MXenes are a recently discovered class of 2D materials with an excellent potential for energy storage applications. Because MXene surfaces are hydrophilic and attractive interaction forces between ...the layers are relatively weak, water molecules can spontaneously intercalate at ambient humidity and significantly influence the key properties of this 2D material. Using complementary X-ray and neutron scattering techniques, we demonstrate that intercalation with potassium cations significantly improves structural homogeneity and water stability in MXenes. In agreement with molecular dynamics simulations, intercalated potassium ions reduce the water self-diffusion coefficient by 2 orders of magnitude, suggesting greater stability of hydrated MXene against changing environmental conditions.
Client-owned cats who underwent a post-mortem examination (n = 3,108) at a veterinary medical teaching hospital between 1989 and 2019 were studied to determine longevity and factors affecting ...mortality. Demographic factors, environmental factors, age, and causes of death were assessed. Sexes included 5.66% intact females, 39.86% spayed females, 6.95% intact males and 47.49% neutered males. 84.2% were mixed breed cats. Age at death was known for 2,974 cases with a median of 9.07 years. Cancer was the most common pathophysiologic cause of death (35.81%) and was identified in 41.3% of cats. When categorized by organ system, mortality was most attributed to multiorgan/systemic (21.72%). Renal histologic abnormalities were noted in 62.84% of cats but was considered the primary cause of death in only 13.06% of cats. Intact female and male cats had significantly shorter lifespans than their spayed or neutered counterparts. FeLV positive status was associated with decreased longevity (P<0.0001) while FIV status was not. This study reports on risk factors associated with mortality and highlights areas of research that may contribute to improved lifespan in cats.
We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report ...correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance.
In dogs with non-resectable hepatic neoplasia, treatment options are limited. The objectives of this study were to describe the use of a novel drug-eluting embolic microsphere containing paclitaxel ...for use during transarterial chemoembolization (TACE), to compare results of liver-specific owner questionnaires and tumor volume pre- and post-TACE, and to measure systemic paclitaxel concentration post-TACE. Client-owned dogs with non-resectable hepatic neoplasia were prospectively enrolled. All owners completed questionnaires validated for the assessment of subjective outcomes in dogs with cancer before the TACE procedure and approximately 4 weeks after the TACE procedure. A CT scan was performed before TACE and 1 month after TACE; results were compared. Blood samples were obtained at specified time points post-TACE to determine systemic paclitaxel concentrations. Seven dogs (median weight: 8.9 kg; range, 4.3-31 kg) were enrolled. TACE was successfully performed in all dogs, and no intra-procedural complications were encountered. Questionnaire scores improved significantly post-TACE. Among the 6 dogs for which full data were available, median pre-TACE tumor volume was 390 cc (range 152-1,484; interquartile range 231-1,139) and median post-TACE tumor volume was 203 cc (range 98-889; interquartile range 151-369), which was significantly (P = .028) lower. All 6 dogs had a reduction in volume at the post-TACE measurement. Mean percent change in tumor volume was -45.6% (95%CI -58.6 to -32.6%). The mean plasma paclitaxel concentration in canine blood peaked at 4 days post-TACE procedure and was 25.7 ng/mL (range = 3.09-110 ng/mL) Median survival time was 629 days (95%CI 18 to upper limit not reached). The use of a novel paclitaxel-eluting microsphere in this cohort of dogs successfully decreased tumor volume significantly after TACE and improved clinical signs. Future investigation into the use of TACE and other similar therapies is warranted due to the promising outcomes noted in this cohort.
To determine whether open (O) or closed (C) geriatric ankle fractures had different patient characteristics or outcomes.
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Retrospective cohort study.
Urban Level 1 trauma center.
Patients, age 60 ...years and older, who underwent operative fixation of a rotational ankle fracture (OTA/AO 44A-C) between January 2012 and September 2021.
Morbidity, defined as 90-day reoperation, 90-day readmission, or loss of mobility, as well as 1-year mortality compared between patients with closed and open fractures.
The open cohort was older (75 years vs. 68 years; P = 0.003) but had similar Charlson comorbidity indices (4.6 O vs. 4.0 C; P = 0.323) and preinjury rates of independent ambulation (70.4% O vs. 80.9% C; P = 0.363). There were higher rates of 1-year mortality (11% vs. 0%; P < 0.001), deep infection (14.8% vs. 3.9%; P = 0.019), and loss of mobility (64.7% vs. 23.0%; P < 0.001) in the open cohort. Multivariate regression identified open fracture as an independent predictor of 90-day reoperation (OR: 20.6; P = 0.022) and loss of mobility (OR: 5.1; P = 0.011).
Despite having comorbidities and preinjury function similar to the closed geriatric ankle fracture cohort, open ankle fracture was independently predictive of greater loss of mobility. Nearly two-thirds of geriatric patients with open ankle fractures experienced a decline in functional independence, compared with 1 in 4 of those with closed fractures. Open fracture was associated with higher rates of deep infection, reoperation, and 1-year mortality.
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
ABSTRACT
Aims
Low serum albumin levels are associated with poor prognosis in numerous chronic disease states but the relationship between albumin and outcomes in patients with heart failure (HF) and ...secondary mitral regurgitation (SMR) has not been described.
Methods and results
The randomized COAPT trial evaluated the safety and effectiveness of transcatheter edge‐to‐edge repair (TEER) with the MitraClipTM plus guideline‐directed medical therapy (GDMT) versus GDMT alone in patients with symptomatic HF and moderate‐to‐severe or severe SMR. Baseline serum albumin levels were measured at enrolment. Among 614 patients enrolled in COAPT, 559 (91.0%) had available baseline serum albumin levels (median 4.0 g/dl, interquartile range 3.7–4.2 g/dl). Patients with albumin <4.0 g/dl compared with ≥4.0 g/dl were older and more likely to have ischaemic cardiomyopathy and a hospitalization within the year prior to enrolment. After multivariable adjustment, patients with albumin <4.0 g/dl had higher 4‐year rates of all‐cause death (63.7% vs. 47.6%; adjusted hazard ratio 1.34, 95% confidence interval 1.02–1.74; p = 0.032), but there were no significant differences in HF hospitalizations (HFH) or all‐cause hospitalizations according to baseline serum albumin level. The relative effectiveness of TEER plus GDMT versus GDMT alone was consistent in patients with low and high albumin levels (pinteraction = 0.19 and 0.35 for death and HFH, respectively).
Conclusion
Low baseline serum albumin levels were independently associated with reduced 4‐year survival in patients with HF and severe SMR enrolled in the COAPT trial, but not with HFH. Patients treated with TEER derived similarly robust reductions in both death and HFH regardless of baseline albumin level.
Patients with heart failure with moderate‐severe/severe mitral regurgitation stratified by serum albumin level. CI, confidence interval; GDMT, guideline‐directed medical therapy; HFH, heart failure hospitalization; HR, hazard ratio; TEER, transcatheter edge‐to‐edge repair.
The objective of this study was to define the danger zone at which the anterior tibial artery (ATA) is at risk during anterolateral plating of the distal tibia using a novel 3D computed tomography ...angiography (CTA) modeling technique.
116 patients (232 lower extremities) who underwent lower extremity CTAs between April 2020 and April 2022 were identified. Those with lower extremity trauma, evidence of a previously healed tibial fracture, or poor visualization of the ATA were excluded. The remaining 150 lower extremities (92 patients) were modeled with an anterolateral distal tibia plate using Sectra IDS7 software. The distance of the ATA from bony landmarks was measured perpendicular to the level at which the vessel intersected the plate.
The ATA intersected the plate proximally at a mean distance of 10.5 cm (95% confidence intervals, 10.2-10.9) and at a mean distance of 4.6 cm (95% confidence intervals, 4.4-4.9) distally from the central tibial plafond. The ATA intersected with the plate as far distal as hole number 1 and as proximal as hole 14 of the plate. The greatest injury risk was associated with plate holes 3-8. In this region, the artery was at risk in 46-99 percent of specimens.
The ATA is at risk when screws are placed percutaneously in an anterolateral distal tibia plate. The artery can be as close as 4.4 cm and as far as 10.9 cm proximal to the tibial plafond when crossing the plate, correlating to a risk of injury to the ATA at plate holes 1 through 14.
BACKGROUND:The development of a deep wound infection in the presence of hardware after open reduction and internal fixation presents a clinical dilemma, and there is scant literature to aid in ...decision-making. The purpose of the present study was to determine the prevalence of osseous union with maintenance of hardware after the development of postoperative infection within six weeks after internal fixation of a fracture.
METHODS:The present study included 121 patients from three level-I trauma centers, retrospectively identified from billing and trauma registries, in whom 123 postoperative wound infections with positive intraoperative cultures had developed within six weeks after internal fixation of acute fractures. The incidence of fracture union without hardware removal was calculated, and the parameters that predicted success or failure were evaluated.
RESULTS:Eighty-six patients (eighty-seven fractures; 71%) had fracture union with operative débridement, retention of hardware, and culture-specific antibiotic treatment and suppression. Predictors of treatment failure were open fracture (p = 0.03) and the presence of an intramedullary nail (p = 0.01). Several variables were not significant but trended toward an association with failure, including smoking, infection with Pseudomonas species, and involvement of the femur, tibia, ankle, or foot.
CONCLUSIONS:Deep infection after internal fixation of a fracture can be treated successfully with operative débridement, antibiotic suppression, and retention of hardware until fracture union occurs. These results may be improved by patient selection based on certain risk factors and the specific bacteria and implants involved.
LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.
We have previously shown that radiotherapy (RT) augments natural killer (NK) functions in pre-clinical models of human and mouse cancers, including sarcomas. Since dogs are an excellent outbred model ...for immunotherapy studies, we sought to assess RT plus local autologous NK transfer in canine sarcomas.
Dog NK cells (CD5
, NKp46+) were isolated from PBMCs and expanded with irradiated K562-C9-mIL21 feeder cells and 100 IU/mL recombinant human IL-2. NK homing and cytotoxicity ± RT were evaluated using canine osteosarcoma tumor lines and dog patient-derived xenografts (PDX). In a first-in-dog clinical trial for spontaneous osteosarcoma, we evaluated RT and intra-tumoral autologous NK transfer.
After 14 days, mean NK expansion and yield were 19.0-fold (±8.6) and 258.9(±76.1) ×10
cells, respectively. Post-RT, NK cytotoxicity increased in a dose-dependent fashion in vitro reaching ~ 80% at effector:target ratios of ≥10:1 (P < 0.001). In dog PDX models, allogeneic NK cells were cytotoxic in ex vivo killing assays and produced significant PDX tumor growth delay (P < 0.01) in vivo. After focal RT and intravenous NK transfer, we also observed significantly increased NK homing to tumors in vivo. Of 10 dogs with spontaneous osteosarcoma treated with focal RT and autologous NK transfer, 5 remain metastasis-free at the 6-month primary endpoint with resolution of suspicious pulmonary nodules in one patient. We also observed increased activation of circulating NK cells after treatment and persistence of labelled NK cells in vivo.
NK cell homing and cytotoxicity are increased following RT in canine models of sarcoma. Results from a first-in-dog clinical trial are promising, including possible abscopal effects.
Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the ...sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy.
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