Chronic toxicity of nano metallics on red swamp crayfish (Procambarus clarkii) in laboratory and mesocosm studies

Nanotechnology has become integrated in commercial, industrial and medical products, and its use has grown exponentially in the past several years. Although potential applications of nanoparticles (NPs) are numerous, concerns about their water quality, environmental, and human health impacts remain unclear. Crayfish are ubiquitous to streams and wetland habitats, are used as a food source, and inhabit areas that could be impacted by water quality issues. Numerous studies have been conducted on the toxicity of various classes of agricultural pesticides and oils to crayfish (Procambarus clarkii) as a non-target organism. However, there is little evidence published on chronic toxicity of NP to crayfish. The first objective of this study was to estimate the 28 day toxicity and bioaccumulation of the three most produced nanoparticles, Ag, ZnO, and TiO2, in a laboratory adult crayfish model. The organisms were exposed to different Ag, ZnO, and TiO2 nanoparticle solutions at concentrations of 0, 100, 500, and 1000 g/mL. AgNO3 and KNO3, and Zn(NO3)2•6H2O and KNO3 were used as bulk controls for Ag and ZnO treatments, respectively. Dead crayfish were removed and preserved then examined for metal accumulation and pathological changes in behavior. Metal accumulation in major organs was determined by inductively coupled plasma optical emission spectrometry (ICP-OES). Results indicate that as the concentration of NP increases the uptake of metal in tissue also increases. In this case, the chemical rankings of toxicity are as follows: AgNO₃ \u3e Zn(NO₃)₂ \u3e AgNP \u3e ZnO \u3e KNO₃ \u3e TiO₂. Silver accumulated in gill tissue 3 times more in AgNO3 treatments than in AgNP treatments. In abdominal tissue, silver accumulated 4 times more in AgNO3 treatments than in AgNP treatments. Zinc accumulated in gill tissue 2 times more in Zn(NO₃)₂ treatments than in ZnO treatments. The second objective was to estimate the bioaccumulation of the nanoparticles: Ag, ZnO, and TiO2 in a mesocosm adult crayfish model. From previous experiments, we determined the following concentrations for each tank: AgNPs 20 mg/L, ZnO 50 mg/L, and TiO2 100 mg/L. A 0 mg/L control tank was also used. Three crayfish were removed from each tank and preserved for analysis weekly. Soil samples were taken bi-weekly. ICP-OES was used to look at the accumulation of the metals in the gill and abdominal tissues as well as the soil samples. Results indicate that bioaccumulation occurs in tissues in fluctuating trend rather than an increasing trend

Body mass estimates of phytosaurs (Archosauria: Parasuchidae) from the Petrified Forest Formation (Chinle Group: Revueltian : early-mid Norian) based on skull and limb bone measurements

Phytosaurs were the largest and most common semi-aquatic predators of the Late Triassic. Although their skulls are relatively common in the fossil record, articulated, or even associated skeletons are extremely rare, so it has always been difficult to gauge just how large (mass or length) an individual phytosaur may have been. Body mass in particular is an important physiological variable, often used for the scaling of organs, biomass determination, biomechanics, and locomotion. We take advantage of phytosaurs’ general similarity to extant crocodilians to attempt to reconstruct body mass and length based on measurements of the skulls and limbs of phytosaurs from the Upper Triassic Snyder and Canjilon quarries in north-central New Mexico. These quarries, in the Painted Desert Member of the Petrified Forest Formation (Revueltian: early-mid Norian) preserve catastrophic death assemblages that appear to well-represent discrete populations of phytosaurs. We also utilize a snout-vent measurement based on an articulated skeleton from the Canjilon quarry to compare the accuracy of different equations based on discrete limb elements. Body mass estimates for Snyder quarry phytosaurs range between 25 and 500 kg, with most specimens yielding estimates of approximately 200-350 kg. The Canjilon quarry sample encompasses fewer juveniles and more robust adults, including one individual that may have weighed as much as 535 kg. From equations based on nine extant crocodilian genera, these Revueltian phytosaurs appear to have approached 4.5 m total body length for a ~ 400 kg phytosaur. The prevalence of subadult to adult phytosaurs in both quarries based on body mass estimates corroborates qualitative estimates of the population structure based on skull sizes alone, thereby reinforcing the hypothesis that both quarries are catastrophic assemblages

Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Donepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d.</p> <p>Method</p> <p>Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed.</p> <p>Results</p> <p>The safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%).</p> <p>Discussion</p> <p>The 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d.</p> <p>Conclusion</p> <p>The good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00478205">NCT00478205</a></p

Resting-state fMRI Activity Profile in Prodromal Alzheimer’s Disease and Older Adults with Cognitive Complaints

poster abstractBackground: Resting-state functional MRI (RS-fMRI) has been proposed to detect neurodegenerative disease-related network alterations before brain atrophy has emerged. Disrupted resting-state connectivity in the posterior cingulate cortex (PCC) and hippocampus has been reported in AD (Grecius, 2004), yet results in prodromal AD including MCI vary. Other methods have suggested the feasibility of earlier detection in euthymic older adults with marked cognitive complaints (CC) but normal neuropsychological test performance (Saykin, 2006). The current study was designed to assess RS-fMRI patterns in CC compared with MCI, AD and healthy controls (HC). Methods: To date, 13 CC, 9 HC, 4 MCI and 3 AD participants were scanned at rest with eyes closed on a Siemens 3T. RS-fMRI was analyzed using FSL, AFNI and SPM8. For each individual, the sum of amplitude of low frequency fluctuation (ALFF; 0.01–0.1 Hz) was calculated at each voxel (Biswal, 2010). Using PCC seed ROIs adapted from Fox et al (2005) voxel-wise cross-correlation maps were generated for each subject. Group comparisons and covariate analyses were performed using SPM8 with age as a covariate. Results: Compared to HC, MCI/AD showed decreased ALFF in the PCC (p CC > MCI/AD, p<0.05, effect size: 0.61), and ALFF of hippocampus (HC < CC < MCI/AD, p<0.01, effect size: 0.75). ALFF of PCC was positively correlated with neuropsychological performance (MMSE, DRS and CVLT; r=0.45 to 0.56, p<0.01), while hippocampal ALFF was negatively correlated with performance (r=-0.48 to -0.67, p<0.01). PCC seeded crosscorrelation maps showed decreased hippocampal connectivity in MCI/AD compared to HC or CC (p<0.01). Conclusions: RS-fMRI appears sensitive to early prodromal neurodegenerative changes in regions associated with AD, notably including pre-MCI individuals with CC. While there is decreased functional connectivity between PCC and hippocampus, regionally increased ALFF in hippocampus may indicate a compensatory mechanism in early prodromal AD

The Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs

This Review initiates a wide-ranging discussion over 2023 by selecting and exploring core themes to be investigated more deeply in papers submitted to the Vaccines Special Issue on the "Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs". To tackle the SARS-CoV-2 pandemic, an acceleration of vaccine development across different technology platforms resulted in the emergency use authorization of multiple vaccines in less than a year. Despite this record speed, many limitations surfaced including unequal access to products and technologies, regulatory hurdles, restrictions on the flow of intellectual property needed to develop and manufacture vaccines, clinical trials challenges, development of vaccines that did not curtail or prevent transmission, unsustainable strategies for dealing with variants, and the distorted allocation of funding to favour dominant companies in affluent countries. Key to future epidemic and pandemic responses will be sustainable, global-public-health-driven vaccine development and manufacturing based on equitable access to platform technologies, decentralised and localised innovation, and multiple developers and manufacturers, especially in low- and middle-income countries (LMICs). There is talk of flexible, modular pandemic preparedness, of technology access pools based on non-exclusive global licensing agreements in exchange for fair compensation, of WHO-supported vaccine technology transfer hubs and spokes, and of the creation of vaccine prototypes ready for phase I/II trials, etc. However, all these concepts face extraordinary challenges shaped by current commercial incentives, the unwillingness of pharmaceutical companies and governments to share intellectual property and know-how, the precariousness of building capacity based solely on COVID-19 vaccines, the focus on large-scale manufacturing capacity rather than small-scale rapid-response innovation to stop outbreaks when and where they occur, and the inability of many resource-limited countries to afford next-generation vaccines for their national vaccine programmes. Once the current high subsidies are gone and interest has waned, sustaining vaccine innovation and manufacturing capability in interpandemic periods will require equitable access to vaccine innovation and manufacturing capabilities in all regions of the world based on many vaccines, not just "pandemic vaccines". Public and philanthropic investments will need to leverage enforceable commitments to share vaccines and critical technology so that countries everywhere can establish and scale up vaccine development and manufacturing capability. This will only happen if we question all prior assumptions and learn the lessons offered by the current pandemic. We invite submissions to the special issue, which we hope will help guide the world towards a global vaccine research, development, and manufacturing ecosystem that better balances and integrates scientific, clinical trial, regulatory, and commercial interests and puts global public health needs first

Visual contrast sensitivity is associated with the presence of cerebral amyloid and tau deposition

Visual deficits are common in neurodegenerative diseases including Alzheimer’s disease. We sought to determine the association between visual contrast sensitivity and neuroimaging measures of Alzheimer’s disease-related pathophysiology, including cerebral amyloid and tau deposition and neurodegeneration. A total of 74 participants (7 Alzheimer’s disease, 16 mild cognitive impairment, 20 subjective cognitive decline, 31 cognitively normal older adults) underwent the frequency doubling technology 24-2 examination, a structural MRI scan and amyloid PET imaging for the assessment of visual contrast sensitivity. Of these participants, 46 participants (2 Alzheimer’s disease, 9 mild cognitive impairment, 12 subjective cognitive decline, 23 cognitively normal older adults) also underwent tau PET imaging with [18F]flortaucipir. The relationships between visual contrast sensitivity and cerebral amyloid and tau, as well as neurodegeneration, were assessed using partial Pearson correlations, covaried for age, sex and race and ethnicity. Voxel-wise associations were also evaluated for amyloid and tau. The ability of visual contrast sensitivity to predict amyloid and tau positivity were assessed using forward conditional logistic regression and receiver operating curve analysis. All analyses first were done in the full sample and then in the non-demented at-risk individuals (subjective cognitive decline and mild cognitive impairment) only. Significant associations between visual contrast sensitivity and regional amyloid and tau deposition were observed across the full sample and within subjective cognitive decline and mild cognitive impairment only. Voxel-wise analysis demonstrated strong associations of visual contrast sensitivity with amyloid and tau, primarily in temporal, parietal and occipital brain regions. Finally, visual contrast sensitivity accurately predicted amyloid and tau positivity. Alterations in visual contrast sensitivity were related to cerebral deposition of amyloid and tau, suggesting that this measure may be a good biomarker for detecting Alzheimer’s disease-related pathophysiology. Future studies in larger patient samples are needed, but these findings support the power of these measures of visual contrast sensitivity as a potential novel, inexpensive and easy-to-administer biomarker for Alzheimer’s disease-related pathology in older adults at risk for cognitive decline

The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests

BACKGROUND: The perception of cognitive decline by individuals and those who know them well ("informants") has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms. OBJECTIVE: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms. METHODS: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models. RESULTS: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant. CONCLUSION: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome

Cognitive complaints in older adults at risk for Alzheimer's disease are associated with altered resting-state networks

INTRODUCTION: Pathophysiological changes that accompany early clinical symptoms in prodromal Alzheimer's disease (AD) may have a disruptive influence on brain networks. We investigated resting-state functional magnetic resonance imaging (rsfMRI), combined with brain connectomics, to assess changes in whole-brain functional connectivity (FC) in relation to neurocognitive variables. METHODS: Participants included 58 older adults who underwent rsfMRI. Individual FC matrices were computed based on a 278-region parcellation. FastICA decomposition was performed on a matrix combining all subjects' FC. Each FC pattern was then used as a response in a multilinear regression model including neurocognitive variables associated with AD (cognitive complaint index [CCI] scores from self and informant, an episodic memory score, and an executive function score). RESULTS: Three connectivity independent component analysis (connICA) components (RSN, VIS, and FP-DMN FC patterns) associated with neurocognitive variables were identified based on prespecified criteria. RSN-pattern, characterized by increased FC within all resting-state networks, was negatively associated with self CCI. VIS-pattern, characterized by an increase in visual resting-state network, was negatively associated with CCI self or informant scores. FP-DMN-pattern, characterized by an increased interaction of frontoparietal and default mode networks (DMN), was positively associated with verbal episodic memory. DISCUSSION: Specific patterns of FC were differently associated with neurocognitive variables thought to change early in the course of AD. An integrative connectomics approach relating cognition to changes in FC may help identify preclinical and early prodromal stages of AD and help elucidate the complex relationship between subjective and objective indices of cognitive decline and differences in brain functional organization

Refining the global spatial limits of dengue virus transmission by evidence-based consensus.

BACKGROUND: Dengue is a growing problem both in its geographical spread and in its intensity, and yet current global distribution remains highly uncertain. Challenges in diagnosis and diagnostic methods as well as highly variable national health systems mean no single data source can reliably estimate the distribution of this disease. As such, there is a lack of agreement on national dengue status among international health organisations. Here we bring together all available information on dengue occurrence using a novel approach to produce an evidence consensus map of the disease range that highlights nations with an uncertain dengue status. METHODS/PRINCIPAL FINDINGS: A baseline methodology was used to assess a range of evidence for each country. In regions where dengue status was uncertain, additional evidence types were included to either clarify dengue status or confirm that it is unknown at this time. An algorithm was developed that assesses evidence quality and consistency, giving each country an evidence consensus score. Using this approach, we were able to generate a contemporary global map of national-level dengue status that assigns a relative measure of certainty and identifies gaps in the available evidence. CONCLUSION: The map produced here provides a list of 128 countries for which there is good evidence of dengue occurrence, including 36 countries that have previously been classified as dengue-free by the World Health Organization and/or the US Centers for Disease Control. It also identifies disease surveillance needs, which we list in full. The disease extents and limits determined here using evidence consensus, marks the beginning of a five-year study to advance the mapping of dengue virus transmission and disease risk. Completion of this first step has allowed us to produce a preliminary estimate of population at risk with an upper bound of 3.97 billion people. This figure will be refined in future work

Olfactory identification in subjective cognitive decline and mild cognitive impairment: Association with tau but not amyloid positron emission tomography

Introduction We investigated the association between olfactory identification and Alzheimer's disease biomarkers, including amyloid, tau, and neurodegeneration. Methods Thirty-four older adults, including 19 cognitively normal (CN), 10 subjective cognitive decline (SCD), and 5 mild cognitive impairment, underwent amyloid positron emission tomography, magnetic resonance imaging, and the University of Pennsylvania Smell Identification Test (UPSIT). Twenty-six also underwent tau positron emission tomography. Associations between the UPSIT and regionally sampled amyloid, tau, and temporal atrophy were evaluated. Voxel-wise regression models were also utilized. Analyses were conducted with the full sample and only CN/SCD. Results Lower UPSIT scores were associated with increased temporal and parietal tau burden in regional and voxel-wise analyses in the full sample and in CN and SCD only. Temporal lobe atrophy was associated with lower UPSIT score. Amyloid was not associated with the UPSIT. Discussion Impairment on the UPSIT may be a good marker for tau and neurodegeneration in preclinical or prodromal Alzheimer's disease