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Background: Informative, readily accessible plasma biomarkers of pathology, neuroinflammation, and neurodegeneration in Alzheimer's disease (AD) could enhance targeted approaches to AD trial design and treatment. In post‐hoc analyses, we examined whether plasma biomarkers (Aβ1‐40, Aβ1‐42, total tau, p‐tau‐181, NfL, and GFAP) predicted 48‐week change in cognitive (ADAS‐Cog11), global function (CDR‐SB), and volumetric MRI (6 cortical regions and 2 whole brain measures) outcomes in T2 Protect AD, a phase‐2 placebo‐controlled RCT of troriluzole in mild‐to‐moderate AD (NCT03605667). Method: At least one baseline biomarker measurement was available for 319 of 350 trial participants, forming the analytic sample. No significant treatment effects were found in T2 Protect AD (Feldman 2021, JPAD 8(4):s46); thus, treatment arms were pooled for this analysis. Baseline levels of, and 48‐week changes in, plasma biomarkers were assessed for association with 48‐week change in outcomes using linear regression adjusted for relevant covariates. Combinations of baseline plasma biomarkers that best predicted 48‐week decline on the ADAS‐Cog11 and CDR‐SB were identified using LASSO regression. Statistical significance level was 5%; p‐values were Bonferroni corrected for multiple comparisons. Result: Participant characteristics are presented in Table 1. Higher baseline plasma NfL predicted greater 48‐week decline on ADAS‐Cog11 (p = 0.026) and CDR‐SB (p = 0.048; Fig. 1A). LASSO revealed that the combination of baseline plasma NfL, total tau, and Aβ42/40 ratio best predicted 48‐week decline on ADAS‐Cog11, whereas baseline NfL alone best predicted 48‐week decline on CDR‐SB. Regarding MRI outcomes, baseline NfL predicted increase in ventricular volume (p = 0.018; Fig 1A). Baseline NfL, GFAP, and p‐tau‐181 each predicted 48‐week decline in mid‐temporal cortical volume (all p<0.02; Fig.1B); LASSO results were similar. The only significant association between 48‐week biomarker change and clinical outcomes was between increased plasma NfL and worsening CDR‐SB. Conclusion: Elevated baseline plasma NfL predicted greater 48‐week decline on cognitive, global function, and MRI measures in a clinical trial of mild‐to‐moderate AD. Furthermore, greater increase in plasma NfL over time was associated with greater clinical decline. Plasma NfL is an easily accessible biomarker that may enhance AD clinical trial design and treatment strategies. Acknowledgement: Trial funding by Biohaven Pharmaceuticals; data and trial coordination by the Alzheimer's Disease Cooperative Study (ADCS). [ABSTRACT FROM AUTHOR]

Background: Nicotinamide is a co‐enzyme involved in cellular oxidation‐reduction reactions that can act as an inhibitor of the class III histone deacetylases (HDACs), or sirtuins. HDAC inhibition may have myriad therapeutic pathways, including reducing phosphorylation of tau. Method: We performed a randomized, placebo‐controlled, Phase 2a proof‐of‐concept trial to evaluate the safety and tolerability of nicotinamide, and its effects on change in cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 231 (p‐tau231) and other Alzheimer's disease (AD) biomarkers and clinical measures in participants with early AD (Mild Cognitive Impairment or mild dementia) as confirmed by CSF biomarkers. We tested whether 1500 mg BID nicotinamide was superior to placebo in reducing CSF p‐tau231 (primary outcome), with secondary outcomes of p‐tau181, total tau, amyloid beta 40 (Ab40), Ab42, ADAS‐cog13, ADCS‐ADL‐MCI, and CDR‐SB. Result: Arms were well balanced for demographic and clinical characteristics (Table 1). Of 47 participants enrolled, one dropped out prior to treatment initiation and six dropped before completion, 2 in the nicotinamide and 4 in the placebo arm. Nicotinamide was well‐tolerated; adverse events were largely balanced by study arm, with few attributed to treatment. There was no statistically significant benefit of nicotinamide on the primary outcome of change in CSF p‐tau231 (ANCOVA; estimated mean difference in change between arms = 2.06, std. error = 4.03; p = 0.61), although the observed mean decline in CSF p‐tau231 was greater in the nicotinamide arm (‐4.7±14.5) than in the placebo arm (‐2.3±10.6; Table 2). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p‐tau181, Ab40, Ab42, and total tau) in similar models (all p‐values>0.05), although observed mean changes in CSF p‐tau181 (0.4±29.8 vs 10.4±41.8) and total tau (8.4±228.6 vs 60.5±237.5) favored nicotinamide compared to placebo. Nicotinamide was associated with significantly less change on CDR‐SB (MMRM; estimate = ‐1.42, std. error = 0.65; p = 0.03), but not on cognitive (ADAS‐cog; estimate = ‐1.93, std. error = 1.93; p = 0.32) or functional (ADCS‐ADL‐MCI; estimate = ‐3.10, std. error = 1.86; p = 0.10) assessments. No adjustments for multiple comparisons were performed. Conclusion: These results may suggest that nicotinamide warrants further study as a treatment for early AD. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to demonstrate the efficacy of a multifaceted performance improvement regimen to reduce the incidence of adverse events following a spectrum of head and neck surgical procedures.Methods: We conducted a chart review of patients who underwent a head and neck procedure between January 1, 2013, and October 30, 2015, at our institution, including 392 patients (450 procedures) before the quality improvement regimen was implemented (October 1, 2013) and 942 patients (1136 procedures) after implementation. Multivariate statistical models were used to investigate the association of clinical parameters and the intervention with postoperative adverse event rate.Results: The incidence of adverse events decreased from 12.9% to 7.2% (95% CI, 2.46%-9.38%) after the intervention. Male sex (adjusted odds ratio [ORadj] = 1.57; 95% CI, 1.06-2.31) and the intervention (ORadj = 0.51; 95% CI, 0.35-0.74) were predictive of overall adverse event incidence by univariate and multivariate analyses. Although patient comorbid status, quantified with the Charlson Comorbidity Index, was not found to affect overall adverse event risk, each 1-point increase in index score was associated with a 17% relative increase (ORadj = 1.17; 95% CI, 1.03-1.33) in the odds of a high-grade adverse event.Discussion: Comprehensive performance improvement programs can improve perioperative adverse event risk in head and neck surgery. Patient comorbid status and sex are considerations during assessment of the likelihood of high-grade and overall adverse event risk, respectively.Implications For Practice: Given the cost of surgical complications, a comprehensive approach to perioperative risk mitigation is warranted. [ABSTRACT FROM AUTHOR]

Background: The EXERT trial (NCT02814526) was a Phase 3, multicenter, randomized single‐blind study that examined the effects of regular exercise on cognition and other measures of brain function in a planned sample of 300 older adults with amnestic mild cognitive impairment (MCI). Method: The Alzheimer's Disease Cooperative Study (ADCS) coordinated the trial, in partnership with Wake Forest and the YMCA of the USA. Participants were randomized to moderate intensity aerobic training (AX), or to stretching, balance and range of motion (SBR) for 18 months. In the first 12 months, exercise was supervised 2x/week and completed independently 2x/week. All exercise was unsupervised in Months 13‐18. Outcomes assessments were completed at baseline and every 6 months. The primary endpoint was 12‐month change from baseline on the ADAS‐Cog‐Exec, a validated measure of global cognitive function. In addition, 12‐month changes in the ADAS‐Cog‐Exec and CDR‐SB were compared for EXERT intervention groups relative to other cohorts to estimate effects of intervention versus no intervention (i.e., "Usual Care"). Result: 296 participants were enrolled, and over 31,000 exercise sessions were completed during the first 12 months. Attendance remained high (AX: 81%; SBR: 87%), and >60% of participants reported continued exercise through the pandemic. Neither the AX group nor the SBR group showed 12‐month declines on the ADAS‐Cog‐Exec and CDR‐SB. There were no significant treatment differences between AX and SBR on these outcomes. In the Usual Care analysis comparing ADNI‐1 and EXERT participants matched on key variables (demographics, baseline cognitive function, APOE4), ADNI‐1 MCI participants showed the expected 12‐month decline on the ADAS‐Cog‐Exec, but the EXERT AX and SBR groups did not (ADNI‐1 vs. AX: p = 0.012; vs. SBR: p = 0.00049). Conclusion: Global cognitive function did not change over 12 months of follow‐up for MCI participants in EXERT, suggesting that both the AX and SBR interventions may have stalled cognitive decline. EXERT is the longest exercise trial conducted in MCI to date, and greater 'volume' of exercise may have provided more protection, regardless of exercise intensity. Both groups received equal amounts of weekly socialization, which may have contributed to this protection. Our results are noteworthy given that trial was conducted during the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

Background: Improved Phase 2 study designs may increase success rates in late stage AD trials. Varoglutamstat (PQ912) is an oral small molecule glutaminyl cyclase inhibitor designed to address several key disease mechanisms. A Phase 2A study (NCT02389413) of 120 early AD patients treated for 12 weeks provided preliminary evidence of safety and tolerability, and effects on working memory, CSF biomarkers, and synaptic function (EEG theta‐power). Objective: To design a well‐powered, safe, and efficient study of varoglutamstat in early AD incorporating adaptive dose selection in Phase 2A, a futility analysis testing pharmacological, biological and cognitive criteria, and a seamless transition to a larger Phase 2B study investigating longer‐term efficacy and safety. Methods: An efficient and safe selection rule across 3 descending doses (600mg, 300mg, 150 mg BID) was established using a continuously monitored Pocock safety boundary targeting a set of treatment emergent AE's of interest. Well‐powered stage‐gate criteria at a planned interim futility analysis included thresholds for target occupancy in plasma, and would detect negative effects on a cognitive composite or absence of benefit on EEG theta‐power. The Phase 2B study was powered to detect an effect size of 0.7 points on the Clinical Dementia Rating – Sum of Boxes score at 18 months, an established approvable endpoint. Results: The on‐going Phase 2A adaptive dose‐finding trial (NCT03919162) is randomizing 180 subjects with MCI or mild probable AD, initially to 24+ weeks of 600mg varoglutamstat dose or placebo, BID. If the safety boundary is hit, the dose will be discontinued and all subjects titrated down, with similar sequential testing of lower doses as needed. The interim futility analysis will occur when the first 180 randomized subjects have been on study for at least 24 weeks. If this stage‐gate is passed, Phase 2B will enroll 234 additional patients to achieve 414 total patients treated for 72 weeks at full dose of varoglutamstat or placebo. Conclusion: This novel study design enables adaptive dose selection, an early interim futility analysis, and longer‐term determination of cognitive and functional efficacy, and should support robust proof‐of‐concept for varoglutamstat using a total sample of 414 subjects treated for 72 weeks. [ABSTRACT FROM AUTHOR]

Background We evaluated the use of intraoperative fluorescence guidance by enzymatically cleavable ratiometric activatable cell-penetrating peptide (RACPPPLGC(Me)AG) containing Cy5 as a fluorescent donor and Cy7 as a fluorescent acceptor for salivary gland cancer surgery in a mouse model. Methods Surgical resection of small parotid gland cancers in mice was performed with fluorescence guidance or white light (WL) imaging alone. Tumor identification accuracy, operating time, and tumor-free survival were compared. Results RACPP guidance aided tumor detection (positive histology in 90% [27/30] vs 48% [15/31] for WL; p < .001). An approximate 25% ratiometric signal increase as the threshold to distinguish between tumor and adjacent tissue, yielded >90% detection sensitivity and specificity. Operating time was reduced by 54% ( p < .001), and tumor-free survival was increased with RACPP guidance ( p = .025). Conclusion RACPP provides real-time intraoperative guidance leading to improved survival. Ratiometric signal thresholds can be set according to desired detection accuracy levels for future RACPP applications. © 2015 Wiley Periodicals, Inc. Head Neck 38: 715-723, 2016 [ABSTRACT FROM AUTHOR]

Observational data show that nonsteroidal anti-inflammatory drug ( NSAID) use is associated with a lower rate of breast cancer. We evaluated the effect of etodolac, an FDA-approved NSAID reported to inhibit cyclooxygenase ( COX) enzymes and the retinoid X receptor alpha ( RXR), on rationally identified potential biomarkers in breast cancer. Patients with resectable breast cancer planned for initial management with surgical resection were enrolled and took 400 mg of etodolac twice daily prior to surgery. Protein and gene expression levels for genes related to COX-2 and RXR α were evaluated in tumor samples from before and after etodolac exposure. Thirty subjects received etodolac and 17 subjects were assayed as contemporaneous or opportunistic controls. After etodolac exposure mean cyclin D1 protein levels, assayed by immunohistochemistry, decreased ( P = 0.03). Notably, pre- versus post cyclin D1 gene expression change went from positive to negative with greater duration of etodolac exposure ( r = −0.64, P = 0.01). Additionally, etodolac exposure was associated with a significant increase in COX-2 gene expression levels (fold change: 3.25 [95% CI: 1.9, 5.55]) and a trend toward increased β-catenin expression (fold change: 2.03 [95% CI: 0.93, 4.47]). In resectable breast cancer relatively brief exposure to the NSAID etodolac was associated with reduced cyclin D1 protein levels. Effect was also observed on cyclin D1 gene expression with decreasing levels with longer durations of drug exposure. Increased COX-2 gene expression was seen, possibly due to compensatory feedback. These data highlight the utility of even small clinical trials with access to biospecimens for pharmacodynamic studies. [ABSTRACT FROM AUTHOR]

In this paper, we describe the implementation and evaluation of a cluster-based enrichment strategy to call hits from a high-throughput screen using a typical cell-based assay of 160,000 chemical compounds. Our focus is on statistical properties of the prospective design choices throughout the analysis, including how to choose the number of clusters for optimal power, the choice of test statistic, the significance thresholds for clusters and the activity threshold for candidate hits, how to rank selected hits for carry-forward to the confirmation screen, and how to identify confirmed hits in a data-driven manner. Whereas previously the literature has focused on choice of test statistic or chemical descriptors, our studies suggest that cluster size is the more important design choice. We recommend clusters to be ranked by enrichment odds ratio, not by p-value. Our conceptually simple test statistic is seen to identify the same set of hits as more complex scoring methods proposed in the literature do. We prospectively confirm that such a cluster-based approach can outperform the naive top X approach and estimate that we improved confirmation rates by about 31.5% from 813 using the top X approach to 1187 using our cluster-based method. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A cost- and time-efficient means to define the prognosis of patients with chronic lymphocytic leukemia (CLL) is desirable but does not yet exist. On the basis of the evidence that CLL cells have enhanced expression of the cyclic nucleotide phosphodiesterase isoform 7B (PDE7B), we hypothesized that PDE7B expression might provide such information. We assessed PDE7B mRNA expression using quantitative real-time PCR in peripheral blood mononuclear cells isolated from 85 patients and 30 normal subjects. We compared PDE7B mRNA expression with that of other disease features to determine if its expression correlates with the prognosis of patients with CLL. We found that CLL patients with PDE7B mRNA levels in the top quartile (greater than ninefold elevation relative to normal controls) have a several-year shorter median time-to-treatment (TTT, 36 months) compared to that of patients whose CLL cells express lower levels of PDE7B mRNA (TTT, 77 months, p = 0.001). High PDE7B mRNA expression correlates with expression of zeta-chain-associated protein kinase 70 (ZAP-70), unmutated immunoglobulin heavy chain variable (IGHV) region genes and β2 microglobulin (β2M), but use of a multivariate Cox model revealed that high PDE7B mRNA expression independently predicts a short TTT, even after adjusting for several other disease characteristics (ZAP-70 or CD38 expression, IGHV mutation status and Rai status). High expression of PDE7B is an unfavorable characteristic in CLL. Assessment of PDE7B mRNA expression thus appears to be a clinically useful biomarker to define the prognosis of patients with CLL. [ABSTRACT FROM AUTHOR]

Aim To examine the association between smoking mentholated cigarettes and smoking cessation, separately for different racial/ethnic groups. Design Secondary data analysis of the 2003 and 2006DS07 Tobacco Use Supplements to the Current Population Survey. Setting United States. Participants African American, Asian American/Pacific Islander, Hispanic/Latino, Native American, non-Hispanic white adults. Measurements Examined relations between the use of mentholated cigarettes and measures of smoking cessation. Findings Among African Americans (ORadj = 1.62, 95% CI: 1.35DS1.95) and Hispanics/Latinos (ORadj = 1.21, 95% CI: 1.00DS1.47), those who currently smoked mentholated cigarettes were more likely be seriously considering quitting in the next six months than were non-menthol smokers, after adjusting for sociodemographic factors. African Americans (ORadj = 1.87, 95% CI: 1.60DS 2.19) and Hispanics/Latinos (ORadj = 1.34, 95% CI: 1.11DS1.62) who smoked mentholated cigarettes were also significantly more likely to have a positive estimation of successfully quitting in the next six months compared to non-menthol smokers. These associations were not found among Asian Americans/Pacific Islanders, Native Americans/Alaska Natives and Non-HispanicWhites. Among former smokers, across racial/ethnic groups, those who smoked mentholated cigarettes (vs. non-menthols) were significantly less likely to have successfully quit for at least six months: African Americans (ORadj = 0.23, 95% CI: 0.17DS0.31), Asian Americans/Pacific Islanders (ORadj = 0.22, 95% CI: 0.11DS0.45), Hispanics/Latinos (ORadj = 0.48, 95% CI: 0.34DS0.69) and Non-HispanicWhites (ORadj = 0.28, 95% CI: 0.25DS0.33). Conclusion Across race/ethnic groups, those who used to regularly smoke mentholated cigarettes were less likely to have experienced long-term quitting success. Cessation programs should consider the type of cigarette typically smoked by participants, particularly menthols. [ABSTRACT FROM AUTHOR]

Objectives: To facilitate more efficient Phase I/II cancer immunotherapy trials by incorporating statistically rigorous safety analysis. Setting: The standard Phase I oncology trial is designed to find the maximum tolerated dose (MTD) in a setting where serious drug-related toxicity is expected. However, many newer agents hope to show the efficacy without increasing the background rate of adverse events. Formal statistical designs in this setting are needed. Results: The Phase I/II toxicity-evaluation design is suitable when the therapeutic dose is expected to be well below the MTD. In Phase I, the design enrolls multiple cohorts at the target dose, possibly after an initial dose titration stage, and tests a formal safety hypothesis using a standard 3 + 3 enrollment scheme. Phase I serves as an interim safety analysis before proceeding to Phase II efficacy testing. We give an exact upper confidence limit on the toxicity rate at the therapeutic dose using the combined Phase I/II toxicity data, as well as the maximum likelihood estimate of the toxicity rate. We describe an example where the design has been used for a Phase I/II trial of immunotherapy in leukemia. Conclusions: Phase I/II toxicity-evaluation designs are simple to execute and may be suitable for some cancer immunotherapy trials. We show how to compute power, expected sample size, and expected number of dose-limiting toxicities, as well as the maximum likelihood estimator and exact small sample confidence intervals for the toxicity rate at the therapeutic dose. More flexible designs are briefly discussed. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In epidemiologic studies of exposure-disease association, often only a surrogate measure of exposure is available for the majority of the sample. A validation sub-study may be conducted to estimate the relation between the surrogate measure and true exposure levels. In this article, we discuss three methods of estimation for such a main study/validation study design: (i) maximum likelihood (ML), (ii) multiple imputation (MI) and (iii) regression calibration (RC). For logistic regression, we show how each method depends on a different numerical approximation to the likelihood, and we adapt standard software to compute both MI and ML estimates. We use simulation to compare the performance of the estimators for both realistic and extreme settings, and for both internal and external validation designs. Our results indicate that with large measurement error or large enough sample sizes, ML performs as well as or better than MI and RC. However, for smaller measurement error and small sample sizes, either ML or RC may have the advantage. Interestingly, in most cases the relative advantage of RC versus ML was determined by the relative variance rather than the bias of the estimators. Software code for all three methods in SAS is provided. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article shows how a heteroscedasticity-consistent covariance matrix estimator and associated statistics can be computed from the output of an instrumental variables regression. It details the performance of the least squares regression and the retrieval of the residuals. Explanatory variables and dependent variables are defined. The article suggests that the procedures should be useful in any computer package allowing ordinary least square and two-stage least squares estimation.

Summary Probability weights have been widely used in addressing selection bias arising from a variety of contexts. Common examples of probability weights include sampling weights, missing data weights, and propensity score weights. Frequency weights, which are used to control for varying variabilities of aggregated outcomes, are both conceptually and analytically different from probability weights. Popular software such as R, SAS and STATA support both types of weights. Many users, including professional statisticians, become bewildered when they see identical estimates, but different standard errors and p$$ p $$‐values when probability weights are treated as frequency weights. Some even completely ignore the difference between the two types of weights and treat them as the same. Although a large body of literature exists on each type of weights, we have found little, if any, discussion that provides head‐to‐head comparisons of the two types of weights and associated inference methods. In this paper, we unveil the conceptual and analytic differences between the two types of weights within the context of parametric and semi‐parametric generalised linear models (GLM) and discuss valid inference for each type of weights. To the best of our knowledge, this is the first paper that looks into such differences by identifying the conditions under which the two types of weights can be treated the same analytically and providing clear guidance on the appropriate statistical models and inference procedures for each type of weights. We illustrate these considerations using real study data. [ABSTRACT FROM AUTHOR]

We examined the extracellular vesicle (EV) and RNA composition of pooled normal cerebrospinal fluid (CSF) samples and CSF from five major neurological disorders: Alzheimer’s disease (AD), Parkinson’s disease (PD), low-grade glioma (LGG), glioblastoma multiforme (GBM), and subarachnoid haemorrhage (SAH), representing neurodegenerative disease, cancer, and severe acute brain injury. We evaluated: (I) size and quantity of EVs by nanoparticle tracking analysis (NTA) and vesicle flow cytometry (VFC), (II) RNA yield and purity using four RNA isolation kits, (III) replication of RNA yields within and between laboratories, and (IV) composition of total and EV RNAs by reverse transcription–quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing (RNASeq). The CSF contained ~106 EVs/μL by NTA and VFC. Brain tumour and SAH CSF contained more EVs and RNA relative to normal, AD, and PD. RT-qPCR and RNASeq identified disease-related populations of microRNAs and messenger RNAs (mRNAs) relative to normal CSF, in both total and EV fractions. This work presents relevant measures selected to inform the design of subsequent replicative CSF studies. The range of neurological diseases highlights variations in total and EV RNA content due to disease or collection site, revealing critical considerations guiding the selection of appropriate approaches and controls for CSF studies. [ABSTRACT FROM PUBLISHER]

In this article the author discusses a research paper which analysis the effectiveness of implementing smoke-free policies on teen smoking in Australia using representative triennial state wide surveys. It is given that the paper was significantly used by the by the International Agency for Research on Cancer (IARC) as an evidence for analyzing the effectiveness of smoke-free policies. He also reflects on the comparison between home smoking restrictions and work place policies.