Automated Software Transplantation

Automated program repair has excited researchers for more than a decade, yet it has yet to find full scale deployment in industry. We report our experience with SAPFIX: the first deployment of automated end-to-end fault fixing, from test case design through to deployed repairs in production code. We have used SAPFIX at Facebook to repair 6 production systems, each consisting of tens of millions of lines of code, and which are collectively used by hundreds of millions of people worldwide. In its first three months of operation, SAPFIX produced 55 repair candidates for 57 crashes reported to SAPFIX, of which 27 have been deem as correct by developers and 14 have been landed into production automatically by SAPFIX. SAPFIX has thus demonstrated the potential of the search-based repair research agenda by deploying, to hundreds of millions of users worldwide, software systems that have been automatically tested and repaired. Automated software transplantation (autotransplantation) is a form of automated software engineering, where we use search based software engineering to be able to automatically move a functionality of interest from a ‘donor‘ program that implements it into a ‘host‘ program that lacks it. Autotransplantation is a kind of automated program repair where we repair the ‘host‘ program by augmenting it with the missing functionality. Automated software transplantation would open many exciting avenues for software development: suppose we could autotransplant code from one system into another, entirely unrelated, system, potentially written in a different programming language. Being able to do so might greatly enhance the software engineering practice, while reducing the costs. Automated software transplantation manifests in two different flavors: monolingual, when the languages of the host and donor programs is the same, or multilingual when the languages differ. This thesis introduces a theory of automated software transplantation, and two algorithms implemented in two tools that achieve this: µSCALPEL for monolingual software transplantation and τSCALPEL for multilingual software transplantation. Leveraging lightweight annotation, program analysis identifies an organ (interesting behavior to transplant); testing validates that the organ exhibits the desired behavior during its extraction and after its implantation into a host. We report encouraging results: in 14 of 17 monolingual transplantation experiments involving 6 donors and 4 hosts, popular real-world systems, we successfully autotransplanted 6 new functionalities; and in 10 out of 10 multlingual transplantation experiments involving 10 donors and 10 hosts, popular real-world systems written in 4 different programming languages, we successfully autotransplanted 10 new functionalities. That is, we have passed all the test suites that validates the new functionalities behaviour and the fact that the initial program behaviour is preserved. Additionally, we have manually checked the behaviour exercised by the organ. Autotransplantation is also very useful: in just 26 hours computation time we successfully autotransplanted the H.264 video encoding functionality from the x264 system to the VLC media player, a task that is currently done manually by the developers of VLC, since 12 years ago. We autotransplanted call graph generation and indentation for C programs into Kate, (a popular KDE based test editor used as an IDE by a lot of C developers) two features currently missing from Kate, but requested by the users of Kate. Autotransplantation is also efficient: the total runtime across 15 monolingual transplants is 5 hours and a half; the total runtime across 10 multilingual transplants is 33 hours

Evaluation of interface quality in organ-cultured lamellar corneal transplants

Background: With increasing numbers of lamellar keratoplasties, eye banks are challenged to deliver precut lamellar donor tissue. In Europe, the most common technique of corneal storage is organ culture which requires a deswelling process before surgical processing. The aim of this study was to investigate the influence of different deswelling times on the cutting plane quality after microkeratome-assisted lamellar dissection. Methods: Eight paired donor corneas (16 specimens) not suitable for transplantation were organ cultured under standard conditions at the Eye Bank of the Ludwig-Maximilians Universität, Munich, Germany. Pairs of corneal buttons were analyzed during the deswelling process in dextrane-containing medium. While one cornea was cut at an early time point during the deswelling process and put back into deswelling medium thereafter, the partner cornea was completely deswollen and dissected after 72 hours. Specimens were then further processed for scanning electron microscopy. Surface quality was assessed both digitally using Scanning Probe Imaging Processing software, and manually by three blinded graders. Results: The corneal buttons processed at the beginning of the deswelling process had a smoother surface when compared to the partner cornea that was cut at the end of the deswelling process. In our setting, no relevant difference was detectable between manual and automated microkeratome dissection. Conclusion: For lamellar keratoplasty, organ-cultured corneas should be processed at an early stage during the deswelling process. We interpret the smoother dissection plane during early deswelling as a result of mechanical properties in a highly hydrated cornea

Macrophage polarization impacts tunneling nanotube formation and intercellular organelle trafficking.

Tunneling nanotubes (TNTs) are cellular extensions enabling cytosol-to-cytosol intercellular interaction between numerous cell types including macrophages. Previous studies of hematopoietic stem and progenitor cell (HSPC) transplantation for the lysosomal storage disorder cystinosis have shown that HSPC-derived macrophages form TNTs to deliver cystinosin-bearing lysosomes to cystinotic cells, leading to tissue preservation. Here, we explored if macrophage polarization to either proinflammatory M1-like M(LPS/IFNγ) or anti-inflammatory M2-like M(IL-4/IL-10) affected TNT-like protrusion formation, intercellular transport and, ultimately, the efficacy of cystinosis prevention. We designed new automated image processing algorithms used to demonstrate that LPS/IFNγ polarization decreased bone marrow-derived macrophages (BMDMs) formation of protrusions, some of which displayed characteristics of TNTs, including cytoskeletal structure, 3D morphology and size. In contrast, co-culture of macrophages with cystinotic fibroblasts yielded more frequent and larger protrusions, as well as increased lysosomal and mitochondrial intercellular trafficking to the diseased fibroblasts. Unexpectedly, we observed normal protrusion formation and therapeutic efficacy following disruption of anti-inflammatory IL-4/IL-10 polarization in vivo by transplantation of HSPCs isolated from the Rac2-/- mouse model. Altogether, we developed unbiased image quantification systems that probe mechanistic aspects of TNT formation and function in vitro, while HSPC transplantation into cystinotic mice provides a complex in vivo disease model. While the differences between polarization cell culture and mouse models exemplify the oversimplicity of in vitro cytokine treatment, they simultaneously demonstrate the utility of our co-culture model which recapitulates the in vivo phenomenon of diseased cystinotic cells stimulating thicker TNT formation and intercellular trafficking from macrophages. Ultimately, we can use both approaches to expand the utility of TNT-like protrusions as a delivery system for regenerative medicine

The residual STL volume as a metric to evaluate accuracy and reproducibility of anatomic models for 3D printing: application in the validation of 3D-printable models of maxillofacial bone from reduced radiation dose CT images.

BackgroundThe effects of reduced radiation dose CT for the generation of maxillofacial bone STL models for 3D printing is currently unknown. Images of two full-face transplantation patients scanned with non-contrast 320-detector row CT were reconstructed at fractions of the acquisition radiation dose using noise simulation software and both filtered back-projection (FBP) and Adaptive Iterative Dose Reduction 3D (AIDR3D). The maxillofacial bone STL model segmented with thresholding from AIDR3D images at 100 % dose was considered the reference. For all other dose/reconstruction method combinations, a "residual STL volume" was calculated as the topologic subtraction of the STL model derived from that dataset from the reference and correlated to radiation dose.ResultsThe residual volume decreased with increasing radiation dose and was lower for AIDR3D compared to FBP reconstructions at all doses. As a fraction of the reference STL volume, the residual volume decreased from 2.9 % (20 % dose) to 1.4 % (50 % dose) in patient 1, and from 4.1 % to 1.9 %, respectively in patient 2 for AIDR3D reconstructions. For FBP reconstructions it decreased from 3.3 % (20 % dose) to 1.0 % (100 % dose) in patient 1, and from 5.5 % to 1.6 %, respectively in patient 2. Its morphology resembled a thin shell on the osseous surface with average thickness <0.1 mm.ConclusionThe residual volume, a topological difference metric of STL models of tissue depicted in DICOM images supports that reduction of CT dose by up to 80 % of the clinical acquisition in conjunction with iterative reconstruction yields maxillofacial bone models accurate for 3D printing

Single injection dual phase CBCT technique ameliorates results of trans-arterial chemoembolization for hepatocellular cancer

Cone-beam CT (CBCT) application to the field of trans-arterial chemoembolization has been recently the focus of several researches. This imaging modality is performed with a rotation of the C-arm around the patient, without needs of patient repositioning. Datasets are immediately processed, obtaining volumetric CT-like images with the possibility of post-processing and reconstruction of images. Dual phase CBCT recently introduced in clinical practice consists in a first arterial acquisition followed by a delayed acquisition corresponding to a venous phase. The introduction of this feature has overcome the limit of single-phase acquisitions, allowing lesions characterization. Moreover these recent advantages have several intra-procedural implications. Detailed technical and acquisition parameters will be widely exposed in this review with particular attention to: catheter positioning, acquisition delay, injection parameters, patient positioning and contrast dilution. Comparison with standard of practice second line imaging [multidetector computer tomography (MDCT) and MDCT/arteriography] demonstrate the capability of detecting occult nodules providing some clinical implications thus potentially identifying a sub set of patients with aggressive disease behaviour. Other intra-procedural advantages of dual phase CBCT usage consist in a better tumor feeder visualization, reduction of proper DSA and fluoroscopic time, suggestion the presence of an extrahepatic parasitic feeder thus resulting in a more accurate treatment. Finally, the volumetrical intraprocedural evaluation of accumulation of embolic agent has proved to be correlate with treatment response if compared with MRI

Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy.

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates ≥98% of peripheral immune cells with ≥4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

Effect of a reduction in glomerular filtration rate after nephrectomy on arterial stiffness and central hemodynamics: rationale and design of the EARNEST study

Background: There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group.<p></p> Hypotheses: The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure.<p></p> Methods: This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease.<p></p> Conclusions: These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program.<p></p&gt