU patients, compared with control subjects, at both 6 months (hazard ratio: 2.10; 95% CI: 1.50-2.95; P < 0.001) and 12 months (hazard ratio: 1.39; 95% CI: 1.05-1.84; P = 0.022). CONCLUSIONS: Despite a statistically significantly higher 6- and 12-month risk for myocardial infarction among 5-FU patients compared with population control subjects, the absolute risk for myocardial infarction was low, and the clinical significance of these differences appears to be limited in the context of the significant competing risk for death in this population.

Immune Checkpoint Inhibitor Treatment and Ophthalmologist Consultations in Patients with Malignant Melanoma or Lung Cancer-A Nationwide Cohort Study.

PURPOSE: To estimate the frequency of first-time ocular events in patients treated with immune checkpoint inhibitors (ICI). METHODS: Patients with cancer in 2011-2018 in Denmark were included and followed. The outcomes were first-time ophthalmologist consultation and ocular inflammation. One-year absolute risks of outcomes and hazard ratios were estimated. RESULTS: 112,289 patients with cancer were included, and 2195 were treated with ICI. One year after the first ICI treatment, 6% of the patients with cancer, 5% and 8% of the lung cancer (LC) and malignant cutaneous melanoma (MM) patients, respectively, had a first-time ophthalmologist consultation. The risk of ocular inflammation was 1% (95% confidence interval (CI) 0.4-1.2). Among patients with MM, ICI was associated with ocular inflammation in women (HR 12.6 (95% CI 5.83-27.31) and men (4.87 (95% CI 1.79-13.29)). Comparing patients with and without ICI treatment, the risk of first-time ophthalmologist consultation was increased in patients with LC (HR 1.74 (95% CI 1.29-2.34) and MM (HR 3.21 (95% CI 2.31-4.44). CONCLUSIONS: The one-year risks of first-time ophthalmologist consultation and ocular inflammation were 6% and 1%, respectively, in patients treated with ICI. In patients with LC and MM, the risk was increased in patients with ICI compared with patients without ICI.

The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study.

AIMS: The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma. METHODS AND RESULTS: The study included consecutive patients with lung cancer or malignant melanoma in 2011-17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8-12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8-11.3) and 7.5% (3.7-11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50-3.05) in patients with lung cancer and 4.30 (1.38-13.42) and 4.93 (2.45-9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27-4.02) for patients with lung cancer and 3.48 (1.91-6.35) for patients with malignant melanoma and CTLA-4i. CONCLUSIONS: Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).