Abstract 219: Use of Machine Learning Models to Identify Atherosclerotic Cardiovascular Disease Patients at Very High Risk for Future Events in a Multi-state Health Care System

Background: In the 2018 AHA/ACC Blood Cholesterol Guideline, it is recommended that ASCVD patients be classified as very high-risk (VHR) vs not-VHR (NVHR) to guide treatment decisions. This has important implications for ezetimibe and PCSK9 inhibitor eligibility. We aimed to develop a tool that could assist in more easily identifying VHR patients based on machine learning (ML) techniques. This approach offers a powerful, assumption-free alternative to conventional methods, such as logistic regression, to identify potential interactions among risk factors while incorporating the hierarchy of interaction among variables. Method: We used EHR-derived ICD-10 codes to identify patients within our health system with ASCVD. VHR was defined by ≥2 major ASCVD events (ACS ≤12 months, history of MI \u3e12 months, ischemic stroke, or symptomatic PAD) or 1 major ASCVD event and ≥2 high-risk conditions (age ≥65, diabetes, hypertension, smoking, heterozygous familial hypercholesterolemia, CKD, CHF, persistently elevated LDL-C ≥100 mg/dl, or prior CABG/PCI). Patients not meeting these criteria were classified as NVHR. We randomly assigned patients into a training set and a testing set. Classification and regression tree (CART) modeling was performed on the training set and validated on the testing set. The results were compared with a random forest model. Variables in both models included age, sex, race, ethnicity, and each of the VHR criteria above. The primary outcome for both models was VHR classification. Performance of the two models were compared using area under the curve (AUC). Result: A total of 180,669 ASCVD patients were identified in 2018: 104,123 (58%) were VHR and 76,546 (42%) were NVHR. Mean age and sex were 73.1±11.9 years, 55% male and 70.1±13.4 years, 54% male for the VHR and NVHR groups, respectively. Half the population was randomly selected as the training dataset (n=90,334) and the other half was used as the testing dataset (n=90,335). Both CART and random forest models identified recent ACS, ischemic stroke, hypertension, PAD, and history of MI as the top five predictors of VHR status. Ninety-six percent of patients with recent ACS were classified as VHR. Among patients with no recent ACS, 95% were classified as VHR if they had a stroke and hypertension. Among patients with no ACS or stroke, 89% were classified as VHR if they had PAD. Finally, among patients with no ACS, stroke or PAD, 90% were classified as VHR if they had a history of MI. The misclassification rate of the CART model on the testing set was 4.3%. The AUC for the CART and random forest models was 0.949 and 0.968, respectively. Conclusion: Both ML methods were highly predictive of VHR status among those with ASCVD. Use of this approach affords a simplified means to drive clinical decision making at the point of care

Curcumin Enhances Bortezomib Treatment of Myeloma by Inhibiting Heat Shock Protein 90 Expression

Purpose: To investigate whether curcumin augments bortezomib-induced apoptosis in myeloma cells (MM1.R line), and to explore the molecular mechanism with regard to heat shock protein 90 (HSP90) expression.Methods: MTT cell viability assay was used to assess growth inhibition of MM1.R cells at different concentrations of curcumin alone and also combined with 0.01 mM bortezomib. Annexin V and propidium iodide (PI) labeling were used to detect apoptosis. Caspase 3, caspase 9, NF-κB, and HSP 90 protein expression were measured by Western blotting.Results: Curcumin alone inhibited MM1.R cell growth and increased apoptosis in a concentration dependent manner. When curcumin was combined with low concentration (0.01 mM) bortezomib, both effects（viability inhibition and apoptosis induction increased (p < 0.05), whereas bortezomib alone had no effect (p > 0.05). Western blotting revealed that for curcumin and combined treatments, expression of the apoptotic markers, caspase 3 and caspase 9, increased while expression of NF-κB and HSP 90 decreased (p < 0.05). Again, low concentration bortezomib alone had no effect, whereas the combined treatment showed the largest effect, thus suggesting that the actions of curcumin and bortezomib are synergistic.Conclusion: Curcumin increased MM1.R cell sensitivity to bortezomib, which may be due to suppression of NF-κB and HSP90 activity.Keywords: Curcumin, Bortezomib, Myeloma cells, Cell growth, Apoptosis, Heat shock protein 9

Improved harmony search methods to replace variational principle in geotechnical problems

2010-2011 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Increased risk of noninfluenza respiratory virus infections associated with receipt of inactivated influenza vaccine

We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95 confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses. © 2012 The Author.postprin

Economic factors influencing zoonotic disease dynamics: demand for poultry meat and seasonal transmission of avian influenza in Vietnam

While climate is often presented as a key factor influencing the seasonality of diseases, the importance of anthropogenic factors is less commonly evaluated. Using a combination of methods-wavelet analysis, economic analysis, statistical and disease transmission modelling-we aimed to explore the influence of climatic and economic factors on the seasonality of H5N1 Highly Pathogenic Avian Influenza in the domestic poultry population of Vietnam. We found that while climatic variables are associated with seasonal variation in the incidence of avian influenza outbreaks in the North of the country, this is not the case in the Centre and the South. In contrast, temporal patterns of H5N1 incidence are similar across these 3 regions: periods of high H5N1 incidence coincide with Lunar New Year festival, occurring in January-February, in the 3 climatic regions for 5 out of the 8 study years. Yet, daily poultry meat consumption drastically increases during Lunar New Year festival throughout the country. To meet this rise in demand, poultry production and trade are expected to peak around the festival period, promoting viral spread, which we demonstrated using a stochastic disease transmission model. This study illustrates the way in which economic factors may influence the dynamics of livestock pathogens

Protective efficacy against pandemic influenza of seasonal influenza vaccination in children in Hong Kong: a randomized controlled trial

BACKGROUND: The efficacy of seasonal influenza vaccination against 2009 pandemic influenza A(H1N1) remains unclear. METHODS: One child aged 6-17 years in each of 796 households was randomized to receive 2009-2010 seasonal trivalent inactivated influenza vaccine (TIV) or saline placebo between August 2009 and February 2010. Households were followed up with serology, symptom diaries, and collection of respiratory specimens during illnesses. The primary outcomes were influenza infection confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or a >/=4-fold rise in serum antibody titer measured by hemagglutination inhibition assay. RESULTS: Receipt of TIV led to 8-13-fold mean geometric rises in antibody titers against seasonal A and B viruses, but only 1.5-fold mean geometric rises against the pandemic A(H1N1) virus that was not included in the vaccine. Children who received TIV had a reduced risk of seasonal influenza B confirmed by RT-PCR, with a vaccine efficacy estimate of 66% (95% confidence interval [CI], 31%-83%). Children who received TIV also a had reduced risk of pandemic influenza A(H1N1) indicated by serology, with a vaccine efficacy estimate of 47% (95% CI, 15%-67%). CONCLUSIONS: Seasonal TIV prevented pandemic influenza A(H1N1) and influenza B infections in children. Pandemic A(H1N1) circulated at the time of vaccination and for a short time afterward with no substantial seasonal influenza activity during that period. The potential mechanism for seasonal TIV to provide protection, possibly short lived, for children against pandemic A(H1N1) infection despite poor cross-reactive serologic response deserves further investigation. Clinical Trials Registration. NCT00792051.postprin

Colonist, 1889-02-15

The Colonist began on 6 March 1886, changing its name to The Newfoundland Colonist after 18 July 1891. Having printed local and international news Monday to Saturday for six years, the paper came to an abrupt end when its offices were destroyed in The Great Fire of 8 July 1892.Title variations recorded in Alternative Title, as needed

Generation and Characterization of Mouse Models for Skeletal Disease

Our laboratories have used genetically engineered mouse models (GEMMs) to assess genetic contributions to skeletal diseases such as osteoporosis and osteoarthritis. Studies on the genetic contributions to OA are often done by assessing how GEMMs respond to surgical methods that induce symptoms modeling OA. Here, we will describe protocols outlining the induction of experimental OA in mice as well as detailed descriptions of methods for analyzing skeletal phenotypes using micro-computerized tomography and skeletal histomorphometry

A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus