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The migratory phase is a critical time for Fasciola hepatica as it must locate, penetrate and migrate through the alimentary tract to the liver parenchyma whilst under attack from the host immune response. Here, scanning and transmission electron microscopy were used to monitor the in vitro effects of sera (with, and without, complement depletion) on F. hepatica newly excysted juveniles (NEJs) and flukes recovered at 7, 35, 70 and 98 days post infection (dpi) from the liver and bile ducts of rats. Test sera were from these F. hepatica-infected rats. A F. hepatica NEJ-specific rabbit antiserum was also used. All fluke stages demonstrated release of the tegumental glycocalyx and microvesicles and intense activity within the tegumental syncytium characterized by eccrine secretion of T-0/T-1/T-2 secretory bodies with subsequent microvillar formation and shedding of microvesicles from the apical plasma membrane. Exposure of both NEJs and 35 dpi flukes to 35 and 70 dpi rat sera produced significant amounts of eccrine-derived secretory material and putative attached immunocomplex. Rabbit anti-F. hepatica NEJ-specific antiserum produced similar responses at the NEJ tegument, including binding of putative immunocomplex to the surface, but with additional blistering of some regions of the apical plasma membrane. Our data suggest that immune sera stimulates multiple interrelated secretory mechanisms to maintain the integrity of the tegumental barrier in response to immune attack. Concurrent release of microvesicles may also serve to both divert the immune response away from the fluke itself and permit delivery of immunomodulatory cargo to immune effector cells.
A new formulation of pyroxasulfone + encapsulated saflufenacil has been developed. Combining these two herbicides extends the application window to early postemergence. Pyroxasulfone, saflufenacil (suspension concentrate), and pyroxasulfone + encapsulated saflufenacil (microcapsule suspension) were applied to corn preemergence and evaluated for corn injury, corn yield, and visible weed control; in addition, the interaction (antagonistic, additive, or synergistic) was ascertained for each parameter. Six field trials were conducted at three locations in southwestern Ontario in 2022 and 2023. Pyroxasulfone was applied at 90, 120, and 150 g ai ha−1; saflufenacil was applied at 56, 75, and 95 g ai ha−1; and pyroxasulfone + encapsulated saflufenacil was applied at 146, 195, 245 g ai ha−1, equal to the combined rates of pyroxasulfone and saflufenacil. All pyroxasulfone, encapsulated saflufenacil, and pyroxasulfone + encapsulated saflufenacil treatments caused no corn injury. Weed control varied based on application rate and weed species. Reduced weed interference with pyroxasulfone + encapsulated saflufenacil at 195 and 245 g ai ha−1 resulted in corn yield that was similar to the weed-free control and the industry standard of S-metolachlor/atrazine/mesotrione/bicyclopyrone. The interaction between pyroxasulfone and encapsulated saflufenacil for weed control was additive.
Community-engaged partnerships (community/academia/government) can play a role in developing effective protocols that address public health crises. Systemic racism, prioritization of money over humanity, and the repression of the local democratic processes through the State of Michigan Emergency Manager Law (Order of Act 439) all played a role in the Flint Water Crisis. Despite decades of collaboration between Flint-based community organizations and academic institutions, ways to navigate such crises and conduct relevant research were ineffective.
Methods:
The Michigan Institute for Clinical and Health Research Community Engagement program at the University of Michigan and Flint’s Community Based Organization Partners co-developed the Research Readiness and Partnership Protocol (R2P2) to provide community-engaged recommendations that inform a rapid research response to public health emergencies. The R2P2 Workgroup conducted an extensive literature review and key interviews to inform protocol development.
Results:
This manuscript provides an overview of the Workgroup’s methods, key interview findings, and the main principles identified. Detailed recommendations and key elements to address prior to and during a crisis will be presented including methods for: establishing and maintaining trust, ensuring transparency, supporting clear communication, establishing a “front door” to academic institutions including a means to “sound the alarm,” addressing academic incentives, achieving equitable resource sharing, and addressing systemic racism.
Conclusion:
This manuscript of community perspectives provides essential elements to develop meaningful community-academic research partnerships to address public health crises impacting communities, particularly communities of color. Furthermore, this work highlights an opportunity for greater acknowledgment and utilization of community-based participatory research (CBPR) by academic institutions.
Objectives/Goals: Youth-onset diabetes and its risk factors are increasing in ethnic and racial minority communities. Our mixed-methods study aimed to explore the associations between participation in a community youth sports program and key diabetes risk factors in youth, including mental health, physical activity, nutrition, and weight status. Methods/Study Population: We used a single cohort, mixed-methods design focused on the Community Leadership Revolution (CLR) Academy, a local youth sports program. Participants, ethnic and racial minority youth ages 5–14, were recruited to assess their mental health, physical activity, and nutrition using validated and reliable questionnaires. Weight status was measured via bioelectrical impedance. Group interviews with youth and individual interviews with staff provided context for the quantitative results. A thematic analysis of the qualitative data will further explore how CLR Academy may impact diabetes risk factors. Results/Anticipated Results: We recruited 24 CLR participants (16 boys/8 girls) and 4 CLR staff (3 males/1 female). Sixteen youth identified as African-American, while the rest identified as multiracial. Correlations revealed that higher attendance at CLR Academy was negatively associated with mental health scores, specifically total, externalizing, and hyperactive scores (all p < 0.01). Higher CLR attendance was negatively associated with physical activity during spare time (p < 0.05), waist circumference (p< 0.05), and waist-to-height ratio (p < 0.01). Being a girl was associated with lower diet quality and physical activity (both p < 0.05). Qualitative data highlighted life skills and supportive relationships in CLR as key factors in improving health outcomes. Thematic analysis is ongoing to clarify these relationships. Discussion/Significance of Impact: This study highlights how participation in programs like CLR Academy may improve ethnic and racial minority youth diabetes risk factors. Staff and participant insights on mechanisms driving these health improvements may offer strategies that can be applied to similar programs focused on reducing marginalized youth’s diabetes risk.
This study introduces a novel method for gait analysis using a single inertial measurement unit placed on the sacrum. This method is valid not only on level ground but also on incline and decline conditions. The method leverages the “crackle” function, the third derivative of the sacral resultant acceleration, to identify right and left gait events. This approach is particularly effective in capturing the initial peak in acceleration data during foot impact with the ground, often overlooked by other methods. The study aimed to demonstrate the method’s accuracy in identifying the right- and left-side impacts during level ground, incline, and decline runs across a range of speeds. Additionally, the algorithm was applied in outdoor running scenarios, where it performed very well, further validating its robustness and reliability. The results are compared with other existing methods to highlight the effectiveness of this approach.
Runoff contributions from glacierized catchments are changing in response to accelerating mass loss. We reconstruct the 1980–2022 mass balance, runoff and water budget of the ∼70% glacierized Kaskawulsh River headwaters in Yukon, Canada, using an enhanced temperature-index model driven by downscaled and bias-corrected reanalysis data. Debris is treated using melt-scaling factors based on site-specific measurements of the critical debris thickness. Accumulation is estimated from downscaled precipitation bias corrected based on in situ measurements. Model tuning incorporates observations of the 2007–18 geodetic mass balance and seasonal snowline positions on the Kaskawulsh Glacier. We assess model sensitivity to the representation of supraglacial debris and accumulation, including treatments of these processes that can be applied in the absence of in situ data. Different representations of debris produce <1% variation in the catchment-wide runoff and water budget. In contrast, accumulation estimates that omit in situ data produce 33–40% variations in modelled runoff relative to those that use these data. This work identifies site-specific measurements of accumulation as critical to accurate estimates of mass balance and runoff for the Kaskawulsh Glacier, in contrast to site-specific characterization of the effects of debris which influence estimated thinning rates at the glacier terminus but have little impact on the glacier-wide runoff.
A formal theory of appropriateness for statistical operations is presented which incorporates features of Stevens’ theory of appropriate statistics and Suppes’ theory of empirical meaningfulness. It is proposed that a statistic be regarded as appropriate relative to statements made about it in case the truths of these statements are invariant under permissible transformations of the measurement scale. It is argued that the use of inappropriate statistics leads to the formulation of statements which are either semantically meaningless or empirically nonsignificant.
Trace amine-associated receptor 1 (TAAR1) agonists offer a new approach, but there is uncertainty regarding their effects, exact mechanism of action and potential role in treating psychosis.
Aims
To evaluate the available evidence on TAAR1 agonists in psychosis, using triangulation of the output of living systematic reviews (LSRs) of animal and human studies, and provide recommendations for future research prioritisation.
Method
This study is part of GALENOS (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis). In the triangulation process, a multidisciplinary group of experts, including those with lived experience, met and appraised the first co-produced living systematic reviews from GALENOS, on TAAR1 agonists.
Results
The animal data suggested a potential antipsychotic effect, as TAAR1 agonists reduced locomotor activity induced by pro-psychotic drug treatment. Human studies showed few differences for ulotaront and ralmitaront compared with placebo in improving overall symptoms in adults with acute schizophrenia (four studies, n = 1291 participants, standardised mean difference (SMD) 0.15, 95% CI −0.05 to 0.34). Large placebo responses were seen in ulotaront phase three trials. Ralmitaront was less efficacious than risperidone (one study, n = 156 participants, SMD = −0.53, 95% CI −0.86 to −0.20). The side-effect profile of TAAR1 agonists was favourable compared with existing antipsychotics. Priorities for future studies included (a) using different animal models of psychosis with greater translational validity; (b) animal and human studies with wider outcomes including cognitive and affective symptoms and (c) mechanistic studies and investigations of other potential applications, such as adjunctive treatments and long-term outcomes. Recommendations for future iterations of the LSRs included (a) meta-analysis of individual human participant data, (b) including studies that used different methodologies and (c) assessing other disorders and symptoms.
Conclusions
This co-produced, international triangulation examined the available evidence and developed recommendations for future research and clinical applications for TAAR1 agonists in psychosis. Broader challenges included difficulties in assessing the risk of bias, reproducibility, translation and interpretability of animal models to clinical outcomes, and a lack of individual and clinical characteristics in the human data. The research will inform a separate, independent prioritisation process, led by lived experience experts, to prioritise directions for future research.
Following the application of MCPA/MCPB at 1.7 kg ae ha−1 at a field site near Dresden, ON, Canada, poor control (<50% visible control) of green pigweed (Amaranthus powellii S. Watson) was observed. Amaranthus powellii is a common weed in Ontario crop production, and its evolution of resistance to synthetic auxin herbicides (SAHs) could pose a risk to crop yields. The suspected resistant A. powellii population (R) was used in dose–response and field experiments to determine resistance to SAHs. The objective of these studies was to determine whether this population of A. powellii is resistant to MCPA and cross-resistant to other SAHs. The GR50 (herbicide dose that causes a 50% reduction in plant aboveground biomass) values were determined by fitting plant dry weight data, obtained following application with seven SAHs, to a four-parameter log-logistic equation and were compared between the suspected-resistant (R) population and a known susceptible (S) population of A. powellii. The field trial was conducted in 2017, 2018, 2019, and 2021 in corn (Zea mays L.) and consisted of 11 postemergence SAH treatments. The GR50 values differed between the R and S populations following application with MCPA, aminocyclopyrachlor, dichlorprop-p, and mecoprop, resulting in resistance factors of 4.4, 3.0, 2.5, and 2.4, respectively. In the field study, dicamba and MCPA ester controlled A. powellii 84% and 30%, respectively, at 8 wk after treatment application (WAA). The control of Amaranthus powellii with all SAHs applied POST in corn was poor (<90% visible control) at 8 WAA. Both studies confirmed resistance to SAHs in this population of A. powellii, which will create limitations for farmers aiming to control this weed.
Enrollment into a prospective cohort study of mother–preterm infant dyads during the COVID-19 pandemic progressed slower than anticipated. Enrollment occurred during the first week after preterm birth, while infants were still hospitalized. We hypothesized that slower enrollment was attributable to mothers testing positive for COVID-19 as hospital policies restricted them from entering the neonatal intensive care unit, thus reducing interactions with research staff. However, only 4.5% of 245 screened mothers tested COVID-19 positive. Only 24.9% of those screened, far fewer than anticipated, were eligible for enrollment. Assumptions about pandemic-related enrollment barriers were not substantiated in this pediatric cohort.
Improving community attitudes and behaviours is core to improving inclusion for people with disability. To identify ways to achieve such change, we analysed data from qualitative interviews with sixty-one expert stakeholders in Australia, informed by our preceding literature review on effective interventions. We identified five themes describing factors with the potential to change attitudes and behaviours to improve inclusion and reduce discrimination: ensuring people with disability have active presence across all life domains; leadership by people with disability, together with organisational and governmental leadership that values the diverse contribution of people with disability; a holistic approach to policy and interventions that targets multiple levels of change; long-term and adequately resourced initiatives to achieve structural and sustained change; and commitment to measuring and monitoring change interventions, to inform decisions and maintain accountability.
The trace element selenium is known to protect against oxidative damage which is known to contribute to cognitive impairment with ageing (1,2). The aim of this study was to explore the association between selenium status (serum selenium and selenoprotein P (SELENOP)) and global cognitive performance at baseline and after 5 years in 85-year-olds living in the Northeast of England.
Serum selenium and SELENOP concentrations were measured at baseline by total reflection X-ray fluorescence (TXRF) and enzyme-linked immunosorbent assay (ELISA), respectively, in 757 participants from the Newcastle 85+ study. Global cognitive performance was assessed using the Standardized Mini-Mental State Examination (SMMSE) where scores ≤25 out of 30 indicated cognitive impairment. Logistic regressions explored the associations between selenium status and global cognition at baseline. Linear mixed models explored associations between selenium status and global cognition prospectively after 5 years. Covariates included sex, body mass index, physical activity, high sensitivity C-reactive protein, alcohol intake, self-rated health, medications and smoking status.
At baseline, in fully adjusted models, there was no increase in odds of cognitive impairment with serum selenium (OR 1.004, 95% CI 0.993-1.015, p = 0.512) or between SELENOP (OR 1.006, 95% CI 0.881-1.149, p = 0.930). Likewise, over 5 years, in fully adjusted models there was no association between serum selenium and cognitive impairment (β 7.20E-4 ± 5.57E-4, p = 0.197), or between SELENOP and cognitive impairment (β 3.50E-3 ± 6.85E-3, p = 0.610).
In this UK cohort of very old adults, serum selenium or SELENOP was not associated with cognitive impairment at baseline and 5 years. This was an unexpected finding despite SELENOP’s key role in the brain and the observed associations in other studies. Further research is needed to explore the effect of selenium on global cognition in very old adults.
OBJECTIVES/GOALS: Prostate cancer treatment is associated with significant genitourinary side effects. There is a critical need for treatment with decreased morbidity. We report the development of a novel treatment paradigm combining irreversible electroporation and lower dose radiation to provide prostate cancer patients with a less morbid treatment. METHODS/STUDY POPULATION: Intermediate risk prostate cancer patients will undergo focal irreversible electroporation followed by low dose, whole gland radiation therapy. The primary endpoint is freedom from clinically significant cancer on biopsy at 12-month follow up. Secondary endpoints include safety profile, oncologic efficacy, effectiveness of RT and need for secondary treatment. This trial (NCT05345444) and currently actively recruiting patients after initial feasibility trial. Sample size is calculated to detect an increase in the proportion of patients who are cancer free at 1-year, from 0.80 to 0.95. An exact binomial test with a 10% one-sided significance level will have 94.3% power to detect the difference between the null and alternative hypothesis when the sample size is 42. RESULTS/ANTICIPATED RESULTS: This is a clinical trial in progress. DISCUSSION/SIGNIFICANCE: Combined irreversible electroporation (IRE) and a lower dose radiotherapy (RTIRE) may provide prostate cancer patients a treatment with minimal side effects.
Waterhemp has evolved resistance to Group 2, 5, 9, 14, and 27 herbicides in Ontario, Canada, making control of this challenging weed even more difficult. Acetochlor is a Group 15, chloroacetanilide herbicide that has activity on many small-seeded annual grasses and some small-seeded annual broadleaf weeds, including waterhemp. The objective of this study was to ascertain if acetochlor mixtures with broadleaf herbicides (dicamba, metribuzin, diflufenican, sulfentrazone, or flumioxazin), applied preemergence (PRE), increase multiple-herbicide-resistant (MHR) waterhemp control in soybean. Five trials were conducted over 2 yr (2021 and 2022). The acetochlor mixtures caused ≤7% soybean injury, except acetochlor + flumioxazin, which caused 19% soybean injury. Acetochlor applied PRE controlled MHR waterhemp 89% at 4 wk after application (WAA). Dicamba, metribuzin, diflufenican, sulfentrazone, or flumioxazin controlled MHR waterhemp 59%, 67%, 58%, 64%, and 86%, respectively, at 4 WAA. Acetochlor applied in a mixture with dicamba, metribuzin, diflufenican, sulfentrazone, or flumioxazin provided good to excellent control of MHR waterhemp; control ranged from 91% to 98% but was similar to acetochlor applied alone. Acetochlor alone reduced MHR waterhemp density and biomass 98% and 93%; acetochlor + flumioxazin reduced waterhemp density and biomass by an additional 2% and 7%, respectively. This research concludes that acetochlor applied in a mixture with flumioxazin was the most efficacious mixture evaluated for MHR waterhemp control.
To determine whether poorer performance on the Boston Naming Test (BNT) in individuals with transactive response DNA-binding protein 43 pathology (TDP-43+) is due to greater loss of word knowledge compared to retrieval-based deficits.
Methods:
Retrospective clinical-pathologic study of 282 participants with Alzheimer’s disease neuropathologic changes (ADNC) and known TDP-43 status. We evaluated item-level performance on the 60-item BNT for first and last available assessment. We fit cross-sectional negative binomial count models that assessed total number of incorrect items, number correct of responses with phonemic cue (reflecting retrieval difficulties), and number of “I don’t know” (IDK) responses (suggestive of loss of word knowledge) at both assessments. Models included TDP-43 status and adjusted for sex, age, education, years from test to death, and ADNC severity. Models that evaluated the last assessment adjusted for number of prior BNT exposures.
Results:
43% were TDP-43+. The TDP-43+ group had worse performance on BNT total score at first (p = .01) and last assessments (p = .01). At first assessment, TDP-43+ individuals had an estimated 29% (CI: 7%–56%) higher mean number of incorrect items after adjusting for covariates, and a 51% (CI: 15%–98%) higher number of IDK responses compared to TDP-43−. At last assessment, compared to TDP-43−, the TDP-43+ group on average missed 31% (CI: 6%–62%; p = .01) more items and had 33% more IDK responses (CI: 1% fewer to 78% more; p = .06).
Conclusions:
An important component of poorer performance on the BNT in participants who are TDP-43+ is having loss of word knowledge versus retrieval difficulties.
Waterhemp is a summer annual, broadleaf weed with high fecundity, short seed longevity in the soil, and wide genetic diversity. Populations have evolved resistance to five herbicide modes of action (Groups 2, 5, 9, 14, and 27), which are present across southern Ontario; this has increased the challenge of controlling this competitive weed species in corn, the most important grain crop produced worldwide and the highest-value agronomic crop in Ontario. Acetochlor is a Group 15 soil-applied residual herbicide that has activity on many grass and broadleaf weeds but has yet to be registered in Canada. The objective of this study was to ascertain whether mixtures of acetochlor with flumetsulam, dicamba, atrazine, isoxaflutole/diflufenican, or mesotrione + atrazine applied preemergence would increase the control of multiple-herbicide-resistant (MHR) waterhemp in corn. Five field trials were conducted between 2022 and 2023. No corn injury was observed. Acetochlor applied alone controlled MHR waterhemp 97% 12 wk after application (WAA). All herbicide mixtures controlled MHR waterhemp similarly at ≥98% 12 WAA; there were no differences among herbicide mixtures. Flumetsulam, dicamba, and atrazine provided lower MHR waterhemp control than all other herbicide treatments and did not reduce density or biomass. Acetochlor reduced waterhemp density 98%, while the acetochlor mixtures reduced density similarly at 99% to 100%. This study concludes that the acetochlor mixtures evaluated provide excellent waterhemp control; however, control was not greater than acetochlor alone. Herbicide mixtures should be used as a best management practice to mitigate the evolution of herbicide resistance.
Shared genetic risk between schizophrenia (SCZ) and bipolar disorder (BD) is well-established, yet the extent to which they share environmental risk factors remains unclear. We compare the associations between environmental exposures during childhood/prior to disorder onset with the risk of developing SCZ and BD.
Methods:
We conducted a Swedish register-based nested case–control study using 4184 SCZ cases and 18 681 BD cases diagnosed 1988–2013. Cases were matched to five controls by birth year, birth region, and sex. Conditional logistic regression was used to estimate incidence rate ratios (IRR) for SCZ and BD for each exposure (severe childhood infections, adverse childhood experiences (ACEs), substance use disorders (SUDs), urban birth/longest residence).
Results:
All SUD types were associated with very high risk (IRR 4.9–25.5), and all forms of ACEs with higher risk (IRR 1.5–4.3) for both disorders. In the mutually adjusted models, ACEs demonstrated slightly higher risk for BD (SCZ IRR 1.30, 1.19-1.42; BD IRR 1.49, 1.44–1.55), while for SUD, risk was higher for SCZ (SCZ IRR 9.43, 8.15–10.92; BD IRR 5.50, 5.15–5.88). Infections were associated with increased risk of BD (IRR 1.21, 1.17–1.26) but not SCZ. Urban birth and urban longest residence were associated with higher risk of SCZ (IRR 1.19, 1.03–1.37), while only the combination of urban birth and rural longest residence showed higher risk for BD (IRR 1.24, 1.13–1.35).
Conclusions:
There were both shared and unique environmental risk factors: SUDs and ACEs were risk factors for both disorders, while infections were more strongly associated with BD and urbanicity with SCZ.
We compared dissociative seizure specific cognitive behavior therapy (DS-CBT) plus standardized medical care (SMC) to SMC alone in a randomized controlled trial. DS-CBT resulted in better outcomes on several secondary trial outcome measures at the 12-month follow-up point. The purpose of this paper is to evaluate putative treatment mechanisms.
Methods
We carried out a secondary mediation analysis of the CODES trial. 368 participants were recruited from the National Health Service in secondary / tertiary care in England, Scotland, and Wales. Sixteen mediation hypotheses corresponding to combinations of important trial outcomes and putative mediators were assessed. Twelve-month trial outcomes considered were final-month seizure frequency, Work and Social Adjustment Scale (WSAS), and the SF-12v2, a quality-of-life measure providing physical (PCS) and mental component summary (MCS) scores. Mediators chosen for analysis at six months (broadly corresponding to completion of DS-CBT) included: (a) beliefs about emotions, (b) a measure of avoidance behavior, (c) anxiety and (d) depression.
Results
All putative mediator variables except beliefs about emotions were found to be improved by DS-CBT. We found evidence for DS-CBT effect mediation for the outcome variables dissociative seizures (DS), WSAS and SF-12v2 MCS scores by improvements in target variables avoidance behavior, anxiety, and depression. The only variable to mediate the DS-CBT effect on the SF-12v2 PCS score was avoidance behavior.
Conclusions
Our findings largely confirmed the logic model underlying the development of CBT for patients with DS. Interventions could be additionally developed to specifically address beliefs about emotions to assess whether it improves outcomes.