Citations

Objective: To report the preliminary safety, tolerability, and cerebral spinal fluid (CSF) sampling utility of serial injections of concentrated intraventricular nicardipine (IVN) in the treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: We report the clinical, radiographic, and laboratory safety and tolerability data of a retrospective case series from a single academic medical center. All patients with aSAH developed vasospasm despite enteral nimodipine and received serial injections of concentrated IVN (2.5 mg/mL). CSF injection safety, tolerability, and utility are defined and reported. Results: A total of 59 doses of concentrated IVN were administered to three patients with poor-grade SAH. In Case 1, a 33-year-old man with modified Fisher scale (mFS) grade 4 and Hunt-Hess scale (HH) score 4 received 26 doses; in Case 2, a 36-year-old woman with mFS grade 4 and HH score 5 received 13 doses; and in Case 3, a 70-year-old woman with mFS grade 3 and HH score 4 received 20 doses. No major safety or tolerability events occurred. Two patients were discharged to a rehabilitation facility, and one died after discharge from the hospital. Conclusions: A concentrated 4 mg IVN dose (2.5 mg/mL) in a 1.6 mL injection appears relatively safe and tolerable and potentially offers a second-line strategy for treating refractory vasospasm in poor-grade SAH without compromising intracranial pressure or cerebral perfusion pressure.

Although the precise mechanisms for neurodegeneration in Parkinson’s disease (PD) are unknown, evidence suggests that neuroinflammation is a critical factor in the pathogenic process. Here, we sought to determine whether the voltage-gated proton channel, Hv1 (HVCN1), which is expressed in microglia and regulates NADPH oxidase, is associated with dopaminergic neurodegeneration. We utilized data mining to evaluate the mRNA expression of HVCN1 in the brains of PD patients and controls and uncovered increased expression of the gene encoding Hv1, HVCN1, in the brains of PD patients compared to controls, specifically in male PD patients. In an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 16 mg/kg) mouse model of PD, Hvcn1 gene expression was increased 2-fold in the striatum. MPTP administration to wild-type (WT) mice resulted in a ~65% loss of tyrosine hydroxylase positive neurons (TH+) in the substantia nigra (SN), while a ~39% loss was observed in Hv1 knockout (KO) mice. Comparable neuroprotective effects of Hv1 deficiency were found in a repeated-dose LPS model. Neuroprotection was associated with decreased pro-inflammatory cytokine levels and pro-oxidant factors in both neurotoxicant animal models. These in vivo results were confirmed in primary microglial cultures, with LPS treatment increasing Hvcn1 mRNA levels and Hv1 KO microglia failing to exhibit the LPS-mediated inflammatory response. Conditioned media from Hv1 KO microglia treated with LPS resulted in an attenuated loss of cultured dopamine neuron cell viability compared to WT microglia. Taken together, these data suggest that Hv1 is upregulated and mediates microglial pro-inflammatory cytokine production in parkinsonian models and therefore represents a novel target for neuroprotection.

Abstract We present the case of a 61-year-old woman with a history of orthotopic heart transplant who was hospitalized with new-onset headache. Magnetic resonance imaging (MRI) of the brain revealed T2 hyperintense signal involving the left occipital lobe with leptomeningeal enhancement and mild vasogenic edema. Initial neurologic examination was normal; however, after 7 days she developed imbalance, visual disturbances, night sweats, bradyphrenia, alexia without agraphia, and right hemianopsia. Brain MRI showed enlargement of the left occipital mass and worsening edema. Stereotactic needle biopsy showed nondiagnostic necrosis. The patient continued to deteriorate despite dexamethasone. Cerebrospinal fluid (CSF) suggested infection, and cytomegalovirus CSF polymerase chain reaction (PCR) was positive. The patient received vancomycin, imipenem, and ganciclovir. After obtaining a positive serum beta-D-glucan (Fungitell), amphotericin was added. Despite best medical efforts, the patient died. Postmortem broad-range PCR sequencing of the brain tissue was positive for rare amoeba Balamuthia mandrillaris.

Aims:Increased left ventricular (LV) wall thickness is frequently encountered in transthoracic echocardiography (TTE). While accurate and early diagnosis is clinically important, given the differences in available therapeutic options and prognosis, an extensive workup is often required to establish the diagnosis. We propose the first echo-based, automated deep learning model with a fusion architecture to facilitate the evaluation and diagnosis of increased left ventricular (LV) wall thickness. Methods and Results: Patients with an established diagnosis of increased LV wall thickness (hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and hypertensive heart disease (HTN)/others) between 1/2015 and 11/2019 at Mayo Clinic Arizona were identified. The cohort was divided into 80%/10%/10% for training, validation, and testing sets, respectively. Six baseline TTE views were used to optimize a pre-trained InceptionResnetV2 model. Each model output was used to train a meta-learner under a fusion architecture. Model performance was assessed by multiclass area under the receiver operating characteristic curve (AUROC). A total of 586 patients were used for the final analysis (194 HCM, 201 CA, and 191 HTN/others). The mean age was 55.0 years, and 57.8% were male. Among the individual view-dependent models, the apical 4-chamber model had the best performance (AUROC: HCM: 0.94, CA: 0.73, and HTN/other: 0.87). The final fusion model outperformed all the view-dependent models (AUROC: HCM: 0.93, CA: 0.90, and HTN/other: 0.92). Conclusion: The echo-based InceptionResnetV2 fusion model can accurately classify the main etiologies of increased LV wall thickness and can facilitate the process of diagnosis and workup.

AbstractINTRODUCTIONThe fraction of dementia attributable to hypertension might vary depending on the age of the population considered and the age through which dementia occurs.METHODSIn the Atherosclerosis Risk in Communities study, we quantified population attributable fractions (PAF) of dementia by age 80 and 90 from hypertension assessed at ages of 45–54 (n = 7572), 55–64 (n = 12,033), 65–74 (n = 6561), and 75–84 (n = 2086).RESULTSThe PAF for dementia by age 80 from all non‐normal blood pressure at ages 45–54 was 15.3% (95% confidence interval [CI] = 6.9%–22.3%), 19.1% (95% CI = 9.9%–26.9%) at ages 55–64, and 19.9% (95% CI = −4.4%–38.5%) at ages 65–74. The strongest PAFs were from stage 2 hypertension (11.9%–21.3%). For dementia by age 90, PAFs from non‐normal blood pressure up through age 75 were smaller (10.9%–13.8%), and non‐significant by age 75–84.DISCUSSIONInterventions targeting hypertension even in early late life might reduce a sizeable proportion of dementia.Highlights We estimated prospective population attributable risks of dementia for hypertension. 15%–20% of dementia cases by age 80 are from non‐normal blood pressure (BP). Associations between hypertension and dementia persisted through age 75. Midlife to early late‐life BP control might reduce a large proportion of dementia.

Anxiety is associated with development of cardiovascular disease. Although the sympathetic nervous system is a likely mediator of this relationship, populations with chronic anxiety have shown little, if any, alteration in resting levels of directly recorded muscle sympathetic nerve activity (MSNA). The present study is the first to reveal an independent relationship between trait anxiety, resting blood pressure, and MSNA in a large cohort of healthy males and females devoid of cardiometabolic comorbidities.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

Evaluate the quantitative, subjective (Deauville score [DS]) and reader agreement differences between standard ordered subset expectation maximization (OSEM) and Bayesian penalized likelihood (BPL) positron emission tomography (PET) reconstruction methods. A retrospective review of 104 F-18 fluorodeoxyglucose PET/computed tomography (CT) exams among 52 patients with diffuse large B-cell lymphoma. An unblinded radiologist moderator reviewed both BPL and OSEM PET/CT exams. Four blinded radiologists then reviewed the annotated cases to provide a visual DS for each annotated lesion. Significant (P < .001) differences in BPL and OSEM PET methods were identified with greater standard uptake value (SUV) maximum and SUV mean for BPL. The DS was altered in 25% of cases when BPL and OSEM were reviewed by the same radiologist. Interobserver DS agreement was higher for OSEM (>1 cm lesion = 0.89 and ≤1 cm lesion = 0.84) compared to BPL (>1 cm lesion = 0.85 and ≤1 cm lesion = 0.81). Among the 4 readers, average intraobserver visual DS agreement between OSEM and BPL was 0.67 for lesions >1cm and 0.4 for lesions ≤1 cm. F-18 Fluorodeoxyglucose PET/CT of diffuse large B-cell lymphoma reconstructed with BPL has higher SUV values, altered DSs and reader agreement when compared to OSEM. This report finds volumetric PET measurements such as metabolic tumor volume to be similar between BPL and OSEM PET reconstructions. Efforts such as adoption of European Association Research Ltd accreditation should be made to harmonize PET data with an aim at balancing the need for harmonization and sensitivity for lesion detection.

Background Methods: The question prompt list content was derived through a modified Delphi process consisting of 3 rounds. In round 1, experts provided 5 answers to the prompts “What general questions should patients ask when given a new diagnosis of Barrett’s esophagus” and “What questions do I not hear patients asking, but given my expertise, I believe they should be asking?” Questions were reviewed and categorized into themes. In round 2, experts rated questions on a 5-point Likert scale. In round 3, experts rerated questions modified or reduced after the previous rounds. Only questions rated as “essential” or “important” were included in Barrett’s esophagus question prompt list (BE-QPL). To improve usability, questions were reduced to minimize redundancy and simplified to use language at an eighth-grade level (Fig. 1). Results: Twenty-one esophageal medical and surgical experts participated in both rounds (91% males; median age 52 years). The expert panel comprised of 33% esophagologists, 24% foregut surgeons, and 24% advanced endoscopists, with a median of 15 years in clinical practice. Most (81%), worked in an academic tertiary referral hospital. In this 3-round Delphi technique, 220 questions were proposed in round 1, 122 (55.5%) were accepted into the BE-QPL and reduced down to 76 questions (round 2), and 67 questions (round 3). These 67 questions reached a Flesch Reading Ease of 68.8, interpreted as easily understood by 13 to 15 years olds. Conclusions: With multidisciplinary input, we have developed a physician-derived BE-QPL to optimize patient-physician communication. Future directions will seek patient feedback to distill the questions further to a smaller number and then assess their usability.

AbstractBackgroundIt is unknown whether serum procalcitonin (PCT) concentration monitoring can differentiate between bacterial infection or cytokine release syndrome (CRS) when chimeric antigen receptor T‐cell (CAR‐T) recipients present with a constellation of signs and symptoms that may represent both complications.ObjectiveThe objective of the study was to assess the utility of serum PCT concentrations as a biomarker of bacterial infection in CAR‐T recipients.Study designThis single‐center, retrospective, medical record review evaluated patients prescribed CAR‐T therapy until death or 30 days after infusion. Logistic regression modeling determined the association between elevated serum PCT concentrations within 48 h of fever onset and microbiologically confirmed infection. Secondary outcomes included clinically suspected infection, CAR‐T toxicity rates, and broad‐spectrum antibiotic usage. Predictive performance of PCT was assessed by area under the receiver operating characteristic curve (AUC).ResultsThe 98 included patients were a median age of 63 (IQR: 55–69) years old, 47 (48%) were male, and 87 (89%) were Caucasian. Baseline demographics and clinical characteristics were similar between patients with and without a bacterial infection. Serum PCT >0.4 ng/mL within 48 h of fever was significantly associated with a microbiologically confirmed bacterial infection (OR: 2.75 [95% CI: 1.02–7.39], p = 0.045). Median PCT values in patients with and without confirmed infections were 0.40 ng/mL (IQR: 0.26, 0.74) and 0.26 ng/mL (IQR: 0.13, 0.47), respectively. The AUC for PCT to predict bacterial infection was 0.62 (95% CI 0.48–0.76). All patients experienced CRS of some grade, with no difference in CRS severity based on elevated PCT. Broad‐spectrum antibiotics were used for a median of 45% and 23% of days in those with and without confirmed infection, respectively (p = 0.075).ConclusionElevated serum PCT concentrations above 0.4 ng/mL at time of first fever after CAR‐T infusion was significantly associated with confirmed bacterial infection. Furthermore, rigorous, prospective studies should validate our findings and evaluate serial PCT measurements to optimize antimicrobial use after CAR‐T therapy.