Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Reexamining the Incidence of Nonarteritic Anterior Ischemic Optic Neuropathy: A Rochester Epidemiology Project Study.

BACKGROUND: This study aims to determine the population-based incidence and characterize the features of nonarteritic anterior ischemic optic neuropathy (NAION) using the Rochester Epidemiology Project (REP). METHODS: All patients diagnosed with an optic neuropathy from January 1, 1990, to December 31, 2016, were retrospectively reviewed to identify incident cases of NAION using the REP database, which is a record-linkage system of medical records for all patient-physician encounters among Olmsted County, Minnesota residents. The overall incidence of NAION was estimated using the age-specific and sex-specific population figures for Olmsted County census data for 1990 through 2016. Visual outcomes and risk factors were evaluated. The systemic risk factors were compared with age-matched controls. RESULTS: One hundred four patients were diagnosed with NAION during the 26-year study period. The overall age and sex adjusted incidence was 3.89 per 100,000 individuals (95% confidence interval [CI]: 3.14-4.65). The incidence was 7.73 (CI: 6.24-9.22) in patients aged 40 years or older and 10.19 (CI: 8.15-12.23) in patients aged 50 years or older. Median age at diagnosis was 65 years (range, 40-90 years), and 59 (56.7%) were male. The median logMAR visual acuity at presentation was 0.35 (Snellen equivalent of 20/40) with 14 patients (13.5%) having vision of counting fingers or worse. Among the 91 patients with final visual acuity outcome data available, the median visual acuity was 0.40 (Snellen equivalent of 20/50) with 12 patients (13.2%) having vision of counting fingers or worse. Twenty-four patients (26.4%) were noted to have final acuity at least 3 Snellen lines worse than at presentation, whereas 17 patients (18.7%) were noted to improve by at least 3 lines. The median mean deviation on automated visual field testing was -10.2 dB at presentation and -11.1 dB at follow-up. Twenty-two patients (21.2%) suffered NAION in the fellow eye; the median interval between involvement of the first and second eyes was 1.39 years. Systemic diseases present in the NAION cohort included hypertension (79.8%), diabetes mellitus (39.4%), obstructive sleep apnea (23.1%), and hyperlipidemia (74.0%), which were all statistically higher than age-matched controls. CONCLUSIONS: NAION is a relatively common optic neuropathy in elderly patients with vascular risk factors. Our data indicate that the incidence of NAION has remained relatively stable in the population of Olmsted County over the past 4 decades.

Comparison of qualitative information obtained with the echocardiographic assessment using subcostal-only view and focused transthoracic echocardiography examinations: a prospective observational study.

PURPOSE: To evaluate whether echocardiographic assessment using the subcostal-only window (EASy) compared with focused transthoracic echocardiography (FTTE) using three windows (parasternal, apical, and subcostal) can provide critical information to serve as an entry-point technique for novice sonographers. METHODS: We conducted a retrospective study to compare diagnostic information acquired during EASy and FTTE examinations on qualitative left ventricular (LV) size, LV contractility, right ventricular (RV) size, RV contractility, interventricular septal position, and the presence of a significant pericardial effusion. Anesthesiology residents (novice users) performed FTTE for hemodynamic instability and/or respiratory distress or to define volume status in the perioperative setting, and later collected images were grouped into EASy and FTTE examinations. Both examinations were reviewed independently by a board-certified cardiologist and an anesthesiologist proficient in critical care echocardiography. FTTE and EASy findings were compared utilizing Gwet's AC1 coefficient to consider disagreement due to chance. RESULTS: We reviewed 102 patients who received FTTE over a period of 14 months. Of those, 82 had usable subcostal views and were included in the analysis. There was substantial agreement for qualitatively evaluating RV size (Gwet's AC1, 0.70; 95% confidence interval [CI], 0.54 to 0.85), LV size (Gwet's AC1, 0.73; 95% CI, 0.58 to 0.88), and LV contractility (Gwet's AC1, 0.73; 95% CI, 0.58 to 0.88) utilizing EASy and FTTE. Additionally, there was an almost perfect agreement when assessing the presence of pericardial effusion (Gwet's AC1, 0.98; 95% CI, 0.95 to 1.0) and RV contractility (Gwet's AC1, 0.84; 95% CI, 0.74 to 0.95) and evaluating the motion of the interventricular septum (Gwet's AC1, 0.92; 95% CI, 0.85 to 0.99). CONCLUSIONS: When images could be obtained from the subcostal window (the EASy examination), qualitative diagnostic information was sufficiently accurate compared with information obtained during FTTE examination. Our findings suggest that the EASy examination can serve as the entry point technique to FTTE for novice clinicians.

RéSUMé: OBJECTIF: Déterminer si l'évaluation échocardiographique se fondant sur la fenêtre unique sous-costale (EASy) par rapport à une échocardiographie transthoracique ciblée (ETTC) fondée sur trois fenêtres (parasternale, apicale et sous-costale) pouvait fournir des informations critiques et servir de technique de départ pour enseigner l'échographie aux novices. MéTHODE: Nous avons réalisé une étude rétrospective afin de comparer les informations diagnostiques acquises lors des examens échocardiographiques EASy et ETTC concernant la taille qualitative du ventricule gauche (VG), la contractilité du VG, la taille du ventricule droit (VD), la contractilité du VD, la position septale interventriculaire et la présence d'un épanchement péricardique significatif. Les résidents en anesthésiologie (utilisateurs novices) ont réalisé une ETTC pour détecter une instabilité hémodynamique et / ou une détresse respiratoire ou pour définir l'état volémique dans un contexte périopératoire; par la suite les images colligées ont été regroupées en examens EASy et ETTC. Les deux examens ont été indépendamment passés en revue par un cardiologue certifié et un anesthésiologiste formé en échocardiographie de soins intensifs. Les résultats des examens d'ETTC et d'EASy ont été comparés en utilisant le coefficient AC1 de Gwet pour tenir compte des désaccords dus au hasard. RéSULTATS: Nous avons passé en revue 102 patients ayant reçu une ETTC sur une période de 14 mois. De ce nombre, 82 ont présenté des vues sous-costales utilisables qui ont été incluses dans l'analyse. Il y avait une importante concordance entre les examens EASy et ETTC pour évaluer qualitativement la taille du VD (AC1 de Gwet, 0,70; intervalle de confiance [IC] à 95 %, 0,54 à 0,85), la taille du VG (AC1 de Gwet, 0,73; IC 95 %, 0,58 à 0,88) et la contractilité du VG (AC1 de Gwet, 0,73; IC 95 %, 0,58 à 0,88). De plus, il y avait une concordance quasi parfaite lors de l'évaluation de la présence d'épanchement péricardique (AC1 de Gwet, 0,98; IC 95 %, 0,95 à 1,0) et de la contractilité du VD (AC1 de Gwet, 0,84; IC 95 %, 0,74 à 0,95) et de l'évaluation du mouvement du septum interventriculaire (AC1 de Gwet, 0,92; IC 95 %, 0,85 à 0,99). CONCLUSION: Lorsque les images pouvaient être obtenues à partir de la fenêtre sous-costale (examen EASy), les informations diagnostiques qualitatives étaient suffisamment précises par rapport aux informations obtenues lors de l'examen d'ETTC. Nos résultats suggèrent que l'examen EASy peut servir de technique d'apprentissage précédant l'ETTC pour les cliniciens novices.

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors.

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.

Utility of 24-hour ambulatory blood pressure monitoring in potential living kidney donors.

INTRODUCTION: Hypertension (HTN) is a risk factor for cardiovascular disease; therefore, it is imperative to risk stratify potential kidney donors during evaluation. Clinic blood pressure (CBP) measurement is inaccurate in assessing presence or absence of HTN. There is paucity of data about utility of 24-h ambulatory blood pressure monitoring (ABPM) during kidney donor evaluation. METHODS: 24-h ABPM is performed on all kidney donors at Mayo Clinic Florida. We conducted retrospective review of 264 consecutive potential kidney donors from 1/1/2012 to 12/31/2017. Demographic, comorbid conditions, laboratory results and 24-h ABPM data were collected. Subjects were divided into two groups: Group1: Subjects with no prior history of HTN and new diagnosis of HTN using 24-h ABPM; Group 2: Subjects with no prior history of hypertension and normal BP on 24-h ABPM. RESULTS: Baseline demographic included mean age 46.40 years, 39% males, 78.4% Caucasians, and mean BMI was 26.94. Twenty one subjects (8.0%) had prior diagnosis of HTN. Among 243 subjects without prior HTN, 62 (25.5%) were newly diagnosed with HTN using 24-h ABPM. CBP was high only in 27 out of 62 (43.6%) of newly diagnosed HTN subjects. Thirty-five subjects (14.4%) had masked HTN and 14 subjects (5.8%) had white-coat HTN. Newly diagnosed hypertensive subjects were more likely to be males as compared to Group 2 (53.2% vs 34.3% P = 0.008). There was a trend of more non-Caucasians subjects (30.6% vs 19.9% P = 0.08) and more active smokers (17.7% vs 11.6%, P = 0.054) in Group1 as compared to Group 2. Only 17 (27.4%) out of 62 newly diagnosed hypertensive subjects were deemed suitable for kidney donation as compared to 105 (58.0%) out of 181 normotensive subjects (P < 0.001). CONCLUSION: In our cohort, use of ABPM resulted in new diagnosis of HTN in 1 out of 4 potential kidney donors. Newly diagnosed HTN was more common in men, those with non-Caucasian race, and in active smokers. There was a significantly reduced acceptance rate for kidney donation among newly diagnosed HTN subjects. Further studies are needed to determine the value of 24-h ABPM among these high risk groups.

Assessment of psychiatric comorbidities and serotonergic or noradrenergic medication use on blood pressure using 24-hour ambulatory blood pressure monitoring.

In this study, the authors aimed to assess both nighttime and daytime blood pressure (BP) variability using 24-hour ambulatory BP monitoring (ABPM) in persons with and without psychiatric conditions and with or without selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) treatment. In this retrospective study, patients who underwent psychiatric evaluation and ABPM within 6 months of each other between January 1, 2012 and December 31, 2017 were identified using billing data. Participants were divided into three groups-participants with no psychiatric diagnosis and no psychiatric medicine (-Diagnosis/-Medication), those with psychiatric diagnosis and on SSRIs/SNRIs (+Diagnosis/+Medication), and psychiatric diagnosis but no psychiatric medications (+Diagnosis/-Medication). Day and nighttime systolic and diastolic BPs were compared between groups controlling for relevant variables using multivariable linear regression models. A total of 475 participants met inclusion criteria including 135 in the -Diagnosis/-Medication group, 232 in the +Diagnosis/+Medication group, and 108 in the +Diagnosis/-Medication group. In adjusted multivariable analysis, the +Diagnosis/+Medication group had higher nighttime systolic BP (median 120 vs 110 mm (Hg); p = .01) and nighttime diastolic BP (median 68 vs 63 mm (Hg); p = .006) as compared to -Diagnosis/-Medication. No statistically significant differences in BPs between the -Diagnosis/-Medication and +Diagnosis/-Medication groups were observed, after adjustment. Use of SSRIs/SNRIs was associated with significantly higher nocturnal systolic and diastolic BP among patients with psychiatric diagnosis using SSRIs/SNRIs but not associated with psychiatric diagnosis without SSRI/SNRI use. SSRIs/SNRIs use may be associated with higher BP levels and this merits future prospective studies using ABPM to assess day and nighttime BP changes with SSRIs/SNRIs use.

Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer's disease.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients.

OBJECTIVE: To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized coronavirus 2019 (COVID-19) patients, having previously demonstrated safety in 5000 hospitalized patients. PATIENTS AND METHODS: From April 3 to June 2, 2020, the US Food and Drug Administration Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma. RESULTS: The incidence of all serious adverse events was low; these included transfusion reactions (n=78; <1%), thromboembolic or thrombotic events (n=113; <1%), and cardiac events (n=677, ~3%). Notably, the vast majority of the thromboembolic or thrombotic events (n=75) and cardiac events (n=597) were judged to be unrelated to the plasma transfusion per se. The 7-day mortality rate was 13.0% (12.5%, 13.4%), and was higher among more critically ill patients relative to less ill counterparts, including patients admitted to the intensive care unit versus those not admitted (15.6 vs 9.3%), mechanically ventilated versus not ventilated (18.3% vs 9.9%), and with septic shock or multiple organ dysfunction/failure versus those without dysfunction/failure (21.7% vs 11.5%). CONCLUSION: These updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19, and support the notion that earlier administration of plasma within the clinical course of COVID-19 is more likely to reduce mortality.

Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience.

IMPORTANCE: Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. OBJECTIVE: To explore potential signals of efficacy of COVID-19 convalescent plasma. DESIGN: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. SETTING: Multicenter, including 2,807 acute care facilities in the US and territories. PARTICIPANTS: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. INTERVENTION: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality. RESULTS: The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. CONCLUSIONS AND RELEVANCE: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04338360.

Early safety indicators of COVID-19 convalescent plasma in 5000 patients.

BACKGROUNDConvalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.METHODSThus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma.RESULTSThe incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%.CONCLUSIONGiven the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.TRIAL REGISTRATIONClinicalTrials.gov NCT04338360.FUNDINGMayo Clinic, Biomedical Advanced Research and Development Authority (75A50120C00096), National Center for Advancing Translational Sciences (UL1TR002377), National Heart, Lung, and Blood Institute (5R35HL139854 and R01 HL059842), National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07352), Natural Sciences and Engineering Research Council of Canada (PDF-532926-2019), National Institute of Allergy and Infectious Disease (R21 AI145356, R21 AI152318, and AI152078), Schwab Charitable Fund, United Health Group, National Basketball Association, Millennium Pharmaceuticals, and Octapharma USA Inc.

Septic Arthritis in Immunosuppressed Patients: Do Laboratory Values Help?

Previous studies have recommended synovial fluid cell count thresholds of 50,000 cells/mm-3 to diagnose septic arthritis; however, data to support this are limited. It is also unknown if this value is valid in immunosuppressed patients. Methods: We retrospectively reviewed 33 immunosuppressed patients treated at our institution from 2008 to 2018. We compared culture-positive patients with culture-negative patients. Results: We found no statistically significant differences in synovial fluid cell count, percent synovial fluid neutrophils, erythrocyte sedimentation rate, or C-reactive protein between the groups (all P = 0.081). The median synovial fluid cell count in the culture-positive cohort was 29,000 cells/mm-3, with only 31.2% having >50,000 cells/mm-3. Conclusion: Traditional synovial fluid cell thresholds are not a reliable method of diagnosing septic arthritis in immunosuppressed patients.

Stroke Rate, Subtype, and Cardiovascular Risk Factors in Nonarteritic Anterior Ischemic Optic Neuropathy: A Population-Based Study.

BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common cause of acute optic neuropathy in adults and is associated with vascular risk factors. Owing to the overlapping risk factor profiles between NAION and cerebral stroke, previous studies have produced conflicting results with regard to NAION as an independent risk factor for stroke. METHODS: A retrospective chart review was conducted using the Rochester Epidemiology Project database to identify all cases of NAION occurring among Olmsted County, Minnesota residents from January 1, 1990, through December 31, 2016. Stroke events were characterized using clinical and radiologic data. Comparison was made to an age- and sex-matched control group with similar vascular risk factors. RESULTS: One-hundred four patients with NAION and 104 control subjects were analyzed. Median age at diagnosis was 65 years (range, 40-90 years). Thirteen patients (13%) with NAION and 10 controls (10%) had symptomatic strokes after the age of 40 years. Among patients with NAION, 6 (46%) suffered a stroke before the diagnosis of NAION, 5 (39%) at least 5 months after the NAION diagnosis, and 2 patients (15%) suffered strokes both before and after the NAION. The cumulative probability of symptomatic strokes for patients with NAION was not significantly different than for controls (hazard ratio = 1.50, 95% confidence interval: 0.66-3.42; P = 0.34). There were no cardioembolic strokes within 1 month of the NAION diagnosis. The mechanism of symptomatic strokes did not differ between the 2 groups. CONCLUSIONS: NAION does not confer an increased risk of symptomatic stroke beyond the risk posed by age and existing vascular risk factors.

Tetrahydrocannabinol and Cannabidiol Use in an Outpatient Palliative Medicine Population.

BACKGROUND: Palliative medicine physicians are challenged by lack of guidance regarding effectiveness and dosing of cannabis products in the setting of their emerging popularity. OBJECTIVE: The aim of this study was to describe early patterns of tetrahydrocannabinol (THC) and cannabidiol (CBD) use in Florida following passage of the state's first medical marijuana law. We describe here the perceived benefits, side effects, and beliefs expressed by patients in a single outpatient academic palliative medicine practice. METHODS: A cross-sectional survey was performed of a sequential convenience sample of patients who presented to an outpatient academic palliative medicine clinic over a 3-month period. RESULTS: In all, 24% (14/58) of respondents reported THC use, with half using THC on a daily basis. Patients reported improvements in pain, appetite, and nausea. In all, 71% (10/14) began using THC after the diagnosis of their chronic illness, and the most common form of usage was vaping. In all, 24% (14/58) of patients reported CBD use. Patients reported improvements in pain, and the most common form of usage was topical application. None of the patients had used CBD prior to the onset of their chronic illness. In all, 21% (3/14) of THC users and 21% (3/14) of CBD users thought that their substance was helping to cure their illness. Individual reported side effects in both groups were minimal. CONCLUSIONS: Approximately a quarter of outpatient palliative care patients use THC or CBD, often on a daily basis. Palliative care providers should be aware of the frequency, diverse usage, and beliefs behind cannabis product use in this patient population.

Treatment of migraine in patients with CADASIL: A systematic review and meta-analysis.

BACKGROUND: Migraine is a common and often refractory feature for individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) without consensus guidelines for treatment. Migraine treatment poses a theoretical risk within this unique population with precarious cerebrovascular autoregulation, given the vasomodulatory influence of many antimigraine medications. In this systematic review and meta-analysis, we evaluate the frequency and efficacy of treatments for migraine in individuals with CADASIL. METHODS: A search protocol was designed to include all available publications reporting antimigraine therapies for CADASIL. Individual responses to medications were categorized as unfavorable, neutral, or favorable. Responses across medication classes were compared using the Mann-Whitney U test. RESULTS: Thirteen studies were included, yielding a cohort of 123 individuals with a median age of 53 years (range: 23-83 years), with 61% (75/123) being women. No controlled trials were identified. Simple analgesics (35.8%, 44/123) and beta-blockers (22.0%, 27/123) were the most common abortive and prophylactic strategies, respectively. Over half (54.4%) of all patients had used more than 1 medication sequentially or concomitantly. Beta-blockers were significantly associated with a neutral or unfavorable response (13.5%, 22/163, p = 0.004). We found no significant associations among other medication categories. CONCLUSIONS: Migraine in CADASIL remains a formidable therapeutic challenge, with patients often tried on several medications. Antimigraine prophylaxis with beta-blockers may be contraindicated relative to other common therapies in CADASIL. Controlled studies are needed to rigorously evaluate the safety and efficacy of antimigraine therapies in this population.

Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease.

Importance: Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. Objective: To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. Design, Setting, and Participants: In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. Main Outcomes and Measures: Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. Results: In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (ß, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (ß, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (ß, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (ß, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (ß, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. Conclusions and Relevance: These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.

Cerebral Small Vessel Disease Burden and All-Cause Mortality: Mayo Clinic Florida Familial Cerebrovascular Diseases Registry.

GOAL: Cerebral small vessel disease (CSVD) leads to cognitive decline, gait disturbances, mood changes, and an increased risk of stroke. The goal of this study is to describe the relationship between a composite radiographic CSVD score and all-cause mortality. MATERIALS AND METHODS: Data were collected from a prospective registry of patients with and without cerebrovascular disease from November 2010 through April 2018. The radiographic Total CSVD Score (tSVD) ranges from 0 (minimal disease) to 4 (severe disease), based on detection of lacunar infarcts, cerebral microbleeds, perivascular spaces, and subcortical or periventricular white matter hyperintensities. All-cause mortality served as the primary endpoint. The independent relationship between CSVD burden and all-cause mortality was assessed using Cox regression models with significance being P < .05. FINDINGS: Four hundred and forty-nine patients were included (mean age, 63 years; 50.1% [225 of 449] women). The hazard ratio for mortality significantly increased with advancing score (1.92, P = .014 score 1; 2.92, P < .001 score 2; 4.23, P < .001 combined scores 3 and 4). Significance remained despite adjustment for coexistent cerebrovascular risk factors aside from age. CONCLUSIONS: The clinically practical tSVD score may serve as a predictor for all-cause mortality in populations with high disease prevalence. Continued investigations are needed to better understand the effects of risk factor modification on mortality and pathogenesis with the goal of developing disease modifying therapies.

Application of Ice for Postoperative Total Knee Incisions - Does this Make Sense? A Pilot Evaluation of Blood Flow Using Fluorescence Angiography.

Introduction Total knee arthroplasty (TKA) is a common procedure with significant advances over the past several years, many pertaining to improved perioperative pain control. Cryotherapy is one method thought to decrease swelling and pain postoperatively. To our knowledge no study has directly visualized the effect cryotherapy has on skin blood flow following TKA. The primary aim was to determine if cryotherapy (icing) affects peri-incisional skin blood flow and if this is lessened with an alternate placement of the ice. We hypothesized that blood flow would decrease following cryotherapy, and this decrease would be greater with ice placed directly over the incision as compared to placement along the posterior knee. Methods This study included 10 patients who underwent TKA. During the postoperative hospitalization, they were given an injection of indocyanine green dye. A baseline image was recorded of the skin blood flow. Images were then collected following a five-minute interval placement of ice over the incision. The experiment was then repeated with the ice placed along the posterior knee.  Results There was an approximate 40% decrease in skin blood flow following placement of the ice compared to baseline. We observed a greater decrease in blood flow when ice was placed over the incision as compared to when ice was placed posterior to the knee (p ≤ 0.020). Conclusion We found a significant decrease in peri-incisional blood flow with icing of the knee. Physicians should be cognizant of this when recommending cryotherapy to patients after surgery, especially in at-risk wounds.

Population-Based Evaluation of Lumbar Puncture Opening Pressures.

Importance: Prior studies evaluating opening pressure (OP) have mostly involved lumbar puncture (LP) for diagnosis of neurologic disease or small cohorts of healthy volunteers and therefore the normal OP is not well-defined. Objective: The goal of this study was to establish the normal range of OP in a community-based population using the Mayo Clinic Study of Aging (MCSA) and to evaluate factors that contribute to OP variability. Design: LP OP were obtained from participants aged 32-95 years between 11/1/07 and 10/1/17, as part of routine data collection for the MCSA, a longitudinal, population-based study of residents of Olmsted County, Minnesota. Setting: A longitudinal, population-based study of residents of Olmsted County, Minnesota. Participants: There were 639 participants (56.8% male; 98.5% white) who underwent LP with recorded OP as part of the MCSA. Intervention: LP. Main Outcome(s) and Measure(s): LP OP was recorded along with variables that could possibly influence its variability, including age, body mass index (BMI), and obstructive sleep apnea (OSA). Results: Six hundred thirty-nine participants (56.8% men) underwent LP with recorded OP; average age was 71.0 years (SD 10.9) with a mean BMI of 28.0 (SD 4.6). Mean OP was 155.4 mmH2O (SD 41.9) with a 95% reference interval of 82-242 mmH2O (range 60-314; Q1, Q3: 124, 182). Increasing age was associated with lower OP (p < 0.001), while increasing BMI was associated with higher OP (p < 0.001). Twelve (2%) participants had OP ≥ 250 mmH2O; they were younger [58.5 (SD 8.2), p < 0.001], had higher BMI [33.6 (SD 4.6), p < 0.001], and were more likely to have OSA (75%, p < 0.001). Among the 79 participants with repeat LPs within 2.5 years, the coefficient of repeatability (CR) was 64.9. Ten (12.7%) had an OP difference ≥50 mmH2O between serial LPs. Conclusions and Relevance: This large population-based study showed that LP OP can vary significantly among individuals. Higher OPs were associated with higher BMI and younger age.

A Collaborative Approach to Pain Control Reduces In-hospital Opioid Use and Improves Range of Motion following Total Knee Arthroplasty.

INTRODUCTION: Opioid pain medications are commonly prescribed following orthopedic procedures, with overprescribing of these pain medications implicated as a driver of the current opioid epidemic. In an effort to reduce reliance on opioid pain medications, surgeons are relying on periarticular injections or peripheral nerve blocks. The purpose of this study was to compare numerical rating scale (NRS) pain scores and oral morphine equivalents (OMEs) in patients who underwent primary total knee arthroplasty (TKA) with a periarticular injection alone to those who underwent a collaborative approach with a periarticular injection in the posterior tissue and an adductor canal catheter for anterior knee analgesia. METHODS: In this study, 236 patients underwent a primary TKA between December 2017 and April 2018. Forty patients received an adductor canal catheter and 196 underwent a periarticular injection alone. RESULTS: We found no difference in patient demographics between the cohorts (p>0.05). The patients that underwent the collaborative approach with a periarticular injection and adductor canal catheter had lower NRS pain scores on post-operative day 0, 1, and 2 (all P≤0.033). These patients demonstrated a reduction of 43% in opioid consumption during the hospitalization (P<0.001). These patients also demonstrated improved range of motion (ROM) (96 vs. 92 degrees) on the day of discharge (P=0.013). CONCLUSION: This study provides strong evidence that in patients undergoing TKA, the collaborative approach with the adductor canal catheter and periarticular injection is associated with lower post-operative pain scores, fewer total OMEs per hospital day, and a greater ROM arc prior to discharge compared to patients receiving a periarticular injection alone.