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Experiments were performed that (i) document the effect of the steady spanwise buffer layer blowing on the mean characteristics of the turbulent boundary layer for a range of momentum thickness Reynolds numbers from 4760 to 10 386, and (ii) document the effect of the buffer layer blowing on the unsteady characteristics and coherent vorticity in a boundary layer designed to provide sufficiently high spatial resolution. The spanwise buffer layer blowing of the order of $u_{\tau }$ is produced by a surface array of pulsating direct current (pulsed-DC) plasma actuators. This was found to substantially reduce the wall shear stress that was directly measured with a floating element coupled with a force sensor. The direct wall shear measurements agreed with values derived using the Clauser method to within $\pm 0.85$ %. The degree to which the buffer layer blowing affected $\tau _w$ was found to primarily depend on the inner variable spanwise spacing between the pulsed-DC actuator electrodes, i.e. ‘blowing sites’. Utilizing pairs of $[u,v]$ and $[u,w]$ hot-wire sensors, the latter experiments correlated significant reductions in the $\omega _y$ and $\omega _x$ vorticity components that resulted from the buffer layer blowing and translated into lower Reynolds stresses and turbulence production. The time scale to which these observed changes in the boundary layer characteristics would return to the baseline condition was subsequently documented. This revealed a recovery length of $x^+ \approx 86\,000$ that translated to a streamwise fetch of $x \approx 66\delta$. Finally, a comparison with the recent work by Cheng et al. (2021, J. Fluid Mech. vol. 918, A24) and Wei & Zhou (2024 in TSFP13, June 25–28, 2024) that followed our experimental approach to achieve comparable wall shear stress (drag) reductions has led to a new scaling based on the baseline boundary layer $\textit{Re}_{\tau }$ and buffer layer blowing velocity.
Mild cognitive impairment with Lewy bodies (MCI-LB) may be identified prospectively based on the presence of cognitive impairment and several core clinical features (visual hallucinations, cognitive fluctuations, parkinsonism, and REM sleep behavior disorder). MCI-LB may vary in its presenting features, which may reflect differences in underlying pathological pattern, severity, or comorbidity.
We aimed to assess how clinical features of MCI-LB accumulate over time, and whether this is associated with the rate of cognitive decline.
Methods
In this cohort study, 74 individuals seen with MCI-LB prospectively underwent repeated annual cognitive and clinical assessment up to nine years. Relationships between clinical features (number of core features present and specific features present) and cognitive change on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) were examined with time-varying mixed models. The accumulation of core clinical features over time was examined with a multi-state Markov model.
Results
When an individual with MCI-LB endorsed more clinical features, they typically experienced a faster cognitive decline (ACE-R Score Difference β = −1.1 [−1.7 to −0.5]), specifically when experiencing visual hallucinations (β = −2.1 [−3.5 to −0.8]) or cognitive fluctuations (β = −3.4 [−4.8 to −2.1]).
Individuals with MCI-LB typically acquired more clinical features with the passage of time (25.5% [20.0–32.0%] one-year probability), limiting the prognostic utility of baseline-only features.
Conclusions
The clinical presentation of MCI-LB may evolve over time. The accumulation of more clinical features of Lewy body disease, in particular visual hallucinations and cognitive fluctuations, may be associated with a worse prognosis in clinical settings.
Commercial targeted sprayer systems allow producers to reduce herbicide inputs but risks the possibility of not treating emerging weeds. Currently, targeted applications with the John Deere system have five spray sensitivity settings, and no published literature discusses the effects of these settings on detecting and spraying weeds of varying species, sizes, and positions in crops. Research was conducted in Arkansas, Illinois, Indiana, Mississippi, and North Carolina on plantings of corn, cotton, and soybean to determine how various factors might influence the ability of targeted applications to treat weeds. These data included 21 weed species aggregated to six classes with height, width, and densities ranging from 25 to 0.25 cm, 25 to 0.25 cm, and 14.3 to 0.04 plants m−2, respectively. Crop and weed density did not influence the likelihood of treating the weeds. As expected, the sensitivity setting alters the ability to treat weeds. Targeted applications (across sensitivity settings, median weed height and width, and density of 2.4 plants m−2) resulted in a treatment success of 99.6% to 84.4% for Convolvulaceae, 99.1% to 68.8% for decumbent broadleaf weeds, 98.9% to 62.9% for Malvaceae, 99.1% to 70.3% for Poaceae, 98.0% to 48.3% for Amaranthaceae, and 98.5% to 55.8% for yellow nutsedge. Reducing the sensitivity setting reduced the ability to treat weeds. The size of weeds aided targeted application success, with larger weeds being more readily treated through easier detection. Based on these findings, various conditions can affect the outcome of targeted multinozzle applications. Additionally, the analyses highlight some of the parameters to consider when using these technologies.
Objectives/Goals: Monensin is FDA approved for use in veterinary medicine. Recent studies pointed to its potent anticancer activity. Since de novo drug discovery process typically takes 10 to 15 years and requires an investment of approximately $1.3 to $3 billion, drug repositioning can bypass several steps in this process and increase the potential for success. Methods/Study Population: Cell viability assays were conducted on human MDA-MB-231, MDA-MB-468, and MCF10A breast cancer cell lines and mouse EO771 and 4T1 breast cancer cell lines. MDA-MB-231 cell line was used in all the studies unless specified otherwise. Time course levels of Bcl-2, Bak, p62, and LC3II were assessed via Western blotting with GAPDH as a loading control. Proteomics analysis was conducted by the IDEA National Resource for Quantitative Proteomics. Time course levels of major histocompatibility complex (MHC) I and II and calreticulin were evaluated using flow cytometry. At least three biological replicates have been conducted for each experiment. Results/Anticipated Results: Monensin and several of its novel analogs were potent toward human and mouse breast cancer cell lines. Furthermore, they induced apoptotic cell death as evidenced by Annexin V/PI assay, downregulation of Bcl-2, and upregulation of Bak in MDA-MB-231 cells. Proteomics analysis revealed that several molecular pathways related to MHC class I and II antigen presentation were significantly altered following treatment with these compounds. Additionally, monensin and its analogs significantly increased the expression of MHC class I and II. Our studies also showed that monensin and its analogs increase the surface calreticulin levels. Treatment of MDA-MB-231 cells with these compounds also resulted in an increase in p62 and LC3II expression, suggesting a disruption of the autophagic process. Discussion/Significance of Impact: These results suggest that monensin and its analogs not only exhibit anti-breast cancer cell activity but also modulate immune-related pathways. By disrupting autophagy and enhancing calreticulin levels, these compounds may potentiate antitumor immune responses, providing a promising avenue for drug repositioning in cancer therapy.
Lewy body disease is a common cause of neurodegenerative dementia. The clinical syndrome of dementia with Lewy bodies (DLB) has specific diagnostic, care and management needs, is underrecognized in clinical practice, and often mistaken for Alzheimer’s disease. It may only be identified at autopsy. It typically has a worse prognosis after diagnosis than Alzheimer’s disease. Early, accurate identification is important; improving this at clinical and prodromal stages may assist effective management and reduce patient and caregiver burden. The characteristic clinical features must be recognized: parkinsonism, RBD, fluctuating attention and cognition, complex visual hallucinations. In clinically equivocal cases, diagnosis may be supported by biomarkers specific to Lewy body disease: dopaminergic imaging, cardiac sympathetic imaging, polysomnography. A pattern of cognitive impairment not typical of Alzheimer’s disease may also be seen, with implications for cognitive symptom screening. Screening may be aided by seeking other symptoms of Lewy body disease (hypolfaction, autonomic symptoms, hallucinations other than visual), and other neuropsychiatric symptoms (delusions and mood changes).
Poor diets and food insecurity during adolescence can have long-lasting effects, and Métis youth may be at higher risk. This study, as part of the Food and Nutrition Security for Manitoba Youth study, examines dietary intakes, food behaviours and health indicators of Métis compared with non-Métis youth.
Design:
This observational cross-sectional study involved a cohort of adolescents who completed a self-administered web-based survey on demographics, dietary intake (24-h recall), food behaviours, food security and select health indicators.
Setting:
Manitoba, Canada
Participants:
Participants included 1587 Manitoba grade nine students, with 135 (8·5 %) self-identifying as Métis, a distinct Indigenous nation living in Canada.
Results:
Median intake of sugar was significantly higher in Métis (89·2 g) compared with non-Métis (76·3 g) participants. Percent energy intake of saturated fat was also significantly higher in Métis (12·4 %) than non-Métis (11·6 %) participants. Median intakes of grain products and meat and alternatives servings were significantly lower among Métis than non-Métis (6·0 v. 7·0 and 1·8 v. 2·0, respectively) participants. Intake of other foods was significantly higher in Métis (4·0) than non-Métis (3·0). Significantly more Métis participants were food insecure (33·1 %) compared with non-Métis participants (19·1 %). Significantly more Métis participants ate family dinners and breakfast less often than non-Métis participants and had lower self-reported health. Significantly more Métis participants had a BMI classified as obese compared with non-Métis participants (12·6 % v. 7·1 %).
Conclusions:
The dietary intakes observed in this study, both among Métis and non-Métis youth, are concerning. Many have dietary patterns that put them at risk for developing health issues in the future.
The aim of this study was to determine whether there was a significant change in cardiac [123I]-metaiodobenzylguanidine uptake between baseline and follow-up in individuals with mild cognitive impairment with Lewy bodies (MCI-LB) who had normal baseline scans. Eight participants with a diagnosis of probable MCI-LB and a normal baseline scan consented to a follow-up scan between 2 and 4 years after baseline. All eight repeat scans remained normal; however, in three cases uptake decreased by more than 10%. The mean change in uptake between baseline and repeat was −5.2% (range: −23.8% to +7.0%). The interpolated mean annual change in uptake was −1.6%.
New machine-vision technologies like the John Deere See & Spray™ could provide the opportunity to reduce herbicide use by detecting weeds and target-spraying herbicides simultaneously. Experiments were conducted for 2 yr in Keiser, AR, and Greenville, MS, to compare residual herbicide timings and targeted spray applications versus traditional broadcast herbicide programs in glyphosate/glufosinate/dicamba-resistant soybean. Treatments utilized consistent herbicides and rates with a preemergence (PRE) application followed by an early postemergence (EPOST) dicamba application followed by a mid-postemergence (MPOST) glufosinate application. All treatments included a residual at PRE and excluded or included a residual EPOST and MPOST. Additionally, the herbicide application method was considered, with traditional broadcast applications, broadcasted residual + targeted applications of postemergence herbicides (dual tank), or targeted applications of all herbicides (single tank). Targeted applications provided comparable control to broadcast applications with a ≤1% decrease in efficacy and overall control ≥93% for Palmer amaranth, broadleaf signalgrass, morningglory species, and purslane species. Additionally, targeted sprays slightly reduced soybean injury by at most 5 percentage points across all evaluations, and these effects did not translate to a yield increase at harvest. The relationship between weed area and targeted sprayed area also indicates that nozzle angle can influence potential herbicide savings, with narrower nozzle angles spraying less area. On average, targeted sprays saved a range of 28.4% to 62.4% on postemergence herbicides. On the basis of these results, with specific machine settings, targeted application programs could reduce the amount of herbicide applied while providing weed control comparable to that of traditional broadcast applications.
This Element surveys the main claims of Bernard Williams's ethical philosophy. Topics include ethical scepticism, virtue, reasons for action, the critique of the Morality System, moral realism and the nature of theorising in ethics.
Depression is common in people with dementia, and negatively affects quality of life.
Aims
This paper aims to evaluate the cost-effectiveness of an intervention for depression in mild and moderate dementia caused by Alzheimer's disease over 12 months (PATHFINDER trial), from both the health and social care and societal perspectives.
Method
A total of 336 participants were randomised to receive the adapted PATH intervention in addition to treatment as usual (TAU) (n = 168) or TAU alone (n = 168). Health and social care resource use were collected with the Client Service Receipt Inventory and health-related quality-of-life data with the EQ-5D-5L instrument at baseline and 3-, 6- and 12-month follow-up points. Principal analysis comprised quality-adjusted life-years (QALYs) calculated from the participant responses to the EQ-5D-5L instrument.
Results
The mean cost of the adapted PATH intervention was estimated at £1141 per PATHFINDER participant. From a health and social care perspective, the mean difference in costs between the adapted PATH and control arm at 12 months was −£74 (95% CI −£1942 to £1793), and from the societal perspective was −£671 (95% CI −£9144 to £7801). The mean difference in QALYs was 0.027 (95% CI −0.004 to 0.059). At £20 000 per QALY gained threshold, there were 74 and 68% probabilities of adapted PATH being cost-effective from the health and social care and societal perspective, respectively.
Conclusions
The addition of the adapted PATH intervention to TAU for people with dementia and depression generated cost savings alongside a higher quality of life compared with TAU alone; however, the improvements in costs and QALYs were not statistically significant.
Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD.
Methods
As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men.
Results
Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects.
Conclusions
Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.
Multimorbidity, the presence of two or more health conditions, has been identified as a possible risk factor for clinical dementia. It is unclear whether this is due to worsening brain health and underlying neuropathology, or other factors. In some cases, conditions may reflect the same disease process as dementia (e.g. Parkinson's disease, vascular disease), in others, conditions may reflect a prodromal stage of dementia (e.g. depression, anxiety and psychosis).
Aims
To assess whether multimorbidity in later life was associated with more severe dementia-related neuropathology at autopsy.
Method
We examined ante-mortem and autopsy data from 767 brain tissue donors from the UK, identifying physical multimorbidity in later life and specific brain-related conditions. We assessed associations between these purported risk factors and dementia-related neuropathological changes at autopsy (Alzheimer's-disease related neuropathology, Lewy body pathology, cerebrovascular disease and limbic-predominant age-related TDP-43 encephalopathy) with logistic models.
Results
Physical multimorbidity was not associated with greater dementia-related neuropathological changes. In the presence of physical multimorbidity, clinical dementia was less likely to be associated with Alzheimer's disease pathology. Conversely, conditions which may be clinical or prodromal manifestations of dementia-related neuropathology (Parkinson's disease, cerebrovascular disease, depression and other psychiatric conditions) were associated with dementia and neuropathological changes.
Conclusions
Physical multimorbidity alone is not associated with greater dementia-related neuropathological change; inappropriate inclusion of brain-related conditions in multimorbidity measures and misdiagnosis of neurodegenerative dementia may better explain increased rates of clinical dementia in multimorbidity
OBJECTIVES/GOALS: Although the approval of immune checkpoint inhibitors (ICIs) revolutionized the treatment of metastatic breast cancer (BC), yet about 30% remain unresponsive. Since the potency of ICIs depends on the efficient presentation of tumor-specific antigens by cancer cells, compounds which increase such presentation could increase efficacy of ICIs. METHODS/STUDY POPULATION: A library of the ester and urethane derivatives of polyether ionophore antibiotic, monensin (MON) has been synthesized. MTT cell viability assays were performed on the panel of human and mouse BC cell lines, and non-cancerous breast epithelial cells to determine IC50 values of MON and its derivatives. Selectivity Indexes were calculated to identify the most selective compounds towards cancer versus non-cancer cells. Major Histocompatibility Complex (MHC) class I and II presentation and Programmed death-ligand 1 (PD-L1) expression have been determined using flow cytometry. Proteins involved in apoptosis, autophagy and immunogenic cell death were identified through immunoblotting. At least three biological replicates have been performed for each experiment. RESULTS/ANTICIPATED RESULTS: MON and several of its derivatives shown activity in nanomolar range against MDA-MB-231 human BC cell line. MON and its most potent derivatives significantly increased MHC class I and II presentation and downregulated the expression of PD-L1 in BC cell lines. DISCUSSION/SIGNIFICANCE: Present findings will lead to the development of new therapeutic approaches that can serve as single agents or be used in combination with existing ICIs for the treatment of metastatic BC. By pushing the boundaries of our understanding and developing new therapies, this research can make an impact in improving outcomes for patients with metastatic BC.
My name is Alane Thomas. I have a Master’s degree in Social Work, a Master of Arts in Criminal Justice, and a clinical social work license. I have been in the social work field for 10 years and worked in the victim advocacy field for 2.5 years. I have worked with sexual assault survivors and domestic violence victims, families in child protective services, and clients in a behavioral health hospital setting, and have provided individual, couples, and family therapy in a private practice setting. I have had the opportunity to experience what goes into making decisions to protect children and adults who are at risk of or are actively experiencing abuse and neglect.
Attentional impairments are common in dementia with Lewy bodies and its prodromal stage of mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). People with MCI may be capable of compensating for subtle attentional deficits in most circumstances, and so these may present as occasional lapses of attention. We aimed to assess the utility of a continuous performance task (CPT), which requires sustained attention for several minutes, for measuring attentional performance in MCI-LB in comparison to Alzheimer’s disease (MCI-AD), and any performance deficits which emerged with sustained effort.
Method:
We included longitudinal data on a CPT sustained attention task for 89 participants with MCI-LB or MCI-AD and 31 healthy controls, estimating ex-Gaussian response time parameters, omission and commission errors. Performance trajectories were estimated both cross-sectionally (intra-task progress from start to end) and longitudinally (change in performance over years).
Results:
While response times in successful trials were broadly similar, with slight slowing associated with clinical parkinsonism, those with MCI-LB made considerably more errors. Omission errors were more common throughout the task in MCI-LB than MCI-AD (OR 2.3, 95% CI: 1.1–4.7), while commission errors became more common after several minutes of sustained attention. Within MCI-LB, omission errors were more common in those with clinical parkinsonism (OR 1.9, 95% CI: 1.3–2.9) or cognitive fluctuations (OR 4.3, 95% CI: 2.2–8.8).
Conclusions:
Sustained attention deficits in MCI-LB may emerge in the form of attentional lapses leading to omissions, and a breakdown in inhibitory control leading to commission errors.