Nevin Manimala

Ecol Appl. 2022 May 11:e2654. doi: 10.1002/eap.2654. Online ahead of print.

ABSTRACT

Microplastic (MP) contamination in marine environments is of increasing concern, as plastic particles are globally ubiquitous across ecosystems. A large variety of aquatic taxa ingest MPs, but the extent to which animals accumulate and transfer MPs through food webs is largely unknown. In this study, we quantified MP uptake in bivalves, crabs, echinoderms, and fish feeding at different trophic levels at three sites on southern Vancouver Island. We paired stable isotope food web analysis with MP concentrations in digestive tracts across all trophic levels, and in the fish’s livers. We then used Bayesian generalized linear mixed models to explore whether bioaccumulation and biomagnification were occurring. Our results show that MPs (100-5000 μm along their longest dimension) are not biomagnifying in marine coastal food webs, with no correlation between the digestive tract or fish liver MP concentrations and trophic position of the various species. Ecological traits did, however, affect microplastic accumulation in digestive tracts, with suspension feeder and smaller-bodied planktivorous fish ingesting more microplastics by body weight. Trophic transfer occurred between prey and predator for rockfish, but higher concentrations in full stomachs compared with empty ones suggested rapid excretion of ingested MPs. Collectively, our findings suggest the movement of MP through marine food webs is facilitated by species-specific mechanisms, with contamination susceptibility a function of a species biology, not its trophic position. Furthermore, the statistical methods we employ, including machine learning for classifying unknown particles and a probabilistic way to account for background contamination, are universally applicable to the study of microplastics. Our findings advance understanding of how MPs enter and move through aquatic food webs, suggesting that lower trophic level animals are more at risk of ingesting >100-μm MPs, relative to higher trophic level animals. Our work also highlights the need to advance the study of <100-μm MPs, which are still poorly understood, and may need to be considered separately in ecological risk assessments.

PMID:35543035 | DOI:10.1002/eap.2654

Expert Rev Anticancer Ther. 2022 May 11. doi: 10.1080/14737140.2022.2076670. Online ahead of print.

ABSTRACT

BACKGROUND: Triple-negative-breast-cancer (TNBC) has a poor prognosis if pathologic complete response (pCR) cannot be achieved after receiving neoadjuvant chemotherapy (NAC). The group of patients that benefit most from adjuvant capecitabine remains unclear.

MATERIALS AND METHODS: We collected data from 218 consecutive patients who had previously received NAC and operated for TNBC from eight cancer centers. Data of 160 patients without PCR was included in the statistical analysis. Pathologic response to NAC was defined into two groups as having good-pathologic response (MillerPayneGrading (MPG) IV-III) or poor-pathologic response (MPG I-II). The histopathological characteristics of patients were compared in regard to adjuvant capecitabine usage.

RESULTS: Univariate-analysis revealed that age, histological subtype, clinical stage, size of tumor, number of lymph-nodes, menopausal status, pathological T and N stage, were significantly different between two groups. In multivariate-analysis, menopausal status (p=0.043) and residual tumor size (p<0.001) were found to be independent prognostic factors for pathological response. The hazard ratio for disease recurrence and death in the poor responsive group with adjuvant capecitabin was 2.94 (95% confidence interval (CI), 1.21 to 7.10; p=0.016) and 4.080 (95% CI, 1.22 to 13.64; p=0.022) respectively. DFS (p=0.58) and OS (p=0.89) improvements with adjuvant capecitabine were not demonstrated in good response groups.

CONCLUSION: This multicenter study suggested that only the poor responsive group to NAC achieved benefit from adjuvant capecitabine. Postmenopausal status and residual tumor size were related to poor prognosis.

PMID:35543015 | DOI:10.1080/14737140.2022.2076670

J Prev Alzheimers Dis. 2022;9(2):323-330. doi: 10.14283/jpad.2021.71.

ABSTRACT

OBJECTIVE: To explore the association between the intake of sugar-sweetened beverages and cognitive dysfunction in middle-aged and older adults, so as to provide an evidence-based basis for the early prevention of cognitive dysfunction.

METHODS: A comprehensive search of relevant literature was conducted in PubMed, EMBase, Cochrane, ScienceDirect, and Web of Science from the inception until January 2021. Odds ratios (OR), hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a random-effects, generic inverse variance method. Meta-analysis of the included studies was performed using Review Manager 5.4.

RESULTS: A total of 10 studies on the association between sugary beverages and cognitive dysfunction in middle-aged and older adults were included, of which 3 were cross-sectional studies and the rest were cohort studies. Eight of the ten studies had results suggestive of a negative association. However, Meta-analysis results showed that the association between the intake of sugar-sweetened beverages and the risk of cognitive impairment was not statistically significant (OR=1.59, 95% CI: 0.93-2.74, P=0.08); but from two studies, the hazard ratios of all-cause dementia in middle-aged and older people consuming sugar-sweetened beverages was 2.77 (95%CI: 2.24-3.43, P<0.00001); the hazard ratios of Alzheimer’s disease in middle-aged and older people consuming sugar-sweetened beverages was 2.63 (95%CI: 1.70-4.05, P<0.0001).

CONCLUSION: There is insufficient evidence to state conclusively that sugar-sweetened beverages intake causes cognitive dysfunction in middle-aged and older adults.

PMID:35543006 | DOI:10.14283/jpad.2021.71

J Prev Alzheimers Dis. 2022;9(2):286-296. doi: 10.14283/jpad.2022.13.

ABSTRACT

BACKGROUND: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer’s Disease and/or Alzheimer’s Disease biomarkers. However, the nature of this relationship is currently unknown.

OBJECTIVES: To evaluate the relationship between anxiety and depressive symptoms and amyloid-β deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills.

DESIGN: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357).

SETTING: Data analysis.

PARTICIPANTS: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study.

MEASUREMENTS: We used linear regression to estimate the associations between amyloid-β standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer’s Cognitive Composite (PACC) scores as possible mediational variables.

RESULTS: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-β SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-β SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326).

CONCLUSIONS: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-β deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-β deposition.

PMID:35543002 | DOI:10.14283/jpad.2022.13

J Prev Alzheimers Dis. 2022;9(2):255-261. doi: 10.14283/jpad.2022.17.

ABSTRACT

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer’s disease (AD) secondary prevention trials.

OBJECTIVE: To evaluate the association between amyloid (Aβ) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer’s Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS).

DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis.

SETTING: The EARLY study was conducted at 143 centers across 14 countries.

PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aβ status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aβ levels (Aβ-, n=2,824) and those with pathological Aβ levels (Aβ+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aβ1-42.

MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aβ groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aβ status.

RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aβ+ participants performed worse versus Aβ- participants on all cognitive composites though the magnitude of the Aβ effect was generally small. The Aβ+/- effect size for the PACC (Cohen’s d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aβ+/- effect sizes.

CONCLUSIONS: Cross-sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time.

PMID:35542998 | DOI:10.14283/jpad.2022.17

J Prev Alzheimers Dis. 2022;9(2):247-254. doi: 10.14283/jpad.2021.61.

ABSTRACT

BACKGROUND: Piromelatine is a novel melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptors agonist developed for mild Alzheimer’s disease (AD). In a randomized, placebo-controlled, dose-ranging study (ReCognition) of piromelatine (5, 20, and 50 mg daily for 6 months) in participants with mild dementia due to AD (n=371, age 60-85 years), no statistically significant differences were found between the piromelatine and placebo-treated groups on the primary (i.e., computerized neuropsychological test battery (cNTB)) and secondary outcomes (ADCS-CGIC, ADCS-MCI-ADL, ADAS-cog14, NPI, and Pittsburgh Sleep Quality Index (PSQI)) nor were there safety concerns (https://clinicaltrials.gov/ct2/show/NCT02615002).

OBJECTIVES: This study was aimed at identifying genetic markers predicting piromelatine treatment response using a genome-wide association approach (GWAS).

DESIGN: Variant genotyping of a combined whole genome and whole exome sequencing was performed using DNA extracted from lymphocytes from consenting participants. The general case-control allelic test was performed on piromelatine-treated participants, taking “responders” (i.e., >0.125 change from baseline in the cNTB) as cases and “non responders” as controls, using a Cochran-Armitage trend test.

SETTING: 58 outpatient clinics in the US.

PARTICIPANTS: 371 participants were randomized in the trial; 107 provided informed consent for genotyping.

RESULTS: The GWAS sample did not differ from the full study cohort in demographics, baseline characteristics, or response to piromelatine. Six single-nucleotide polymorphisms (SNPs) in chromosome 2q12 (2:107,510,000-107,540,000) were associated with response (p-value < 1×10 -4 each). Post hoc analyses suggested that the carriers of the 2q12 polymorphism cluster (27% of the GWAS sample) improved significantly on the cNTB on piromelatine as compared to placebo but significantly worsened on the ADAS-Cog14 and PSQI. By contrast, “non-carriers” improved significantly with piromelatine compared to placebo on the ADAS-Cog14 ( 2.91 (N=23) with piromelatine 20 mg vs 1.65 (N=19) with placebo (p=0.03)) and PSQI.

CONCLUSIONS: The 2q12 (2:107,510,000-107,540,000) 5-6 SNPs cluster may predict efficacy of piromelatine for mild AD. These findings warrant further investigation in a larger, prospective early-stage AD clinical trial for patients who are non-carriers of the 2q12 polymorphism cluster.

PMID:35542997 | DOI:10.14283/jpad.2021.61

J Prev Alzheimers Dis. 2022;9(2):197-210. doi: 10.14283/jpad.2022.30.

ABSTRACT

BACKGROUND: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta.

OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease.

DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease.

SETTING: These studies involved 348 sites in 20 countries.

PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia, of which 1812 (55.2%) completed the study.

INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks.

MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints.

RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer’s disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema.

CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.

PMID:35542991 | DOI:10.14283/jpad.2022.30

Sci Prog. 2022 Apr-Jun;105(2):368504221075472. doi: 10.1177/00368504221075472.

ABSTRACT

In this study, a preview repetitive control (PRC) strategy was developed for uncertain nonlinear discrete-time systems subjected to a previewable periodic reference signal. The proposed preview repetitive controller was designed such that the system output tracked a previewable periodic reference signal even with model uncertainties and nonlinear terms. An augmented two-dimensional (2D) model was constructed based on the 2D model approach and state augmented technique. Second, considering the state unmeasured and periodic tracking reference signal, a static output PRC law was designed using the linear matrix inequality (LMI) techniques. Finally, the effectiveness of the proposed controller was verified through two illustrative examples.

PMID:35542984 | DOI:10.1177/00368504221075472

Ann Palliat Med. 2022 May 6:apm-21-3899. doi: 10.21037/apm-21-3899. Online ahead of print.

ABSTRACT

BACKGROUND: Telehealth was expanded worldwide during the COVID-19 pandemic to deliver essential care remotely to patients, including those receiving palliative care. Bipartisan groups of politicians in the United States call for continuing the expanded Medicare coverage of telehealth services beyond the pandemic period. The aim was to understand telehealth’s benefits and risks to hospice and palliative care patients and their families.

METHODS: We conducted a cross-sectional survey of 595 caregivers of seriously ill patients and interviewed 25 hospice leaders across the United States. We used multiple linear regression to analyze the survey data and qualitative methods to determine themes from the interview data.

RESULTS: Our survey showed that a good internet connection, better access to video, and the patient being younger than 65 years old were associated with greater satisfaction with telehealth. The hospice leader interviews highlighted that telehealth can enhance or detract from quality care, depending on the function; confusion over telehealth policies and concern for abuse exists; and telehealth during the pandemic has spurred on technology-enabled innovation and improvements, especially for resource-constrained hospice and palliative care organizations.

CONCLUSIONS: Telehealth used during the pandemic showed that it may work for certain hospice and palliative care services. As telehealth coverage expands, it is important to address its risks and shortcomings upfront. When designed and implemented with the patient and equity in mind, telehealth has the potential to improve access to hospice and palliative care for all.

PMID:35542975 | DOI:10.21037/apm-21-3899

Ann Palliat Med. 2022 Apr 24:apm-22-33. doi: 10.21037/apm-22-33. Online ahead of print.

ABSTRACT

BACKGROUND: Several prognostic tools have been developed to aid clinicians in survival prediction. However, changes in symptoms are rarely included in established prognostic systems. We aimed to investigate the influence of changes in symptoms and quality of life (QOL) on survival time in outpatients with advanced cancer.

METHODS: Study subjects included a subgroup of those with longitudinal symptom and QOL data within a larger, single-site parent study. We assessed patients’ symptoms and QOL at enrollment and follow-up at an approximately 3-month interval. Patients’ symptoms were evaluated by the Korean version of the Edmonton Symptom Assessment System (K-ESAS). QOL was checked by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Participants were categorized into three groups by changes in symptoms or QOL. These groups were: improved (having at least a one level of improvement in the response scale), stable (no change), or worsened (at least a one level of worsening in the scale). We compared survival time in the improved plus stable vs. worsened groups, using a log-rank test.

RESULTS: We analyzed 60 patients, with a median survival time of 346 days. In the Worsened group, depression (P<0.01) and sleep disturbance (P<0.01) by K-ESAS, and dyspnea (P<0.03) per the EORTC QLQ-C30, were statistically significantly related to shorter survival time compared to ‘improved and stable’ group. There was no relationship between changes in other symptoms, overall QOL, and survival.

CONCLUSIONS: Longitudinal assessment of depression, sleep disturbance and dyspnea may be useful in prognostication of patients with advanced cancer. Further studies are needed to confirm our findings with more consecutive assessments in diverse populations.

PMID:35542972 | DOI:10.21037/apm-22-33