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.).

Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

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.

The Relationship Between Anti-SSA-52 and Interstitial Lung Disease.

OBJECTIVE: The aims of this study were to assess whether a relationship between anti-SSA-52 and interstitial lung disease (ILD) can be further defined, and to enhance screening, detection, and potentially guide treatment. METHODS: A historical cohort study of 201 patients was conducted at a single tertiary care center between January 1, 2016 and December 31, 2020. All included patients were anti-SSA-52 antibody positive. Chart review was performed for laboratory values, symptoms, pulmonary function tests, treatment, and imaging. Chest computed tomographies were reviewed by chest radiologists. RESULTS: Among anti-SSA-52 antibody-positive patients, ILD was found in 125 (62.2%) compared with 76 (37.8%) with no ILD (p = 0.001). For those with ILD, 78 (62.4%) were diagnosed with connective tissue disease (CTD)-associated ILD, 28 (22.4%) were diagnosed ILD only, and 19 (15.2%) met the criteria for interstitial pneumonia with autoimmune features. In patients with CTD-ILD, 18 (23.0%) had their ILD diagnosis made over 6 months before a CTD diagnosis, and an additional 43 (55.1%) had their ILD and CTD diagnosed within 6 months of each other (p < 0.001). Common computed tomography patterns were nonspecific interstitial pneumonia/organizing pneumonia overlap in 44 (35.2%), 25 (20.0%) nonspecific interstitial pneumonia, and 15 (12%) usual interstitial pneumonia. Twenty-eight (35.9%) had antisynthetase syndrome, followed by 16 (20.5%) with dermatomyositis, 10 (12.8%) with CTD overlap, and 6 (7.7%) with systemic scleroderma. CONCLUSIONS: There was a significant association between anti-SSA-52 antibodies and ILD across a wide spectrum of rheumatological diagnoses. A significant portion of patients were diagnosed with ILD either at the same time or before their CTD diagnosis. Further study will be needed to assess effective treatment and response.

Upadacitinib as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs for psoriatic arthritis.

OBJECTIVE: To assess the efficacy and safety of upadacitinib (UPA), an oral Janus kinase inhibitor, as monotherapy or in combination with non-biologic DMARDs (nbDMARDs) in patients with PsA. METHODS: Pooled data were analysed from patients with prior inadequate response or intolerance to one or more nbDMARD (SELECT-PsA 1) or one or more biologic DMARD (SELECT-PsA 2) who received placebo, UPA 15 mg once daily (QD) or UPA 30 mg QD as monotherapy or in combination with two or fewer nbDMARDs for 24 weeks. Efficacy outcomes included achievement of ACR responses, Psoriasis Area and Severity Index responses, minimal disease activity and change from baseline and clinically meaningful improvement in the HAQ Disability Index. Adverse events (AEs) were summarized. RESULTS: A total of 1916 patients were included; 574 (30%) received monotherapy and 1342 (70%) received combination therapy. Placebo-subtracted treatment effects for a 20% improvement in ACR criteria at week 12 were 33.7% (95% CI 24.4, 43.1) and 34.0% (95% CI 27.9, 40.1) for UPA 15 mg QD monotherapy and combination therapy, respectively, and 45.7% (95% CI 36.9, 54.5) and 39.6% (95% CI 33.7, 45.5) for UPA 30 mg QD monotherapy and combination therapy, respectively. Treatment effects for other outcomes were consistent between monotherapy and combination therapy. AE frequency was generally similar for UPA monotherapy and combination therapy, although hepatic disorders and creatine phosphokinase elevation were more common with combination therapy vs monotherapy. CONCLUSION: The efficacy and safety of UPA were generally consistent when administered as monotherapy or in combination with nbDMARDs through 24 weeks, supporting the use of UPA with or without nbDMARDs in PsA. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov): SELECT-PsA 1 (NCT03104400), SELECT-PsA 2 (NCT03104374).

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.

Clinical Outcomes following Left Atrial Appendage Occlusion: A Single-Center Experience.

INTRODUCTION: Percutaneous left atrial appendage closure is an established alternative to anticoagulation therapy for stroke prophylaxis among patients with nonvalvular atrial fibrillation. There are currently no guidelines on the choice of antithrombotic therapy following placement of the Watchman® device, the optimal time to discontinue anticoagulation or the duration of follow-up imaging after device deployment. Our main objective was to evaluate clinical outcomes among these patients. METHODS: We conducted a retrospective review of patients who received a Watchman® device at Mayo Clinic sites between January 2010 and December 2018. We constructed Cox-proportional hazard models to evaluate the effect of specific variables on clinical outcomes. RESULTS: 231 patients were identified (33% female), median age was 77 years, CHA2DS2-VASc score was 5 and HASBLED score was 4. We found no difference in clinically significant bleeding based on initial antithrombotic choice. However, patients with prior gastrointestinal bleeding were more likely to have a bleeding event in the first 6 weeks following Watchman® implantation (HR 9.40, 95% CI 2.15-41.09). Device sizes of 24-27 mm were significantly associated with a decreased risk of thromboembolic events (HR 0.15, 95% CI 0.04-0.55) compared to 21-mm devices. Peridevice leak (PDL) sizes appeared to either remain the same or increase on follow-up imaging. DISCUSSION/CONCLUSIONS: This observational study showed no statistically significant difference in bleeding risk related to initial antithrombotic choice. Smaller device sizes were associated with thromboembolic events, and longitudinal PDL assessment using transesophageal echocardiography showed these frequently do not decrease in size. Larger studies are needed.

Trends in glioblastoma: outcomes over time and type of intervention: a systematic evidence based analysis.

INTRODUCTION: Despite aggressive treatment with chemoradiotherapy and maximum surgical resection, survival in patients with glioblastoma (GBM) remains poor. Ongoing efforts are aiming to prolong the lifespan of these patients; however, disparities exist in reported survival values with lack of clear evidence that objectively examines GBM survival trends. We aim to describe the current status and advances in the survival of patients with GBM, by analyzing median overall survival through time and between treatment modalities. METHODS: A systematic review was conducted according to PRISMA guidelines to identify articles of newly diagnosed glioblastoma from 1978 to 2018. Full-text glioblastoma papers with human subjects, ≥ 18 years old, and n ≥ 25, were included for evaluation. RESULTS: The central tendency of median overall survival (MOS) was 13.5 months (2.3-29.6) and cumulative 5-year survival was 5.8% (0.01%-29.1%), with a significant difference in survival between studies that predate versus postdate the implementation of temozolomide and radiation, [12.5 (2.3-28) vs 15.6 (3.8-29.6) months, P < 0.001]. In clinical trials, bevacizumab [18.2 (10.6-23.0) months], tumor treating fields (TTF) [20.7 (20.5-20.9) months], and vaccines [19.2 (15.3-26.0) months] reported the highest central measure of median survival. CONCLUSION: Coadministration with radiotherapy and temozolomide provided a statistically significant increase in survival for patients suffering from glioblastoma. However, the natural history for GBM remains poor. Therapies including TTF pooled values of MOS and provide means of prolonging the survival of GBM patients.

Selective loss of cortical endothelial tight junction proteins during Alzheimer's disease progression.

While the accumulation and aggregation of amyloid-ß and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer's disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer's disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer's disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer's disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer's disease-related proteins, in particular amyloid-ß40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer's disease is associated with insoluble amyloid-ß40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-ß40, amyloid-ß42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer's disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer's disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer's disease pathogenesis in both synergistic and additive manners to typical amyloid-ß and tau pathologies.

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.

Association of antinuclear antibody status with clinical features and malignancy risk in adult-onset dermatomyositis.

BACKGROUND: The clinical significance of antinuclear antibody (ANA) status in adults with dermatomyositis (DM) has yet to be fully defined. OBJECTIVE: We compared the incidence of amyopathic disease, risk of malignancy, and clinical findings in ANA+ and ANA- patients with adult-onset DM. METHODS: This was a retrospective cohort study of patients with ANA+ or ANA- adult-onset DM determined by enzyme-linked immunosorbent assay. RESULTS: Of 231 patients, 140 (61%) were ANA+ and 91 (39%) were ANA-. Compared with the ANA- patients, the ANA+ patients had a lower frequency of dysphagia (15% vs 26% [P = .033]) and heliotrope rash (38% vs 53% [P = .026]). In all, 54 patients (23%) developed malignancy within 3 years of diagnosis of their DM; 11% of the ANA+ patients developed malignancy versus 43% of the ANA- patients (P < .001). There was a strong association between ANA positivity and lower likelihood of malignancy in multivariable analysis (odds ratio, 0.16; P < .001). Conversely, ANA positivity was not associated with amyopathic disease (odds ratio, 0.94; P = .87). LIMITATIONS: The retrospective nature of the study was a limitation. CONCLUSION: In patients with adult-onset DM, ANA negativity is associated with increased likelihood of development of malignancy within 3 years of diagnosis of their DM. Particularly close follow-up and frequent malignancy screening may be warranted in ANA- individuals with DM.

Early In-Hospital Pain Control Is a Stronger Predictor for Patients Requiring a Refill of Narcotic Pain Medication Compared to the Amount of Narcotics Given at Discharge.

BACKGROUND: The United States is combating an opioid epidemic. Orthopedic surgeons are the third highest opioid prescribers and therefore have an opportunity and obligation to assist in the efforts to reduce opioid use and abuse. In this article, we evaluate risk factors for patients requiring an opioid refill after primary total knee arthroplasty, with the goal to reduce opioid prescriptions for those patients at low risk of requiring a refill in order to reduce the amount of unused medication. METHODS: We retrospectively reviewed narcotic-naïve patients who underwent total knee arthroplasty from December 2017 to May 2018. We performed multivariable analysis on demographics and preoperative, operative, and postoperative characteristics to determine risk factors for requiring a prescription refill following hospital discharge. RESULTS: One-hundred fifty-seven patients were included in the analysis. Sixty percent of patients required a prescription refill. Risk factors included younger age (P = .003) and increased pain on postoperative day one (P < .001). The amount of narcotic medication given at discharge did not independently affect the refill rate (P = .21). CONCLUSION: There is strong evidence that elderly patients and those with good pain control on postoperative day 1 are at a lower risk of requiring a narcotic refill postoperatively. With this information, physicians may begin to tailor narcotic prescriptions based on patient risk factors for requiring a prescription refill rather than provide patients with the same number of pills for a given surgery in an effort to reduce unused narcotic medication.

Ethnoracial differences in Alzheimer's disease from the FLorida Autopsied Multi-Ethnic (FLAME) cohort.

INTRODUCTION: Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases. METHODS: A retrospective study was conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539). RESULTS: Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups. DISCUSSION: Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.

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.

Pharmacotherapy for Patients with Atrial Fibrillation and Cerebral Microbleeds.

BACKGROUND: Patients with cerebral microbleeds have increased risk of intracranial hemorrhage and ischemic stroke. No trial specifically informs antithrombotic therapy for patients with cerebral microbleeds and atrial fibrillation. We investigated the safety of anticoagulation versus no anticoagulation with regard to cerebrovascular outcomes and mortality. METHODS: All consecutive atrial fibrillation patients from 2015 to 2018 with MRI evidence of ≥1 cerebral microbleed at time of imaging were reviewed. Patients were treated with warfarin, direct oral anticoagulants, or neither. Primary outcome was all-cause mortality informed by National Death Registry and the composite of ischemic and hemorrhagic stroke. All statistical tests were 2-sided and significant at P < .05. RESULTS: The median interval from patient identification until the end of electronic health record surveillance was 9.93 months (interquartile range, 2.83-19.17 months). We identified 308 atrial fibrillation patients with cerebral microbleeds; 128(41.6%) were on warfarin, 88(28.6%) on direct oral anticoagulants, and 92(29.9%) on neither. Over the surveillance interval, 87 deaths, 51 ischemic strokes, and 14 hemorrhagic strokes occurred. The estimated likelihoods of the composite stroke outcome and ischemic stroke only did not differ significantly among the 3 groups. However, patients taking direct oral anticoagulants had a significantly smaller likelihood of all-cause mortality than patients who were not anticoagulated (adjusted hazard ratio: .44[.23, .83], P=.012). CONCLUSIONS: In patients with coprevalent atrial fibrillation and cerebral microbleeds, we did not detect differences in subsequent ischemic stroke, hemorrhagic stroke, or both, comparing warfarin, direct oral anticoagulants, or neither. Patients treated with direct oral anticoagulants had better survival than nonanticoagulated patients.

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.

Skin Clearance is Associated with Reduced Treatment Failure in Patients with Psoriasis: Real-World Evidence from the CorEvitas Psoriasis Registry.

INTRODUCTION: Complete and near-complete skin clearance have become achievable treatment goals for patients with psoriasis receiving systemic biologic therapies. However, there is limited real-world evidence regarding the impact of the degree of skin clearance on biologic treatment patterns among these patients. METHODS: This longitudinal cohort study assessed the relationship between degree of skin clearance following initiation of a systemic biologic therapy and treatment failure among patients from the CorEvitas Psoriasis Registry (April 2015-August 2021). Patients had Psoriasis Area and Severity Index (PASI) score > 5 at systemic biologic therapy initiation and ≥ 1 follow-up visit(s) within 15 months of initiation. Treatment failure (discontinuation due to poor response/adverse event; addition of non-biologic therapy) and degree of skin clearance (measured by PASI) were assessed following biologic initiation. Proportional hazards regression was used to estimate the association between PASI response level and treatment failure over follow-up. RESULTS: This study included 2701 patient initiations from 2516 unique patients with 3846 total visits over follow-up. Over half of the patient initiations (n = 1412; 52.3%) were among patients with PASI >10. Treatment failure occurred in 1.3% of visits at which PASI100 was achieved, while those achieving PASI90 - < 100 and PASI75 - < 90 had treatment failure rates of 3.4% and 3.5%, respectively. After adjustment for confounders, the risk of treatment failure was two to three times higher in the PASI90 - < 100 (hazard ratio [HR] = 2.61; 95% confidence interval [CI] 1.35, 5.02; p = 0.004) and PASI75 < 90 (HR = 2.97; CI 1.58, 5.58; p = 0.001) groups compared to the PASI100 group. The risk of treatment failure was more than 20 times higher in the < PASI75 group versus the PASI100 group (HR = 22.26; CI 13.32, 37.21; p < 0.001). CONCLUSIONS: The results suggest that patients are more likely to remain on a systemic biologic therapy if they achieve near-complete or complete skin clearance, supporting the continued need to target skin clearance as a treatment goal in psoriasis. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02707341.

Many people with psoriasis are often treated with biologic medications that work to improve symptoms associated with psoriasis, including inflammation. These medications can lead to clear or almost-clear skin for many people. However, there is limited information available about how achieving this goal affects whether patients continue taking their biologic medication or add a new non-biologic medication. The data source for this study was a database of patients with psoriasis (the CorEvitas Psoriasis Registry) that records how clear patients' skin is and what medications they take. Over 1 year after starting a biologic medication, approximately 1 out of every 100 patients that achieved clear skin after taking a biologic medication stopped using that medication, and approximately 3 out of every 100 patients with almost-clear skin after taking a biologic medication stopped using that medication. Meanwhile, around 20 out of every 100 patients that did not have clear or almost-clear skin after taking a biologic medication stopped using that medication. Furthermore, patients who did not have clear or almost-clear skin after taking a biologic medication had more than 20 times greater risk of stopping their medication than those who did have clear or almost-clear skin after taking a biologic medication. These results suggest that patients are more likely to remain on their biologic medication if they experience clear or almost-clear skin after taking a biologic medication and that patients and their providers should aim for this goal when taking a biologic medication.

Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials.

INTRODUCTION: This integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug. METHODS: Safety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020. RESULTS: A total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon. CONCLUSIONS: Upadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib. TRIAL REGISTRATION NUMBERS: SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Psoriatic arthritis is a disease that causes inflammation of the skin and joints. Upadacitinib and adalimumab are medicines that can be used to treat this condition. This analysis combined safety data from two studies of adults with psoriatic arthritis who took upadacitinib, adalimumab, or placebo (no medicine) for up to 3 years. The most common side effects of treatment with upadacitinib were infection and inflammation of the nose and throat and higher amounts of a protein in the blood called creatinine phosphokinase. The total number of cancer cases, heart (cardiovascular) problems, blood clots (embolisms), and deaths were similar across treatment groups, including the placebo (no medicine) group. However, more patients who took upadacitinib than adalimumab or placebo (no medicine) had a painful rash that causes blisters known as herpes zoster (shingles) and infections usually seen in people with a weakened immune system. Most patients had normal blood test results and continued their treatment. Overall, upadacitinib was well tolerated for up to 3 years in patients with psoriatic arthritis. These results agree with what has been found in studies of upadacitinib in patients with rheumatoid arthritis. Safety data of upadacitinib use over a longer time will be reported later.

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.

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.