Evaluation of an automated phenotyping algorithm for rheumatoid arthritis.

To better understand the challenges of generally implementing and adapting computational phenotyping approaches, the performance of a Phenotype KnowledgeBase (PheKB) algorithm for rheumatoid arthritis (RA) was evaluated on a University of California, Los Angeles (UCLA) patient population, focusing on examining its performance on ambiguous cases. The algorithm was evaluated on a cohort of 4,766 patients, along with a chart review of 300 patients by rheumatologists against accepted diagnostic guidelines. The performance revealed low sensitivity towards specific subtypes of positive RA cases, which suggests revisions in features used for phenotyping. A close examination of select cases also indicated a significant portion of patients with missing data, drawing attention to the need to consider data integrity as an integral part of phenotyping pipelines, as well as issues around the usability of various codes for distinguishing cases. We use patterns in the PheKB algorithm's errors to further demonstrate important considerations when designing a phenotyping algorithm.

Outcomes by Class of Anticoagulant Use for Nonvalvular Atrial Fibrillation in Patients With Active Cancer.

Background: The choice of anticoagulant agent for patients with nonvalvular atrial fibrillation (NVAF) in the setting of active cancer has not been well studied. Objectives: The aim of this study was to compare the rates of cerebrovascular accident (CVA), gastrointestinal bleeding (GIB), and intracranial hemorrhage (ICH) in patients treated with direct oral anticoagulant agents (DOACs) compared with warfarin for NVAF in patients with active cancer. Methods: This was a retrospective electronic medical record review of eligible patients treated at a cancer hospital. The outcome events were CVA; GIB; ICH; the composite of GIB, CVA, or ICH; and overall mortality. Propensity score matching (1:1) was conducted to select comparable patients receiving warfarin vs DOACs. Fine-Gray models were fitted for each outcome event. Results: The study cohort included 1,133 patients (mean age 72 ± 8.8 years, 42% women), of whom 74% received DOACs (57% received apixaban). After propensity score matching, 195 patients were included in each anticoagulant agent group. When comparing warfarin with DOACs, there were similar risks for CVA (subdistribution HR: 0.738; 95% CI: 0.334-1.629); ICH (subdistribution HR: 0.295; 95% CI: 0.032-2.709); GIB (subdistribution HR: 1.819; 95% CI: 0.774-4.277); and the composite of GIB, CVA, or ICH (subdistribution HR: 1.151; 95% CI: 0.645-2.054). Conclusions: Patients with active cancer had similar risks for CVA, ICH, and GIB when treated with DOACs compared with warfarin for NVAF.

Myeloid Sarcoma of the Temporal Bone: A Unique Cause of Hearing Loss, Otalgia, and Facial Nerve Weakness.

OBJECTIVE: To characterize a clinical triad of symptoms associated with myeloid sarcomas of the temporal bone via a review of all previously reported cases. METHODS: Case report and Ovid MEDLINE database literature review. RESULTS: A literature search revealed that a clinical triad of hearing loss, otalgia, and facial nerve weakness are commonly associated with this rare presentation of myeloid sarcoma in the temporal bone. 44% (18/41) of patients presented with all three symptoms, while 76% (31/41) presented with at least two. The presence of t(8;21) was reported in nine patients with myeloid sarcomas of the temporal bone. CONCLUSIONS: Although myeloid sarcomas are exceedingly rare, it is necessary to consider them as part of the differential diagnosis for patients who might present with middle ear and mastoid opacification on computed tomography (CT) scan, hearing loss, otalgia, and facial nerve palsy. Physicians should maintain a high degree of suspicion in patients with a history of acute myelogenous leukemia (AML), especially if previous cytogenetic analysis revealed a t(8;21).

TSI-GNN: Extending Graph Neural Networks to Handle Missing Data in Temporal Settings.

We present a novel approach for imputing missing data that incorporates temporal information into bipartite graphs through an extension of graph representation learning. Missing data is abundant in several domains, particularly when observations are made over time. Most imputation methods make strong assumptions about the distribution of the data. While novel methods may relax some assumptions, they may not consider temporality. Moreover, when such methods are extended to handle time, they may not generalize without retraining. We propose using a joint bipartite graph approach to incorporate temporal sequence information. Specifically, the observation nodes and edges with temporal information are used in message passing to learn node and edge embeddings and to inform the imputation task. Our proposed method, temporal setting imputation using graph neural networks (TSI-GNN), captures sequence information that can then be used within an aggregation function of a graph neural network. To the best of our knowledge, this is the first effort to use a joint bipartite graph approach that captures sequence information to handle missing data. We use several benchmark datasets to test the performance of our method against a variety of conditions, comparing to both classic and contemporary methods. We further provide insight to manage the size of the generated TSI-GNN model. Through our analysis we show that incorporating temporal information into a bipartite graph improves the representation at the 30% and 60% missing rate, specifically when using a nonlinear model for downstream prediction tasks in regularly sampled datasets and is competitive with existing temporal methods under different scenarios.

Microbiology, Histopathology, and Radiographic Findings in Silent Sinus Syndrome.

BACKGROUND: The histopathology and microbiology associated with silent sinus syndrome (SSS) have not been well described. OBJECTIVE: This study details the histopathological and microbiological characteristics in addition to radiographic findings of SSS in comparison to those of chronic maxillary sinusitis (CRS). METHODS: 42 patients diagnosed with SSS at Mayo Clinic Hospital in Arizona were identified. Paranasal computed tomography scans of the 42 SSS patients as well as 42 matched CRS patients were analyzed in order to assess differences in the prevalence of septal spurs/deviation. 20 of the SSS patients and 19 of the matched CRS patients also had histopathology and microbiology reports, which were compiled and summarized. Additionally, 19 SSS and 19 matched CRS patients were contacted via phone survey for a more complete patient history regarding maxillary dental disease/surgery. RESULTS: SSS patients have a significantly higher prevalence of septal spurs/deviation than CRS patients. The microbiomes of SSS patients more closely resemble those of healthy controls than those of CRS patients. Analysis of the histopathology of SSS reveals chronic, non-specific inflammation similar to that seen in non-eosinophilic CRS without polyps. SSS patients were significantly more likely to have a history of maxillary dental disease requiring surgery. CONCLUSION: These data support the hypothesis that the pathogenesis of SSS is more likely due to anatomical/mechanical factors than inflammatory/microbiological factors.

Accuracy of Asthma Computable Phenotypes to Identify Pediatric Asthma at an Academic Institution.

OBJECTIVES: Asthma is a heterogenous condition with significant diagnostic complexity, including variations in symptoms and temporal criteria. The disease can be difficult for clinicians to diagnose accurately. Properly identifying asthma patients from the electronic health record is consequently challenging as current algorithms (computable phenotypes) rely on diagnostic codes (e.g., International Classification of Disease, ICD) in addition to other criteria (e.g., inhaler medications)-but presume an accurate diagnosis. As such, there is no universally accepted or rigorously tested computable phenotype for asthma. METHODS: We compared two established asthma computable phenotypes: the Chicago Area Patient-Outcomes Research Network (CAPriCORN) and Phenotype KnowledgeBase (PheKB). We established a large-scale, consensus gold standard (n = 1,365) from the University of California, Los Angeles Health System's clinical data warehouse for patients 5 to 17 years old. Results were manually reviewed and predictive performance (positive predictive value [PPV], sensitivity/specificity, F1-score) determined. We then examined the classification errors to gain insight for future algorithm optimizations. RESULTS: As applied to our final cohort of 1,365 expert-defined gold standard patients, the CAPriCORN algorithms performed with a balanced PPV = 95.8% (95% CI: 94.4-97.2%), sensitivity = 85.7% (95% CI: 83.9-87.5%), and harmonized F1 = 90.4% (95% CI: 89.2-91.7%). The PheKB algorithm was performed with a balanced PPV = 83.1% (95% CI: 80.5-85.7%), sensitivity = 69.4% (95% CI: 66.3-72.5%), and F1 = 75.4% (95% CI: 73.1-77.8%). Four categories of errors were identified related to method limitations, disease definition, human error, and design implementation. CONCLUSION: The performance of the CAPriCORN and PheKB algorithms was lower than previously reported as applied to pediatric data (PPV = 97.7 and 96%, respectively). There is room to improve the performance of current methods, including targeted use of natural language processing and clinical feature engineering.

Carcinoid Heart Disease: a Comprehensive Review.

PURPOSE OF REVIEW: Carcinoid heart disease is a rare disorder that is associated with significant morbidity and mortality. In this review of the literature, we will present current concepts in diagnosis and management of carcinoid heart disease. RECENT FINDINGS: Recent expert consensus guidelines highlight the role of echocardiography and screening with NT-proBNP for the evaluation of carcinoid heart disease. Advances in medical therapy along with better surgical outcomes highlight the experience and expertise that has been gained in the treatment of carcinoid heart disease. Carcinoid heart disease occurs in patients with neuroendocrine tumors who have carcinoid syndrome. Serotonin appears to play a central role in the development of carcinoid heart disease. Cardiac biomarkers and multimodality imaging can be used to aid in screening and diagnosis. The mainstay of treatment of carcinoid heart disease is surgery.

NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism.

NADPH donates high energy electrons for antioxidant defense and reductive biosynthesis. Cytosolic NADP is recycled to NADPH by the oxidative pentose phosphate pathway (oxPPP), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1). Here we show that any one of these routes can support cell growth, but the oxPPP is uniquely required to maintain a normal NADPH/NADP ratio, mammalian dihydrofolate reductase (DHFR) activity and folate metabolism. These findings are based on CRISPR deletions of glucose-6-phosphate dehydrogenase (G6PD, the committed oxPPP enzyme), ME1, IDH1, and combinations thereof in HCT116 colon cancer cells. Loss of G6PD results in high NADP, which induces compensatory increases in ME1 and IDH1 flux. But the high NADP inhibits dihydrofolate reductase (DHFR), resulting in impaired folate-mediated biosynthesis, which is reversed by recombinant expression of E. coli DHFR. Across different cancer cell lines, G6PD deletion produced consistent changes in folate-related metabolites, suggesting a general requirement for the oxPPP to support folate metabolism.

Ultrathin Layered SnSe Nanoplates for Low Voltage, High-Rate, and Long-Life Alkali-Ion Batteries.

2D electrode materials with layered structures have shown huge potential in the fields of lithium- and sodium-ion batteries. However, their poor conductivity limits the rate performance and cycle stability of batteries. Herein a new colloid chemistry strategy is reported for making 2D ultrathin layered SnSe nanoplates (SnSe NPs) for achieving more efficient alkali-ion batteries. Due to the effect of weak Van der Waals forces, each semiconductive SnSe nanoplate stacks on top of each other, which can facilitate the ion transfer and accommodate volume expansion during the charge and discharge process. This unique structure as well as the narrow-bandgap semiconductor property of SnSe simultaneously meets the requirements of achieving fast ionic and electronic conductivities for alkali-ion batteries. They exhibit high capacity of 463.6 mAh g-1 at 0.05 A g-1 for Na-ion batteries and 787.9 mAh g-1 at 0.2 A g-1 for Li-ion batteries over 300 cycles, and also high stability for alkali-ion batteries.

Cardiovascular Risk in Survivors of Cancer.

PURPOSE OF REVIEW: Survivors of childhood and adult cancers face increased risk of cardiovascular disease. We review the current evidence base and guidelines for this rapidly growing population. RECENT FINDINGS: Research continues to show that cardiovascular disease is an important cause of morbidity and mortality in cancer survivors. Cardiotoxicity related to chemotherapy and radiotherapy accounts for part of this increased risk. There is emerging evidence that cancer and cardiovascular disease share a similar biology and risk factors. At present, there are several guidelines and consensus recommendations for the management of cardiovascular risk in cancer survivors. The evidence base is accumulating though additional research is necessary to demonstrate improved outcomes and comparative effectiveness.

OrthoClust: an orthology-based network framework for clustering data across multiple species.

Increasingly, high-dimensional genomics data are becoming available for many organisms.Here, we develop OrthoClust for simultaneously clustering data across multiple species. OrthoClust is a computational framework that integrates the co-association networks of individual species by utilizing the orthology relationships of genes between species. It outputs optimized modules that are fundamentally cross-species, which can either be conserved or species-specific. We demonstrate the application of OrthoClust using the RNA-Seq expression profiles of Caenorhabditis elegans and Drosophila melanogaster from the modENCODE consortium. A potential application of cross-species modules is to infer putative analogous functions of uncharacterized elements like non-coding RNAs based on guilt-by-association.

Control strategies to prevent total hip replacement-related infections: a systematic review and mixed treatment comparison.

OBJECTIVE: To synthesise the available evidence and estimate the comparative efficacy of control strategies to prevent total hip replacement (THR)-related surgical site infections (SSIs) using a mixed treatment comparison. DESIGN: Systematic review and mixed treatment comparison. SETTING: Hospital and other healthcare settings. PARTICIPANTS: Patients undergoing THR. PRIMARY AND SECONDARY OUTCOME MEASURES: The number of THR-related SSIs occurring following the surgical operation. RESULTS: 12 studies involving 123 788 THRs and 9 infection control strategies were identified. The strategy of 'systemic antibiotics+antibiotic-impregnated cement+conventional ventilation' significantly reduced the risk of THR-related SSI compared with the referent strategy (no systemic antibiotics+plain cement+conventional ventilation), OR 0.13 (95% credible interval (CrI) 0.03-0.35), and had the highest probability (47-64%) and highest median rank of being the most effective strategy. There was some evidence to suggest that 'systemic antibiotics+antibiotic-impregnated cement+laminar airflow' could potentially increase infection risk compared with 'systemic antibiotics+antibiotic-impregnated cement+conventional ventilation', 1.96 (95% CrI 0.52-5.37). There was no high-quality evidence that antibiotic-impregnated cement without systemic antibiotic prophylaxis was effective in reducing infection compared with plain cement with systemic antibiotics, 1.28 (95% CrI 0.38-3.38). CONCLUSIONS: We found no convincing evidence in favour of the use of laminar airflow over conventional ventilation for prevention of THR-related SSIs, yet laminar airflow is costly and widely used. Antibiotic-impregnated cement without systemic antibiotics may not be effective in reducing THR-related SSIs. The combination with the highest confidence for reducing SSIs was 'systemic antibiotics+antibiotic-impregnated cement+conventional ventilation'. Our evidence synthesis underscores the need to review current guidelines based on the available evidence, and to conduct further high-quality double-blind randomised controlled trials to better inform the current clinical guidelines and practice for prevention of THR-related SSIs.

Most relevant strategies for preventing surgical site infection after total hip arthroplasty: guideline recommendations and expert opinion.

BACKGROUND: Numerous strategies are available to prevent surgical site infections in hip arthroplasty, but there is no consensus on which might be the best. This study examined infection prevention strategies currently recommended for patients undergoing hip arthroplasty. METHODS: Four clinical guidelines on infection prevention/orthopedics were reviewed. Infection control practitioners, infectious disease physicians, and orthopedic surgeons were consulted through structured interviews and an online survey. Strategies were classified as "highly important" if they were recommended by at least one guideline and ranked as significantly or critically important by ≥75% of the experts. RESULTS: The guideline review yielded 28 infection prevention measures, with 7 identified by experts as being highly important in this context: antibiotic prophylaxis, antiseptic skin preparation of patients, hand/forearm antisepsis by surgical staff, sterile gowns/surgical attire, ultraclean/laminar air operating theatres, antibiotic-impregnated cement, and surveillance. Controversial measures included antibiotic-impregnated cement and, considering recent literature, laminar air operating theatres. CONCLUSIONS: Some of these measures may already be accepted as routine clinical practice, whereas others are controversial. Whether these practices should be continued for this patient group will be informed by modeling the cost-effectiveness of infection prevention strategies. This will allow predictions of long-term health and cost outcomes and thus inform decisions on how to best use scarce health care resources for infection control.

Modeling two-photon calcium fluorescence of episodic V1 recordings using multifrequency analysis.

The use of two-photon microscopy allows for imaging of deep neural tissue in vivo. This paper examines frequency-based analysis to two-photon calcium fluorescence images with the goal of deriving smooth tuning curves. We present a multifrequency analysis approach for improved extraction of calcium responses in episodic stimulation experiments, that is, when the stimulus is applied for a number of frames, then turned off for the next few frames, and so on. Episodic orientation stimulus was applied while recording from the primary visual cortex of an anesthetized mouse. The multifrequency model demonstrated improved tuning curve descriptions of the neurons. It also offers perspective regarding the characteristics of calcium fluorescence imaging of the brain.

Productivity loss resulting from coronary heart disease in Australia.

BACKGROUND: Coronary heart disease (CHD) is the largest single cause of death in Australia. It places a heavy financial burden on the country's health system. To date, no study has systematically assessed CHD-related productivity loss in Australia. OBJECTIVE: To quantify CHD-related productivity loss in Australia using both the human capital method and the friction method. METHODS: Mathematical models adjusting for economic activity, unemployment and the elasticity of productivity loss of labour reduction were proposed for the quantification. Where Australian data were unavailable, parameters were estimated using data from studies in European countries. Sensitivity analysis was conducted around uncertain parameters. RESULTS: The annual potential CHD-related productivity loss was estimated to be Australian dollars ($A)1.79 billion in 2004 using the human capital method. The potential loss was considerably higher than the actual loss, estimated to be $A25.02 million using the friction method. CONCLUSIONS: CHD results in significant productivity loss in Australia. A valid economic evaluation of the full scale of the impact of CHD should consider the potential and actual productivity loss as well as the direct healthcare costs incurred by the disease.

Economic evaluation of the direct healthcare cost savings resulting from the use of walking interventions to prevent coronary heart disease in Australia.

Coronary heart disease (CHD) is the leading cause of death in Australia. Direct healthcare costs of CHD exceed those of any other disease. The purpose of this study was to evaluate the direct healthcare cost savings resulting from walking interventions to prevent CHD in Australia. A meta-analysis was performed to quantify the efficacy of walking interventions in preventing CHD. The etiologic fraction and other mathematical models were applied to quantify the cost savings resulting from walking interventions to prevent CHD. The net direct healthcare cost savings in CHD prevention resulting from 30 min of normal walking a day for 5-7 days a week by the sufficient walking population were estimated at AU$126.73 million in 2004. The cost savings could increase to $419.90 million if all the inactive adult Australians engaged in 1 h of normal walking a day for 5-7 days a week. Given its low injury risk and high adherence, walking should be advocated as a key population-based primary intervention strategy for CHD prevention and healthcare cost reduction.

Quantifying the dose-response of walking in reducing coronary heart disease risk: meta-analysis.

The evidence for the efficacy of walking in reducing the risk of and preventing coronary heart disease (CHD) is not completely understood. This meta-analysis aimed to quantify the dose-response relationship between walking and CHD risk reduction for both men and women in the general population. Studies on walking and CHD primary prevention between 1954 and 2007 were identified through Medline, SportDiscus and the Cochrane Database of Systematic Reviews. Random-effect meta-regression models were used to pool the relative risks from individual studies. A total of 11 prospective cohort studies and one randomized control trial study met the inclusion criteria, with 295,177 participants free of CHD at baseline and 7,094 cases at follow-up. The meta-analysis indicated that an increment of approximately 30 min of normal walking a day for 5 days a week was associated with 19% CHD risk reduction (95% CI = 14-23%; P-heterogeneity = 0.56; I (2) = 0%). We found no evidence of heterogeneity between subgroups of studies defined by gender (P = 0.67); age of the study population (P = 0.52); or follow-up duration (P = 0.77). The meta-analysis showed that the risk for developing CHD decreases as walking dose increases. Walking should be prescribed as an evidence-based effective exercise modality for CHD prevention in the general population.

The re-emerging concept of personalized healthcare.

Personalized healthcare has regained momentum through the unprecedented surge of research in the genomics field and related areas of biology. These new insights compel the optimization of healthcare and therapy for individual subjects. While the potential benefits are large, substantial obstacles need to be overcome for attaining clinical utility in general medial practice. These range from scientific hurdles emerging from biological and genetic complexity, to cultural, economic, legal, regulatory and ethical issues. This article addresses, in broad strokes, these intercalated issues, discussing recent advances, remaining questions and how to move forward. It also highlights recent developments at academic centers devoted to promoting personalized healthcare as an avenue with great potential for improving our healthcare system.