Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

Digital Maturity as a Strategy for Advancing Patient Experience in US Hospitals.

Patient experience is globally recognized as an important indicator of health system performance, linked to health system quality and improving patient outcomes. Post COVID-19, health systems have embraced digital health and advanced digital transformation efforts; however, the relationship between digital health and patient experience outcomes is not well-documented. Using HCAHPS hospital survey data to measure patient experience, and HIMSS EMRAM Maturity Model data to measure digital maturity, a cross-sectional design using multivariate analyses examined the impact of digital maturity on patient experience in US hospitals. Our analysis shows that advanced digital maturity in US hospitals is associated with stronger patient experience outcomes, particularly relative to communication with nurses, doctors, and communication about medicines and therapies. The findings suggest that there are significant differences in patient experience associated with teaching versus nonteaching hospitals, urban versus rural hospitals. As hospitals advance and progress digital transformation initiatives, evidence to inform how transformation efforts can engage and advance patient experience will contribute to health system performance well into the future.

The impacts of rising vapour pressure deficit in natural and managed ecosystems.

An exponential rise in the atmospheric vapour pressure deficit (VPD) is among the most consequential impacts of climate change in terrestrial ecosystems. Rising VPD has negative and cascading effects on nearly all aspects of plant function including photosynthesis, water status, growth and survival. These responses are exacerbated by land-atmosphere interactions that couple VPD to soil water and govern the evolution of drought, affecting a range of ecosystem services including carbon uptake, biodiversity, the provisioning of water resources and crop yields. However, despite the global nature of this phenomenon, research on how to incorporate these impacts into resilient management regimes is largely in its infancy, due in part to the entanglement of VPD trends with those of other co-evolving climate drivers. Here, we review the mechanistic bases of VPD impacts at a range of spatial scales, paying particular attention to the independent and interactive influence of VPD in the context of other environmental changes. We then evaluate the consequences of these impacts within key management contexts, including water resources, croplands, wildfire risk mitigation and management of natural grasslands and forests. We conclude with recommendations describing how management regimes could be altered to mitigate the otherwise highly deleterious consequences of rising VPD.

The necessity of healthcare supply chain resilience for crisis preparedness.

Prior to and during the COVID-19 pandemic, Canadian provincial health systems and governments did not sufficiently consider healthcare supply chain in their crisis preparedness plans, leading to an exposed and vulnerable healthcare system. There have been many opportunities to learn from past Canadian and global crises, which have emphasized the importance of healthcare supply chain resilience in providing essential care to patients; however, considerations of healthcare supply chain resilience remain a significant gap in preparedness planning. Illustrated through the Canadian response to COVID-19 pandemic, this article will explore how healthcare supply chain resilience should be a necessary consideration in any crisis preparedness plans. Further, without this consideration of healthcare supply chain resilience, it is the person (the patient and healthcare worker), and especially vulnerable populations, that are most put at risk in the event of a future crisis.

Effectiveness of piperonyl butoxide and pyrethroid-treated long-lasting insecticidal nets (LLINs) versus pyrethroid-only LLINs with and without indoor residual spray against malaria infection: third year results of a cluster, randomised controlled, two-by-two factorial design trial in Tanzania.

BACKGROUND: After decades of success in reducing malaria through the scale-up of pyrethroid long-lasting insecticidal nets (LLINs), the decline in the malaria burden has stalled, coinciding with the rapid spread of pyrethroid resistance. In a previously reported study, nets treated with a pyrethroid and a synergist, piperonyl butoxide (PBO), demonstrated superior efficacy compared to standard pyrethroid LLINs (std-LLINs) against malaria. Evidence was used to support the public health recommendation of PBO-Pyrethroid-LLIN by the World Health Organization in 2018. This study looks at the third year of rollout of these nets in Muleba district, Tanzania to inform whether policy guidelines need to be updated. METHODS: A four-group cluster randomized trial (CRT) using a two-by-two factorial design was carried out between January 2014 and December 2017. A total of 48 clusters, were randomized in a 1:1:1:1 ratio to the following treatment groups, each intervention being provided once in 2015: 1/std-LLIN; 2/PBO-pyrethroid LLIN; 3/std-LLIN + Indoor Residual Spraying (IRS) and 4/PBO-Pyrethroid-LLIN + IRS. During the third year follow-up, malaria infection prevalence in 80 children per cluster, aged 6 months to 14 years, was measured at 28- and 33-months post-intervention and analysed as intention-to-treat (ITT) and per protocol (PP). Mosquito collections were performed monthly in all clusters, using CDC light traps in 7 randomly selected houses per cluster. RESULTS: At 28 and 33 months, study net usage among household participants was only 47% and 31%, respectively. In ITT analysis, after 28 months malaria infection prevalence among 7471 children was 80.9% in the two std-LLIN groups compared to 69.3% in the two PBO-Pyrethroid-LLIN (Odds Ratio: 0.45, 95% Confidence Interval: 0.21-0.95, p-value: 0.0364). After 33 months the effect was weaker in the ITT analysis (prevalence 59.6% versus 49.9%, OR: 0.60, 95%CI:0.32-1.13, p-value: 0.1131) but still evident in the PP analysis (57.2% versus 44.2%, OR: 0.34, 95%CI: 0.16-0.71, p-value: 0.0051). Mean number of Anopheles per night collected per house was similar between PBO-Pyrethroid-LLIN groups (5.48) and std-LLIN groups (5.24) during the third year. CONCLUSIONS: Despite low usage of PBO- Pyrethroid LLIN, a small impact of those nets on malaria infection prevalence was still observed in the 3rd year with the most protection offered to children still using them. To maximize impact, it is essential that net re-distribution cycles are aligned with this LLIN lifespan to maintain maximum coverage. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov (registration number NCT02288637).

Case report: Spontaneous mandibular body regeneration following unilateral subtotal mandibulectomy in a 3-month-old French bulldog.

Objective: To document a case of spontaneous regeneration of the mandibular body following subtotal mandibulectomy in a juvenile dog. Case summary: A 3-month-old male intact French bulldog was presented with papillary oral squamous cell carcinoma located at the dorsal aspect of the molar region of the left mandible. Initial biopsy of the mass was performed by the primary care veterinarian. Complete clinical staging revealed no signs of metastasis. Computed tomographic images of the head showed minimal contrast enhancement of the mass with no signs of periosteal or bone involvement. Subtotal mandibulectomy was performed. Histopathology indicated complete excision of the tumor. The patient returned 8-weeks later for follow up and cleft palate surgical repair, at which time bone was noted in the mandibulectomy area on palpation. Repeat computed tomography of the head revealed complete regeneration of the left mandibular body from the level of the ramus to the mandibular symphysis. No treatment for malocclusion was necessary due to the reformation of a functional mandible. Clinical relevance: The present case demonstrates that spontaneous regeneration of the mandibular body is possible following subtotal mandibulectomy in immature dogs. Subtotal mandibulectomy is a radical procedure that can lead to long term complications including mandibular drift, malocclusion, and oral pain. This case report provides evidence that these sequelae may be mitigated or eliminated in young patients undergoing this procedure.

Microspatial distribution of trace elements in feline dental hard tissues: early life exposure to essential and toxic elements.

Introduction: Trace elements play a key role in dental tissue development, as dental hard tissues accumulate both essential and toxic trace elements during mineralization. Characterization of the spatial accumulation pattern of trace elements may provide insight into exposure to toxic elements over time and to the nature of disease processes affecting the hard dental tissues. Here, we present the first report of the use of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to map the microspatial distribution of multiple trace elements, essential and toxic, across feline dental hard tissues. Methods: Eleven teeth were extracted from 8 cats. Nine teeth were from 7 cats diagnosed with idiopathic tooth resorption on intraoral radiographs prior to extraction. Two teeth were included from a cadaver that had no signs of tooth resorption on intraoral radiographs. The normal dental tissue was analyzed from each sample using LA-ICP-MS to map the microspatial distribution of essential and toxic trace elements across feline enamel, dentin, and cementum. Results: Results showed a higher accumulation of barium and strontium in coronal dentin as compared to root dentin. The timing of the accumulation mirrors nursing timelines seen in teeth from human and non-human primates, consistent with barium and strontium being sourced from maternal milk. Results also showed a higher uptake of lead in the coronal dentin, suggesting this lead exposure was likely passed from mother to offspring. Discussion: This work characterizes a baseline for elemental distribution in feline teeth linked to early life exposure to toxic elements such as lead and provides a framework for future studies investigating long-term environmental exposures to trace elements, essential and toxic, and their involvement in feline systemic and dental diseases.

Clarifying the effect of biodiversity on productivity in natural ecosystems with longitudinal data and methods for causal inference.

Causal effects of biodiversity on ecosystem functions can be estimated using experimental or observational designs - designs that pose a tradeoff between drawing credible causal inferences from correlations and drawing generalizable inferences. Here, we develop a design that reduces this tradeoff and revisits the question of how plant species diversity affects productivity. Our design leverages longitudinal data from 43 grasslands in 11 countries and approaches borrowed from fields outside of ecology to draw causal inferences from observational data. Contrary to many prior studies, we estimate that increases in plot-level species richness caused productivity to decline: a 10% increase in richness decreased productivity by 2.4%, 95% CI [-4.1, -0.74]. This contradiction stems from two sources. First, prior observational studies incompletely control for confounding factors. Second, most experiments plant fewer rare and non-native species than exist in nature. Although increases in native, dominant species increased productivity, increases in rare and non-native species decreased productivity, making the average effect negative in our study. By reducing the tradeoff between experimental and observational designs, our study demonstrates how observational studies can complement prior ecological experiments and inform future ones.

Soil versus atmospheric drought: A test case of plant functional trait responses.

Climate change alters mean global surface temperatures, precipitation regimes, and atmospheric moisture. Resultant drought affects the composition and diversity of terrestrial ecosystems worldwide. To date, there have been no assessments of the combined impacts of reduced precipitation and atmospheric drying on functional trait distributions of any species in an outdoor experiment. Here, we examined whether soil and atmospheric drought affected the functional traits of a focal grass species (Poa secunda) growing in monoculture and eight-species grass communities in outdoor mesocosms. We focused on specific leaf area (SLA), leaf area, stomatal density, root:shoot ratio, and fine root:coarse root ratio responses. Leaf area and overall growth were reduced with soil drying. Root:shoot ratio only increased for P. secunda growing in monoculture under combined atmospheric and soil drought. Plant energy allocation strategy (measured using principal components) differed when P. secunda was grown in combined soil and atmospheric drought conditions compared with soil drought alone. Given a lack of outdoor manipulations of this kind, our results emphasize the importance of atmospheric drying on functional trait responses more broadly. We suggest that drought methods focused purely on soil water inputs may be imprecisely predicting drought effects on other terrestrial organisms as well (other plants, arthropods, and higher trophic levels).

Equine odontoclastic tooth resorption and hypercementosis (EOTRH): microspatial distribution of trace elements in hypercementosis-affected and unaffected hard dental tissues.

Equine Odontoclastic Tooth Resorption and Hypercementosis (EOTRH) is a common, painful and poorly understood disease. Enamel, dentin and cementum accumulate both essential and toxic trace elements during mineralization. Characterization of the spatial accumulation pattern of trace elements may provide insight into the role that toxic elements play and inform biological processes affecting these hard dental tissues for future research. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to map the distribution of multiple trace elements and heavy metals across equine healthy and diseased (hypercementosis-affected) hard dental tissues among four teeth extracted from horses with EOTRH. Results showed banding patterns of some trace elements (lead, strontium, barium), reflecting the temporal component of accumulation of trace elements during dentin mineralization. Essential elements zinc and magnesium did not show banding patterns. Comparison to the unaffected cementum and dentin adjacent to the hypercementosis region showed that there is an underlying incremental pattern in the uptake of some metals with spatial irregularities. This supports a possible metabolic change involved in hypercementosis lesion development. This represents the first use of LA-ICP-MS to study the microspatial distribution of trace elements in equine teeth, establishing a baseline for elemental distribution in normal and EOTRH impacted dental hard tissue.

The Emerging Features of Healthcare Supply Chain Resilience: Learning from a Pandemic.

The COVID-19 pandemic exposed significant fragilities in the configuration of global healthcare supply chains. This was felt acutely by citizens, patients and healthcare workers across Canada. As demand for critical medical products surged in Canada, and globally, provincial healthcare supply chain teams worked to rapidly stabilize their supply chains. These efforts indicate the emerging features of healthcare supply chain resilience. Results suggest that there are five emerging features: (1) redundancy of supply inventory; (2) diversification of suppliers across geographies; (3) maturity of digital infrastructure to create transparency; (4) proactivity; and (5) equity of distribution to protect the lives of all.

The ability of sweat and buffer solutions to reduce hexavalent chromium of relevance for leather extraction.

The European Union restricted the amount of hexavalent chromium (Cr(VI)) in leather in 2015, but skin allergy cases due to Cr-tanned leather are not declining. Standardized extraction methods have been criticized to both over- and underestimate the expected amount of bioavailable Cr(VI) in leather. This study aims to evaluate the ability of four extraction solutions to reduce or preserve Cr(VI): artificial sweat solutions (ASWs) of pH 4.7, 6.5, and 8.0, and phosphate buffer (PB) of pH 8.0. This was investigated by incubating each solution with added Cr(VI) as a function of time, and then measuring the recovered Cr(VI). All solutions, especially PB, preserved Cr(VI) for 24 h. These solutions were also pre-exposed to Cr-free vegetable-tanned leather (VTL) before incubation with Cr(VI). Released vegetable tannin species strongly reduced Cr(VI), with up to 4000 µg/L added Cr(VI) reduced in all solutions after 24 h. However, after 1 h, Cr(VI) was still detectable in extraction solutions at pH 6.5 and above. The reduction of Cr(VI) in relevant extraction solutions is hence a process dependent on time, pH, and the presence of co-released leather species. All extraction solutions, but least PB, have the potential to underestimate any Cr(VI) present on the surface of leather.

Exploring static and dynamic relationships between burden of disease and research funding in the United States.

BACKGROUND: The relationship between burden of disease and research funding has been examined cross-sectionally, but temporal patterns have not been investigated. It is logical to assume that temporal improvements in disability-adjusted life-years (DALYs) reflect benefits from research funding; such assumptions are tempered by an unknown lag time for emergence of benefits from research. METHODS: We studied National Institutes of Health (NIH) research fund allocations and United States DALY estimates for overlapping disease categories (matched disease categories, MDC, N = 38). Using a general linear model, we separately analysed DALYs for MDCs in 2017 in relation to NIH research allocations in 2017 and 2007. We also examined how changes in DALYs were related to cumulative NIH research funding (2006-2017). After regressing DALY change on summed funding, we obtained model residuals as estimates of the discrepancy for each MDC between observed and expected change in burden, given funding. RESULTS: In 2017, there was a positive association between NIH research fund allocations and DALYs for the same year (F1,36 = 16.087, p = 0.0002921; slope = 0.35020; model R2 = 0.3088), suggesting proportionate allocation. There was a positive association between 2017 DALYs and 2007 NIH research allocation, implying a beneficial impact of research (F1,36 = 15.754, p = 0.0003; slope = 0.8845; model R2 = 0.3044). In contrast, there was a nonsignificant association between summed NIH funding and percent change in DALYs over 2006-2017 (F1,36 = 0.199; p = 0.65; beta coefficient = -1.144). When MDCs were ordered based on residuals, HIV/AIDS ranked first. Mental, neurologic or substance abuse (MNS) disorders comprised most residuals in the lower half. CONCLUSIONS: NIH fund allocation is proportional to DALYs for MDCs. Temporal changes in DALYs vary by MDCs, but they are not significantly related to cumulative research outlays. Further analysis of temporal changes in DALYs could help to inform research outlays for MDCs and to study the impact of research.

Extraskeletal Ewing Sarcoma from Head to Toe: Multimodality Imaging Review.

Extraskeletal Ewing sarcoma (EES) is a rare subtype in the Ewing sarcoma family of tumors (ESFT), which also includes Ewing sarcoma of bone (ESB) and, more recently, primitive neuroectodermal tumors. Although these tumors often have different manifestations, they are grouped on the basis of common genetic translocation and diagnosis from specific molecular and immunohistochemical features. While the large majority of ESFT cases occur in children and in bones, approximately 25% originate outside the skeleton as EES. Importantly, in the adult population these extraskeletal tumors are more common than ESB. Imaging findings of EES tumors are generally nonspecific, with some variation based on location and the tissues involved. A large tumor with central necrosis that does not cross the midline is typical. Despite often nonspecific findings, imaging plays an important role in the evaluation and management of ESFT, with MRI frequently the preferred imaging modality for primary tumor assessment and local staging. Chest CT and fluorine 18 fluorodeoxyglucose PET/CT are most sensitive for detecting lung and other distant or nodal metastases. Management often involves chemotherapy with local surgical excision, when possible. A multidisciplinary treatment approach should be used given the propensity for large tumor size and local invasion, which can make resection difficult. Despite limited data, outcomes are similar to those of other ESFT cases, with 5-year survival exceeding 80%. However, with metastatic disease, the long-term prognosis is poor. ©RSNA, 2022.

Digitally enabled supply chain as a strategic asset for the COVID-19 response in Alberta.

This provincial case study, one of seven conducted as part of a national research program on healthcare supply chain management during COVID-19, focuses on Alberta. With a history of emergency preparedness, Alberta's unique context, one that includes having an already established, centralized, and digital healthcare supply chain strategy, sets this case apart from the others in terms of pandemic responses. A key challenge navigated by Alberta was the inadequacies of traditional sourcing and procurement approaches to meet surges in product demand, which was overcome by the implementation of unique procurement strategies. Opportunities for Alberta included the integration of supply chain teams into senior leadership structures, which enabled access to data to inform public health decision-making. This case demonstrated how Alberta's healthcare supply chain assets-its supply chain infrastructure, data, and leadership expertise, especially-contributed to resilient supply chain capacity across the province.

Supply chain capacity to respond to the COVID-19 pandemic in Ontario: Challenges faced by a health system in transition.

This provincial case study, one of seven conducted as part of a national research program on healthcare supply chain management during COVID-19, focuses on Ontario. The context of significant restructuring of health organizations and regions in Ontario challenged the province's capacity to respond to COVID-19. A complex leadership structure, led by political leaders, with limited healthcare supply chain expertise at decision-making tables and a prioritization of "hospitals first" early in the first wave were described as challenges Ontario faced in managing the pandemic. A lack of supply chain digital infrastructure-and consequently, lack of available data-meant informed decision-making regarding supply utilization and demand forecasting was not possible. The Ontario case presents key lessons learned regarding the unintended consequences of lack of supply chain coordination across organizations, and the prioritization of hospitals and allocation strategies on Canada's most vulnerable population segments.