ACR benchmark testing of a novel high-speed ring-gantry linac kV-CBCT system.

A new generation cone-beam computed tomography (CBCT) system with new hardware design and advanced image reconstruction algorithms is available for radiation treatment simulation or adaptive radiotherapy (HyperSight CBCT imaging solution, Varian Medical Systems-a Siemens Healthineers company). This study assesses the CBCT image quality metrics using the criteria routinely used for diagnostic CT scanner accreditation as a first step towards the future use of HyperSight CBCT images for treatment planning and target/organ delineations. Image performance was evaluated using American College of Radiology (ACR) Program accreditation phantom tests for diagnostic computed tomography systems (CTs) and compared HyperSight images with a standard treatment planning diagnostic CT scanner (Siemens SOMATOM Edge) and with existing CBCT systems (Varian TrueBeam version 2.7 and Varian Halcyon version 2.0).  Image quality performance for all Varian HyperSight CBCT vendor-provided imaging protocols were assessed using ACR head and body ring CT phantoms, then compared to existing imaging modalities. Image quality analysis metrics included contrast-to-noise (CNR), spatial resolution, Hounsfield number (HU) accuracy, image scaling, and uniformity. All image quality assessments were made following the recommendations and passing criteria provided by the ACR. The Varian HyperSight CBCT imaging system demonstrated excellent image quality, with the majority of vendor-provided imaging protocols capable of passing all ACR CT accreditation standards. Nearly all (8/11) vendor-provided protocols passed ACR criteria using the ACR head phantom, with the Abdomen Large, Pelvis Large, and H&N vendor-provided protocols produced HU uniformity values slightly exceeding passing criteria but remained within the allowable minor deviation levels (5-7 HU maximum differences). Compared to other existing CT and CBCT imaging modalities, both HyperSight Head and Pelvis imaging protocols matched the performance of the SOMATOM CT scanner, and both the HyperSight and SOMATOM CT substantially surpassed the performance of the Halcyon 2.0 and TrueBeam version 2.7 systems. Varian HyperSight CBCT imaging system could pass almost all tests for all vendor-provided protocols using ACR accreditation criteria, with image quality similar to those produced by diagnostic CT scanners and significantly better than existing linac-based CBCT imaging systems.

Prevention of iatrogenic fluid overload with naloxone infusions: A patient safety initiative.

A higher number of patients admitted to hospital systems are requiring a naloxone infusion for treatment of opioid toxicity. Although naloxone is a safe antidote for the treatment of opioid toxicity, this is not without the risk of iatrogenic harm. During standard pharmacy medication safety review process, it was identified that our standard naloxone concentration protocol would deliver 4 times the standard maintenance fluid rate to our pediatric patient population. After this risk was identified, a multidisciplinary review process of our naloxone infusion protocol was performed to help mitigate the potential risk of fluid overload. Our updated naloxone infusion protocol will result in close to a 10-fold reduction in fluids required for our naloxone infusion protocol to better align with the American Society of Health-System Pharmacists' Standardize 4 Safety Initiative and reduce the potential for iatrogenic harm.

Ivermectin Toxicokinetics in Rainbow Trout (Oncorhynchus mykiss) following P-glycoprotein Induction.

Alterations in ivermectin (IVM, 22,23-dihydro avermectin B1a+22,23-dihydro avermectin B1b) toxicokinetics following P-glycoprotein (P-gp) induction by clotrimazole (CTZ) were examined in rainbow trout (Oncorhynchus mykiss) to assess the potential importance of P-gp activity levels in xenobiotic distribution and kinetics in fish. Control and fish pretreated with CTZ (30 µmol/kg) were administered 175 µg/kg 3H-IVM into the caudal vasculature. At various time points (0.25, 0.5, 1, 3, 24, 48, 96, and 168 h) following injection, tissues (blood, liver, kidney, gill, intestines, brain [5 regions], eye, gonad and fat) were removed analyzed for IVM-derived radioactivity. IVM concentration declined in blood, liver, kidney and gill, and concentrations in other tissues remained constant over the sampling period. The highest measured concentrations were found in kidney, followed by liver, with the lowest values found in brain, eye and gonad. The highest % of the administered dose was found in the liver and kidney in the immediate hours post-administration, and in the intestines and fat at 24 h post-administration. P-gp induction by CTZ did not alter IVM distribution or any calculated toxicokinetic parameter (AUC, mean residence time, T1/2, clearance rate, volume of distribution), suggesting that P-gp induction may be limited or that P-gp plays a lesser role in xenobiotic kinetics in fish compared to mammals.

Potency and mechanism of p-glycoprotein chemosensitizers in rainbow trout (Oncorhynchus mykiss) hepatocytes.

The membrane efflux transporter P-glycoprotein (P-gp, [ABCB1, MDR1]) exports a wide range of xenobiotic compounds, resulting in a continuous first line of defense against toxicant accumulation at basal expression levels, and contributing to the multixenobiotic resistance (MXR) phenotype at elevated expression levels. Relatively little information exists on P-gp inhibition in fish by chemosensitizers, compounds which lower toxicity thresholds for harmful P-gp substrates in complex mixtures. The effects of four known mammalian chemosensitizers (cyclosporin A [CsA], quinidine, valspodar [PSC833], and verapamil) on the P-gp-mediated transport of rhodamine 123 (R123) and cortisol in primary cultures of rainbow trout (Oncorhynchus mykiss) hepatocytes were examined. Competitive accumulation assays using 25 µM R123 or cortisol and varying concentrations of chemosensitizers (0-500 µM) were used. CsA, quinidine, and verapamil inhibited R123 export (IC50 values ± SE: 132 ± 60, 83.3 ± 27.2, and 43.2 ± 13.6 µM, respectively). CsA and valspodar inhibited cortisol export (IC50 values: 294 ± 106 and 92.2 ± 34.9 µM, respectively). In an ATP depletion assay, hepatocytes incubated with all four chemosensitizers resulted in lower free ATP concentrations, suggesting that they act via competitive inhibition. Chemosensitizers that inhibit MXR transporters are an important class of environmental pollutant, and these results show that rainbow trout transporters are inhibited by similar chemosensitizers (and mostly at similar concentrations) as seen in mammals and other fish species.

A Novel Approach to Emergency Department Readiness for Airborne Precautions Using Simulation-Based Clinical Systems Testing.

STUDY OBJECTIVES: Emergency department (ED) COVID-19 preparations required rethinking workflows and introducing the potential for errors. Simulation provides a nimble methodology integrating into situ training and systems testing to prepare staff, detect potential workflow latent safety threats and provide recommendations for mitigation. METHODS: We developed 5 onsite rapid-cycle ED simulation cases using "tipping points" related to new protocols coupled with a structured observation tool. Staff observed simulations, recorded adherence to protocols, identified safety threats, discussed mitigation strategies, and participants completed an evaluation using a 5-point Likert scale. Latent safety threats were prioritized by risk and escalated to leadership. RESULTS: Through 44 simulations, 76 staff identified 31 unique latent safety threats in the following categories: job aids 9 (29%), isolation measures 8 (26%), communication and personnel 6 (19%), and technology and equipment 8 (26%). Eleven high-priority safety threats were escalated to ED leadership. Sixty-five staff (86% of participants) completed a web-based evaluation reporting that simulations were worth the time (86% strongly agreed), an effective way to test the system (92% strongly agreed), and an acceptable way to improve (92% strongly agreed). CONCLUSION: Our study demonstrated that simulation-based clinical systems test methods are adaptable for rapid preparedness evaluation and training. In combination with rapid-cycle deliberate practice, many latent safety threats were identified prior to clinical implementation. Our work highlights a novel application of simulation systems to increase system preparedness and reduce the potential for errors which may be applicable in diverse settings for designing, evaluating, and training staff in new protocols and procedures.

The Proteome of Circulating Large Extracellular Vesicles in Diabetes and Hypertension.

Hypertension and diabetes induce vascular injury through processes that are not fully understood. Changes in extracellular vesicle (EV) composition could provide novel insights. Here, we examined the protein composition of circulating EVs from hypertensive, diabetic and healthy mice. EVs were isolated from transgenic mice overexpressing human renin in the liver (TtRhRen, hypertensive), OVE26 type 1 diabetic mice and wild-type (WT) mice. Protein content was analyzed using liquid chromatography-mass spectrometry. We identified 544 independent proteins, of which 408 were found in all groups, 34 were exclusive to WT, 16 were exclusive to OVE26 and 5 were exclusive to TTRhRen mice. Amongst the differentially expressed proteins, haptoglobin (HPT) was upregulated and ankyrin-1 (ANK1) was downregulated in OVE26 and TtRhRen mice compared with WT controls. Conversely, TSP4 and Co3A1 were upregulated and SAA4 was downregulated exclusively in diabetic mice; and PPN was upregulated and SPTB1 and SPTA1 were downregulated in hypertensive mice, compared to WT mice. Ingenuity pathway analysis identified enrichment in proteins associated with SNARE signaling, the complement system and NAD homeostasis in EVs from diabetic mice. Conversely, in EVs from hypertensive mice, there was enrichment in semaphroin and Rho signaling. Further analysis of these changes may improve understanding of vascular injury in hypertension and diabetes.

Left atrial measurement in lateral versus sternal recumbency in cats undergoing focused cardiac ultrasound examination.

Objective: To compare left atrial measurements carried out by an emergency and critical care (ECC) clinician on cats in lateral and sternal recumbency. Animals and procedures: A prospective observational study was conducted between December 2019 and January 2021 at the university teaching hospital at University of Liège. One hundred and two hospitalized cats were enrolled. Focused cardiac ultrasound (FOCUS) was performed in right lateral and sternal recumbency by a single FOCUS-trained ECC resident. Standard right parasternal long- and short-axis views were recorded. After randomization of the cineloops, the same blinded resident measured maximal left atrial dimension (LAD) and the ratio of left atrial to aortic diameter (LA:Ao). Reproducibility was assessed using the Bland-Altman method. Results: The LA:Ao and LAD measurements in lateral (LA:Ao median: 1.37, range: 1.02 to 3.22; LAD median: 13.25, range: 7.90 to 32.90) and sternal (LA:Ao median: 1.38, range: 1.06 to 3.22; LAD median: 13.00, range: 8.00 to 32.90) recumbency were not significantly different (bias: -0.003, CI -0.014, 0.007; and bias: -0.101, CI -0.231, 0.029, respectively). Conclusions and clinical relevance: The FOCUS technique was successfully applied in sternal recumbency in almost all cats. The LAD and LA:Ao measured in sternal and lateral recumbency were not significantly different. Cardiac left atrial measurements obtained using FOCUS can be reliably assessed in sternal recumbency in hospitalized, stable cats.

Mesure de l'oreillette gauche en décubitus latéral versus sternal chez les chats soumis à une échographie cardiaque focalisée. Objectif: Comparer les mesures de l'oreillette gauche effectuées par un clinicien des urgences et soins intensifs (ECC) sur des chats en décubitus latéral et sternal. Animaux et procédures: Une étude observationnelle prospective a été menée entre décembre 2019 et janvier 2021 au CHU de l'Université de Liège. Cent deux chats hospitalisés ont été enrôlés. L'échographie cardiaque focalisée (FOCUS) a été réalisée en décubitus latéral droit et sternal par un seul résident ECC formé au FOCUS. Des vues parasternales droites grand et petit axe standards ont été enregistrées. Après randomisation des cineloops, le même résident en aveugle a mesuré la dimension auriculaire gauche maximale (LAD) et le rapport entre le diamètre de l'oreillette gauche et celui de l'aorte (LA:Ao). La reproductibilité a été évaluée à l'aide de la méthode de Bland-Altman. Résultats: Les mesures LA:Ao et LAD en décubitus latéral (LA:Ao médian : 1,37, intervalle : 1,02 à 3,22; LAD médian : 13,25, intervalle : 7,90 à 32,90) et sternal (LA:Ao médian : 1,38, intervalle : 1,06 à 3,22; médiane LAD : 13,00, intervalle : 8,00 à 32,90) n'étaient pas significativement différents (biais : −0,003, IC −0,014, 0,007; et biais : −0,101, IC −0,231, 0,029, respectivement). Conclusions et pertinence clinique: La technique FOCUS a été appliquée avec succès en décubitus sternal chez presque tous les chats. Le LAD et LA:Ao mesurés en décubitus sternal et latéral n'étaient pas significativement différents. Les mesures de l'oreillette cardiaque gauche obtenues à l'aide de FOCUS peuvent être évaluées de manière fiable en décubitus sternal chez les chats hospitalisés et stables.(Traduit par Dr Serge Messier).

Lethal and sublethal effects in Pink salmon (Oncorhynchus gorbuscha) following exposure to five aquaculture chemotherapeutants.

Early life stages of Pink salmon (Oncorhynchus gorbuscha) are at risk of exposure to the active ingredients of chemotherapeutant formulations (hydrogen peroxide [HP], azamethiphos [AZ], emamectin benzoate [EB], cypermethrin [CP] and deltamethrin [DM]) used to control sea lice in salmon aquaculture. LC50 values (95% confidence intervals) for acute 48-h water exposures in order of least to most toxic to seawater-adapted pink salmon fry were: HP (227 [138-418] mg/L), EB (1090 [676-2006] µg/L), AZ (80 [52-161] µg/L), CP (5.1 [3.0-10.5] µg/L), and DM (980 [640-1800] ng/L), and in subchronic 10-d lethality sediment exposure tests: EB (2065 [1384-3720] µg/kg), CP (97 [58-190] µg/kg), and DM (1035 [640-2000] ng/kg). Alterations in behaviour varied between chemicals; no chemical attracted pink salmon fry; fish avoided HP to a limited extent at 50 mg/L), as well as EB (300 µg/L), and AZ (50 µg/L). Significant concentration-dependent decreases in olfactory responsiveness to food extract were seen following AZ, CP and DM exposures that occurred at lower concentrations with longer exposure periods (10 µg/L, 0.5 µg/L and 100 ng/L thresholds at 7 d). Following 10-d sediment exposures, olfaction was only affected by CP exposure at 50 µg/kg. Significant decreases in swimming performance (Ucrit) occured for HP, AZ, CP and DM at concentrations as low as 100 mg/L, 10 µg/L, 2 µg/L and 200 ng/L, respectively. This study provides comprehensive data on the lethal and sublethal effects of aquaculture chemotherapeutant exposure in early life stage pink salmon.

P-glycoprotein inhibition affects ivermectin-induced behavioural alterations in fed and fasted zebrafish (Danio rerio).

The role of the blood-brain barrier ATP-binding cassette protein transporter P-glycoprotein (P-gp) in protecting zebrafish (Danio rerio) from the central nervous system neurotoxicant ivermectin (IVM, 22,23-dihydroavermectin B1a + 22,23-dihydroavermectin B1b) was examined in the absence and presence of the competitive inhibitor cyclosporin A (CsA). Zebrafish injected intraperitoneally with 1, 2, 5, or 10 µmol/kg IVM exhibited mortality 30 min following administration at the highest dose. At sublethal doses > 1 µmol/kg, IVM altered the swimming performance, exploratory behaviour, motor coordination, escape response and olfactory response in exposed fish. When fish were exposed to IVM in the presence of CsA, alterations in swimming and behaviours increased significantly and at the highest IVM/CsA ratio resulted in a complete lack of exploratory and olfactory behaviours. In separate experiments, fish were either fed or fasted, and the effects of IVM and CsA administration were examined. The effects of IVM administration and the exacerbated effects seen with CsA co-administration were not affected by fasting. This study provides evidence that P-gp provides a protective role in the BBB of fish against environmental neurotoxicants. The results also show that P-gp activity is maintained even under conditions of food deprivation, suggesting that this chemical defence system is prioritized over other energy expenditures during diet limitation.

Early Clinical, Functional, and Mortality Outcomes for Heel Ulcers Treated With a Vertical Contour Calcanectomy.

Heel ulcerations are common complications seen in patients suffering from chronic conditions such as diabetes mellitus, peripheral vascular disease, and in bed ridden patients. When these systemic pathologies lead to heel ulcers, an increased risk of calcaneal osteomyelitis often significantly limits the benefits of conventional therapeutic interventions and increases risk of major lower extremity amputation. The Vertical Contour Calcanectomy (VCC) is a novel surgical procedure specific for the surgical management of these complex and often recalcitrant heel ulcerations. The VCC was described as a reproducible procedure in which wide excision of both the soft tissue ulceration as well as defined bone cuts of the calcaneus allows for decreased bioburden and in many cases, for primary soft tissue closure. The present study describes the outcomes related to the VCC and provides guidance based on the objective findings detailed herein. This study, at the time of publication, represents the largest collection of patients that have undergone the VCC (N = 51) and their outcomes at 1 year. Those who remained healed without recurrence, amputation, or mortality at 1-year follow-up were 31.4%. Post-VCC total limb salvage rate is 68.6% at one year, mean follow-up 663.9 ± 464.7 days. One-year all-cause mortality post-VCC was 9.8%. Post-VCC function at 1-year follow-up reflects 79.3% of patients having the same or better function that their perioperative state.

Risks Factors Associated With Major Lower Extremity Amputation After Vertical Contour Calcanectomy.

The primary aim of the study is to determine risks for major lower extremity amputation after undergoing Vertical Contour Calcanectomy. Subanalysis was performed comparing patients who underwent Vertical Contour Calcanectomy who were fully ambulatory to those who were partially or nonambulatory postoperatively. Within the cohort of 63 patients included in the Vertical Contour Calcanectomy 85.71% (54/63) of patients had diabetes mellitus, 53.97% (34/63) had peripheral arterial disease, and 19.05% (12/63) had Charcot Neuroarthropathy. Multivariate logistic regression, found that (1) patients that underwent primary closure at the time of the Vertical Contour Calcanectomy, were 79.9% more likely (odds ratio [OR] 0.20; 95% confidence interval [CI] 0.04-0.96) to have limb salvage and that (2) female patients were 85.4% less likely compared to male patients (OR 0.15; 95% CI 0.02-0.99) to undergo major lower extremity amputation. Patients with coronary artery disease were 5.2 times more likely (OR 5.18; 95% CI 1.120-23.94) and patients that were nonambulatory preoperatively, were 10.3 times more likely (OR 10.28; 95% CI 1.60-66.26), to be partially or nonambulatory after Vertical Contour Calcanectomy. Primary closure at time of Vertical Contour Calcanectomy significantly decreases the risk of major lower extremity amputation, and diminished preoperative ambulatory status as well as coronary artery disease makes it less likely that patients return to full ambulation after Vertical Contour Calcanectomy.

P-glycoprotein induction and its energetic costs in rainbow trout (Oncorhynchus mykiss).

Biological organisms are constantly challenged by xenobiotics and have evolved mechanisms to reduce, neutralize, or repair toxic outcomes. The various chemical defenses all utilize energy, but their specific costs and impacts on energy budgets are currently unknown. In this study, the energetic costs associated with the induction and substrate transport of the efflux transporter P-glycoprotein (P-gp [ABCB1, MDR1]) were examined in rainbow trout. An intraperitoneal injection of the P-gp inducer clotrimazole (0, 0.1, 1.0, and 10 mg/kg) increased P-gp activity (as measured by a competitive rhodamine 123 transport assay in hepatocytes) in a dose-dependent manner reaching a maximum induction of 2.8-fold. Maximum P-gp induction occurred at 50 h post-administration with the highest dose; significant induction of P-gp activity remained elevated over constitutive values until the last sampling time point (168 h). In vitro measurements of hepatocyte respiration indicated that basal P-gp activity transporting R123 as a substrate did not significantly increase respiration rates (range 18.0 to 23.2 ng O2/min/106 cells); however, following the induction of P-gp by clotrimazole and exposure to the P-gp substrate R123, respiration rates increased significantly (3.52-fold) over baseline values. Using whole animal respirometry, it was shown that respiration rates in fish exposed to R123 only or induced with clotrimazole were not different from controls (range 1.2 to 2.1 mg O2/kg/min); however, respiration rates were significantly increased in fish with induced P-gp levels and also exposed to R123. This work indicates that basal and induced levels of P-gp activity do not incur significant energetic costs to fish; however, upon induction of P-gp and concomitant substrate exposures, energetic costs can increase and could pose challenges to organisms facing limited energy resources.

Indications and outcomes for puppies undergoing mechanical ventilation: 59 cases (2006 to 2020).

The medical records of 59 puppies from 6 hospitals undergoing mechanical ventilation (MV) between 2006 and 2020 were reviewed to describe the signalment, underlying disease, duration of ventilation, and outcome. The most common underlying diseases were pneumonia (n = 18), non-cardiogenic pulmonary edema (n = 16), and trauma (n = 8). Twenty-six (44%) puppies were weaned from the ventilator. The overall survival rate was 39% (23/59) including 19 non-brachycephalic dogs and 4 brachycephalics. Median duration of mechanical ventilation was 27 hours (range: 4 to 144 hours). Brachycephalic dogs were less likely to survive than nonbrachycephalic dogs (P = 0.032). English bulldogs were over-represented with pneumonia. No association between age and survival to discharge (P = 0.716) or outcome (P = 0.579) was detected. The survival rate, and underlying disease process and severity for mechanically ventilated puppies was similar to previous studies in adult dogs.

Indications et issues chez les chiots sous ventilation mécanique : 59 cas (2006 à 2020). Les dossiers médicaux de 59 chiots de six hôpitaux soumis à une ventilation mécanique (VM) entre 2006 et 2020 ont été examinés pour décrire le signalement, la maladie sous-jacente, la durée de la ventilation et le résultat. Les maladies sous-jacentes les plus courantes étaient la pneumonie (n = 18), l'oedème pulmonaire non cardiogénique (n = 16) et les traumatismes (n = 8). Vingt-six (44 %) chiots ont été sevrés du ventilateur. Le taux de survie global était de 39 % (23/59) dont 19 chiens non brachycéphales et quatre brachycéphales. La durée médiane de la ventilation mécanique était de 27 heures (intervalle : 4 à 144 heures). Les chiens brachycéphales étaient moins susceptibles de survivre que les chiens non brachycéphales (P = 0,032). Les bouledogues anglais étaient surreprésentés avec la pneumonie. Aucune association entre l'âge et la survie à la sortie (P = 0,716) ou le résultat (P = 0,579) n'a été détectée. Le taux de survie, ainsi que le processus et la gravité de la maladie sous-jacente chez les chiots ventilés mécaniquement étaient similaires à ceux des études précédentes chez les chiens adultes.(Traduit par Dr Serge Messier).

Who benefits from urban green spaces during times of crisis? Perception and use of urban green spaces in New York City during the COVID-19 pandemic.

Urban green spaces (UGS) provide health benefits to city dwellers, which may be even more important during times of crisis such as the COVID-19 pandemic. However, lack of access to UGS or important features of UGS, in addition to concerns about UGS safety or maintenance, could prevent people from receiving these benefits. We designed an online survey to understand how people were using and perceiving UGS during the COVID-19 pandemic in New York City during the spring of 2020. The survey included questions about how people's visits to UGS and perceptions of the importance of UGS for their health had changed since the start of the pandemic, as well as the concerns people had and features of UGS they considered important. Of the 1372 people who took the survey, most respondents were concerned about a lack of social distancing and crowded UGS, and respondents with these concerns were less likely to visit UGS and had visited UGS less often during than before the pandemic. In addition, generalized linear models showed differences in some concerns and important features of UGS across gender, race and ethnicity, demonstrating the importance of considering specific community needs in UGS design and management. Although concerns about lack of access were not common in our study population, these also appeared to prevent people from using UGS, and were more common in certain areas of the city that were also hard-hit by COVID-19 in the beginning of the pandemic. To ensure that people can get health benefits from UGS during times of crisis, cities must eliminate barriers by providing equitable access to UGS, considering what amenities communities need from UGS, and provide consistent communication about public health policies.

Ankle Disarticulation: An Underutilized Approach to Staged Below Knee Amputation-Case Series and Surgical Technique.

The staged approach to below knee amputation has proven to be an effective method of achieving functionality after amputation and reducing risk for postamputation complications. Transtibial or "guillotine" amputations are often used as the first-stage amputation. Disarticulation at the ankle joint is an alternative method that can be used with favorable results and benefits. These include rapid infection decompression while minimizing the blood loss of traditional tibial osteotomy. Here we describe our operative technique, perioperative management, and indications for this surgical procedure.

Differential Bioaccumulation of Mercury and Selenium in Stomach Contents and Tissues of Three Colorado, USA, Cutthroat Trout Populations.

Total mercury (THg) and selenium (TSe) levels were measured in stomach contents (SC) and twelve tissues of cutthroat trout (Oncorhynchus clarkii) occurring in three high-elevation lakes of Colorado, USA, inhabiting watersheds absent past and current mining activities. For 32 of 36 tissues, including muscle, mean THg wet weight (ww) concentrations were greater than in the diet (SC) for all sites, indicating biomagnification. Ranges of THg (µg/kg ww) for SC and stomach tissue (ST) were 1.23-73.54 and 14.55-61.35, respectively. Selenium concentrations in fish muscle were not greater than in the SC indicating a trophic transfer factor < 1.0. However, in several other tissues, mean Se dry weight (dw) levels were greater than in SC for all three lakes. Ranges of TSe for SC and ST were 166-7544 and 797-7523 (µg/kg dw), respectively. The muscle to egg/ovary ratio for Se averaged 2.30, 4.60, and 2.68 for the three populations. The variability of SC (planktonic vs. benthic) and differential distributions of THg and TSe in SC and organ-tissues generated questions focusing on the seasonal, physiological, and genetic drivers of these organometal(loid)s in subalpine trout.

Quantitative Results of Perfusion Utilising Hyperspectral Imaging on Non-diabetics and Diabetics: A Pilot Study.

There is a paucity of quantitative measures of microvascular perfusion values in the skin. Newly developed, handheld hyperspectral imaging devices identify unique spectral fingerprints of oxygenated and deoxygenated haemoglobin in the superficial microvasculature. Establishing value ranges for healthy patients without vascular complications will subsequently help standardise assessments for perfusion defects. In particular, diabetics who are prone to vascular calcifications and lower extremity wounds may benefit. A total of 73 subjects were enrolled in the study and split in two cohorts: 36 'non-diabetic' non-vascularly compromised patients and 37 'diabetic' patients with a formal diagnosis of diabetes but without history of pedal ulceration. Values of oxygenated haemoglobin (HT-Oxy) and deoxygenated haemoglobin (HT-DeOxy) from both devices are analysed.

Beyond COVID-19: Five commentaries on reimagining governance for future crises and resilience.

Several Canadian and international scholars offer commentaries on the implications of the COVID-19 pandemic for governments and public service institutions, and fruitful directions for public administration research and practice. This second suite of commentaries considers the challenges confronting governments as a result of the COVID-19 pandemic and in the decades to come with an increasingly broad lens: the need to understand and rethink the architecture of the state given recent and future challenges awaiting governments; the need to rethink government-civil society relations and policies to deliver services for increasingly diverse citizens and communities; the need for new repertoires and sensibilities on the part of governments for recognizing, anticipating, and engaging on governance risks despite imperfect expert knowledge and public skepticism; how the COVID-19 crisis has caused us to reconceive international and sub-national borders where new "borders" are being drawn; and the need to anticipate a steady stream of crises similar to the COVID-19 pandemic arising from climate change and related challenges, and develop new national and international governance strategies for fostering population and community resilience.

Plusieurs universitaires canadiens et internationaux ont offert des suggestions sur les implications de la pandémie du COVID­19 pour les gouvernements et les institutions de la fonction publique, ainsi que des orientations futures pour la recherche et la pratique en administration publique. Cette deuxième série de commentaires examine les défis que devront affronter les gouvernements en raison de la pandémie de COVID­19 et dans les décennies à venir, dans une optique large. Cette série souligne le besoin de comprendre et de repenser l'architecture de l'État, de revoir les relations entre le gouvernement et la société civile pour fournir des services à des citoyens et des communautés de plus en plus divers, d'élaborer de nouvelles façons d'identifier et d'anticiper les risques, et de s'engager malgré l'imperfection des connaissances d'experts et le scepticisme du public, de repenser les frontières, tout ceci en tenant compte des crises et défis à venir, de façon à promouvoir la résilience de la population et des communautés.

A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84.

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.

PBI-4050 via GPR40 activation improves adenine-induced kidney injury in mice.

PBI-4050 (3-pentylbenzenacetic acid sodium salt), a novel first-in-class orally active compound that has completed clinical Phases Ib and II in subjects with chronic kidney disease (CKD) and metabolic syndrome respectively, exerts antifibrotic effects in several organs via a novel mechanism of action, partly through activation of the G protein receptor 40 (GPR40) receptor. Here we evaluate the effects of PBI-4050 in both WT and Gpr40-/- mice on adenine-induced tubulointerstitial injury, anemia and activation of the unfolded protein response (UPR) pathway. Adenine-induced CKD was achieved in 8-week-old C57BL/6 mice fed a diet supplemented with 0.25% adenine. After 1 week, PBI-4050 or vehicle was administered daily by oral-gavage for 3 weeks. Gpr40-/- mice were also subjected to adenine-feeding, with or without PBI-4050 treatment. PBI-4050 improved renal function and urine concentrating ability. Anemia was present in adenine-fed mice, while PBI-4050 blunted these effects and led to significantly higher plasma erythropoietin (EPO) levels. Adenine-induced renal fibrosis, endoplasmic reticulum (ER) stress and apoptosis were significantly decreased by PBI-4050. In parallel, Gpr40-/- mice were more susceptible to adenine-induced fibrosis, renal function impairment, anemia and ER stress compared with WT mice. Importantly, PBI-4050 treatment in Gpr40-/- mice failed to reduce renal injury in this model. Taken together, PBI-4050 prevented adenine-induced renal injury while these beneficial effects were lost upon Gpr40 deletion. These data reinforce PBI-4050's use as a renoprotective therapy and identify GPR40 as a crucial mediator of its beneficial effects.