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.

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.

Incidence and outcomes of Clostridium difficile-associated disease in hematopoietic cell transplant recipients.

Hematopoietic stem cell transplant (HSCT) recipients are at a high risk of Clostridium difficile-associated disease (CDAD) given frequent hospitalizations, prolonged antibiotic usage and altered integrity of intestinal mucosa. The prevalence and trends of CDAD in HSCT patients have not been extensively studied. In this study, the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to identify CDAD in HSCT patients using a nationwide inpatient sample in the United States from 2000 to 2009. The prevalence of CDAD and in-hospital mortality in HSCT were investigated and compared to those without any transplants. Multivariate analysis was performed to identify if BMT and graft versus host disease (GVHD) were independently associated with mortality in CDAD patients. Of the 344,507 HSCT discharges, 4.7 % had CDAD. This was about 5 times higher when compared to non-transplant discharges. During engraftment admission, rates of CDAD were higher in allogenic group (8.4 vs. 5.7 %, p < 0.001). In subsequent admissions, those with GVHD had higher rates of CDAD (5.7 vs. 3.2 %, p < 0.001). On adjusted analysis in patients with CDAD, during engraftment admission, allogenic group had significantly higher mortality when compared with non-transplants (OR 3.7). Notably, there was no significant difference in mortality between patients with and without CDAD during the engraftment period for the allogeneic group. In subsequent admissions, there was higher mortality in those with GVHD (OR 4.8). Though the prevalence of CDAD in non-transplant population doubled (from 0.44 % in 2000 to 0.99 % in 2008), it has remained stable in HSCT patients (from 4.8 % in 2000 to 5.6 % in 2008). HSCT and GVHD are independently associated with CDAD though its presence does not affect mortality.

Identifying oncological emergencies.

Prompt identification and treatment of life-threatening oncological conditions is of utmost importance and should always be included in the differential diagnosis. Oncological emergencies can have a myriad of presentations ranging from mechanical obstruction due to tumor growth to metabolic conditions due to abnormal secretions from the tumor. Notably, hematologic and infectious conditions may complicate the presentation of oncological emergencies. Advanced testing and imaging is generally required to recognize these serious presentations of common malignancies. Early diagnosis and treatment of these conditions can significantly affect the patient's clinical outcome.

Does the routine echocardiographic exam have a role in the detection and evaluation of cholelithiasis and gallbladder wall thickening?

Cholelithiasis is a very common disease in the United States. Most cases remain asymptomatic but a fraction of these patients can develop serious complications such as cholecystitis which may lead to gallbladder perforation and gallbladder cancer which is much less common. Here, we present three cases of cholelithiasis where transthoracic echocardiography was performed routinely. In each case, echocardiography detected cholelithiasis which prompted three-dimensional (3D) echocardiographic evaluation. Three-dimensional echocardiography allowed for more comprehensive examination of the gallbladder shape, size, and wall thickening and the measurement and composition of the stones in three dimensions, measurement of stone volumes, and minimized shadowing produced by stone calcifications. These cases suggest that routine echocardiography has value in detecting gallstones and that 3D echocardiography has incremental value over two-dimensional echocardiography due to pyramidal data sets which allow sequential slicing through the gallbladder and full gallbladder examination without a technologist who is trained in gallbladder imaging. These pyramidal data sets can be further viewed and cropped by a radiologist specialized in abdominal ultrasound.

Effect of Joint National Committee VII report on hospitalizations for hypertensive emergencies in the United States.

Approximately 1% to 2% of patients with hypertension will have a hypertensive emergency at some time in their life. However, no data are available on the frequency of hospitalizations for a hypertensive emergency after the publication of the Seventh Joint National Committee (JNC7) on the prevention, detection, evaluation, and treatment of high blood pressure. We sought to explore the changes in the frequency of hospitalizations and in-hospital mortality for hypertensive emergencies before and after the JNC7 report. Using the Nationwide Inpatient Sample from 2000 to 2007, adult patients (aged ≥18 years) who were hospitalized with a diagnosis of a hypertensive emergency were identified through appropriate "International Classification of Diseases, 9th revision, Clinical Modification" codes. A total of 456,259 hospitalizations with the diagnosis of hypertensive emergency occurred from the start of calendar year 2000 to the end of calendar year 2007. After adjusting for the United States census for 2000 and American Community Survey estimates for 2007 for adults, the frequency of hospitalizations with a hypertensive emergency increased in United States adults from 101/100,000 in 2000 to 111/100,000 in 2007, an average increase of about 1.11%. Despite the increase in hospitalizations, the all-cause in-hospital mortality rate decreased from 2.8% in the pre-JNC7 era to 2.6% in the post-JNC7 era (odds ratio 0.91, 95% confidence interval 0.86 to 0.96). In conclusion, the results of the present study have shown that although the number of patients with hypertensive emergency increased from 2000 to 2007, the mortality rates decreased significantly after the JNC7 guidelines.

All red is not always bacterial cellulitis: a case of Löfgren's syndrome.

Löfgren's syndrome is a rare variant of sarcoidosis characterized by the triad of hilar adenopathy, acute polyarthritis, and erythema nodosum. It can be the first presentation of underlying sarcoidosis. Also, the initial presentation of Löfgren's syndrome may be confused with cellulitis. This is a self-limiting disease with a very good prognosis. Non steroidal anti-inflammatory drugs (NSAIDs), along with supportive care and close monitoring, are the mainstay for treatment.