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The jurisprudence of international administrative tribunals holds great relevance for international organisations, as seen in the proliferation of these tribunals, the complexity of their jurisprudence, and their practical impact. This book provides a comprehensive and accessible analysis of essential topics in this field, including applicable sources, jurisdiction and admissibility, grounds for review, equality and non-discrimination, and remedies. It also covers key emerging issues, such as the rights of non-staff personnel, the growing application of international human rights law by tribunals, and the protection of acquired rights. Drawing on thousands of decisions, this book is an invaluable resource for both practitioners and scholars. For practitioners, it offers a practical guide to navigating complex cases. For scholars, it highlights common principles and key divergences across the jurisprudence of some thirty tribunals, at the same time illuminating the increasingly sophisticated interplay between international administrative law and public international law.
Tiafenacil is a new nonselective protoporphyrinogen IX oxidase (PPO)–inhibiting herbicide with both grass and broadleaf activity labeled for preplant application to corn, cotton, soybean, and wheat. Early-season corn emergence and growth often coincides in the mid-South with preplant herbicide application in cotton and soybean, thereby increasing opportunity for off-target herbicide movement from adjacent fields. Field studies were conducted in 2022 to identify the impacts of reduced rates of tiafenacil (12.5% to 0.4% of the lowest labeled application rate of 24.64 g ai ha–1) applied to two- or four-leaf corn. Corn injury 1 wk after treatment (WAT) for the two- and four-leaf growth stages ranged from 31% to 6% and 37% to 9%, respectively, whereas at 2 WAT these respective ranges were 21.7% to 4% and 22.5% to 7.2%. By 4 WAT, visible injury following the two- and four-leaf exposure timing was no greater than 8% in all instances except the highest tiafenacil rate applied at the four-leaf growth stage (13%). Tiafenacil had no negative season-long impact, as the early-season injury observed was not manifested in a reduction in corn height 2 WAT or yield. Application of tiafenacil directly adjacent to corn in early vegetative stages of growth should be avoided. In cases where off-target movement does occur, however, affected corn should be expected to fully recover with no impact on growth and yield, assuming adequate growing conditions and agronomic/pest management practices are provided.
We conducted a series of experiments that revealed the formation of mm-scale penitente structures in ice illuminated by broadband light under moderate vacuum conditions between 50 and 2000 Pa. The experimental apparatus consists of a 0.3 m diameter cylindrical vacuum chamber with a cooling jacket surrounding the outer radius and bottom surface. Light shines in through an optical window at the top to illuminate most of the ice surface. We observe penitente-like structures at temperatures between −15$^\circ$C and $-2^\circ$C and pressures close to the equilibrium vapor pressure at the ice surface temperature. The formation of these structures is very sensitive to slight changes in background pressure, and the structures tend to vanish with significant deviations away from the equilibrium curve, resulting in a smooth sublimated crater formation instead of penitentes. Application of the physical model by Claudin and others (2015, doi: 10.1103/PhysRevE.92.033015) at experimental conditions generally agrees with observations for penitente spacing.
There is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies in major depressive disorder (MDD).
Methods
In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10–20 mg daily for 8 weeks. Responders continued escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-1β, IL-6, IL-17, interferon-gamma (IFN)-Γ, tumor necrosis factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2)—measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyzes to assess associations between inflammatory markers and treatment response.
Results
Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Conclusion
Higher pre-treatment levels of IFN-Γ and CCL-2 were associated with non-response to escitalopram. Increasing levels of these pro-inflammatory markers may be associated with non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
OBJECTIVES/GOALS: Silicosis is a highly fatal progressive fibrotic disease of the lungs characterized by accumulation and persistence of fibroblasts that excessively deposit Collagen1a1. We sought to eliminate Collagen1a1-expressing fibroblasts through a targeted genetic ablation strategy and hypothesized that this would arrest the progression of Silicosis. METHODS/STUDY POPULATION: Silicosis was induced with a single intratracheal (i.t.) instillation of silica particles ( RESULTS/ANTICIPATED RESULTS: Targeted ablation of Col1a1+ fibroblast in established Silicosis resulted in a decrease in: 1) Col1a1+ fibroblasts by flow cytometry and within fibrotic nodules by immunofluorescent staining, 2) total lung collagen content by histology and hydroxyproline assay, 3) tissue-associated disease by microCT and an increase in arterial oxygen saturation by pulse oximetry. Cessation of targeted Col1a1+ fibroblast ablation resulted in a rebound effect in Silicosis disease progression. Following ablation, Col1a1+ fibroblasts expanded by proliferation (Ki67+) and total lung collagen levels returned to pre-ablation levels. DISCUSSION/SIGNIFICANCE: Silicosis is a often fatal disease with no FDA approved therapies. These results suggest that targeted loss of Col1a1+ fibroblasts in Silicosis is sufficient to arrest disease progression. Thus, it is essential to understand how targeted loss of pro-fibrotic fibroblasts can alter disease progression as a tool to develop novel therapeutic strategies.
Prediction of treatment outcomes is a key step in improving the treatment of major depressive disorder (MDD). The Canadian Biomarker Integration Network in Depression (CAN-BIND) aims to predict antidepressant treatment outcomes through analyses of clinical assessment, neuroimaging, and blood biomarkers.
Methods
In the CAN-BIND-1 dataset of 192 adults with MDD and outcomes of treatment with escitalopram, we applied machine learning models in a nested cross-validation framework. Across 210 analyses, we examined combinations of predictive variables from three modalities, measured at baseline and after 2 weeks of treatment, and five machine learning methods with and without feature selection. To optimize the predictors-to-observations ratio, we followed a tiered approach with 134 and 1152 variables in tier 1 and tier 2 respectively.
Results
A combination of baseline tier 1 clinical, neuroimaging, and molecular variables predicted response with a mean balanced accuracy of 0.57 (best model mean 0.62) compared to 0.54 (best model mean 0.61) in single modality models. Adding week 2 predictors improved the prediction of response to a mean balanced accuracy of 0.59 (best model mean 0.66). Adding tier 2 features did not improve prediction.
Conclusions
A combination of clinical, neuroimaging, and molecular data improves the prediction of treatment outcomes over single modality measurement. The addition of measurements from the early stages of treatment adds precision. Present results are limited by lack of external validation. To achieve clinically meaningful prediction, the multimodal measurement should be scaled up to larger samples and the robustness of prediction tested in an external validation dataset.
Multiple treatments are effective for major depressive disorder (MDD), but the outcomes of each treatment vary broadly among individuals. Accurate prediction of outcomes is needed to help select a treatment that is likely to work for a given person. We aim to examine the performance of machine learning methods in delivering replicable predictions of treatment outcomes.
Methods
Of 7732 non-duplicate records identified through literature search, we retained 59 eligible reports and extracted data on sample, treatment, predictors, machine learning method, and treatment outcome prediction. A minimum sample size of 100 and an adequate validation method were used to identify adequate-quality studies. The effects of study features on prediction accuracy were tested with mixed-effects models. Fifty-four of the studies provided accuracy estimates or other estimates that allowed calculation of balanced accuracy of predicting outcomes of treatment.
Results
Eight adequate-quality studies reported a mean accuracy of 0.63 [95% confidence interval (CI) 0.56–0.71], which was significantly lower than a mean accuracy of 0.75 (95% CI 0.72–0.78) in the other 46 studies. Among the adequate-quality studies, accuracies were higher when predicting treatment resistance (0.69) and lower when predicting remission (0.60) or response (0.56). The choice of machine learning method, feature selection, and the ratio of features to individuals were not associated with reported accuracy.
Conclusions
The negative relationship between study quality and prediction accuracy, combined with a lack of independent replication, invites caution when evaluating the potential of machine learning applications for personalizing the treatment of depression.
Facilitating the application of machine learning (ML) to materials science problems requires enhancing the data ecosystem to enable discovery and collection of data from many sources, automated dissemination of new data across the ecosystem, and the connecting of data with materials-specific ML models. Here, we present two projects, the Materials Data Facility (MDF) and the Data and Learning Hub for Science (DLHub), that address these needs. We use examples to show how MDF and DLHub capabilities can be leveraged to link data with ML models and how users can access those capabilities through web and programmatic interfaces.
OBJECTIVES/SPECIFIC AIMS: The objective of this study was to determine if dopamine signaling is altered in a mouse model displaying excessive self-grooming and further elucidate the potential utility of compounds targeting the striatal DA system in modulating repetitive behaviors. METHODS/STUDY POPULATION: Here, we report studies using fast-scan cyclic voltammetry (FSCV) in mice lacking the postsynaptic protein SAP90/PSD95-associated protein (SAPAP3 KO mice) as well as control littermates. Rodent self-grooming provides a behavioral output with which one can monitor repetitive, self-directed, patterned behavior that has great translational value to OCD-like disorders. Total time spent grooming was monitored in SAPAP3KO mice and control littermates. To further examine the role of DA in regulating repetitive grooming behaviors the magnitude and kinetics of DA transients were assessed using FSCV in ex vivo slice preparations as well as in anesthetized mice in vivo. DA transients were elicited in the dorsolateral striatum (DLS), dorsomedial striatum (DMS); and nucelus accumbens core (NAcc). In some experiments mice were crossed with DAT-Cre animals and channelrhodopsin 2 (ChR2) was virally expressed in DA neurons to allow optical stimulation of DA transients. RESULTS/ANTICIPATED RESULTS: As previously reported, SAPAP3 KO mice showed excessive grooming compared to control littermates at the age assessed (4-5 months). DA transients evoked by a single electrical pulse in slices from SAPAP3 KO mice were not significantly different from those observed in slices from control littermates in any of the regions tested including the DLS, DMS and NAcc. However, when four electrical pulses were applied at a frequency of 10Hz to mimic DA neuron bursting, the magnitude of DA transients observed in the DMS and NAcc of SAPAP3 mice were greater than those evoked in control littermates.Interestingly, phasic stimulation produced similar DA transients in the DLS of both genotypes suggesting that phasic DA signaling was not globally altered. To confirm this finding we crossed SAPAP3 KO mice with DAT-Cre mice and injected ChR2 containing virus into the midbrain to selectively express ChR2 in DA neurons. Transients were then optically evoked resulting in selective activation of DA neurons. Optical stimulation produced a pronounced enhancement of DA release in SAPAP3 KO mice specifically in the DMS and only following phasic-like stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: These exciting findings suggest that DA signaling in SAPAP3KO mice is dysregulated in a very precise manner that is sub-region specific as well as dependent on the pattern of stimulation. These results suggest that targeted therapies that can modulate these specific modes of dopaminergic signaling in these distinct striatal subregions could provide improved efficacy in OCD patients that are resistant to SSRI treatment.
A field study was conducted in 2015 and 2016 to compare particle drift of glyphosate using a fluorescent tracer dye applied with hooded and open sprayers at four spray qualities (Fine [F], Medium [M], Very-Coarse [VC], and Ultra-Coarse [UC]). F and M spray qualities exhibited up to 86% and 56% less drift, respectively, out to 31 m downwind with the hooded sprayer than with the open sprayer. Conversely, VC and UC spray qualities were not affected by sprayer type out to 31 m downwind. From 43 to 104 m downwind, hooded sprayer applications exhibited approximately 50% less drift than open sprayer applications, regardless of spray quality. From 43 to 89 m downwind, F spray qualities, regardless of sprayer type, exhibited higher drift than all other spray qualities. These data indicate that hooded sprayers considerably reduce drift of all spray qualities at short distances downwind. Additionally, at longer distances downwind, both larger spray qualities and sprayer hoods reduced drift independently.
This study investigated the characteristics of subjective memory complaints (SMCs) and their association with current and future cognitive functions.
Methods:
A cohort of 209 community-dwelling individuals without dementia aged 47–90 years old was recruited for this 3-year study. Participants underwent neuropsychological and clinical assessments annually. Participants were divided into SMCs and non-memory complainers (NMCs) using a single question at baseline and a memory complaints questionnaire following baseline, to evaluate differential patterns of complaints. In addition, comprehensive assessment of memory complaints was undertaken to evaluate whether severity and consistency of complaints differentially predicted cognitive function.
Results:
SMC and NMC individuals were significantly different on various features of SMCs. Greater overall severity (but not consistency) of complaints was significantly associated with current and future cognitive functioning.
Conclusions:
SMC individuals present distinctive features of memory complaints as compared to NMCs. Further, the severity of complaints was a significant predictor of future cognition. However, SMC did not significantly predict change over time in this sample. These findings warrant further research into the specific features of SMCs that may portend subsequent neuropathological and cognitive changes when screening individuals at increased future risk of dementia.
As a response to the ageing population, the United Kingdom (UK) government, like many others, has increased the State Pension Age. This has involved equalising women's State Pension Age with men's, raising it from 60 to 65, with further increases already underway. It has been argued that a key issue with how this change has been implemented is the lack of notice the government gave to the women affected, impacting on their ability to plan for retirement. So far, there has been very little research exploring inequalities in awareness of these developments and, in particular, considering whether women of particular socio-economic backgrounds are less likely to know about the changes. This has implications for potentially further widening inequalities in old age. In this paper we analyse data from the English Longitudinal Study of Ageing. We consider the role of cognitive ability in mediating the relationship between socio-economic background and awareness, given recent debates on deficiencies in financial literacy. We find that socio-economic inequalities exist, especially with respect to labour force status, occupation and education. We also find that cognitive ability, especially numeracy, mediates a sizeable proportion of the relationship. These findings have important implications in terms of implementing future policy changes and awareness campaigns to help mitigate the possibility that they will further entrench inequalities in older age.
OBJECTIVES/SPECIFIC AIMS: (1) Evaluate safety of a novel influenza vaccination strategy in patients with plasma cell disorders. (2) Measure laboratory-confirmed influenza infection rates following a novel influenza vaccination strategy in patients with plasma cell disorders. (3) Evaluate clinical correlates of response following a novel influenza vaccination strategy in patients with plasma cell disorders. METHODS/STUDY POPULATION: We conducted a double-blind, randomized study over the 2015–16 flu season, comparing 2 doses of Fluzone® High-Dose influenza vaccination (separated by 30 d) to the current standard of care influenza vaccination. Patients were allocated to the experimental arm in 2:1 ratio compared with standard of care arm. Standard of care influenza vaccination was considered single age-based vaccination (standard dose for those <65 y and high dosefor those ≥65 y) and patients in this arm received a saline placebo injection at 30 days to assist in blinding. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory-confirmed flu infection rate. Protocol-driven surveillance screened patients for flu-like illnesses and performed laboratory testing for influenza until the end of the flu season in May 2016. Secondary endpoints include HAI titer serologic response rates, clinical correlates of protection from influenza infection, and exploratory studies of cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness. RESULTS/ANTICIPATED RESULTS: In total, 122 plasma cell disorder patients were enrolled (97 with disease requiring therapy and 25 with asymptomatic gammopathy). Of those 48 patients received a single standard of care influenza vaccination and 74 patients received 2 doses of Fluzone® high-dose vaccine. Median age was 67 years (range 42–90). This 2-dose vaccination strategy was safely tolerated in all patients with no grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% of patients receiving 2 vaccine doses developed laboratory confirmed influenza Versus 8.3% of those receiving single vaccine. When compared to the expected CDC influenza infection rate of 10%–15%, 1 sample, 2-tailed binomial testing revealed patients receiving 2 vaccines experienced a significantly lower rate of infection than the expected rate (p<0.05) whereas those receiving single vaccine showed no significant difference (p=0.38). DISCUSSION/SIGNIFICANCE OF IMPACT: This randomized study demonstrates that the 2 dose strategy of Fluzone® high-dose influenza vaccine is safely tolerated in patients with plasma cell disorders and associated with significantly less than expected laboratory-confirmed influenza infections. The results suggest that this novel vaccination strategy may have a clinical benefit in reducing influenza infections in plasma cell disorder patients and thus may have practice changing implications. Final analyses of serologic responses, clinical correlates of response, and cell-mediated immune correlates may provide valuable insights into in vivo “immune-competence” in patients with plasma cell disorders.
When patients are admitted onto psychiatric wards, sleep problems are highly prevalent. We carried out the first trial testing a psychological sleep treatment at acute admission (Oxford Ward sLeep Solution, OWLS).
Methods
This assessor-blind parallel-group pilot trial randomised patients to receive sleep treatment at acute crisis [STAC, plus standard care (SC)], or SC alone (1 : 1). STAC included cognitive–behavioural therapy (CBT) for insomnia, sleep monitoring and light/dark exposure for circadian entrainment, delivered over 2 weeks. Assessments took place at 0, 2, 4 and 12 weeks. Feasibility outcomes assessed recruitment, retention of participants and uptake of the therapy. Primary efficacy outcomes were the Insomnia Severity Index and Warwick–Edinburgh Mental Wellbeing Scale at week 2. Analyses were intention-to-treat, estimating treatment effect with 95% confidence intervals.
Results
Between October 2015 and July 2016, 40 participants were recruited (from 43 assessed eligible). All participants offered STAC completed treatment (mean sessions received = 8.6, s.d. = 1.5). All participants completed the primary end point. Compared with SC, STAC led to large effect size (ES) reductions in insomnia at week 2 (adjusted mean difference −4.6, 95% CI −7.7 to −1.4, ES −0.9), a small improvement in psychological wellbeing (adjusted mean difference 3.7, 95% CI −2.8 to 10.1, ES 0.3) and patients were discharged 8.5 days earlier. One patient in the STAC group had an adverse event, unrelated to participation.
Conclusions
In this challenging environment for research, the trial was feasible. Therapy uptake was high. STAC may be a highly effective treatment for sleep disturbance on wards with potential wider benefits on wellbeing and admission length.
In 1969, Robert E. Gregg collected five species of ants (Hymenoptera: Formicidae) in three Subarctic localities near the town of Churchill, Manitoba, Canada, which he documented in a 1972 publication in The Canadian Entomologist. To determine whether there have been any additions to the local fauna – as might be predicted to occur in response to a warming climate and increased traffic to the Port of Churchill in the intervening 40 years – we re-collected ants from the same localities in 2012. We identified the ants we collected from Gregg’s sampling sites using both traditional morphological preparations and DNA barcoding. In addition, we examined specimens from Gregg’s initial collection that are accessioned at the Field Museum of Natural History (Chicago, Illinois, United States of America). Using this integrative approach we report seven species present at the same sites Gregg sampled 40 years earlier. We conclude that the apparent increase is likely not due to any arrivals from more southerly distributed ants, but to the increased resolution provided by DNA barcodes to resident species complexes with a complicated history. We provide a brief synopsis of these results and their taxonomic context.
Ogier Ghiselin de Busbecq (1522–92) was a Flemish herbalist, diplomat and writer. In 1554, Ferdinand I, soon to be Holy Roman Emperor, dispatched him to Suleiman the Magnificent's court as an ambassador to the Ottoman empire, where Busbecq spent years negotiating a border dispute between his employer and the sultan. While there, he also discovered important manuscripts and sent the first tulip bulbs to Europe. He returned to Vienna in 1562, where he acted as counsellor to Ferdinand, after whose death he continued to serve the Habsburgs. This two-volume work, first published in 1881, contains Busbecq's letters, edited and translated into English from Latin by two Cambridge scholars. Volume 2 contains letters written in France to the Holy Roman Emperors Maximilian II and Rudolph II, and an index and appendix to both volumes, the latter including Busbecq's itineraries and a helpful outline of Hungarian history.
Ogier Ghiselin de Busbecq (1522–92) was a Flemish herbalist, diplomat and writer. In 1554, Ferdinand I, soon to be Holy Roman Emperor, dispatched him to Suleiman the Magnificent's court as an ambassador to the Ottoman empire, where Busbecq spent years negotiating a border dispute between his employer and the sultan. While there, he also discovered important manuscripts and sent the first tulip bulbs to Europe. He returned to Vienna in 1562, where he acted as counsellor to Ferdinand, after whose death he continued to serve the Habsburgs. This two-volume work, first published in 1881, contains Busbecq's letters, edited and translated into English from Latin by two Cambridge scholars. Volume 1 contains a lengthy biography of Busbecq, written by the editors, and his famous Turkish Letters, which are a unique source of information on Ottoman court life in the sixteenth century.
Literature on environmental science and management endorses crossing boundaries between disciplines, types of organizations and countries for environmental conservation. A literature review on interdisciplinarity, interorganizational networks and international cooperation highlights their justifying rationales and strategic practices. Crossing boundaries implies substantial challenges to managing collaboration itself, notably politics and uncertainty. Challenges to collaboration become compounded when crossing multiple boundaries simultaneously, here illustrated using the case of three projects in the south-western Amazon. Strategic practices such as net brokering and organizational courtships are highly important when crossing multiple boundaries. There are important commonalities in strategic practices for crossing different boundaries, such as recognizing grievances to manage politics, constituting functional redundancies in networks to manage uncertainty and non-aligned collaboration to manage both difficulties.