Citations

Abstract A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Background: Pedicle subtraction osteotomy (PSO) is a powerful tool for sagittal plane correction in patients with rigid adult spinal deformity (ASD); however, it is associated with high intraoperative blood loss and the increased risk of durotomy. The objective of the present study was to identify intraoperative techniques and baseline patient factors capable of predicting intraoperative durotomy. Methods: A tri-institutional database was retrospectively queried for all patients who underwent PSO for ASD. Data on baseline comorbidities, surgical history, surgeon characteristics and intraoperative maneuvers were gathered. PSO aggressiveness was defined as conventional (Schwab 3 PSO) or an extended PSO (Schwab type 4). The primary outcome of the study was the occurrence of durotomy intraoperatively. Univariable analyses were performed with Mann–Whitney U tests, Chi-squared analyses, and Fisher’s exact tests. Statistical significance was defined by p < 0.05. Results: One hundred and sixteen patients were identified (mean age 61.9 ± 12.6 yr; 44.8% male), of whom 51 (44.0%) experienced intraoperative durotomy. There were no significant differences in baseline comorbidities between those who did and did not experience durotomy, with the exception that baseline weight and body mass index were higher in patients who did not suffer durotomy. Prior surgery (OR 2.73; 95% CI [1.13, 6.58]; p = 0.03) and, more specifically, prior decompression at the PSO level (OR 4.23; 95% CI [1.92, 9.34]; p < 0.001) was predictive of durotomy. A comparison of surgeon training showed no statistically significant difference in durotomy rate between fellowship and non-fellowship trained surgeons, or between orthopedic surgeons and neurosurgeons. The PSO level, PSO aggressiveness, the presence of stenosis at the PSO level, nor the surgical instrument used predicted the odds of durotomy occurrence. Those experiencing durotomy had similar hospitalization durations, rates of reoperation and rates of nonroutine discharge. Conclusions: In this large multisite series, a history of prior decompression at the PSO level was associated with a four-fold increase in intraoperative durotomy risk. Notably the use of extended (versus) standard PSO, surgical technique, nor baseline patient characteristics predicted durotomy. Durotomies occurred in 44% of patients and may prolong operative times. Additional prospective investigations are merited.

ABSTRACT In the United States (US), biosafety and biosecurity oversight of research on viruses is being reappraised. Safety in virology research is paramount and oversight frameworks should be reviewed periodically. Changes should be made with care, however, to avoid impeding science that is essential for rapidly reducing and responding to pandemic threats as well as addressing more common challenges caused by infectious diseases. Decades of research uniquely positioned the US to be able to respond to the COVID-19 crisis with astounding speed, delivering life-saving vaccines within a year of identifying the virus. We should embolden and empower this strength, which is a vital part of protecting the health, economy, and security of US citizens. Herein, we offer our perspectives on priorities for revised rules governing virology research in the US.

AbstractBackgroundMemory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria.MethodAssessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer’s Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5.ResultData from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%).ConclusionThese data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD.

AbstractBackgroundMost studies on the relationship between neuropsychiatric symptoms (NPS) and cognitive decline focus on NPS data collected over a short period of time. To better understand the association between NPS and cognitive decline, including their temporal relationship, it is important to know NPS status across a person’s life.MethodWe utilized the unique Rochester Epidemiology Project medical record linkage system that has captured medical records as far back as 1907, to abstract the psychiatric history of 1810 cognitively unimpaired participants in the population‐based Mayo Clinic Study of Aging (MCSA). Trained nurse abstractors ascertained the presence of exposure to three common NPS (anxiety, depression, and unspecified emotional distress [UED]), both before and after entry into the MCSA. We conducted Cox Proportional Hazards (PH) models using age as the time scale and adjusting for sex, education, and APOE E4 allele for each NPS in predicting mild cognitive impairment (MCI), or dementia. Additional analyses considering medication use (yes/no) and timing of NPS were also run.ResultAnxiety (Hazard Ratio [HR] = 1.47, p<0.001), depression (HR = 1.36, p = 0.001), and UED (HR = 1.22, p = 0.039) were associated with a higher risk of MCI. These associations were present regardless of medication use for anxiety (With medication: HR = 1.51, p<0.001; without medication: HR = 1.41, p = 0.015), and for those taking medications for depression (With medication: HR = 1.47, p<0.001; without medication: 1.09, p = 0.597). Anxiety was associated with MCI regardless of timing of onset with the strongest relationship being for those with onset of anxiety before 65 that persisted into later life (HR = 1.88, p = 0.004). Depression was associated regardless of timing of onset if the depression was present in late life too. The results were similar for the outcome of dementia (Anxiety: HR = 1.62, p<0.001; depression: HR = 1.31, p = 0.040; UED: HR = 1.37, p = 0.014). The associations accounting for medication use and timing of NPS were similar for the outcome of dementia too.ConclusionNPS is associated with progression to MCI and dementia. Both medication use and timing of NPS might play a role in these associations.

AbstractBackgroundThe DEMQOL (Dementia Quality of Life) scale is a patient reported questionnaire and proxy form that captures subjective life quality. Participants in ALLFTD and their Study Partners (SP) complete these questionnaires at each study visit.MethodWe analyzed the DEMQOL in participants and their SPs when the SP was reported to be a spouse or equivalent. Analyses focused on the final overall quality of life (QoL) rating for the participant (poor, fair, good, or very good).ResultDEMQOL responses from 907 dyads (participant: mean age 58.3±13.4 years, 44% female, and mean education 15.9±2.5 years) were analyzed. Participants rated their overall QoL as very good (45.8%), good (36.5%), fair (14%), and poor (3.5%). SPs rated their participant’s overall QoL as very good (33.6%), good (41%), fair (19.4%), and poor (6%). There was a discordance in ratings between participants and SPs (p<0.0001); in almost 50% of cases, participants rated their QoL better (33.2%) or worse (15.2%) than their SP rated their QoL. When considering disease severity (CDR®+NACC‐FTLD global score), participants rated their QoL better than their SP rated their QoL (CDR®+NACC‐FTLD = 0: 19.4%, CDR®+NACC‐FTLD = 0.5: 42%, and CDR®+NACC‐FTLD = 1+: 33.2%), worse than (CDR®+NACC‐FTLD = 0: 15.1%, CDR®+NACC‐FTLD = 0.5: 13.3%, and CDR®+NACC‐FTLD = 1+: 15.2%), or the same (CDR®+NACC‐FTLD = 0: 65.6%, CDR®+NACC‐FTLD = 0.5: 44.8%, and CDR®+NACC‐FTLD = 1+: 51.6%).ConclusionAmong participants and SPs, similarities and differences in QoL ratings are fairly consistent regardless of global CDR®+NACC‐FTLD rating. Generally, participants are equally or more optimistic about QoL than their SPs. Longitudinal analyses are forthcoming.

AbstractBackgroundFor blood‐based biomarkers to fulfill their potential to revolutionize diagnosis and management of Alzheimer’s disease (AD), additional research in diverse populations remains critical. Here, we analyzed a biracial sample to assess the profiles of blood‐based AD biomarkers and their relationships to cognition and medical comorbidities.MethodsSelf‐reported African‐American (AA; n = 267) and non‐Hispanic White (NHW; n = 268) participants evaluated through the Mayo Jacksonville Alzheimer’s Disease Research Center were matched on age, sex, and clinical diagnosis. Plasma AD biomarkers (Aβ42/40, p‐tau181, GFAP, NfL) were measured using the Quanterix SiMoA HD‐X analyzer. Cognition was assessed with the Mini Mental State Examination. Wilcoxon rank sum tests were used to assess for differences in plasma biomarker levels by sex. Linear models tested for associations of race, chronic kidney disease (CKD), and vascular risk factors with plasma AD biomarker levels, covarying for age and sex. Additional models assessed for interactions between race and plasma biomarkers in predicting cognition, further covarying for education.ResultsThe sample included adults aged 43‐100 years, with 69% women. Education was higher in NHW participants (median 16 vs. 12 years, p<0.001). APOE (apolipoprotein E) ε4 positivity was higher in AA participants (43% vs. 34%; p = 0.04). There were no differences in plasma AD biomarker levels between AA and NHW participants. These findings were unchanged after stratifying by cognitive status (unimpaired versus impaired). Although the association between p‐tau181 and cognition appeared stronger in NHW participants while the association between Aβ42/40 and cognition appeared stronger in AA participants, these findings did not survive after excluding individuals with CKD. Women displayed higher GFAP (p = 0.002) and lower p‐tau181 (p = 0.001) levels than men. Diabetes was inversely associated with GFAP levels (p<0.001).ConclusionsIn a biracial, community‐based sample, we observed that sex differences, CKD, and vascular risk factors contributed to variation in plasma AD biomarkers, while self‐reported race did not. Our results reinforce the critical need to account for sex and systemic medical comorbidities in equitably deploying blood‐based AD biomarkers in the general population.