Citations

ObjectiveIdentifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR‐tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR‐tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms.MethodsCross‐sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non‐carriers had sequential characterization of N‐terminal/mid‐domain phosphorylated tau (p‐tau) followed by MTBR‐tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy.ResultsCSF MTBR‐tau species located within the putative “border” region and one species corresponding to the “core” region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The “border” MTBR‐tau species were associated with amyloid pathology and CSF p‐tau; whereas the “core” MTBR‐tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs.InterpretationChanges in CSF soluble MTBR‐tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R‐specific MTBR‐tau (border) to the NFT (core) MTBR‐tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR‐tau species in the CSF may serve as a marker of tau‐related disease progression and target engagement of anti‐tau therapeutics. ANN NEUROL 2023;93:1158–1172

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.

AbstractBackgroundTraditional management of olfactory neuroblastoma (ONB) includes margin‐negative resection with removal of cribriform plate, dura, and olfactory bulb, regardless of intracranial disease. This approach may be overtreating certain patients. Our investigation examines risk factors associated with occult intracranial disease to optimize therapeutic outcomes.MethodsThis retrospective, multi‐institutional cohort study examined clinical covariates associated with occult intracranial involvement. Patient demographics, staging, Hyam's grade, and pathologic involvement of dura, olfactory bulb/tract, and brain were collected. Diagnostic imaging was reviewed. Positive and negative predictive value (NPV) were estimated along with effect size estimates. Cox hazard regression examined associations with overall survival (OS) and disease‐free survival (DFS).ResultsA total of 224 subjects with new diagnoses of ONB (2005–2021) were identified. Skull base bone involvement on computed tomography (CT) had the highest NPV for pathologic dura (88.0%), olfactory bulb (88%), and brain involvement (97.3%). Hyam's grade category was significantly associated with dural involvement (φC = 0.26; 95% confidence interval [CI]: 0.16, 0.42). Subjects without radiologic skull base involvement (n = 66) had pathologic positivity of 12.1%. Within this subgroup, Hyam's grade was clinically significant for dural positivity (φ = 0.34; 95% CI: −0.12, 0.71) with 28.6% involvement in high grade tumors. Neither clinical nor pathologic positivity of intracranial structures were associated with significantly different OS or DFS.ConclusionsBoth CT and magnetic resonance imaging (MRI) had reasonably good NPV for involvement of dura and olfactory bulb. Higher Hyam's grade was associated with dural involvement. Patients with low‐grade tumors not involving the skull base may be suitable for avoiding skull base resection; however, further investigation is warranted.

Abstract The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post‐mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. Highlights Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance

Abstract Antimicrobial susceptibility testing (AST) is a critical function of the clinical microbiology laboratory and is essential for optimizing care of patients with infectious diseases, monitoring antimicrobial resistance (AMR) trends, and informing public health initiatives. Several methods are available for performing AST including broth microdilution, agar dilution, and disk diffusion. Technological advances such as the development of commercial automated susceptibility testing platforms and the advent of rapid diagnostic tests have improved the rapidity, robustness, and clinical application of AST. Numerous accrediting and regulatory agencies are involved in the process of AST and setting and revising breakpoints, including the U.S. Food and Drug Administration and the Clinical and Laboratory Standards Institute. Challenges to optimizing AST include the emergence of new resistance mechanisms, the development of new antimicrobial agents, and generation of new data requiring updates and revisions to established methods and breakpoints. Together, the challenges in AST methods and their interpretation create important opportunities for well‐informed clinicians to improve patient outcomes and provide value to antimicrobial stewardship programs, especially in the setting of rapidly changing and increasing AMR. Addressing AST challenges will involve continued development of new technologies along with collaboration between clinicians and the laboratory to facilitate optimal antimicrobial use, combat the increasing burden of AMR, and inform the development of novel antimicrobials. This updated primer serves to reinforce important principles of AST, and to provide guidance on their implementation and optimization.

Objectives The aim of this study was to evaluate the high-helical pitch, multienergy (ME) scanning mode of a clinical dual-source photon-counting detector (PCD) computed tomography (CT) and the benefit of virtual monoenergetic images (VMIs) for low-contrast-dose coronary CT angiography (CTA). Materials and Methods High-pitch (3.2) ME coronary CTA was performed in PCD-CT in 27 patients using low contrast dose (30 mL of iohexol 350 mg/mL) and in 26 patients at routine contrast dose (60 mL). Low-energy-threshold 120 kV images (also known as T3D images) and 50 kiloelectron volts (50 keV) and 100 kiloelectron volts (100 keV) VMIs were reconstructed using a 1024 × 1024 matrix and 0.6-mm slices. The CT numbers, noise, and contrast-to-noise ratio (CNR) were measured in the ascending aorta (AA), left main coronary artery (LMCA), and distal left anterior descending (LAD) artery. Confidence in grading luminal stenosis with calcific plaque, noncalcific plaque, and stent was evaluated by 2 independent readers on a 0–100 scale (0 the lowest), and a CAD-RADS score was assigned. Image contrast enhancement, sharpness, noise, artifacts, and overall image quality were rated using a 5-point ordinal scale (1 the lowest). Results The radiation doses (CTDI) in low- and routine-contrast cohorts were 2.5 ± 0.6 mGy and 3.1 ± 1.7 mGy, respectively ( P = 0.12). At all measured locations, the mean CT number was >300 HU in 120 kV (LMCA 382.9 ± 76.2, distal LAD 341.0 ± 53.9, AA 399.5 ± 76.1) and 50 keV images (LMCA 667.5 ± 139.9, distal LAD 578.1 ± 121.5, AA 700.8 ± 142.5) in the low-contrast cohort, with a 96% increase in CT numbers for 50 keV over 120 kV. The CT numbers were significantly higher ( P < 0.0001) in 50 keV than 120 kV and 100 keV VMI. The CNR was also significantly ( P < 0.0001) higher in 50 keV than 120 kV and 100 keV images in all vessels. Confidence in the assessment of luminal stenosis in the presence of calcific plaque was significantly higher ( P = 0.001) with the addition of 100 keV VMI (median score, 100) than using 50 keV alone (median score, 70) and 120 kV (median score, 70) for reader 1, but no significant differences were seen for reader 2 who had same median scores of 100 for all image types. The confidence in the assessment of luminal stenosis within a stent improved with the use of 100 keV images for both readers (reader 1: median scores for 50 + 100 keV = 100, 50 keV = 82.5, 120 kV = 82.5; reader 2: 50 + 100 keV = 100, 50 keV = 90, 120 kV = 90). There were no significant differences in confidence scores for assessment of luminal stenosis from noncalcific plaques for both readers. The reader-averaged qualitative scores for vascular enhancement and overall image quality were significantly higher for 50 keV VMI than for 120 kV images in both low- and routine-contrast dose cohorts. The image sharpness was nonsignificantly higher at 50 keV VMI than 120 kV images, and the artifact score was comparable for 50 keV VMI and 120 kV images. The noise was higher in 50 keV VMI than in 120 kV images. Conclusions High-pitch ME PCD-CT mode produced diagnostic quality coronary CTA images at low radiation and iodinated contrast doses. The availability of ME VMIs significantly improved the CNR, overall image quality, and confidence in assessment of luminal stenosis in the presence of calcific plaques and stents, and resulted in change of CAD-RADS categories in 9 patients.

» Benzoyl peroxide (BPO) 5% has been shown to reduce Cutibacterium acnes load on the skin. BPO 5% with miconazole nitrate (MN) 2% may be beneficial, whereas BPO 5% with clindamycin cream 1% to 1.2% does not seem to have additive effects when compared with BPO 5% alone. Chlorhexidine gluconate solutions reduce the total bacterial load on the skin, but do not seem to have a significant effect on C. acnes . » ChloraPrep seems to be the best surgical skin preparation to decrease overall positive skin cultures. Preincisional hydrogen peroxide 3% application has been shown to be a cost-effective practice to inhibit growth of C. acnes . Vancomycin powder before deltopectoral interval closure has antimicrobial effects against C. acnes and is a cost-effective practice. Finally, Bactisure surgical lavage is protective against the formation of biofilms. » IV cefazolin has been shown to be more effective for shoulder arthroplasty infection prophylaxis than antibiotic alternatives such as vancomycin. Thus, patients with a questionable history of penicillin allergy should undergo additional testing. » For shoulder surgery infection prophylaxis, we recommend the use of BPO 5% cream for 5 days preoperatively with chlorhexidine wipes the night before and the morning of surgery. IV cefazolin should be administered perioperatively, and patients with a questionable history of penicillin allergy should be tested. Surgeons should consider preincisional application of hydrogen peroxide 3% for 5 minutes, followed by standard ChloraPrep preparation. Normal saline should be used for preclosure lavage. Finally, application of vancomycin powder deep to the deltopectoral interval closure should be considered.

Background: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network. Methods: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . FH variant prevalence and penetrance (defined as low-density lipoprotein cholesterol >155 mg/dL) were estimated after excluding participants enrolled on the basis of hypercholesterolemia. Multivariable logistic regression was used to estimate the odds of CHD compared to age- and sex-matched controls without FH-associated variants. Process (eg, referral to a specialist or ordering new tests), intermediate (eg, new diagnosis of FH), and clinical (eg, treatment modification) outcomes within 1 year after return of results were ascertained by electronic health record review. Results: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00–4.53]) and premature CHD (odds ratio, 3.68 [2.34–5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results. Conclusions: In a multisite cohort of electronic health record–linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record–linked biobanks to detect FH.

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.

AbstractBackgroundThe Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system has become the gold standard for outcomes reporting in endoscopic orbital surgery for orbital cavernous hemangiomas (OCHs). A recent systematic review demonstrated similar outcomes between OCHs and other primary benign orbital tumors (PBOTs). Therefore, we hypothesized that a simplified and more comprehensive classification system could be developed to predict surgical outcomes of other PBOTs.MethodsPatient and tumor characteristics as well as surgical outcomes from 11 international centers were recorded. All tumors were retrospectively assigned an Orbital Resection by Intranasal Technique (ORBIT) class and stratified based on surgical approach as either exclusively endoscopic or combined (endoscopic and open). Outcomes based on approach were compared using chi‐squared or Fisher's exact tests. The Cochrane‐Armitage test for trend was used to analyze outcomes by class.ResultsFindings from 110 PBOTs from 110 patients (age 49.0 ± 15.0 years, 51.9% female) were included in the analysis. Higher ORBIT class was associated with a lower likelihood of gross total resection (GTR). GTR was more likely to be achieved when an exclusively endoscopic approach was utilized (p < 0.05). Tumors resected using a combined approach tended to be larger, to present with diplopia, and to have an immediate postoperative cranial nerve palsy (p < 0.05).ConclusionEndoscopic treatment of PBOTs is an effective approach, with favorable short‐term and long‐term postoperative outcomes as well as low rate of adverse events. The ORBIT classification system is an anatomic‐based framework that effectively facilitates high‐quality outcomes reporting for all PBOTs.