Herpes zoster diagnosis and treatment in relation to incident dementia: A population-based retrospective matched cohort study.

BACKGROUND: Evidence suggests that some infectious diseases, such as herpes zoster (HZ), are associated with elevated risk of subsequent dementia, while certain anti-viral medications are associated with lower risk. We sought to evaluate associations between HZ diagnosis and treatment with incident dementia in a large, retrospective matched cohort. METHODS: Using ICD-9 and ICD-10 diagnosis codes in electronic medical records, we identified members of Kaiser Permanente Northwest age 50 and older from 2000-2019 with a HZ diagnosis during this period. A comparison group without HZ diagnosis was individually matched 3:1 on age at HZ diagnosis date (index date), sex, and membership length prior to index date. We excluded subjects with dementia diagnosed before the index date. Antiherpetic medication was identified using pharmacy fills 1 month before to 12 months after the index date. We employed survival analysis to examine the associations between dementia and HZ diagnosis and antiherpetic medication, adjusting multivariable models for demographic and clinical factors. We stratified on age and sex and conducted a sensitivity analysis with a 5-year lag period. RESULT: The study included 101,328 persons, 25,332 with HZ. Over a median follow-up of 4.8 years, 6,000 developed dementia. HZ diagnosis was not associated with higher hazard of dementia (hazard ratio (HR) = 0.99, 95% CI 0.93-1.05) in the primary analysis. Among persons with HZ diagnoses, the HR for receipt of any antiherpetic medication was 0.79 (95% CI 0.70-0.90) in univariate analysis and 0.88 (95% CI 0.77-1.00) after adjustment for demographic and clinical factors. Dementia was not associated with trends in duration of medication use or cumulative dose. CONCLUSIONS: We found little evidence for an association between HZ diagnosis and dementia overall. Antiherpetic medication prescribed around the time of HZ diagnosis was statistically associated with lower risk of subsequent dementia in some but not all analyses and subgroups.

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study.

Background and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course. Clinicaltrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Midlife Hemostasis Measures, 20-Year Cognitive Decline, and Incident Dementia.

BACKGROUND AND OBJECTIVES: Blood concentrations of hemostatic factors affect thrombosis and bleeding diathesis and may contribute to cognitive impairment through modifiable vascular pathologies. Whether hemostasis, assessed in middle age, is associated with late-life cognitive impairment remains largely unknown in a community-dwelling population. METHODS: Using data from 14,128 participants with cognitive function measurements in 1990-1992 from the Atherosclerosis Risk in Communities study, we assessed the associations of hemostasis measures with 20-year changes in cognitive performance and incident dementia. Activated partial thromboplastin time (aPTT) and level of fibrinogen, von Willebrand factor (VWF), factor VIII, factor VII, factor XI, d-dimer, and soluble thrombomodulin were measured in 1987-1989 or 1993-1995. Hemostasis measures were categorized into quintiles, with the lowest quintile indicating low coagulability. Cognitive performance was characterized using a combined z-score from 3 tests (that is, delayed word recall test [DWRT], digit symbol substitution [DSST], and word fluency test [WFT]), assessed in 1990-1992, 1996-1998, and 2011-2013. Dementia was determined either from in-person evaluations or using dementia surveillance through 2017. Mixed-effects models and Cox proportional hazards models were used to assess cognitive trajectories and risk of dementia, respectively. RESULTS: Among 12,765 participants with hemostasis measures in 1987-1989, who were aged 47-70 years at the first cognitive assessment, we observed significant trends of shorter aPTT (p for trend <0.001; difference in 20-year cognitive decline for fifth vs first quintile [Q5 vs Q1]: -0.104 [95% CI -0.160 to -0.048]) and higher levels of factor VII (p < 0.002; Q5 vs Q1: -0.085 [-0.142, -0.028]) and factor VIII (p = 0.033; Q4 vs Q1: -0.055 [-0.111, -0.000]) with greater 20-year cognitive declines. The associations with the decline in DSST were stronger than those with the decline in WFT or DWRT. Consistently, shorter aPTT and higher factor VIII levels were associated with higher dementia risk with HRs for Q5 vs Q1 of 1.23 (95% CI 1.07 to 1.42) and 1.17 (1.01-1.36), respectively, and p for trend of 0.008 and 0.024, respectively. DISCUSSION: Overall, our study found consistent trend associations of aPTT and factor VIII measured in midlife with cognitive decline and incident dementia over 20 years, likely driven by vascular pathologies.

Hearing, ß-Amyloid Deposition and Cognitive Test Performance in Black and White Older Adults: The ARIC-PET Study.

BACKGROUND: Hearing loss is a risk factor for dementia; whether the association is causal or due to a shared pathology is unknown. We estimated the association of brain ß-amyloid with hearing, hypothesizing no association. As a positive control, we quantified the association of hearing loss with neurocognitive test performance. METHODS: Cross-sectional analysis of Atherosclerosis Risk in Communities-Positron Emission Tomography study data. Amyloid was measured using global cortical and temporal lobe standardized uptake value ratios (SUVRs) calculated from florbetapir-positron emission tomography scans. Composite global and domain-specific cognitive scores were created from 10 neurocognitive tests. Hearing was measured using an average of better-ear air conduction thresholds (0.5-4 kHz). Multivariable-adjusted linear regression estimated mean differences in hearing by amyloid and mean differences in cognitive scores by hearing, stratified by race. RESULTS: In 252 dementia-free adults (72-92 years, 37% Black race, and 61% female participants), cortical or temporal lobe SUVR was not associated with hearing (models adjusted for age, sex, education, and APOE ε4). Each 10 dB HL increase in hearing loss was associated with a 0.134 standard deviation lower mean global cognitive factor score (95% CI: -0.248, -0.019), after adjustment for demographic and cardiovascular factors. Observed hearing-cognition associations were stronger in Black versus White participants. CONCLUSIONS: Amyloid is not associated with hearing, suggesting that pathways linking hearing and cognition are independent of this pathognomonic Alzheimer's-related brain change. This is the first study to show that the impact of hearing loss on cognition may be stronger in Black versus White adults.

Prevalence of cardiovascular disease among Asian, Pacific Islander and multi-race populations in Hawai'i and California.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of death in the US. CVD incidence is influenced by many demographic, clinical, cultural, and psychosocial factors, including race and ethnicity. Despite recent research, there remain limitations on understanding CVD health among Asians and Pacific Islanders (APIs), particularly some subgroups and multi-racial populations. Combining diverse API populations into one study group and difficulties in defining API subpopulations and multi-race individuals have hampered efforts to identify and address health disparities in these growing populations. METHODS: The study cohort was comprised of all adult patients at Kaiser Permanente Hawai'i and Palo Alto Medical Foundation in California during 2014-2018 (n = 684,363). EHR-recorded ICD-9 and ICD-10 diagnosis codes were used to indicate coronary heart disease (CHD), stroke, peripheral vascular disease (PVD), and overall CVD. Self-reported race and ethnicity data were used to construct 12 mutually exclusive single and multi-race groups, and a Non-Hispanic White (NHW) comparison group. Logistic regression models were used to derive prevalence estimates, odds ratios, and confidence intervals for the 12 race/ethnicity groups. RESULTS: The prevalence of CHD and PVD varied 4-fold and stroke and overall CVD prevalence varied 3-fold across API subpopulations. Among Asians, the Filipino subgroup had the highest prevalence of all three CVD conditions and overall CVD. Chinese people had the lowest prevalence of CHD, PVD and overall CVD. In comparison to Native Hawaiians, Other Pacific Islanders had significantly higher prevalence of CHD. For the multi-race groups that included Native Hawaiians and Other Pacific Islanders, the prevalence of overall CVD was significantly higher than that for either single-race Native Hawaiians or Other Pacific Islanders. The multi-race Asian + White group had significantly higher overall CVD prevalence than both the NHW group and the highest Asian subgroup (Filipinos). CONCLUSIONS: Study findings revealed significant differences in overall CVD, CHD, stroke, and PVD among API subgroups. In addition to elevated risk among Filipino, Native Hawaiian, and Other Pacific Islander groups, the study identified particularly elevated risk among multi-race API groups. Differences in disease prevalence are likely mirrored in other cardiometabolic conditions, supporting the need to disaggregate API subgroups in health research.

Longitudinal assessment of neurocognitive function in people with relapsing multiple sclerosis initiating alemtuzumab in routine clinical practice: LEM-COG study results.

BACKGROUND: Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS. METHODS: This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression. RESULTS: Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest. CONCLUSION: The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.

Plasma neurofilament light chain in children with relapsing MS receiving teriflunomide or placebo: A post hoc analysis of the randomized TERIKIDS trial.

BACKGROUND: The phase 3 TERIKIDS study demonstrated efficacy and manageable safety for teriflunomide versus placebo in children with relapsing multiple sclerosis (RMS). OBJECTIVE: Evaluate plasma neurofilament light chain (pNfL) concentrations in TERIKIDS. METHODS: Patients received placebo or teriflunomide (14 mg adult equivalent) for up to 96 weeks in the double-blind (DB) period. In the open-label extension (OLE), all patients received teriflunomide until up to 192 weeks after randomization. pNfL was measured using single-molecule array assay (Simoa® NF-light™). RESULTS: Baseline mean age was 14.5 years; 69.4% were female. Baseline geometric least square mean pNfL levels were similar for teriflunomide (n = 78) and placebo (n = 33) patients (19.83 vs 18.30 pg/mL). Over the combined DB and OLE periods, pNfL values were lower for teriflunomide versus placebo (analysis of variance p < 0.01; Week 192: 10.61 vs 17.32 pg/mL). Observed between-group pNfL differences were attenuated upon adjustment for gadolinium (Gd)-enhancing or new/enlarged T2 lesion counts at DB Week 24. Higher baseline pNfL levels were associated with shorter time since first MS symptom onset, higher baseline Gd-enhancing lesion counts and T2 lesion volume, and increased hazard of high magnetic resonance imaging activity or clinical relapse during the DB period. CONCLUSION: Teriflunomide treatment was associated with significantly reduced pNfL levels in children with RMS. CLINICALTRIALS.GOV IDENTIFIER: NCT02201108.

Effectiveness and safety of switching to teriflunomide in older patients with relapsing multiple sclerosis: A real-world retrospective multicenter analysis.

BACKGROUND: The prevalence of multiple sclerosis (MS) in older people is increasing due to population aging and availability of effective disease-modifying therapies (DMTs). Treating older people with MS is complicated by age-related and MS-related comorbidities, immunologic effects of prior DMTs, and immunosenescence. Teriflunomide is a once-daily oral immunomodulator that has demonstrated efficacy and acceptable safety in clinical trials of adults with relapsing forms of MS (RMS). However, there are limited clinical trial and real-world data regarding teriflunomide use in people with MS aged >55 years. We analyzed real-world data to assess the effectiveness and safety of teriflunomide in older people with RMS who had switched to this agent from other DMTs. METHODS: People with RMS (relapsing remitting and active secondary progressive MS) aged ≥55 years who had switched from other DMTs to teriflunomide (7 mg or 14 mg) for ≥1 year were identified retrospectively by chart review at four sites in the United States. Data were extracted from medical records from 1 year pre-index to 2 years post-index (index defined as the teriflunomide start date). Assessments of effectiveness included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging (MRI) outcomes. Assessments of safety included lymphocyte counts, infections, and malignancies. We examined the effectiveness outcomes and lymphocyte counts within sub-groups defined by age (55-64, ≥65 years), sex, MS type, and prior route of DMT administration (oral, injectable, infusible). RESULTS: In total, 182 patients with RMS aged ≥55 years who switched from other DMTs to teriflunomide were identified (mean [SD] age: 62.5 [5.4] years). Mean ARR decreased from the start of teriflunomide treatment (mean [SD]: 0.43 [0.61]) to year 1 post-index (0.13 [0.65]) and year 2 post-index (0.05 [0.28]). Mean EDSS score remained unchanged from index (mean [SD]: 4.5 [1.8]) to 1 year post-treatment (4.5 [1.8]) and increased slightly at 2 years post-treatment (4.7 [1.7]). MRI scans from index and years 1 and 2 post-index compared with scans from the previous year indicated that most patients had stable or improved MRI outcomes at index (87.7%) and remained stable or improved at years 1 (96.0%) and 2 (93.6%). Lymphopenia decreased at years 1 (21.4%) and 2 post-index (14.8%, compared to index (23.5%). By 1 year post-index, fewer patients had grade 3 or 4 lymphopenia, and at 2 years post-index, there were no patients with grade 3 or 4 lymphopenia. Infection incidence was low (n = 40, 22.0%) and none were related to teriflunomide. The decreases in lymphopenia were driven by decreases among people who switched from a prior oral DMT; there were no notable differences in lymphopenia across the other sub-groups examined. ARR, EDSS score, and MRI outcomes across all sub-groups were similar to the results of the overall population. CONCLUSION: Our multicenter, longitudinal, retrospective study demonstrated that patients with RMS aged 55 or older switching to teriflunomide from other DMTs had significantly improved ARR, stable disability, and stable or improved MRI over up to 2 years' follow up. Safety results were acceptable with fewer patients exhibiting lymphopenia at years 1 and 2 post-index.

Satisfaction with alemtuzumab in relapsing multiple sclerosis patients: Results from the real-world PRO-ACT study.

Background: Patient-reported outcomes are increasingly used in the management of patients with multiple sclerosis to understand the patient's perspective of disease and treatment. These measures provide insights into important factors including treatment satisfaction, physical and psychological function, and quality of life. Objective: To present results from the real-world PRO-ACT study in patients with multiple sclerosis who switched to alemtuzumab from another disease-modifying therapy. Methods: This 24-month, prospective, multicenter, observational study had a primary endpoint of change in overall satisfaction, measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4. Secondary endpoints included the Multiple Sclerosis Impact Scale-29 (MSIS-29), Modified Fatigue Impact Scale-5 (MFIS-5), and the Patient-Determined Disease Steps (PDDS). Safety was monitored with adverse events (AEs). Results: Of 199 enrolled patients, improvements were observed in mean TSQM scores for overall satisfaction (baseline, 50.3; year 2, + 13.2; p < 0.0001), effectiveness (49.3 and + 12.2; p < 0.0001), and side effects (77.6 and + 4.5; p = 0.04). Improvements were also observed in MSIS-29 physical (52.4 and -6.0; p < 0.0001), MSIS-29 psychological (53.4 and -7.0; p = 0.0003), and MFIS-5 (12.8 and -1.7; p < 0.0001). Most (95.0%) patients experienced ≥ 1 AE (88.4% mild, 67.8% moderate). Conclusions: The primary endpoint was met; the safety of alemtuzumab was consistent with pivotal studies.

Incidence, Etiology, and Healthcare Utilization for Acute Gastroenteritis in the Community, United States.

Knowledge of the epidemiology of sporadic acute gastroenteritis (AGE) in the United States is limited. During September 2016-September 2017, we surveyed Kaiser Permanente Northwest members in Oregon and Washington, USA, to collect data on the 30-day prevalence of dually defined AGE and diarrhea disease and related health-seeking behavior; from a subset of participants, we obtained a stool specimen. Using the iterative proportional fitting algorithm with raked weights, we generated AGE prevalence and annualized rate estimates. We detected norovirus, rotavirus, astrovirus, and sapovirus from submitted stool specimens through real-time quantitative reverse transcription PCR (qRT-PCR). We estimated a 30-day prevalence of 10.4% for AGE and 7.6% for diarrhea only; annual rates were 1.27 cases/person/year for AGE and 0.92 cases/person/year for diarrhea only. Of those with AGE, 19% sought medical care. Almost one quarter (22.4%) of stool specimens from those reporting AGE tested positive for ≥1 viral pathogen, compared with 8.2% from those without AGE.

Evaluation of isatuximab in patients with soft-tissue plasmacytomas: An analysis from ICARIA-MM and IKEMA.

The Phase 3 ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) studies demonstrated that isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) or carfilzomib (K) and d (Isa-Kd) improved progression-free survival (PFS) versus Pd or Kd in patients with relapsed and/or refractory multiple myeloma. In this post hoc analysis of patients with soft-tissue plasmacytomas, we evaluated Isa-Pd/Isa-Kd efficacy using central radiology and central laboratory assessments. Given the low incidence of soft-tissue plasmacytomas (7.8 %, ICARIA-MM; 6.3 %, IKEMA), efficacy data were pooled across the two studies. PFS (HR, 0.47; 95 % CI, 0.21-1.08), overall response rate (50.0 % vs 17.7 %), and very good partial response or better rate (26.9 % vs 11.8 %) were improved with Isa-Pd/Isa-Kd versus Pd/Kd, with consistent improvements within individual studies. Patients with soft-tissue plasmacytomas who received Isa-Pd/Isa-Kd had similar median PFS compared with those without soft-tissue plasmacytomas and received Pd/Kd. Safety is reported individually per study. Longer median treatment duration and more Grade ≥ 3 treatment-emergent adverse events occurred in the Isa versus control arms in ICARIA-MM (36.9 vs 8.4 weeks; 85.7 % vs 70.0 %) and IKEMA (41.9 vs 29.9 weeks; 100.0 % vs 57.1 %); however, Isa did not increase the percentage of patients with fatal events or drug discontinuation. Isa-Pd or Isa-Kd is a potential new treatment option and partially overcomes the poor prognosis associated with soft-tissue plasmacytomas in relapsed and/or refractory multiple myeloma.

Evaluating the Implementation of a Digital Diabetes Prevention Program in an Integrated Health Care Delivery System Among Older Adults: Results of a Natural Experiment.

The purpose of this natural experiment study was to assess the effectiveness of a 12-month digital Diabetes Prevention Program (DPP) for adults aged 65-75 years with prediabetes and obesity within a large, integrated health care system. Adjusting for propensity scores and covariates, patients who enrolled and participated in the digital DPP had a mean weight loss of 8.6 lb over 12 months and 5.7 lb by 24 months, compared with a steady, minimal weight loss of 1.3 lb over 12 months and 2.8 lb by 24 months among patients not enrolled. There was a significant difference in mean change in A1C between enrolled and nonenrolled patients over 12 months (-0.10%), but not by 24 months (-0.06%). Digital DPP appears to be an effective weight loss option and potential diabetes prevention intervention for older adults at high risk for type 2 diabetes.

Associations of Modifiable Behavioral Risk Factor Combinations at 65 to 74 Years Old With Cognitive Health Span for 20 Years.

OBJECTIVE: Behavioral risk factors for dementia tend to co-occur and interrelate, especially poor diet, physical inactivity, sleep disturbances, and depression. Having multiple of these modifiable behavioral risk factors (MBRFs) may predict a particularly shortened cognitive health span and therefore may signal high-risk status/high intervention need. METHODS: These secondary analyses of data from the Cardiovascular Health Study included 3149 participants aged 65 to 74 years (mean [standard deviation {SD}] age = 69.5 [2.5] years; 59.6% female). MBRF exposures were self-reports regarding a) diet, b) activity, c) sleep, and d) depression symptoms. We primarily analyzed MBRF counts. For up to 26 years of follow-up, we assessed the a) number of remaining cognitively healthy life-years (CHLYs) and b) percentage of remaining life-years (LYs) that were CHLYs (%CHLY). We estimated CHLYs as time before a dementia diagnosis, cognitive screener scores indicating impairment, proxy report indicating significant cognitive decline, or dementia medication use. RESULTS: Participants averaged a remaining 16 LYs (SD = 7 LYs), 12.2 CHLYs (SD = 6.6 CHLYs), and 78.1% of LYs being CHLYs (SD = 25.6 CHLYs). Compared with having no MBRFs, having one was associated with ~1 less LY and CHLY, but not a relatively lower %CHLY. In contrast, having 3+ MBRFs was associated with about 2 to 3 fewer LYs and CHLYs as well as about 6% lower %CHLY (95% confidence interval = -9.0 to -2.5 %CHLYs; p = .001). CONCLUSIONS: MBRF-related reductions in the cognitive health span are most apparent when people have multiple MBRFs. Future research is needed to determine if/how behavioral risks converge mechanistically and if dementia prevention efficacy improves when targeting MBRF combinations.

Acute infusion effects in relapsing multiple sclerosis patients receiving alemtuzumab under a modified prophylaxis regimen.

BACKGROUND: Use of alemtuzumab in relapsing multiple sclerosis (RMS) is limited by safety concerns, notably risk of rare, serious vascular events. Along with other vital sign (VS) changes, acute increase in systolic blood pressure (SBP) is monitored as a marker of vascular risk. Peri-infusion prophylaxis is used to manage clinical risk by moderating cytokine release; protocols are not fully specified and vary across sites. Here, we report a modified prophylaxis regimen developed at Maritime Neurology. This single-center observational cohort study (NCT04633967) aimed to examine acute responses (VS events and infusion-associated reactions) in RMS patients receiving alemtuzumab infusion under this regimen. In a post hoc analysis, we examined incidence of acute SBP increase at this clinic versus the Bayshore network of Canadian infusion centers, where a standard prophylaxis regimen is used. METHODS: Alemtuzumab was infused on 5 consecutive days (Course 1; n = 29) and 3 consecutive days one year later (Course 2; n = 28). In addition to intravenous methylprednisolone 500mg on each infusion day, patients received daily prophylactic treatment with oral prednisone 50mg from 5 days before to 5 days after treatment (infusion days excepted) and oral H1 and H2 antihistaminics from 7 days before to 7 days after treatment. Excursions in SBP and other VS were relative to prespecified ranges; persistent excursions were those for which two sequential measurements were outside these ranges. In comparing VS events at Maritime Neurology and the Bayshore centers, acute SBP increase was defined as ≥20 mmHg increase in mean SBP, or any SBP reading ≥20% over patient's pre-course baseline. RESULTS: Mean (SD) VS were within range at pre-course and all other daily baselines. VS changes, including persistent excursions, were generally subclinical; all infusion-associated reactions were mild. One patient discontinued treatment after Course 1 due to immune thrombocytopenia purpura. Acute SBP increase occurred in 11/28 (39%) Maritime Neurology versus 367/610 (60%) Bayshore (p = 0.028). CONCLUSION: The modified peri-infusion prophylaxis regimen was well tolerated and may reduce incidence of acute SBP increase. FUNDING: This project was funded by Sanofi, Canada.

Brain Imaging Features Associated with 20-Year Cognitive Decline in a Community-Based Multiethnic Cohort without Dementia.

INTRODUCTION: This study aimed to characterize the association of cognitive decline starting in midlife with brain pathology in late life in the absence of dementia. METHODS: Nondemented Atherosclerosis Risk in Communities participants with brain imaging, all cognitive factor scores (CFSs), and nonmissing covariates were included. CFSs were collected at three visits across 21 years (1990-2013) (short-term cognitive change [1990-1996], long-term cognitive change [1990-2013]), and brain magnetic resonance imaging and florbetapir positron emission tomography (PET) imaging were collected in 2011-13 (PET subset n = 327). Outcomes of interest were total and regional brain volumes (cm3), log2 (white matter hyperintensity volume), white matter integrity (fractional anisotropy, mean diffusivity), ≥1 lacunar infarct (3-20 mm), and elevated brain ß-amyloid (SUVR >1.2). Multivariable linear/logistic regression related outcomes to CFS slopes after adjusting for demographics and total intracranial volume. RESULTS: At baseline, the 1,734 participants had a mean (SD) age of 55 (5.2) years, and were 60% female and 26% Black. After adjustment, a 1-SD larger long-term decline in CFS was associated with a smaller relative total brain volume by 1.2% (95% CI: 1.0, 1.5), a smaller relative temporal lobe meta region volume by 1.9% (1.5, 2.3), a 13% (9, 17) larger volume of white matter hyperintensities, a 1.3-fold (1.2, 1.4) higher odds of having ≥1 lacune, and 1.7-fold (1.3, 2.2) higher odds of elevated brain ß-amyloid deposition and worse white matter integrity. Some long-term associations were also found for midlife short-term declines in CFS. CONCLUSIONS: This study provides evidence that starting in midlife, short-term and long-term declines in cognition are associated with multiple deleterious late-life differences in nondemented brains.

The association of bowel function, participation in life activities, and quality of life in rectal cancer survivors.

PURPOSE: To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. METHODS: We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. RESULTS: Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. CONCLUSIONS: Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors.

Precision Patient Navigation to Improve Rates of Follow-up Colonoscopy, An Individual Randomized Effectiveness Trial.

BACKGROUND: Colorectal cancer screening by annual fecal immunochemical test (FIT) with follow-up on abnormal results is a cost-effective strategy to reduce colorectal cancer incidence and mortality. Unfortunately, many patients with abnormal results do not complete a follow-up colonoscopy. We tested whether navigation targeted to patients who are unlikely to complete the procedure may improve adherence and long-term outcomes. METHODS: Study participants were patients at a large, integrated health system (Kaiser Permanente Northwest) who were ages 50 to 75 and were due for a follow-up colonoscopy after a recent abnormal FIT result. Probability of adherence to follow-up was estimated at baseline using a predictive risk model. Patients whose probability was 70% or lower were randomized to receive patient navigation or usual care, with randomization stratified by probability category (<50%, 50% < 60%, 60% < 65%, 65% ≤ 70%). We compared colonoscopy completion within 6 months between the navigation and usual care groups using Cox proportional hazards regression. RESULTS: Participants (n = 415; 200 assigned to patient navigation, 215 to usual care) had a mean age of 62 years, 54% were female, and 87% were non-Hispanic white. By 6 months, 76% of the patient navigation group had completed a colonoscopy, compared with 65% of the usual care group (HR = 1.35; 95% confidence interval, 1.07-1.72; log-rank P value = 0.027). CONCLUSIONS: In this randomized trial, patient navigation led to improvements in follow-up colonoscopy adherence. IMPACT: More research is needed to assess the value of precision-directed navigation programs.

Reflection on modern methods: shared-parameter models for longitudinal studies with missing data.

A primary goal of longitudinal studies is to examine trends over time. Reported results from these studies often depend on strong, unverifiable assumptions about the missing data. Whereas the risk of substantial bias from missing data is widely known, analyses exploring missing-data influences are commonly done either ad hoc or not at all. This article outlines one of the three primary recognized approaches for examining missing-data effects that could be more widely used, i.e. the shared-parameter model (SPM), and explains its purpose, use, limitations and extensions. We additionally provide synthetic data and reproducible research code for running SPMs in SAS, Stata and R programming languages to facilitate their use in practice and for teaching purposes in epidemiology, biostatistics, data science and related fields. Our goals are to increase understanding and use of these methods by providing introductions to the concepts and access to helpful tools.

Risk of Progression to Diabetes Among Older Adults With Prediabetes.

Importance: The term prediabetes is used to identify individuals at increased risk for diabetes. However, the natural history of prediabetes in older age is not well characterized. Objectives: To compare different prediabetes definitions and characterize the risks of prediabetes and diabetes among older adults in a community-based setting. Design, Setting, and Participants: In this prospective cohort analysis of 3412 older adults without diabetes from the Atherosclerosis Risk in Communities Study (baseline, 2011-2013), participants were contacted semiannually through December 31, 2017, and attended a follow-up visit between January 1, 2016, and December 31, 2017 (median [range] follow-up, 5.0 [0.1-6.5] years). Exposures: Prediabetes defined by a glycated hemoglobin (HbA1c) level of 5.7% to 6.4%, impaired fasting glucose (IFG) level (FG level of 100-125 mg/dL), either, or both. Main Outcomes and Measures: Incident total diabetes (physician diagnosis, glucose-lowering medication use, HbA1c level ≥6.5%, or FG level ≥126 mg/dL). Results: A total of 3412 participants without diabetes (mean [SD] age, 75.6 [5.2] years; 2040 [60%] female; and 572 [17%] Black) attended visit 5 (2011-2013, baseline). Of the 3412 participants at baseline, a total of 2497 participants attended the follow-up visit or died. During the 6.5-year follow-up period, there were 156 incident total diabetes cases (118 diagnosed) and 434 deaths. A total of 1490 participants (44%) had HbA1c levels of 5.7% to 6.4%, 1996 (59%) had IFG, 2482 (73%) met the HbA1c or IFG criteria, and 1004 (29%) met both the HbA1c and IFG criteria. Among participants with HbA1c levels of 5.7% to 6.4% at baseline, 97 (9%) progressed to diabetes, 148 (13%) regressed to normoglycemia (HbA1c, <5.7%), and 207 (19%) died. Of those with IFG at baseline, 112 (8%) progressed to diabetes, 647 (44%) regressed to normoglycemia (FG, <100 mg/dL), and 236 (16%) died. Of those with baseline HbA1c levels less than 5.7%, 239 (17%) progressed to HbA1c levels of 5.7% to 6.4% and 41 (3%) developed diabetes. Of those with baseline FG levels less than 100 mg/dL, 80 (8%) progressed to IFG (FG, 100-125 mg/dL) and 26 (3%) developed diabetes. Conclusions and Relevance: In this community-based cohort study of older adults, the prevalence of prediabetes was high; however, during the study period, regression to normoglycemia or death was more frequent than progression to diabetes. These findings suggest that prediabetes may not be a robust diagnostic entity in older age.

Evaluating the Implementation of Digital and In-Person Diabetes Prevention Program in a Large, Integrated Health System: Natural Experiment Study Design.

INTRODUCTION: Implementation of a Diabetes Prevention Program (DPP) in both in-person and digital health-care settings has been increasing. The purpose of this article is to describe the protocol of a mixed-methods, natural experiment study designed to evaluate the implementation of DPP in a large, integrated health system. METHODS: Kaiser Permanente Northwest patients who were 19 to 75 years with prediabetes (hemoglobin A1c or glycated hemoglobin, 5.7-6.4) and obesity (body mass index ≥ 30 kg/m2) were invited, via the Kaiser Permanente Northwest patient portal, to participate in the digital (n = 4124) and in-person (n = 2669) DPP during 2016 through 2018. Primary (weight) and secondary (hemoglobin A1c or glycated hemoglobin level) outcome data will be obtained from electronic health records. A cost-effectiveness analysis as well as qualitative interviews with patients (enrolled and not enrolled in the DPP) and stakeholders will be conducted to examine further implementation, acceptability, and sustainability. CONCLUSION: The mixed-methods, natural experiment design we will use to evaluate Kaiser Permanente Northwest's implementation of the digital and in-person DPP builds on existing evidence related to the effectiveness of these two DPP delivery modes and will contribute new knowledge related to best practices for implementing and sustaining the DPP within large health systems over the long term.