Ferumoxytol-enhanced MRI assessment of venous Thrombus resolution and macrophage content in a murine deep vein thrombosis model.

BACKGROUND: Imaging evaluation of acute deep vein thrombosis (DVT) or post-thrombotic syndrome (PTS) in animal or clinical models is limited to anatomical assessment of the location and extent of thrombi. We hypothesize that Fe-MRI, used to evaluate macrophage content in other inflammatory diseases, can be useful to evaluate the thromboinflammatory features after DVT over time. METHODS: Nineteen wild-type CD-1 mice underwent surgical IVC ligation to induce DVT. Mice received either saline or 5 mg/kg of 14E11, a Factor XI inhibitor, before the procedure. Fe-MRI was performed on days 6-7 after ligation to evaluate thrombus volume, perfusion, and macrophage content via T2-weighted images. Mice were euthanized at days 3-15 after surgery. The thrombi and adjacent vein walls were excised, weighed, formalin-fixed, and paraffin-embedded for immunohistological analysis. Specimens were stained with specific antibodies to evaluate macrophage content, collagen deposition, neovascularization, and recanalization. Significance was determined using the Mann-Whitney U or Student's t-test. RESULTS: After IVC-ligation in control mice, thrombus weights decreased by 59 % from day 3 to 15. Thrombus volumes peaked on day 5 before decreasing by 85 % by day 13. FXI inhibition led to reduced macrophage content in both thrombi (p = .008) and vein walls (p = .01), decreased thrombus volume (p = .03), and decreased thrombus mass (p = .01) compared to control mice. CCR2+ staining corroborated these findings, showing significantly reduced macrophage presence in the thrombi (p = .002) and vein wall (p = .002). CONCLUSIONS: Fe-MRI T2 relaxation times can be used to characterize and quantify post-thrombotic changes of perfusion, macrophage content, and thrombus volume over time in a surgical mouse model of venous thrombosis. This approach could lead to better quantification of in vivo inflammation correlating monocyte and macrophage content within resolving thrombi and veins and may serve as a useful tool for research and clinically in the evaluation of the post-thrombotic environment.

Limited bedding and nesting increases ethanol drinking in female rats.

Prenatal opioid exposure (POE) and postnatal adverse experiences are early life adversities (ELA) that often co-occur and increase problematic alcohol (EtOH) drinking during adolescence. We investigated the relationship between POE, postnatal adversity, and adolescent EtOH drinking in rats. We also sought to determine whether ELAs affect alpha-adrenoceptor density in the brain because the noradrenergic system is involved in problematic alcohol drinking and its treatment. We hypothesized that the combination of POE and postnatal adversity will increase alcohol drinking in rats compared to rats with exposure to either adversity alone or to control. We also predicted that POE and postnatal adversity would increase α1-adrenoceptor density and decrease α2-adrenoceptor density in brain to confer a stress-responsive phenotype. Pregnant rats received morphine (15 mg/kg/day) or saline via subcutaneous minipumps from gestational day 9 until birth. Limited bedding and nesting (LBN) procedures were introduced from postnatal day (PD) 3-11 to mimic early life adversity-scarcity. Offspring rats (PD 31-33) were given opportunities to drink EtOH (20 %, v/v) using intermittent-access, two-bottle choice (with water) procedures. Rats given access to EtOH were assigned into sub-groups that were injected with either yohimbine (1 mg/kg, ip) or vehicle (2 % DMSO, ip) 30 min prior to each EtOH access session to determine the effects of α2-adrenoceptor inhibition on alcohol drinking. We harvested cortices, brainstems, and hypothalami from EtOH-naïve littermates on either PD 30 or PD 70 and conducted radioligand receptor binding assays to quantify α1- and α2-adrenoceptor densities. Contrary to our hypothesis, only LBN alone increased EtOH intake in female adolescent rats compared to female rats with POE. Neither POE nor LBN affected α1- or α2-adrenoceptor densities in the cortex, brainstem, or hypothalamus of early- or late-aged adolescent rats. These results suggest a complex interaction between ELA type and sex on alcohol drinking.

Stochastic modelling of pesticide transport to drinking water sources via runoff and resulting human health risk assessment.

A modelling framework was developed to facilitate a probabilistic assessment of health risks posed by pesticide exposure via drinking water due to runoff, with the inclusion of influential site conditions and in-stream processes. A Monte-Carlo based approach was utilised to account for the inherent variability in pesticide and population properties, as well as site and climatic conditions. The framework presented in this study was developed with an ability to integrate different data sources and adapt the model for various scenarios and locations to meet the users' needs. The results from this model can be used by farm advisors and catchment managers to identify lower risk pesticides for use for given soil and site conditions and implement risk mitigation measures to protect water resources. Pesticide concentrations in surface water, and their risk of regulatory threshold exceedances, were simulated for fifteen pesticides in an Irish case study. The predicted concentrations in surface water were then used to quantify the level of health risk posed to Irish adults and children. The analysis indicated that herbicides triclopyr and MCPA occur in the greatest concentrations in surface water, while mecoprop was associated with the highest potential for health risks. The study found that the modelled pesticides posed little risk to human health under current application patterns and climatic conditions in Ireland using international acceptable intake values. A sensitivity study conducted examined the impact seasonal conditions, timing of application, and instream processes, have on the transport of pesticides to drinking water.

Online activity - A beaming good initiative! Delivering alternative exercise opportunities for people with cystic fibrosis.

BACKGROUND: Increasing physical activity in people with Cystic Fibrosis (pwCF) can positively influence their physical and mental wellbeing. Online activities provide opportunity for outpatient CF populations to enhance physical activity. METHODS: PwCF within a large Scottish CF unit were invited to participate in a pilot study of online exercise and education sessions. Those participating shared opinions on motivation, fitness habits, types of activities enjoyed pre and during shielding, and desirable goals for online activity. Subsequently, an online activity timetable was created offering daily exercise classes. Educational presentations driven by patient request were delivered in context appropriate to health, wellbeing, and infection control needs during the pandemic and the advent of modulator therapies. Twenty-eight group exercise sessions and 12 educational sessions occurred over the six-week pilot, following which, a post-pilot questionnaire was sent to those who had participated in the sessions. Risk assessment and exercise modifications ensured safe practice and accommodation for all levels of respiratory disease. RESULTS: Twenty-six pwCF attended one or more exercise sessions and 37 pwCF attended one or more education sessions. Group exercise and education improved time efficiency compared to in-person face-to-face delivery. The post-pilot questionnaire demonstrated increases in motivation and perceived fitness, with positive comments regarding peer support and enhanced socialization. Personal fitness goals were fully or partially achieved by 91% of participants. CONCLUSION: Patient feedback suggested the implementation of online exercise and education sessions for pwCF was a satisfactory and convenient way to deliver exercise allowing for optimization and progression of personal goals.

Impact of historical legacy pesticides on achieving legislative goals in Europe.

Pesticides are widely used in agriculture to optimise food production. However, the movement of pesticides into water bodies negatively impacts aquatic environments. The European Union (EU) aims to make food systems fair, healthy and environmentally friendly through its current Farm to Fork strategy. As part of this strategy, the EU plans to reduce the overall use and risk of chemical pesticides by 50 % by 2030. The attainment of this target may be compromised by the prevalence of legacy pesticides arising from historical applications to land, which can persist in the environment for several decades. The current EU Farm to Fork policy overlooks the potential challenges of legacy pesticides and requirements for their remediation. In this review, the current knowledge regarding pesticide use in Europe, as well as pathways of pesticide movement to waterways, are investigated. The issues of legacy pesticides, including exceedances, are examined, and existing and emerging methods of pesticide remediation, particularly of legacy pesticides, are discussed. The fact that some legacy pesticides can be detected in water samples, more than twenty-five years after they were prohibited, highlights the need for improved EU strategies and policies aimed at targeting legacy pesticides in order to meet future targets.

Microflow size exclusion chromatography to preserve micromolar affinity complexes and achieve subunit separations for native state mass spectrometry.

For high throughput native mass spectrometry (MS) protein characterization, it is advantageous to desalt and separate proteins by size exclusion chromatography (SEC). Sensitivity, resolution, and speed in these methods remain limited by standard SEC columns. Moreover, the efficient packing of small bore columns is notoriously difficult. SEC sensitivity is inherently limited because solutes are not focused into concentrated bands and low affinity native complexes may dissociate on column. Recent work evaluated the suitability of crosslinked gel media in small bore formats for online desalting. Here, small bore format online SEC for native MS studies is again investigated but with alternative materials. We systematically studied the utility of diol and hydroxy terminated polyethylene oxide (PEO) bonded 1.7 µm organosilica particles as packed into 1 mm ID stainless steel (SS) hardware and hardware treated with hydrophilic hybrid surface technology (h-HST). For the equivalent diol-bonded particle and hardware, UV limits of detection (LODs) were reduced 32 to 89% with a microflow separation (15 µL/min) on a 1 × 50 mm column as compared to a 4.6 × 150 mm high-flow separation (300 µL/min) at the same linear velocity. Run times were also shortened by 45%. A switch from SS to h-HST hardware led to a significant reduction in secondary interactions and a corresponding improvement in detection limits for trastuzumab, myoglobin, IgG and albumin for both UV and MS. Coupling of the small bore columns to multichannel microflow emitters resulted in 10 to 100-fold gains in MS sensitivity, depending on the analyte. MS LOD values were significantly reduced into the low attomole ranges. Columns were then evaluated for their effects on the preservation of complexes, including concanavalin A, in its apo and ligand-bound states, and three therapeutically relevant noncovalent systems previously undetected on large column formats. The results suggest that the detection of large complexes by SEC is not just a function of sensitivity but is directly affected by chemical secondary interactions. The ability to detect 0.1 to 1 MDa complexes, with between 1 and 40 micromolar dissociation constants, represents a critical advancement for high-throughput native MS workflows as applied to the analysis of therapeutics.

Batch adsorption of herbicides from aqueous solution onto diverse reusable materials and granulated activated carbon.

This study reports the kinetics and isotherms of the adsorption of five herbicides, MCPA, mecoprop-P, 2,4-D, fluroxypyr and triclopyr, from aqueous solutions onto a range of raw and pyrolysed waste materials originating from an industrial setting. The raw waste materials investigated demonstrated little capability for any herbicide adsorption. Granulated activated carbon (GAC) was capable of the best removal of the herbicides, with >95% removal observed. A first order kinetic model fitted the data best for GAC adsorption of 2,4-D, while a pseudo-first order model fitted the data best for GAC adsorption of fluroxypyr and triclopyr, indicating that adsorption was via physisorption. A pseudo-second order kinetic model fitted the GAC adsorption of MCPA and mecoprop-P, which is indicative of chemisorption. The adsorption of the herbicides in all cases was best described by the Freundlich model, indicating that adsorption occurred onto heterogeneous surfaces.

A risk ranking of pesticides in Irish drinking water considering chronic health effects.

This paper presents a novel scoring system which facilitates a relative ranking of pesticide risk to human health arising from contaminated drinking water. This method was developed to identify risky pesticides to better inform monitoring programmes and risk assessments. Potential risk was assessed considering pesticide use, chronic human health effects and environmental fate. Site-specific soil conditions, such as soil erodibility, hydrologic group, soil depth, clay, sand, silt, and organic carbon content of soil, were incorporated to demonstrate how pesticide fate can be influenced by the areas in which they are used. The indices of quantity of use, consequence and likelihood of exposure, hazard score and quantity-weighted hazard score were used to describe the level of concern that should be attributed to a pesticide. Metabolite toxicity and persistence were also considered in a separate scoring to highlight the contribution metabolites make to overall pesticide risk. This study presents two sets of results for 63 pesticides in an Irish case study, (1) risk scores calculated for the parent compounds only and (2) a combined pesticide-metabolite risk score. In both cases the results are assessed for two locations with differing soil and hydrological properties. The method developed in this paper can be adapted by pesticide users to assess and compare pesticide risk at site level using pesticide hazard scores. Farm advisors, water quality monitors, and catchment managers can apply this method to screen pesticides for human health risk at a regional or national level.

A cattle graph genome incorporating global breed diversity.

Despite only 8% of cattle being found in Europe, European breeds dominate current genetic resources. This adversely impacts cattle research in other important global cattle breeds, especially those from Africa for which genomic resources are particularly limited, despite their disproportionate importance to the continent's economies. To mitigate this issue, we have generated assemblies of African breeds, which have been integrated with genomic data for 294 diverse cattle into a graph genome that incorporates global cattle diversity. We illustrate how this more representative reference assembly contains an extra 116.1 Mb (4.2%) of sequence absent from the current Hereford sequence and consequently inaccessible to current studies. We further demonstrate how using this graph genome increases read mapping rates, reduces allelic biases and improves the agreement of structural variant calling with independent optical mapping data. Consequently, we present an improved, more representative, reference assembly that will improve global cattle research.

Distribution and abundance of microplastics in coastal sediments depends on grain size and distance from sources.

Microplastic deposition in marine sediments is a geographically widespread problem. This study examines microplastics in intertidal and subtidal sediments at 87 locations in habitats designated as Special Areas of Conservation (SACs) and Special Protection Areas (SPAs) on the coastline of Ireland. Established methodological approaches including, organic matter digestion, density separation, particle extraction and polymer identification were applied. Microplastic abundance was closely related with distance from known sources and concentrations were greater in intertidal as opposed to subtidal sediments. Colourless, polyethylene fibres and polypropylene fragments were the most abundant MP recorded and finer grained sediments were shown to entrap more MPs than coarser sediments. The results demonstrate that an understanding of potential sources of pollution, sediment type and hydrodynamic conditions are very important in terms of MP abundance and distribution in marine sediments and also in terms of effective waste management strategies and policy aimed at reducing the global plastics problem.

A feasibility study using time-driven activity-based costing as a management tool for provider cost estimation: lessons from the national TB control program in Zimbabwe in 2018.

BACKGROUND: Insufficient cost data and limited capacity constrains the understanding of the actual resources required for effective TB control. This study used process maps and time-driven activity-based costing to document TB service delivery processes. The analysis identified the resources required to sustain TB services in Zimbabwe, as well as several opportunities for more effective and efficient use of available resources. METHODS: A multi-disciplinary team applied time-driven activity-based costing (TDABC) to develop process maps and measure the cost of clinical pathways used for Drug Susceptible TB (DS-TB) at urban polyclinics, rural district and provincial hospitals, and community based targeted screening for TB (Tas4TB). The team performed interviews and observations to collect data on the time taken by health care worker-patient pairs at every stage of the treatment pathway. The personnel's practical capacity and capacity cost rates were calculated on five cost domains. An MS Excel model calculated diagnostic and treatment costs. FINDINGS: Twenty-five stages were identified in the TB care pathway across all health facilities except for community targeted screening for TB. Considerable variations were observed among the facilities in how health care professionals performed client registration, taking of vital signs, treatment follow-up, dispensing medicines and processing samples. The average cost per patient for the entire DS-TB care was USD324 with diagnosis costing USD69 and treatment costing USD255. The average cost for diagnosis and treatment was higher in clinics than in hospitals (USD392 versus USD256). Nurses in clinics were 1.6 time more expensive than in hospitals. The main cost components were personnel (USD130) and laboratory (USD119). Diagnostic cost in Tas4TB was twice that of health facility setting (USD153 vs USD69), with major cost drivers being demand creation (USD89) and sputum specimen transportation (USD5 vs USD3). CONCLUSION: TDABC is a feasible and effective costing and management tool in low-resource settings. The TDABC process maps and treatment costs revealed several opportunities for innovative improvements in the NTP under public health programme settings. Re-engineering laboratory testing processes and synchronising TB treatment follow-up with antiretroviral treatments could produce better and more uniform TB treatments at significantly lower cost in Zimbabwe.

Beliefs about inevitable decline among home-living older adults at risk of malnutrition: a qualitative study.

BACKGROUND: Approximately 14% of free-living adults aged ≥65 years are at risk of malnutrition. Malnutrition screen and treat interventions in primary care are few, show mixed results, and the advice given is not always accepted and followed. We need to better understand the experiences and contexts of older adults when aiming to develop interventions that are engaging, optimally persuasive and relevant. METHODS: Using the Person-based Approach, we carried out 23 semi-structured interviews with purposively selected adults ≥65 years with chronic health or social conditions associated with malnutrition risk. Thematic analysis informed the development of key principles to guide planned intervention development. RESULTS: We found that individuals' beliefs about an inevitable decline in appetite and eating in older age compound the many and varied physical and physiological barriers that they experience. Also, we found that expectations of decline in appetite and physical ability may encourage resignation, reduce self-efficacy to overcome barriers, and reduce motivation to address weight loss and/or recognise it as an issue that needs to be addressed. Fear of loss of independence may also reduce the likelihood of asking general practitioners for advice. CONCLUSIONS: The key findings identified include a sense of resignation, multiple different barriers to eating and a need for independence, each underpinned by the expectation of a decline in older adulthood. Interventions need to address misperceptions about the inevitability of decline, highlight how and why diet recommendations are somewhat different from recommendations for the general population, and suggest easy ways to increase food intake that address common barriers.

Enhancing tuberculosis case finding in Tanzania: implementation of a quality improvement initiative.

Tuberculosis (TB) is one of the major causes of morbidity and mortality in Tanzania. A quality improvement (QI) initiative was implemented by the National Tuberculosis Programme with support from The Global Fund to enhance TB case finding. The initiative involved identifying gaps in the quality of services, introducing tools, building capacity of health workers, and strengthening laboratory and referral services. The initiative was piloted at sub-national level and subsequently scaled-up nationally. Overall, 1280 health workers were trained, leading to an 81% cumulative increase in notified TB cases in the pilot region and 4000 additional TB cases notified nationally. The QI initiative could serve as a model for the improvement of TB case notification in other settings.

La tuberculose (TB) est une des causes majeures de morbidité et de mortalité en Tanzanie. Une initiative d'amélioration de la qualité (QI) en trois points a été mise en œuvre par le Programme National Tuberculose avec un soutien du Fonds Mondial pour améliorer la détection des cas de TB. L'initiative a impliqué l'identification des failles de qualité des services de TB, l'introduction d'outils, le renforcement des capacités du personnel de santé, le renforcement du laboratoire TB et des services de référence. L'initiative a été pilotée au niveau sous national et ensuite étendue au niveau national : 1280 personnels de santé ont été formés, la coordination de la QI a été renforcée et ceci a contribué à 81% de l'augmentation cumulée des cas de TB notifiés dans la région pilote et à la notification de 4000 cas de TB supplémentaires au niveau national. L'initiative QI pourrait servir de modèle pour améliorer la notification des cas de TB dans d'autres contextes.

La tuberculosis (TB) es una de las principales causas de morbilidad y mortalidad en Tanzanía. El Programa Nacional contra la Tuberculosis introdujo, con el apoyo del Fondo Mundial, una iniciativa triple de mejoramiento de la calidad (QI) encaminada a reforzar la búsqueda de casos de TB. La iniciativa comportaba el reconocimiento de las deficiencias en la calidad de los servicios de TB, la introducción de instrumentos, el fortalecimiento de la capacidad de los trabajadores de salud y el refuerzo de los laboratorios de TB y los servicios de remisiones. Después de un ensayo piloto a escala subnacional, se amplió la iniciativa a todo el país. Se capacitaron 1280 trabajadores de salud y se reforzó la coordinación de la QI, con lo cual se propició un aumento acumulado de 81% de los casos de TB notificados en la región piloto y la notificación de 4000 casos de TB adicionales a escala nacional. La iniciativa de QI podría servir como modelo para mejorar la notificación de casos de TB en otros entornos.

Characterization of Black Pigmenturia in a Cat with Apocrine Gland Cystadenocarcinoma.

An 8-year-old neutered female domestic shorthair cat was presented for further management of an apocrine gland cystadenocarcinoma. Extensive nodal metastasis was diagnosed and the cat was humanely destroyed 2 months after presentation. Post-mortem histopathology of the cystadenocarcinoma revealed areas of yellow-brown granular pigmentation on light microscopy, staining positively for reducing substances with Schmorl's stain and demonstrating autofluorescence on confocal microscopy. The cat's urine was black and also exhibited autofluorescence, and further analysis revealed increased free pentosidine. Based on these findings, it was presumed that the apocrine gland cystadenocarcinoma was producing lipofuscin-like pigments and that the characteristics of the urine were at least partially secondary to advanced glycation end-products.

High Prevalence of Spinal Cord Cavernous Malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort.

BACKGROUND AND PURPOSE: Cavernous malformations occur most often in the brain but can occur in the spinal cord. Small studies of patients with familial cerebral cavernous malformations suggested a prevalence of spinal cord cavernous malformations of 20%-42%. We aimed to review our familial cohort and prospectively estimate the prevalence of spinal cord cavernous malformations. MATERIALS AND METHODS: We initially reviewed our familial cerebral cavernous malformations cohort for spinal cord cavernous malformations and reviewed clinical spine MR imaging examinations for sequence sensitivity. We then prospectively performed research MR imaging of the spinal cord in 29 patients from the familial cohort to estimate the prevalence. RESULTS: Gradient-based sequences identified the most spinal cord cavernous malformations on clinical MR images, forming the basis for developing our screening MR imaging. Screening spinal cord MR imaging demonstrated a prevalence of 72.4%, and a positive correlation with patient age and number of cerebral cavernous malformations. CONCLUSIONS: Spinal cord cavernous malformations occur commonly in the familial cerebral cavernous malformation population. Gradient-based sequences are the most sensitive and should be used when spinal cord cavernous malformations are suspected. This study establishes the prevalence in the familial population at around 70% and supports the idea that this condition is a progressive systemic disease that affects the entire central nervous system.

Situating Moral Agency: How Postphenomenology Can Benefit Engineering Ethics.

This article identifies limitations in traditional approaches to engineering ethics pedagogy, reflected in an overreliance on disaster case studies. Researchers in the field have pointed out that these approaches tend to occlude ethically significant aspects of day-to-day engineering practice and thus reductively individualize and decontextualize ethical decision-making. Some have proposed, as a remedy for these defects, the use of research and theory from Science and Technology Studies (STS) to enrich our understanding of the ways in which technology and engineering practice are intricated in social and institutional contexts. While endorsing this approach, this article also argues that STS scholarship may not sufficiently address the kinds of questions about normativity and agency that are essential to engineering ethics. It proposes making use of the growing body of research in a field called "postphenomenology," an approach that combines STS research with the traditional phenomenological concern with the standpoint of lived-experience. Postphenomenology offers a method of inquiry that combines STS's investigation into social and institutional dimensions of technology with phenomenological reflection on our lived experience of embodied engagement with technical objects and sociotechnical systems, particularly the ways in which these involvements affect our moral perception and agency. The aim in using this approach in engineering ethics is thus to illuminate moral dimensions of everyday professional life of which practitioners may not typically be aware. The article concludes with some concrete curricular interventions for engineering ethics classrooms.

Experimental evidence on promotion of electric and improved biomass cookstoves.

Improved cookstoves (ICS) can deliver "triple wins" by improving household health, local environments, and global climate. Yet their potential is in doubt because of low and slow diffusion, likely because of constraints imposed by differences in culture, geography, institutions, and missing markets. We offer insights about this challenge based on a multiyear, multiphase study with nearly 1,000 households in the Indian Himalayas. In phase I, we combined desk reviews, simulations, and focus groups to diagnose barriers to ICS adoption. In phase II, we implemented a set of pilots to simulate a mature market and designed an intervention that upgraded the supply chain (combining marketing and home delivery), provided rebates and financing to lower income and liquidity constraints, and allowed households a choice among ICS. In phase III, we used findings from these pilots to implement a field experiment to rigorously test whether this combination of upgraded supply and demand promotion stimulates adoption. The experiment showed that, compared with zero purchase in control villages, over half of intervention households bought an ICS, although demand was highly price-sensitive. Demand was at least twice as high for electric stoves relative to biomass ICS. Even among households that received a negligible price discount, the upgraded supply chain alone induced a 28 percentage-point increase in ICS ownership. Although the bundled intervention is resource-intensive, the full costs are lower than the social benefits of ICS promotion. Our findings suggest that market analysis, robust supply chains, and price discounts are critical for ICS diffusion.