Reverse engineering morphogenesis through Bayesian optimization of physics-based models.

Morphogenetic programs coordinate cell signaling and mechanical interactions to shape organs. In systems and synthetic biology, a key challenge is determining optimal cellular interactions for predicting organ shape, size, and function. Physics-based models defining the subcellular force distribution facilitate this, but it is challenging to calibrate parameters in these models from data. To solve this inverse problem, we created a Bayesian optimization framework to determine the optimal cellular force distribution such that the predicted organ shapes match the experimentally observed organ shapes. This integrative framework employs Gaussian Process Regression, a non-parametric kernel-based probabilistic machine learning modeling paradigm, to learn the mapping functions relating to the morphogenetic programs that maintain the final organ shape. We calibrated and tested the method on Drosophila wing imaginal discs to study mechanisms that regulate epithelial processes ranging from development to cancer. The parameter estimation framework successfully infers the underlying changes in core parameters needed to match simulation data with imaging data of wing discs perturbed with collagenase. The computational pipeline identifies distinct parameter sets mimicking wild-type shapes. It enables a global sensitivity analysis to support the regulation of actomyosin contractility and basal ECM stiffness to generate and maintain the curved shape of the wing imaginal disc. The optimization framework, combined with experimental imaging, identified that Piezo, a mechanosensitive ion channel, impacts fold formation by regulating the apical-basal balance of actomyosin contractility and elasticity of ECM. This workflow is extensible toward reverse-engineering morphogenesis across organ systems and for real-time control of complex multicellular systems.

Balancing competing effects of tissue growth and cytoskeletal regulation during Drosophila wing disc development.

How a developing organ robustly coordinates the cellular mechanics and growth to reach a final size and shape remains poorly understood. Through iterations between experiments and model simulations that include a mechanistic description of interkinetic nuclear migration, we show that the local curvature, height, and nuclear positioning of cells in the Drosophila wing imaginal disc are defined by the concurrent patterning of actomyosin contractility, cell-ECM adhesion, ECM stiffness, and interfacial membrane tension. We show that increasing cell proliferation via different growth-promoting pathways results in two distinct phenotypes. Triggering proliferation through insulin signaling increases basal curvature, but an increase in growth through Dpp signaling and Myc causes tissue flattening. These distinct phenotypic outcomes arise from differences in how each growth pathway regulates the cellular cytoskeleton, including contractility and cell-ECM adhesion. The coupled regulation of proliferation and cytoskeletal regulators is a general strategy to meet the multiple context-dependent criteria defining tissue morphogenesis.

Reverse engineering morphogenesis through Bayesian optimization of physics-based models.

Morphogenetic programs direct the cell signaling and nonlinear mechanical interactions between multiple cell types and tissue layers to define organ shape and size. A key challenge for systems and synthetic biology is determining optimal combinations of intra- and inter-cellular interactions to predict an organ's shape, size, and function. Physics-based mechanistic models that define the subcellular force distribution facilitate this, but it is extremely challenging to calibrate parameters in these models from data. To solve this inverse problem, we created a Bayesian optimization framework to determine the optimal cellular force distribution such that the predicted organ shapes match the desired organ shapes observed within the experimental imaging data. This integrative framework employs Gaussian Process Regression (GPR), a non-parametric kernel-based probabilistic machine learning modeling paradigm, to learn the mapping functions relating to the morphogenetic programs that generate and maintain the final organ shape. We calibrated and tested the method on cross-sections of Drosophila wing imaginal discs, a highly informative model organ system, to study mechanisms that regulate epithelial processes that range from development to cancer. As a specific test case, the parameter estimation framework successfully infers the underlying changes in core parameters needed to match simulation data with time series imaging data of wing discs perturbed with collagenase. Unexpectedly, the framework also identifies multiple distinct parameter sets that generate shapes similar to wild-type organ shapes. This platform enables an efficient, global sensitivity analysis to support the necessity of both actomyosin contractility and basal ECM stiffness to generate and maintain the curved shape of the wing imaginal disc. The optimization framework, combined with fixed tissue imaging, identified that Piezo, a mechanosensitive ion channel, impacts fold formation by regulating the apical-basal balance of actomyosin contractility and elasticity of ECM. This framework is extensible toward reverse-engineering the morphogenesis of any organ system and can be utilized in real-time control of complex multicellular systems.

The multimodal action of G alpha q in coordinating growth and homeostasis in the Drosophila wing imaginal disc.

Background: G proteins mediate cell responses to various ligands and play key roles in organ development. Dysregulation of G-proteins or Ca 2+ signaling impacts many human diseases and results in birth defects. However, the downstream effectors of specific G proteins in developmental regulatory networks are still poorly understood. Methods: We employed the Gal4/UAS binary system to inhibit or overexpress Gαq in the wing disc, followed by phenotypic analysis. Immunohistochemistry and next-gen RNA sequencing identified the downstream effectors and the signaling cascades affected by the disruption of Gαq homeostasis. Results: Here, we characterized how the G protein subunit Gαq tunes the size and shape of the wing in the larval and adult stages of development. Downregulation of Gαq in the wing disc reduced wing growth and delayed larval development. Gαq overexpression is sufficient to promote global Ca 2+ waves in the wing disc with a concomitant reduction in the Drosophila final wing size and a delay in pupariation. The reduced wing size phenotype is further enhanced when downregulating downstream components of the core Ca 2+ signaling toolkit, suggesting that downstream Ca 2+ signaling partially ameliorates the reduction in wing size. In contrast, Gαq -mediated pupariation delay is rescued by inhibition of IP 3 R, a key regulator of Ca 2+ signaling. This suggests that Gαq regulates developmental phenotypes through both Ca 2+ -dependent and Ca 2+ -independent mechanisms. RNA seq analysis shows that disruption of Gαq homeostasis affects nuclear hormone receptors, JAK/STAT pathway, and immune response genes. Notably, disruption of Gαq homeostasis increases expression levels of Dilp8, a key regulator of growth and pupariation timing. Conclusion: Gαq activity contributes to cell size regulation and wing metamorphosis. Disruption to Gαq homeostasis in the peripheral wing disc organ delays larval development through ecdysone signaling inhibition. Overall, Gαq signaling mediates key modules of organ size regulation and epithelial homeostasis through the dual action of Ca 2+ -dependent and independent mechanisms.

MAPPER: An Open-Source, High-Dimensional Image Analysis Pipeline Unmasks Differential Regulation of Drosophila Wing Features.

Phenomics requires quantification of large volumes of image data, necessitating high throughput image processing approaches. Existing image processing pipelines for Drosophila wings, a powerful genetic model for studying the underlying genetics for a broad range of cellular and developmental processes, are limited in speed, precision, and functional versatility. To expand on the utility of the wing as a phenotypic screening system, we developed MAPPER, an automated machine learning-based pipeline that quantifies high-dimensional phenotypic signatures, with each dimension quantifying a unique morphological feature of the Drosophila wing. MAPPER magnifies the power of Drosophila phenomics by rapidly quantifying subtle phenotypic differences in sample populations. We benchmarked MAPPER's accuracy and precision in replicating manual measurements to demonstrate its widespread utility. The morphological features extracted using MAPPER reveal variable sexual dimorphism across Drosophila species and unique underlying sex-specific differences in morphogen signaling in male and female wings. Moreover, the length of the proximal-distal axis across the species and sexes shows a conserved scaling relationship with respect to the wing size. In sum, MAPPER is an open-source tool for rapid, high-dimensional analysis of large imaging datasets. These high-content phenomic capabilities enable rigorous and systematic identification of genotype-to-phenotype relationships in a broad range of screening and drug testing applications and amplify the potential power of multimodal genomic approaches.

Patient characteristics, care patterns, and outcomes of atrial fibrillation associated hospitalizations in patients with chronic kidney disease and end-stage renal disease.

BACKGROUND: Chronic Kidney Disease (CKD) and end-stage renal disease (ESRD) are associated with poor outcomes in patients with cardiovascular disease. There is a paucity of contemporary data on in-hospital outcomes and care patterns of atrial fibrillation (AF) associated hospitalizations CKD and ESRD. METHODS: Outcomes and care patterns were evaluated in GWTG-AFIB database (Jan 2013-Dec 2018), including in-hospital mortality, use of a rhythm control strategy, and oral anticoagulation (OAC) prescription at discharge among eligible patients. Generalized logistic regression models with generalized estimating equations were used to ascertain differences in outcomes. Hospital-level variation in OAC prescription and rhythm control was also evaluated. RESULTS: Among 50,154 patients from 105 hospitals the median age was 70 years (interquartile range 61-79) and 47.3% were women. The prevalence of CKD was 36.0% while that of ESRD was 1.6%. Among eligible patients, discharge OAC prescription rates were 93.6% for CKD and 89.1% for ESRD. After adjustment, CKD and ESRD were associated with higher in-hospital mortality (odds ratio [OR] 3.08, 95% confidence interval [CI] 1.57-6.03 for ESRD and OR 2.02, 95% CI 1.52-2.67 for CKD), lower odds of OAC prescription at discharge (OR 0.59, 95% CI 0.44-0.79 for ESRD and OR 0.84, 95% CI 0.75-0.94 for CKD) compared with normal renal function. CKD was associated with lower utilization of rhythm control strategy (OR 0.92, 95% CI 0.87-0.98) with no significant difference between ESRD and normal renal function (OR 1.32, 95% CI 0.79-1.11). There was large hospital-level variation in OAC prescription at discharge (MOR 2.34, 95% CI 2.05-2.76) and utilization of a rhythm control strategy (MOR 2.69, 95% CI 2.34-3.21). CONCLUSIONS: CKD/ESRD is associated with higher in-hospital mortality, less frequent rhythm control, and less OAC prescription among patients hospitalized for AF. There is wide hospital-level variation in utilization of a rhythm control strategy and OAC prescription at discharge highlighting potential opportunities to improve care and outcomes for these patients, and better define standards of care in this patient population.

Diabetes and atrial fibrillation in hospitalized patients in the United States.

BACKGROUND: Data on the burden of atrial fibrillation (AF) associated with diabetes among hospitalized patients are scarce. We assessed the AF-related hospitalizations trends in patients with diabetes, and compared AF outcomes in patients with diabetes to those without diabetes. HYPOTHESIS: AF-related health outcomes differ between patient with diabetes and without diabetes. METHODS: Using the National Inpatient Sample (NIS) 2004-2014, we studied trends in AF hospitalization rate among diabetic patients, and compared in-hospital case fatality rate, length of stay (LOS), cost and utilization of rhythm control therapies, and 30-day readmission rate between patients with and without diabetes. Logistic or Cox regression models were used to assess the differences in AF outcomes by diabetes status. RESULTS: Over the study period, there were 4 325 522 AF-related hospitalizations, of which 1 075 770 (24.9%) had a diagnosis of diabetes. There was a temporal increase in AF hospitalization rate among diabetic patients (10.4 to 14.4 per 1000 hospitalizations among patients with diabetes; +4.4% yearly change, p-trend < .0001). Among AF patients, those with diabetes had a lower in-hospital mortality (adjusted odds ratio [aOR]: 0.68; 95% CI: 0.65-0.72) and LOS (aOR: 0.95; 95% CI: 0.94-0.96), but no difference in costs (aOR: 0.95; 95% CI: 0.94-0.96) and a higher 30-day rate of readmissions compared with no diabetes (aHR 1.05; 95% CI: 1.01-1.08), compared to individuals without diabetes. CONCLUSION: AF and diabetes coexist among hospitalized patients, with rising trends over the last decade. Diabetes is associated with lower rates in-hospital adverse AF outcomes, but a higher 30-day readmission risk.

Epithelial organ shape is generated by patterned actomyosin contractility and maintained by the extracellular matrix.

Epithelial sheets define organ architecture during development. Here, we employed an iterative multiscale computational modeling and quantitative experimental approach to decouple direct and indirect effects of actomyosin-generated forces, nuclear positioning, extracellular matrix, and cell-cell adhesion in shaping Drosophila wing imaginal discs. Basally generated actomyosin forces generate epithelial bending of the wing disc pouch. Surprisingly, acute pharmacological inhibition of ROCK-driven actomyosin contractility does not impact the maintenance of tissue height or curved shape. Computational simulations show that ECM tautness provides only a minor contribution to modulating tissue shape. Instead, passive ECM pre-strain serves to maintain the shape independent from actomyosin contractility. These results provide general insight into how the subcellular forces are generated and maintained within individual cells to induce tissue curvature. Thus, the results suggest an important design principle of separable contributions from ECM prestrain and actomyosin tension during epithelial organogenesis and homeostasis.

Microfluidics on the fly: Inexpensive rapid fabrication of thermally laminated microfluidic devices for live imaging and multimodal perturbations of multicellular systems.

Microfluidic devices provide a platform for analyzing both natural and synthetic multicellular systems. Currently, substantial capital investment and expertise are required for creating microfluidic devices using standard soft-lithography. These requirements present barriers to entry for many nontraditional users of microfluidics, including developmental biology laboratories. Therefore, fabrication methodologies that enable rapid device iteration and work "out-of-the-box" can accelerate the integration of microfluidics with developmental biology. Here, we have created and characterized low-cost hybrid polyethylene terephthalate laminate (PETL) microfluidic devices that are suitable for cell and micro-organ culture assays. These devices were validated with mammalian cell lines and the Drosophila wing imaginal disc as a model micro-organ. First, we developed and tested PETLs that are compatible with both long-term cultures and high-resolution imaging of cells and organs. Further, we achieved spatiotemporal control of chemical gradients across the wing discs with a multilayered microfluidic device. Finally, we created a multilayered device that enables controllable mechanical loading of micro-organs. This mechanical actuation assay was used to characterize the response of larval wing discs at different developmental stages. Interestingly, increased deformation of the older wing discs for the same mechanical loading suggests that the compliance of the organ is increased in preparation for subsequent morphogenesis. Together, these results demonstrate the applicability of hybrid PETL devices for biochemical and mechanobiology studies on micro-organs and provide new insights into the mechanics of organ development.

Tools to reverse-engineer multicellular systems: case studies using the fruit fly.

Reverse-engineering how complex multicellular systems develop and function is a grand challenge for systems bioengineers. This challenge has motivated the creation of a suite of bioengineering tools to develop increasingly quantitative descriptions of multicellular systems. Here, we survey a selection of these tools including microfluidic devices, imaging and computer vision techniques. We provide a selected overview of the emerging cross-talk between engineering methods and quantitative investigations within developmental biology. In particular, the review highlights selected recent examples from the Drosophila system, an excellent platform for understanding the interplay between genetics and biophysics. In sum, the integrative approaches that combine multiple advances in these fields are increasingly necessary to enable a deeper understanding of how to analyze both natural and synthetic multicellular systems.

Burden of 30-Day Readmissions Associated With Discharge Against Medical Advice Among Inpatients in the United States.

BACKGROUND: Discharges against medical advice are common among inpatients in the United States. The impact of discharge against medical advice on readmission rates and subsequent hospitalization outcomes is uncertain. We sought to ascertain the effect of discharge against medical advice on 30-day readmission rates and outcomes of readmission. METHODS: We used the 2014 Nationwide Readmissions Database to identify index hospitalizations among patients older than 18 years of age. The primary exposure variable was discharge against medical advice, and the primary outcome measure was all-cause unplanned 30-day readmission. We used multivariate hierarchical logistic regression modeling to ascertain the effect of discharge against medical advice on 30-day readmission rates. RESULTS: There were an estimated 23,110,641 index hospitalizations nationwide with an overall unplanned 30-day readmission rate of 10.2%. 1.3% of index admissions resulted in a discharge against medical advice. Patients who were discharged against medical advice were younger (mean age 47.1 years vs 56.5 years, P < 0.001) with a higher proportion of males (61.1% vs 39.5%, P < 0.001) compared with patients with a routine discharge. Discharge against medical advice was associated with significantly higher odds of 30-day readmission (risk-adjusted odds ratio [OR] 2.06, 95% confidence interval [CI] 2.03-2.09, P < 0.001). Discharge against medical advice was associated with higher odds of readmission to a different hospital (OR 2.35, 95% CI 2.22-2.49, P < 0.001) and repeat discharge against medical advice after readmission (OR 18.41, 95% CI 17.46-19.41, P < 0.001). The most common cause of readmission after discharge against medical advice was alcohol-related disorders (9%). Hospital-level rates of discharge against medical advice ranged from 0% to 12.5%. CONCLUSIONS: Discharge against medical advice is associated with over twice the odds of all-cause unplanned 30-day readmission compared with routine discharge. There is large hospital-level variation in rates of discharge against medical advice. Interventions to reduce discharges against medical advice, particularly at hospitals with high rates of such discharges, may reduce the overall readmission burden in this challenging and high-risk patient population.

Hospitalization Trends for Acute Kidney Injury in Kidney Transplant Recipients in the United States, 2004-2014.

BACKGROUND: The incidence of acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) in the general population is increasing. However, there is limited information on the epidemiology of AKI-related hospitalizations in the prevalent US kidney transplant population. METHODS: We analyzed trends in the incidence of hospitalizations with primary diagnosis of AKI and secondary diagnosis of AKI and AKI-D using data from the National Inpatient Sample 2004-2014. Co-primary endpoints were in-hospital mortality, length of stay (LOS), and cost. Survey analysis techniques were used to compute national estimates. Linear trends in outcomes were evaluated using linear regression. RESULTS: There were a total of 37 562 hospitalizations for primary AKI, 136 628 for secondary AKI, and 10 731 for AKI-D during the study period. We found an increase in hospitalizations for all 3 diagnoses over time (13.7-24.7 per thousand kidney transplant recipients [KTRs] for primary AKI, 37.4-108.0 per thousand KTRs for secondary AKI, and 4.2-6.0 per thousand KTRs for AKI-D; all P trend < 0.01). This was accompanied by significant improvements in in-hospital mortality (3.2%-0.5% for primary and 6.1%-4.4% for secondary AKI; both P trend < 0.01), average LOS (5.3-4.6 days for primary and 8.4-7.2 days for secondary AKI; both P trend < 0.001), and cost ($11 635-$8234 for primary and $21 373-$17 470 for secondary AKI; P trend < 0.001 for both). CONCLUSIONS: The incidence of hospitalizations for AKI and AKI-D among KTRs is rapidly rising. This has been accompanied by significant improvements in in-hospital mortality, LOS, and cost.

Acute kidney injury after aortic valve replacement in a nationally representative cohort in the USA.

Background: Randomized trials have consistently shown lower rates of acute kidney injury (AKI) with transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR). Comparative rates of AKI for TAVR versus SAVR, and predictors and prognostic implications of AKI after aortic valve replacement (AVR) have not been well studied in nationally representative real-world data. Objectives: First, to compare rates of AKI and dialysis requiring AKI in TAVR versus SAVR. Second, to determine predictors of AKI and prognostic implications of AKI in patients undergoing TAVR or SAVR. Methods: We used the 2011-14 National Inpatient Sample to identify all patients undergoing isolated TAVR or SAVR using validated international classification of diseases, ninth revision ICD-9 codes. Rates of AKI and AKI requiring dialysis (AKI-D) were compared between the two groups using a propensity-matched design. Predictors of AKI and prognostic impact of AKI on in-hospital outcomes were ascertained using multivariate logistic regression. Results: A total of 8004 unweighted TAVR procedures and 29 355 unweighted SAVR procedures representative of 39 898 TAVR and 143 608 SAVR procedures nationwide were included in the analysis. Mean age of all patients undergoing AVR was 70.9 years and 42.3% were females. In a propensity-matched cohort of 4889 pairs of TAVR and SAVR procedures, TAVR was associated with significantly lower rates of AKI [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.66-0.80, P < 0.001] and AKI-D (OR 0.69, 95% CI 0.50-0.96, P = 0.03) compared with SAVR. AKI was associated with significantly higher rates of in-hospital mortality for TAVR (OR 7.16, 95% CI 5.52-9.29, P < 0.001) as well as SAVR (OR 9.43, 95% CI 7.71-11.55, P < 0.001). Conclusions: In a large propensity-matched cohort of TAVR and SAVR procedures, TAVR was associated with significantly lower rates of AKI and AKI-D compared with SAVR. AKI and AKI-D are predictors of poor in-hospital outcomes in TAVR as well as SAVR.

Thirty-Day Readmissions After Hospitalization for Hypertensive Emergency.

Hypertensive emergency is a clinical entity with potentially serious health implications and high healthcare utilization. There is a lack of nationally representative data on incidence, causes, and predictors of 30-day readmission after hospitalization for hypertensive emergency. We used the 2013 to 2014 Nationwide Readmissions Database to identify index hospitalizations for hypertensive emergency. Primary outcome was all-cause unplanned 30-day readmission. Multivariable hierarchical logistic regression was used to identify independent predictors of readmission. There were 166 531 index hospitalizations for hypertensive emergency representative of 355 627 (SE, 9401) hospitalizations nationwide in 2013 to 2014. Mean age was 66.0 (SE, 0.14) years, and 53.7% were women. The overall incidence of unplanned 30-day readmissions was 17.8%. The most common causes of readmission were heart failure (14.2%), hypertension with complications (10.2%), sepsis (5.9%), acute kidney injury (5.1%), and cerebrovascular accident (5.1%). Noncardiovascular causes accounted for 57.9% of readmissions. We found age <65 years (odds ratio, 1.21; 95% CI, 1.17-1.25; P<0.001), female sex (odds ratio, 1.09; 95% CI, 1.07-1.12; P<0.001), comorbid disease burden, substance use disorders, and socioeconomic risk factors to be significant predictors of readmission. One out of 6 patients hospitalized for hypertensive emergency had an unplanned 30-day readmission. Heart failure, uncontrolled hypertension, and stroke were among the most frequent causes of readmission; however, over half of all readmissions were because of noncardiovascular causes.

Condom catheter induced penile skin erosion.

Condom catheters are known to be discrete, reliable, comfortable and very easy to use which makes them preferable to bladder catheter (Saint et al. (Urinary catheters: What type do men and their nursesprefer? J Am Geriatr SOC 1999;47:1453-1457); Hirsh et al. (Do condom catheter collecting systems cause urinary tract infection? J Am Med Assoc 1979;2:0-1)). Condom catheters are widely used in the management of male urinary incontinence, bedridden patient and geriatric population. They are considered to be safe, however, they are associated with complications in care of an incorrect use. In our hospital setup a 73-year-old male bedridden patient attended the surgical opd with complain of penile skin erosion following condom catheter application for 4 days for which dressing was done to remove the slough for 2 days then circumcision was done. Henceforth, although a less known complications are associated with the condom catheter but if not attended promptly can lead to a grave condition like penile gangrene, necrosis, death (Özkan et al. (Penile strangulation and necrosis due to condom catheter. Int Wound J 2015;12:248-9. doi: 10.1111/iwj.12102. Epub 2013 Jun 11); Johnson (The condom catheter: urinary tract infection and other complications. South Med J 1983;76:579-82)).

Comparison of Outcomes of Transfemoral Versus Transapical Approach for Transcatheter Aortic Valve Implantation.

Post hoc analyses of clinical trials have shown superior outcomes for a transfemoral (TF) compared with a transapical (TA) approach for transcatheter aortic valve implantation (TAVI). There are few contemporary data on utilization and outcomes of TF versus TA TAVI in real-world patient populations. Using the National Inpatient Sample 2011 to 2014, we identified TF-TAVI and TA-TAVI procedures using ICD-9 procedure codes 35.05 and 35.06, respectively. A propensity-matched cohort of TF and TA TAVI procedures balanced on 23 baseline characteristics was assembled. Outcomes included in-hospital mortality, acute kidney injury (AKI), AKI requiring dialysis (AKI-D) and postoperative stroke. A total of 7,973 TAVI procedures representative of 39,745 procedures nationally were included in the study. Of these, 80.2% were performed using a TF approach while 19.8% used a TA approach. Patients in the TF-TAVI group were older (mean age 81.7 vs 80.4 years, p < 0.001), with a higher prevalence of heart failure (12.7% vs 7.6%, p < 0.001) and lower prevalence of peripheral vascular disease (28.0% vs 35.5%, p < 0.001) compared with the TA-TAVI group. In 1,576 propensity-matched pairs of TF-TAVI and TA-TAVI procedures, TF-TAVI was associated with significantly lower in-hospital mortality (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.42 to 0.88, p = 0.01), lower rates of AKI (0.53, 95% CI 0.44 to 0.63, p < 0.001), similar rates of AKI-D (OR 0.77, 95% CI 0.44 to 1.38, p = 0.38) and postoperative stroke (OR 1.19, 95% CI 0.67 to 2.10, p = 0.56) compared with TA-TAVI. In conclusion, TF-TAVI is associated with lower rates of in-hospital mortality and AKI compared with TA-TAVI. A TF approach should be preferred over a TA approach for TAVI whenever possible.

Seasonal and Geographic Patterns in Seeking Cardiovascular Health Information: An Analysis of the Online Search Trends.

OBJECTIVE: To ascertain whether temporal and geographic interest in seeking cardiovascular disease (CVD) information online follows seasonal and geographic patterns similar to those observed in real-world data. METHODS: We searched Google Trends for popular search terms relating to CVD. Relative search volumes (RSVs) were obtained for the period January 4, 2004, to April 19, 2014, for the United States and Australia. We compared average RSVs by month and season and used cosinor analysis to test for seasonal variation in RSVs. We also assessed correlations between state-level RSVs and CVD burden using an ecological correlational design. RESULTS: RSVs were 15% higher in the United States and 45% higher in Australia for winter compared with summer (P<.001 for difference for both). In the United States, RSVs were 36% higher in February compared with August, while in Australia, RSVs were 75% higher in August compared with January. On cosinor analysis, we found a significant seasonal variability in RSVs, with winter peaks and summer troughs for both the United States and Australia (P<.001 for zero amplitude test for both). We found a significant correlation between state-level RSVs and mortality from CVD (r=0.62; P<.001), heart disease (r=0.58; P<.001), coronary heart disease (r=0.48; P<.001), heart failure (r=0.51; P<.001), and stroke (r=0.60; P<.001). CONCLUSION: Google search query volumes related to CVD follow strong seasonal patterns with winter peaks and summer troughs. There is moderate to strong positive correlation between state-level search query volumes and burden of CVD mortality.

The Emerging Role of Mobile-Health Applications in the Management of Hypertension.

PURPOSE OF REVIEW: Mobile-health technology, frequently referred to as m-health, encompasses smartphone, tablet, or personal computer use in the management of chronic disease. There has been a rise in the number of commercially available smartphone applications and website-based platforms which claim to help patients manage hypertension. Very little research has been performed confirming whether or not use of these applications results in improved blood pressure (BP) outcomes. In this paper, we review existing literature on m-health systems and how m-health can affect hypertension management. RECENT FINDINGS: M-health systems help patients manage hypertension in the following ways: (1) setting alarms and reminders for patients to take their medications, (2) linking patients' BP reports to their electronic medical record for their physicians to review, (3) providing feedback to patients about their BP trends, and (4) functioning as point-of-care BP sensors. M-health applications with alarms and reminders can increase medication compliance while applications that share ambulatory BP data with patients' physicians can foster improved patient-physician dialog. However, the most influential tool for achieving positive BP outcomes appears to be patient-directed feedback about BP trends. A large number of commercially available m-health applications may facilitate self-management of hypertension by enhancing medication adherence, maintaining a log of blood pressure measurements, and facilitating physician-patient communication. A small number of applications function as BP sensors, thereby transforming the smartphone into a medical device. Such BP sensors often generate unreliable recordings. Patients must be cautioned regarding the use of smartphones for BP measurement at least until these applications have been more extensively validated.