Twisted [(R3P)PdX] groups above dicarbaborane ligands: 4-dimethylsulfido-3-iodo-3-triphenylphosphine-closo-3-pallada-1,2-dicarbadodecaborane and 3-dimethylphenylphosphine-3-chloro-4-dimethylsulfido-closo-3-pallada-1,2-dicarbadodecaborane

The structural analyses of [3-(PPh₃)-3-I-4-(SMe₂)-closo-3,1,2-PdC₂B₉H₁₀] or [Pd(C₄H₁₆B₉S)I(C₁₈H₁₅P)], (I), and [3-(PPhMe₂)-3-Cl-4-(SMe₂)-closo-3,1,2-PdC₂B₉H₁₀] or [Pd(C₄H₁₆B₉S)Cl(C₈H₁₁P)], (II), show that in comparison with [3-(PR₃)2-closo-3,1,2-PdC₂B₉H₁₁] the presence of the 4-SMe₂ group causes the [PdX(PR₃)] unit (X = halogen) to twist about an axis passing through the Pd atom and the directly opposite B atom of the carbaborane ligand. The halogen atoms are located almost directly above a C atom in the C₂B₃ face, and the conformations of the [PdX(PR₃)] units above the C₂B₃ faces are not those predicted from molecular orbital calculations of the closo-3,1,2-PdC₂B₉ system. The fact that the variation from the predicted conformation is greater in the case of (I) than in (II) may be ascribed to the greater steric interactions induced by the I atom in (I) compared with the Cl atom in (II)

Cost-effectiveness of routine mediastinoscopy in computed tomography– and positron emission tomography–screened patients with stage I lung cancer

ObjectiveAccurate preoperative staging is essential for the optimal management of patients with lung cancer. An important goal of preoperative staging is to identify mediastinal lymph node metastasis. Computed tomography and positron emission tomography may identify mediastinal lymph node metastasis with sufficient sensitivity to allow omission of mediastinoscopy. This study utilizes our experience with patients with clinical stage I lung cancer to perform a decision analysis addressing whether mediastinoscopy should be performed in clinical stage I lung cancer patients staged by computed tomography and positron emission tomography.MethodsWe retrospectively reviewed our thoracic surgery database for cases between May 1999 and May 2004. Patients deemed clinical stage I by computed tomography and positron emission tomography were chosen for further study. Individual computed tomography, positron emission tomography, and operative and pathology reports were reviewed. The postresection pathologic staging and long-term survival were recorded. A decision model was created using TreeAgePro software and our observed data for the prevalence of mediastinal lymph node metastases and for the rate of benign nodules. Data reported in the literature were also utilized to complete the decision analysis model. A sensitivity analysis of key variables was performed.ResultsA total of 248 patients with clinical stage I lung tumors were identified. One hundred seventy-eight patients (72%) underwent mediastinoscopy before resection, and 5/178 (3%) showed N2 disease. An additional 9 patients were found to have N2 metastasis in the final resected specimen, resulting in a total of 14/248 patients (5.6%) with occult mediastinal lymph node metastases. Benign nodules were found in 19/248 (8%) of patients. Decision analysis determined that mediastinoscopy added 0.008 years of life expectancy at a cost of $250,989 per life-year gained. The outcome was sensitive to the prevalence of N2 disease in the population and the benefit of induction versus adjuvant therapy for N2 lung cancer. If the prevalence of N2 disease exceeds 10$100,000 per life-year gained.ConclusionPatients with clinical stage I lung cancer staged by computed tomography and positron emission tomography benefit little from mediastinoscopy. The survival advantage it confers is very small and is dependent on the prevalence of N2 metastasis and the unproven superiority of induction therapy over adjuvant therapy

A thoracic surgery clinic dedicated to indeterminate pulmonary nodules: Too many scans and too little pathology?

ObjectiveWidespread application of computed tomographic scans has increased detection of asymptomatic pulmonary nodules. A dedicated clinic was established to encourage referral and manage large numbers of patients with such nodules.MethodsPatients were evaluated periodically by a nurse practitioner with surgeon oversight, and follow-up imaging was centralized. Patients were rescanned at intervals on the basis of radiologist recommendation.ResultsA total of 414 patients, 189 male and 225 female with a median age of 60.2 years (20.7–84.1 years), were evaluated since April 2000. Median follow-up was 1.51 years (0–6.65 years). Thirty-seven percent (153/414) were older than 60 years with at least 10 pack-years of tobacco use, whereas 30% (123/414) had never smoked. A total of 286 patients completed at least 2 years of follow-up computed tomographic evaluation. After 2 years, 24.2% (69/286) were deemed in stable condition and were discharged from further follow-up, whereas 22.4% (64/286) of patients were followed up longer than 2 years owing to the development of new nodules. Forty-five percent (127/286) of patients did not complete their recommended follow-up at our clinic. Overall, 3% (13/414) of our patients have been shown to have a malignant tumor. Only 5 patients underwent curative resection of a primary lung cancer.ConclusionIn a population of patients with indeterminate nodules in routine clinical practice, few patients required intervention and few cancers were detected. Although the benefits of a “nodule” clinic may include patient reassurance and convenience to referring physicians, a significant number of patients did not complete their follow-up in our clinic

Leveraging Explainable Artificial Intelligence to Optimize Clinical Decision Support

OBJECTIVE: To develop and evaluate a data-driven process to generate suggestions for improving alert criteria using explainable artificial intelligence (XAI) approaches. METHODS: We extracted data on alerts generated from January 1, 2019 to December 31, 2020, at Vanderbilt University Medical Center. We developed machine learning models to predict user responses to alerts. We applied XAI techniques to generate global explanations and local explanations. We evaluated the generated suggestions by comparing with alert\u27s historical change logs and stakeholder interviews. Suggestions that either matched (or partially matched) changes already made to the alert or were considered clinically correct were classified as helpful. RESULTS: The final dataset included 2 991 823 firings with 2689 features. Among the 5 machine learning models, the LightGBM model achieved the highest Area under the ROC Curve: 0.919 [0.918, 0.920]. We identified 96 helpful suggestions. A total of 278 807 firings (9.3%) could have been eliminated. Some of the suggestions also revealed workflow and education issues. CONCLUSION: We developed a data-driven process to generate suggestions for improving alert criteria using XAI techniques. Our approach could identify improvements regarding clinical decision support (CDS) that might be overlooked or delayed in manual reviews. It also unveils a secondary purpose for the XAI: to improve quality by discovering scenarios where CDS alerts are not accepted due to workflow, education, or staffing issues

Anthropogenic Disturbance and Population Viability of Woodland Caribou in Ontario

One of the most challenging tasks in wildlife conservation and management is to clarify how spatial variation in land cover due to anthropogenic disturbance influences wildlife demography and long‐term viability. To evaluate this, we compared rates of survival and population growth by woodland caribou (Rangifer tarandus caribou) from 2 study sites in northern Ontario, Canada that differed in the degree of anthropogenic disturbance because of commercial logging and road development, resulting in differences in predation risk due to gray wolves (Canis lupus). We used an individual‐based model for population viability analysis (PVA) that incorporated adaptive patterns of caribou movement in relation to predation risk and food availability to predict stochastic variation in rates of caribou survival. Field estimates of annual survival rates for adult female caribou in the unlogged ( x̄ = 0.90) and logged ( x̄ = 0.76) study sites recorded during 2010–2014 did not differ significantly (P \u3e 0.05) from values predicted by the individual‐based PVA model (unlogged:  x̄ = 0.87; logged:  x̄ = 0.79). Outcomes from the individual‐based PVA model and a simpler stage‐structured matrix model suggest that substantial differences in adult survival largely due to wolf predation are likely to lead to long‐term decline of woodland caribou in the commercially logged landscape, whereas the unlogged landscape should be considerably more capable of sustaining caribou. Estimates of population growth rates (λ) for the 2010–2014 period differed little between the matrix model and the individual‐based PVA model for the unlogged (matrix model  x̄ = 1.01; individual‐based model x̄ = 0.98) and logged landscape (matrix model x̄ = 0.88; individual‐based model x̄ = 0.89). We applied the spatially explicit PVA model to assess the viability of woodland caribou across 14 woodland caribou ranges in Ontario. Outcomes of these simulations suggest that woodland caribou ranges that have experienced significant levels of commercial forestry activities in the past had annual growth rates 0.96. These differences were strongly related to regional variation in wolf densities. Our results suggest that increased wolf predation risk due to anthropogenic disturbance is of sufficient magnitude to cause appreciable risk of population decline in woodland caribou in Ontario. © 2020 The Authors. The Journal of Wildlife Management published by Wiley Periodicals, Inc. on behalf of The Wildlife Society

Global DNA Hypomethylation Is Associated with High Serum-Persistent Organic Pollutants in Greenlandic Inuit

Background: Persistent organic pollutants (POPs) may influence epigenetic mechanisms; therefore, they could affect chromosomal stability and gene expression. DNA methylation, an epigenetic mechanism, has been associated with cancer initiation and progression. Greenlandic Inuit have some of the highest reported POP levels worldwide. Objective: Our aim in this study was to evaluate the relationship between plasma POPs concentrations and global DNA methylation (percent 5-methylcytosine) in DNA extracted from blood samples from 70 Greenlandic Inuit. Blood samples were collected under the Arctic Monitoring and Assessment Program and previously analyzed for a battery of POPs. Methods: We used pyrosequencing to estimate global DNA methylation via Alu and LINE-1 assays of bisulfite-treated DNA. We investigated correlations between plasma POP concentrations and global DNA methylation via correlation coefficients and linear regression analyses. Results: We found inverse correlations between percents methylcytosine and many of the POP concentrations measured. Linear regressions, adjusting for age and cigarette smoking, showed statistically significant inverse linear relationships mainly for the Alu assay for p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane; \u3b2 = -0.26), p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene; \u3b2 = -0.38], \u3b2-hexachlorocyclohexane (\u3b2 = -0.48), oxychlordane (\u3b2 = -0.32), \u3b1-chlordane (\u3b2 = -0.75), mirex (\u3b2 = -0.27), sum of polychlorinated biphenyls (\u3b2 = -0.56), and sum of all POPs (\u3b2 = -0.48). Linear regressions for the LINE-1 assay showed \u3b2 estimates of similar magnitudes to those using the Alu assay, however, none was statistically significant. Conclusions: This is the first study to investigate environmental exposure to POPs and DNA methylation levels in a human population. Global methylation levels were inversely associated with blood plasma levels for several POPs and merit further investigation

Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

Background: Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods: We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB)-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA). Results: We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA)-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion: While ETRB antagonists reduce the viability of glioma cells in vitro, it appears unlikely that this effect is mediated by ETRB inhibition or cross-reaction with ETRA. Instead, we present evidence that A-192621 affects glioma and melanoma viability by activating stress/DNA damage response pathways, which leads to cell cycle arrest and apoptosis. This is the first evidence linking ETRB antagonist treatment to enhanced expression of DNA damage-inducible genes

Special topic: The association between pulse ingredients and canine dilated cardiomyopathy: addressing the knowledge gaps before establishing causation.

In July 2018, the Food and Drug Administration warned about a possible relationship between dilated cardiomyopathy (DCM) in dogs and the consumption of dog food formulated with potatoes and pulse ingredients. This issue may impede utilization of pulse ingredients in dog food or consideration of alternative proteins. Pulse ingredients have been used in the pet food industry for over 2 decades and represent a valuable source of protein to compliment animal-based ingredients. Moreover, individual ingredients used in commercial foods do not represent the final nutrient concentration of the complete diet. Thus, nutritionists formulating dog food must balance complementary ingredients to fulfill the animal's nutrient needs in the final diet. There are multiple factors that should be considered, including differences in nutrient digestibility and overall bioavailability, the fermentability and quantity of fiber, and interactions among food constituents that can increase the risk of DCM development. Taurine is a dispensable amino acid that has been linked to DCM in dogs. As such, adequate supply of taurine and/or precursors for taurine synthesis plays an important role in preventing DCM. However, requirements of amino acids in dogs are not well investigated and are presented in total dietary content basis which does not account for bioavailability or digestibility. Similarly, any nutrient (e.g., soluble and fermentable fiber) or physiological condition (e.g., size of the dog, sex, and age) that increases the requirement for taurine will also augment the possibility for DCM development. Dog food formulators should have a deep knowledge of processing methodologies and nutrient interactions beyond meeting the Association of American Feed Control Officials nutrient profiles and should not carelessly follow unsubstantiated market trends. Vegetable ingredients, including pulses, are nutritious and can be used in combination with complementary ingredients to meet the nutritional needs of the dog

Protein kinetics of superoxide dismutase-1 in familial and sporadic amyotrophic lateral sclerosis

OBJECTIVE: Accumulation of misfolded superoxide dismutase-1 (SOD1) is a pathological hallmark of SOD1-related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. METHODS: We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. RESULTS: In participants with heterozygous SOD1 INTERPRETATION: These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03449212