School of Medicine

Coronavirus Disease 2019 (COVID-19) has had an enormous impact on both the medical community as well as society as a whole. Research on the pathogenesis and the treatment of the disease is rapidly emerging, with new observations and hypotheses appearing daily. One aspect that has been receiving increasing attention is the occurrence of both arterial and venous thrombotic complications in patients with COVID-19. We report three cases of thromboembolic complications in patients affected by COVID-19 and discuss clinical features, pathophysiology, and the proposed approaches to management of vascular complications in these patients. Through our discussion, we also urge physicians to be vigilant for any symptoms or signs suggestive of thrombosis in patients with COVID-19.

Introduction: Evaluation recommendations for patients on anticoagulant and antiplatelet (ACAP) therapy that present after mild traumatic brain injury (TBI) are controversial. At our institution, an initial noncontrast head computed tomography (HCT) is performed, with a subsequent HCT performed six hours later to exclude delayed intracranial hemorrhage (ICH). This study was performed to evaluate the yield and advisability of this approach.

Methods: We performed a retrospective review of subjects undergoing evaluation for ICH after mild TBI in patients on ACAP therapy between January of 2012 and April of 2013. We assessed for the frequency of ICH on both the initial noncontrast HCT and on the routine six-hour follow-up HCT. Additionally, chart review was performed to evaluate the clinical implications of ICH, when present, and to interrogate whether pertinent clinical and laboratory data may predict the presence of ICH prior to imaging. We used multivariate generalized linear models to assess whether presenting Glasgow Coma Score (GCS), loss of consciousness (LOC), neurological or physical examination findings, international normalized ratio, prothrombin time, partial thromboplastin time, platelet count, or specific ACAP regimen predicted ICH.

Results: 144 patients satisfied inclusion criteria. Ten patients demonstrated initial HCT positive for ICH, with only one demonstrating delayed ICH on the six-hour follow-up HCT. This patient was discharged without any intervention required or functional impairment. Presenting GCS deviation (p<0.001), LOC (p=0.04), neurological examination findings (p<0.001), clopidogrel (p=0.003), aspirin (p=0.03) or combination regimen (p=0.004) use were more commonly seen in patients with ICH.

Conclusion: Routine six-hour follow-up HCT is likely not indicated in patients on ACAP therapy, as our study suggests clinically significant delayed ICH does not occur. Additionally, presenting GCS deviation, LOC, neurological examination findings, clopidogrel, aspirin or combination regimen use may predict ICH, and, in the absence of these findings, HCT may potentially be forgone altogether. [West J Emerg Med. 2015;16(1):-0.]

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Results of the impact of reading books and viewing television on neurodevelopment have been mixed, without definitive evaluation to date. Using data from 11,875 US adolescents in the Adolescent Brain and Cognitive Development (ABCD) study, we investigated the associations between reading and television viewing on brain morphology and neurocognitive performance. After quality control, 8,125 participants' MRI scans and cognitive tests were analyzed in relation to their reading and TV habits. Greater reading time was associated with higher cognitive performance and regionally-selective increases in cortical area, while greater TV viewing had a much smaller association with lower cognitive performance and decreased cortical area. Regionally, areas of spatial overlap in associations included the lateral temporal, inferior parietal, and inferior frontal lobes, while significant associations in the ventral and inferior temporal cortex and cingulate cortex were unique to reading habits. These relationships persisted after adjusting for demographics, socioeconomic factors, genetic ancestry, and imaging factors. The magnitude of reading associations exceeded those of TV viewing and was similar to established contributions of parental income and education on neurodevelopment. This study provides a comprehensive evaluation of how these behaviors correlate with early adolescent brain development across a large diverse population.

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BACKGROUND: Accurate donor-recipient matching of the femoral condyle radius of curvature (ROC) in osteochondral allograft (OCA) transplantation may aid in minimizing articular surface incongruities. Matching linear femorotibial dimensions, such as the femoral condyle anterior-posterior length (APL), femoral condyle width (lateral-medial length, LML), femoral hemicondyle width (HCW), and tibial plateau width (TPW), can provide similar results if they correlate well with ROC. This study investigates the relationship between femorotibial dimensions and ROC at the cartilage surface using magnetic resonance imaging (MRI). METHODS: Deidentified MRI images of 63 patients (35 men, 33 ± 10 years old, and 28 women, 27 ± 8 years old) were analyzed. Axial images were used for APL, LML, and TPW (TPW-Ax) measurements, while coronal images were used for HCW and TPW (TPW-Cor) measurements. Cartilage was segmented in true sagittal images at the medial femoral condyle (MFC) and lateral femoral condyle (LFC) to calculate their specific cartilage surface ROCs. Linear regression models were used to determine the relationship between the femorotibial dimensions and ROC. RESULTS: Cartilage ROC was significantly correlated with all the linear femorotibial dimensions at the MFC (P < 0.01, R2 = 0.78, 0.69, 0.67, 0.59, and 0.37 for ROC correlations with APL, LML, TPW-Ax, TPW-Cor, and HCW, respectively), and the LFC (P < 0.01, R2 = 0.81, 0.61, 0.56, 0.54, and 0.41 for ROC correlations with APL, LML, TPW-Ax, TPW-Cor, and HCW, respectively). CONCLUSIONS: The APL was the most predictive femorotibial dimension of the cartilage surface ROC. Donor-recipient APL matching in OCA transplantation may provide a similar level of matching to that achievable by direct ROC measurements. The APL matching may help reduce cartilage incongruities, particularly for patients with large osteochondral lesions, in which the ROC measurement cannot be accurately determined.

While clozapine is the most effective antipsychotic drug, its use is limited due to hematological adverse effects involving the reduction of granulocyte counts with potential life-threatening agranulocytosis. It is not yet possible to predict or prevent the risk of agranulocytosis, and the mechanisms are unknown but likely related to clozapine metabolism. Genome-wide association studies (GWASs) of clozapine metabolism and clozapine-induced agranulocytosis have identified few genetic loci. We used the largest available GWAS summary statistics of clozapine metabolism (clozapine-to-norclozapine ratio) and clozapine-induced agranulocytosis, applying the conditional false discovery rate (condFDR) method to increase power for genetic discovery by conditioning on granulocyte counts variants. To investigate potential causal effects of shared loci, we performed Mendelian Randomization analyses. After conditioning on granulocyte counts, we identified two novel loci associated with clozapine-to-norclozapine ratio. These loci were significantly associated with clozapine metabolism in a validation sample of 392 clozapine-treated individuals. For clozapine-induced agranulocytosis, five loci were identified after conditioning on granulocyte counts. These five loci were significantly associated with reduced granulocyte counts in a small independent sample of clozapine-treated individuals. Genetic liability to slow clozapine metabolism (high clozapine-to-norclozapine ratio) showed evidence of a causal effect on reduced neutrophil counts, and genetic liability to low neutrophil counts exhibited weak evidence of a causal effect on clozapine-induced agranulocytosis. Our findings of shared genetic variants associated with clozapine metabolism and granulocyte counts may form the basis for developing prediction models for clozapine-induced agranulocytosis.

BACKGROUND: Metabolic processes form the basis of the development, functioning and maintenance of the brain. Despite accumulating evidence of the vital role of metabolism in brain health, no study to date has comprehensively investigated the link between circulating markers of metabolic activity and in vivo brain morphology in the general population. METHODS: We performed uni- and multivariate regression on metabolomics and MRI data from 24,940 UK Biobank participants, to estimate the individual and combined associations of 249 circulating metabolic markers with 91 measures of global and regional cortical thickness, surface area and subcortical volume. We investigated similarity of the identified spatial patterns with brain maps of neurotransmitters, and used Mendelian randomization to uncover causal relationships between metabolites and the brain. RESULTS: Intracranial volume and total surface area were highly significantly associated with circulating lipoproteins and glycoprotein acetyls, with correlations up to .15. There were strong regional associations of individual markers with mixed effect directions, with distinct patterns involving frontal and temporal cortical thickness, brainstem and ventricular volume. Mendelian randomization provided evidence of bidirectional causal effects, with the majority of markers affecting frontal and temporal regions. DISCUSSION: The results indicate strong bidirectional causal relationships between circulating metabolic markers and distinct patterns of global and regional brain morphology. The generated atlas of associations provides a better understanding of the role of metabolic pathways in structural brain development and maintenance, in both health and disease.

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Multiparametric magnetic resonance imaging (mpMRI) is strongly recommended by current clinical guidelines for improved detection of clinically significant prostate cancer (csPCa). However, the major limitations are the need for intravenous (IV) contrast and dependence on reader expertise. Efforts to address these issues include use of biparametric magnetic resonance imaging (bpMRI) and advanced, quantitative magnetic resonance imaging (MRI) techniques. One such advanced technique is the Restriction Spectrum Imaging restriction score (RSIrs), an imaging biomarker that has been shown to improve quantitative accuracy of patient-level csPCa detection. Advanced Restriction imaging and reconstruction Technology for Prostate MRI (ART-Pro) is a multisite, multinational trial that aims to evaluate whether IV contrast can be avoided in the setting of standardized, state-of-the-art image acquisition, with or without addition of RSIrs. Additionally, RSIrs will be evaluated as a stand-alone, quantitative, objective biomarker. ART-Pro will be conducted in two stages and will include a total of 500 patients referred for multiparametric prostate MRI with a clinical suspicion of prostate cancer at the participating sites. ART-Pro-1 will evaluate bpMRI, mpMRI, and RSIrs on the accuracy of expert radiologists detection of csPCa and will evaluate RSIrs as a stand-alone, quantitative, objective biomarker. ART-Pro-2 will evaluate the same MRI techniques on the accuracy of nonexpert radiologists detection of csPCa, and findings will be evaluated against the expertly created dataset from ART-Pro-1. The primary endpoint is to evaluate whether bpMRI is noninferior to mpMRI among expert (ART-Pro-1) and nonexpert (ART-Pro-2) radiologists for the detection of grade group ≥2 csPCa. This trial is registered in the US National Library of Medicine Trial Registry (NCT number: NCT06579417) at ClinicalTrials.gov. Patient accrual at the first site (UC San Diego) began in December 2023. Initial results are anticipated by the end of 2026.