Citations

Abstract Study Objectives Isolated REM sleep behavior disorder (iRBD) carries a high lifetime risk for phenoconversion to a defined neurodegenerative disease (NDD) including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. We aimed to examine iRBD patient values and preferences regarding prognostic counseling. Methods One hundred thirteen iRBD patient participants enrolled in the Mayo Clinic iRBD Patient Registry were sent an email survey concerning their values and preferences concerning NDD prognostic counseling and their experiences following diagnosis with iRBD. Results Of 81 respondents (71.7% response rate), the majority were men (74.0%) with an average age of 65.7 (±9.7) years. Responses indicated a strong preference toward receiving prognostic information about possible future NDD development. 92.5% of respondents felt knowledge concerning personal NDD risk was important, while 87.6% indicated prognostic discussions were important to maintaining trust in their physician. 95.7% indicated a desire for more information, while only 4.3% desired less information regarding their NDD prognostic risk. Most respondents strongly agreed that prognostic information was important to discuss with their family and friends and inform future life planning, and most expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia. Conclusions Most iRBD patients indicated strong preferences for disclosure of NDD prognostic risk and indicated that prognostic information was important for family discussions and future life planning. Future broader surveys and qualitative studies of clinic-based and ultimately community dwelling iRBD patients’ values and preferences are needed to guide appropriately tailored and individualized prognostic counseling approaches following iRBD diagnosis.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

AbstractIntroductionThe Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50‐60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022.MethodsADNI4 will recruit URPs using community‐engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50‐60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in‐clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials.Results and DiscussionADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

ObjectiveTo determine the characteristics of participants with amyloid‐related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD).Methods142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β‐amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross‐sectional and longitudinal analyses evaluated potential ARIA‐related risk factors.ResultsEleven participants developed ARIA‐E, including 3 with mild symptoms. No ARIA‐E was reported under solanezumab while gantenerumab was associated with ARIA‐E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE‐ɛ4 carriers were more likely to develop ARIA‐E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA‐E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA‐E occurrence, all ARIA‐E participants were amyloid‐PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA‐H. Most ARIA‐E radiologically resolved after dose adjustment and developing ARIA‐E did not significantly increase odds of trial discontinuation. ARIA‐E was more frequently observed in the occipital lobe (90%). ARIA‐E severity was associated with age at time of ARIA‐E.InterpretationIn DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA‐E risk, with additional risk for individuals APOE‐ɛ4(+) or with microhemorrhage. ARIA‐E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729–744

BACKGROUND: The modified Japanese Orthopedic Association (mJOA) score is a widely used and validated metric for assessing severity of myelopathy. Its relationship to functional and quality-of-life outcomes after surgery has not been fully described. OBJECTIVE: To quantify the association of the mJOA with the Neck Disability Index (NDI) and EuroQol-5 Dimension (EQ-5D) after surgery for degenerative cervical myelopathy. METHODS: The cervical module of the prospectively enrolled Quality Outcomes Database was queried retrospectively for adult patients who underwent single-stage degenerative cervical myelopathy surgery. The mJOA score, NDI, and EQ-5D were assessed preoperatively and 3 and 12 months postoperatively. Improvement in mJOA was used as the independent variable in univariate and multivariable linear and logistic regression models. RESULTS: Across 14 centers, 1121 patients were identified, mean age 60.6 ± 11.8 years, and 52.5% male. Anterior-only operations were performed in 772 patients (68.9%). By univariate linear regression, improvements in mJOA were associated with improvements in NDI and EQ-5D at 3 and 12 months postoperatively (all P < .0001) and with improvements in the 10 NDI items individually. These findings were similar in multivariable regression incorporating potential confounders. The Pearson correlation coefficients for changes in mJOA with changes in NDI were −0.31 and −0.38 at 3 and 12 months postoperatively. The Pearson correlation coefficients for changes in mJOA with changes in EQ-5D were 0.29 and 0.34 at 3 and 12 months. CONCLUSION: Improvements in mJOA correlated weakly with improvements in NDI and EQ-5D, suggesting that changes in mJOA may not be a suitable proxy for functional and quality-of-life outcomes.

AbstractBackgroundProstatic specific antigen (PSA) has well‐recognized limitations as a marker for treatment response and disease progression. Post hoc analysis of the PREVAIL trial reported 24.5% of chemotherapy naïve metastatic castration‐resistant prostate cancer (mCRPC) patients on enzalutamide had radiographic progression on conventional imaging with nonrising PSA. In this study, we sought to study the discordance of imaging with PSA kinetics in mCRPC patients on second generation anti‐androgens (SGA) post‐chemotherapy using combined conventional imaging, and new generation imaging in the form of C‐11 choline positron emission tomography/computed tomography (C[11] choline PET/CT) scan.MethodsWe retrospectively reviewed the medical records of 123 patients with mCRPC treated with SGA (Abiraterone or Enzalutamide) after docetaxel between 2016 and 2019. Patients underwent PSA testing, and C[11] choline PET/CT scan at baseline level before starting treatment with SGA, then every 3–6 months as part of their follow up evaluation. Loss of response to SGA was defined by increase in corrected maximum standardized uptake value (SUVmax) of pretreatment lesions on C‐11 Choline PET/CT, and/or development of new lesions. Suspicious new lesions were confirmed by biopsy and/or conventional imaging.ResultsWe identified 123 mCRPC patients who received SGA (Abiraterone, n = 106; Enzalutamide, n = 17) after docetaxel. Median duration of therapy was 13.9 months (interquartile range: 8.75–21.14). Approximately 43% (n = 53) of subjects in this study exhibited an increase in choline avidity while on SGA. Of this group, 60.4% of patients experienced a parallel rise in PSA (Group‐A), whereas 39.6% displayed a paradoxical response (PR) (Group‐B), defined as increased choline avidity combined with stable or down‐trending PSA. Median PSA at time of increase in choline avidity was 3.1 ng/ml for Group‐A, and 1.3 ng/ml for Group‐B (p = 0.0176). Median SUVmax was similar in both groups (4.9 for Group‐A, 4.6 for Group‐B; p = 0.6072). The median time for increase in choline avidity was 9.5 versus 3.9 months for Group‐A versus Group‐B, respectively (Log‐Rank = 0.0063).ConclusionNearly 40% of mCRPC patients placed on SGA post docetaxel chemotherapy will exhibit paradoxical responses to therapy, therefore, warranting close follow up with imaging. C‐11 choline PET/CT imaging is a useful tool that can help in early predication of disease progression or treatment failure.

ImportanceThere was a shift in patient volume from in-person to video telemedicine visits during the COVID-19 pandemic.ObjectiveTo determine the concordance of provisional diagnoses established at a video telemedicine visit with diagnoses established at an in-person visit for patients presenting with a new clinical problem.Design, Setting, and ParticipantsThis is a diagnostic study of patients who underwent a video telemedicine consultation followed by an in-person outpatient visit for the same clinical problem in the same specialty within a 90-day window. The provisional diagnosis made during the video telemedicine visit was compared with the reference standard diagnosis by 2 blinded, independent medical reviewers. A multivariate logistic regression model was used to determine factors significantly related to diagnostic concordance. The study was conducted at a large academic integrated multispecialty health care institution (Mayo Clinic locations in Rochester, Minnesota; Scottsdale and Phoenix, Arizona; and Jacksonville, Florida; and Mayo Clinic Health System locations in Iowa, Wisconsin, and Minnesota) between March 24 and June 24, 2020. Participants included Mayo Clinic patients residing in the US without age restriction. Data analysis was performed from December 2020 to June 2021.ExposuresNew clinical problem assessed via video telemedicine visit to home using Zoom Care Anyplace integrated into Epic.Main Outcomes and MeasuresConcordance of provisional diagnoses established over video telemedicine visits compared against a reference standard diagnosis.ResultsThere were 2393 participants in the analysis. The median (IQR) age of patients was 53 (37-64) years; 1381 (57.7%) identified as female, and 1012 (42.3%) identified as male. Overall, the provisional diagnosis established over video telemedicine visit was concordant with the in-person reference standard diagnosis in 2080 of 2393 cases (86.9%; 95% CI, 85.6%-88.3%). Diagnostic concordance by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision chapter ranged from 64.7% (95% CI, 42.0%-87.4%) for diseases of the ear and mastoid process to 96.8% (95% CI, 94.7%-98.8%) for neoplasms. Diagnostic concordance by medical specialty ranged from 77.3% (95% CI, 64.9%-89.7%) for otorhinolaryngology to 96.0% (92.1%-99.8%) for psychiatry. Specialty care was found to be significantly more likely than primary care to result in video telemedicine diagnoses concordant with a subsequent in-person visit (odds ratio, 1.69; 95% CI, 1.24-2.30; P &amp;lt; .001).Conclusions and RelevanceThis diagnostic study of video telemedicine visits yielded a high degree of diagnostic concordance compared with in-person visits for most new clinical concerns. Some specific clinical circumstances over video telemedicine were associated with a lower diagnostic concordance, and these patients may benefit from timely in-person follow-up.

Abstract Background Although telehealth holds promise in expanding access to orthopaedic surgical care, high-speed internet connectivity remains a major limiting factor for many communities. Despite persistent federal efforts to study and address the health information technology needs of patients, there is limited information regarding the current high-speed internet landscape as it relates to access to orthopaedic surgical care. Questions/purposes (1) What is the distribution of practicing orthopaedic surgeons in the United States relative to the presence of broadband internet access? (2) What geographic, demographic, and socioeconomic factors are associated with the absence of high-speed internet and access to a local orthopaedic surgeon? Methods The Federal Communications Commission (FCC) Mapping Broadband in America interactive tool was used to determine the proportion of county residents with access to broadband-speed internet for all 3141 US counties. Data regarding the geographic distribution of orthopaedic surgeons and county-level characteristics were obtained from the 2015 Physician Compare National Downloadable File and the Area Health Resource File, respectively. The FCC mapping broadband public use files are considered the most comprehensive datasets describing high-speed internet infrastructure within the United States. The year 2015 represents the most recently available FCC data for which county-level broadband penetration estimates are available. Third-party audits of the FCC data have shown that broadband expansion has been slow over the past decade and that many large improvements have been driven by changes in the reporting methodology. Therefore, we believe the 2015 FCC data still hold relevance. The primary outcome measure was the simultaneous absence of at least 50% broadband penetration and at least one orthopaedic surgeon practicing in county limits. Statistical analyses using Kruskal-Wallis tests and multivariable logistic regression were conducted to assess for factors associated with inaccessibility to orthopaedic telehealth. All statistical tests were two-sided with a significance threshold of p < 0.05. Results In 2015, 14% (448 of 3141) of counties were considered “low access” in that they both had no orthopaedic surgeons and possessed less than 50% broadband access. A total of 4,660,559 people lived within these low-access counties, representing approximately 1.4% (4.6 million of 320.7 million) of the US population. After controlling for potential confounding variables, such as the age, sex, income level, and educational attainment, lower population density per square mile (OR 0.92 [95% confidence interval (CI) 0.90 to 0.94]; p < 0.01), a lower number of primary care physicians per 100,000 (OR 0.88 [95% CI 0.81 to 0.97]; p < 0.01), a higher unemployment level (OR 1.3 [95% CI 1.2 to 1.4]; p < 0.01), and greater number preventable hospital stays per 100,000 (OR 1.01 [95% CI 1.01 to 1.02]; p < 0.01) were associated with increased odds of being a low-access county (though the effect size of the finding was small for population density and number of primary care physicians). Stated another way, each additional person per square mile was associated with an 8% (95% CI 6% to 10%; p < 0.01) decrease in the odds of being a low-access county, and each additional percentage point of unemployment was associated with a 30% (95% CI 20% to 40%) increase in the odds of being a low-access county. Conclusion Despite the potential for telehealth programs to improve the delivery of high-quality orthopaedic surgical care, broadband internet access remains a major barrier to implementation. Until targeted investments are made to expand broadband infrastructure across the country, health systems, policymakers, and surgeon leaders must capitalize on existing federal subsidy programs, such as the lifeline or affordability connectivity initiatives, to reach unemployed patients living in economically depressed regions. The incorporation of internet access questions into clinic-based social determinants screening may facilitate the development of alternative follow-up protocols for patients unable to participate in synchronous videoconferencing. Clinical Relevance Some orthopaedic patients lack the broadband capacity necessary for telehealth visits, in which case surgeons may pursue alternative methods of follow-up such as mobile phone–based surveillance of postoperative wounds, surgical sites, and clinical symptoms.

Abstract The aim of this cross‐sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical‐linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.