Development and validation of a deep learning system for detection of small bowel pathologies in capsule endoscopy: a pilot study in a Singapore institution.

INTRODUCTION: Deep learning models can assess the quality of images and discriminate among abnormalities in small bowel capsule endoscopy (CE), reducing fatigue and the time needed for diagnosis. They serve as a decision support system, partially automating the diagnosis process by providing probability predictions for abnormalities. METHODS: We demonstrated the use of deep learning models in CE image analysis, specifically by piloting a bowel preparation model (BPM) and an abnormality detection model (ADM) to determine frame-level view quality and the presence of abnormal findings, respectively. We used convolutional neural network-based models pretrained on large-scale open-domain data to extract spatial features of CE images that were then used in a dense feed-forward neural network classifier. We then combined the open-source Kvasir-Capsule dataset (n = 43) and locally collected CE data (n = 29). RESULTS: Model performance was compared using averaged five-fold and two-fold cross-validation for BPMs and ADMs, respectively. The best BPM model based on a pre-trained ResNet50 architecture had an area under the receiver operating characteristic and precision-recall curves of 0.969±0.008 and 0.843±0.041, respectively. The best ADM model, also based on ResNet50, had top-1 and top-2 accuracies of 84.03±0.051 and 94.78±0.028, respectively. The models could process approximately 200-250 images per second and showed good discrimination on time-critical abnormalities such as bleeding. CONCLUSION: Our pilot models showed the potential to improve time to diagnosis in CE workflows. To our knowledge, our approach is unique to the Singapore context. The value of our work can be further evaluated in a pragmatic manner that is sensitive to existing clinician workflow and resource constraints.

Cronkhite-Canada Syndrome Masquerading as Inflammatory Bowel Disease.

Cronkhite-Canada syndrome (CCS) is a rare nonhereditary gastrointestinal polyposis syndrome. We illustrate a case with clinical presentation of dysgeusia, chronic diarrhea and weight loss, and endoscopic features of diffuse gastric mucosa nodularity with circumferential nodular pancolitis and a solitary colonic polyp initially mimicking inflammatory bowel disease. After multidisciplinary discussion, the diagnosis of CCS was made. The patient received steroids with resultant clinical, endoscopic, and histological improvement. We discuss the treatment and risk of neoplasia in CCS.

Quantitative Determination of Ethylene Using a Smartphone-Based Optical Fiber Sensor (SOFS) Coupled with Pyrene-Tagged Grubbs Catalyst.

For rapid and portable detection of ethylene in commercial fruit ripening storage rooms, we designed a smartphone-based optical fiber sensor (SOFS), which is composed of a 15 mW 365 nm laser for fluorescence signal excitation and a bifurcated fiber system for signal flow direction from probe to smartphone. Paired with a pyrene-tagged Grubbs catalyst (PYG) probe, our SOFS showed a wide linearity range up to 350 ppm with a detection limit of 0.6 ppm. The common gases in the warehouse had no significant interference with the results. The device is portable (18 cm × 8 cm × 6 cm) with an inbuilt power supply and replaceable optical fiber sensor tip. The images are processed with a dedicated smartphone application for RGB analysis and ethylene concentration. The device was applied in detection of ethylene generated from apples, avocados, and bananas. The linear correlation data showed agreement with data generated from a fluorometer. The SOFS provides a rapid, compact, cost-effective solution for determination of the fruit ethylene concentration dynamic during ripening for better fruit harvest timing and postharvest management to minimize wastage.

Development of the Revision Hip Complexity Classification using a modified Delphi technique.

AIMS: The aim of this modified Delphi process was to create a structured Revision Hip Complexity Classification (RHCC) which can be used as a tool to help direct multidisciplinary team (MDT) discussions of complex cases in local or regional revision networks. METHODS: The RHCC was developed with the help of a steering group and an invitation through the British Hip Society (BHS) to members to apply, forming an expert panel of 35. We ran a mixed-method modified Delphi process (three rounds of questionnaires and one virtual meeting). Round 1 consisted of identifying the factors that govern the decision-making and complexities, with weighting given to factors considered most important by experts. Participants were asked to identify classification systems where relevant. Rounds 2 and 3 focused on grouping each factor into H1, H2, or H3, creating a hierarchy of complexity. This was followed by a virtual meeting in an attempt to achieve consensus on the factors which had not achieved consensus in preceding rounds. RESULTS: The expert group achieved strong consensus in 32 out of 36 factors following the Delphi process. The RHCC used the existing Paprosky (acetabulum and femur), Unified Classification System, and American Society of Anesthesiologists (ASA) classification systems. Patients with ASA grade III/IV are recognized with a qualifier of an asterisk added to the final classification. The classification has good intraobserver and interobserver reliability with Kappa values of 0.88 to 0.92 and 0.77 to 0.85, respectively. CONCLUSION: The RHCC has been developed through a modified Delphi technique. RHCC will provide a framework to allow discussion of complex cases as part of a local or regional hip revision MDT. We believe that adoption of the RHCC will provide a comprehensive and reproducible method to describe each patient's case with regard to surgical complexity, in addition to medical comorbidities that may influence their management. Cite this article: Bone Jt Open 2022;3(5):423-431.

Hip Hemiarthroplasty: The Misnomer of a Narrow Femoral Canal and the Cost Implications.

Objective Hemiarthroplasty has been identified as the treatment of choice for displaced intracapsular femoral neck fractures. A modular prosthesis is sometimes preferred for its sizing options in narrow femoral canals, despite its higher cost and no advantage in clinical outcomes. Thus, in this study, we investigated the factors affecting surgeons' choice of prosthesis, hypothesizing that modular hemiarthroplasty is overused for narrow femoral canals compared to monoblock hip hemiarthroplasty. Methods A retrospective study of a regional level 1 trauma center was conducted. Patients who had sustained femoral neck fractures from March 2013 to December 2016 were included in this study. Inclusion criterion was modular hemiarthroplasty for a narrow femoral canal. A matched group of patients who underwent monobloc hemiarthroplasty (MH) was created through randomization. The main outcome measurements were sex, age, Dorr classification, and femoral head size. We measured the protrusion of the greater trochanter beyond the level of the lateral femoral cortex postoperatively. Modular hemiarthroplasty patients were templated on radiographs using TraumaCad for Stryker Exeter Trauma Stem (ETS®). Results In total, 533 hemiarthroplasty procedures were performed, of which 27 were modular for a narrow femoral canal. The ratio of modular to monobloc was 1:18. Average head size was 46.7 mm ± 3.6 mm for monobloc and 44.07 ± 1.5 for modular (P= 0.001). There were four malaligned stems in the monobloc group versus 14 in the modular group (P= 0.008). Unsatisfactory lateralization was noted in 18 patients (7 mm ± 2.9 mm) in the modular group compared with 8 (4.7 mm ± 3.9 mm) in the monobloc group (P= 0.029). Dorr classification was A or B in 24 patients in the modular group and 18 in the monobloc group (P = 0.006). Templating revealed that modular was not required in 25 patients. Conclusions As per our findings, it was determined that patients with a narrow femoral canal intraoperatively should not receive modular hemiarthroplasty. This is especially true for female patients with small femoral head and narrow femoral canal dimensions (Dorr A and B). They would require extensive careful planning. Surgical techniques should be explored through education intraoperatively to achieve lateralization during femoral stem preparation. This may avoid prolonged anesthetic time and achieve potential cost savings.

Functional outcomes & metal ion levels following ceramic on metal total hip arthroplasty: 9 Year follow-up.

In this study, we evaluate the mid-term functional and radiological outcomes of Ceramic on Metal Total Hip Arthroplasty (CoM THA) THA. 66 CoM THAs were performed between 2008 and 2010. These were evaluated and followed up in 2017-18, at a mean follow-up of 9 years to record the Oxford Hip Score [OHS] and whole blood Cobalt and Chrome levels. Our all cause revision rate was 4.5% (3 out of 66). At mid-term follow up, patients with CoM THAs are mostly asymptomatic with reasonable functional outcomes, we have reported similar revision rates in conjunction with raised blood metal ion levels and frequency of radiolucent lines.

Curation of over 10 000 transcriptomic studies to enable data reuse.

Vast amounts of transcriptomic data reside in public repositories, but effective reuse remains challenging. Issues include unstructured dataset metadata, inconsistent data processing and quality control, and inconsistent probe-gene mappings across microarray technologies. Thus, extensive curation and data reprocessing are necessary prior to any reuse. The Gemma bioinformatics system was created to help address these issues. Gemma consists of a database of curated transcriptomic datasets, analytical software, a web interface and web services. Here we present an update on Gemma's holdings, data processing and analysis pipelines, our curation guidelines, and software features. As of June 2020, Gemma contains 10 811 manually curated datasets (primarily human, mouse and rat), over 395 000 samples and hundreds of curated transcriptomic platforms (both microarray and RNA sequencing). Dataset topics were represented with 10 215 distinct terms from 12 ontologies, for a total of 54 316 topic annotations (mean topics/dataset = 5.2). While Gemma has broad coverage of conditions and tissues, it captures a large majority of available brain-related datasets, accounting for 34% of its holdings. Users can access the curated data and differential expression analyses through the Gemma website, RESTful service and an R package. Database URL: https://gemma.msl.ubc.ca/home.html.

Is the use of antibiotic-loaded bone cement associated with a lower risk of revision after primary total hip arthroplasty?

AIMS: The aim of this study was to investigate whether the use of antibiotic-loaded bone cement influenced the risk of revision surgery after primary total hip arthroplasty (THA) for osteoarthritis. METHODS: The study involved data collected by the National Joint Registry (NJR) for England and Wales, Northern Ireland and the Isle of Man between 1 September 2005 and 31 August 2017. Cox proportional hazards were used to investigate the association between use of antibiotic-loaded bone cement and the risk of revision due to prosthetic joint infection (PJI), with adjustments made for the year of the initial procedure, age at the time of surgery, sex, American Society of Anesthesiologists (ASA) grade, head size, and body mass index (BMI). We looked also at the association between use of antibiotic-loaded bone cement and the risk of revision due to aseptic loosening or osteolysis. RESULTS: The cohort included 418,857 THAs of whom 397,896 had received antibiotic-loaded bone cement and 20,961 plain cement. After adjusting for putative confounding factors, the risk of revision for PJI was lower in those in whom antibiotic-loaded bone cement was used (hazard ration (HR) 0.79; 95% confidence interval (CI) 0.64 to 0.98). There was also a protective effect on the risk of revision due to aseptic loosening or osteolysis, in the period of > 4.1 years after primary THA, HR 0.57, 95% CI 0.45, 0.72. CONCLUSION: Within the limits of registry analysis, this study showed an association between the use of antibiotic-loaded bone cement and lower rates of revision due to PJI. The findings support the continued use of antibiotic-loaded bone cement in cemented THA. Cite this article: Bone Joint J 2020;102-B(8):997-1002.

The outcomes of Perthes' disease.

AIMS: To identify a suite of the key physical, emotional, and social outcomes to be employed in clinical practice and research concerning Perthes' disease in children. METHODS: The study follows the guidelines of the COMET-Initiative (Core Outcome Measures in Effectiveness Trials). A systematic review of the literature was performed to identify a list of outcomes reported in previous studies, which was supplemented by a qualitative study exploring the experiences of families affected by Perthes' disease. Collectively, these outcomes formed the basis of a Delphi survey (two rounds), where 18 patients with Perthes' disease, 46 parents, and 36 orthopaedic surgeons rated each outcome for importance. The International Perthes Study Group (IPSG) (Dallas, Texas, USA (October 2018)) discussed outcomes that failed to reach any consensus (either 'in' or 'out') before a final consensus meeting with representatives of surgeons, patients, and parents. RESULTS: In total, 23 different outcome domains were identified from the systematic review, and a further ten from qualitative interviews. After round one of the Delphi survey, participants suggested five further outcome domains. A total of 38 outcomes were scored in round two of the Delphi. Among these, 16 outcomes were scored over the prespecified 70% threshold for importance (divided into six main categories: adverse events; life impact; resource use; pathophysiological manifestations; death; and technical considerations). Following the final consensus meeting, 14 outcomes were included in the final Core Outcome Set (COS). CONCLUSION: Core Outcome Sets (COSs) are important to improve standardization of outcomes in clinical research and to aid communication between patients, clinicians, and funding bodies. The results of this study should be a catalyst to develop high-quality clinical research in order to determine the optimal treatments for children with Perthes' disease. Cite this article: Bone Joint J 2020;102-B(5):611-617.

Magnitude of Therapeutic STING Activation Determines CD8+ T Cell-Mediated Anti-tumor Immunity.

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.

STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium tuberculosis Infection.

There are a limited number of adjuvants that elicit effective cell-based immunity required for protection against intracellular bacterial pathogens. Here, we report that STING-activating cyclic dinucleotides (CDNs) formulated in a protein subunit vaccine elicit long-lasting protective immunity to Mycobacterium tuberculosis in the mouse model. Subcutaneous administration of this vaccine provides equivalent protection to that of the live attenuated vaccine strain Bacille Calmette-Guérin (BCG). Protection is STING dependent but type I IFN independent and correlates with an increased frequency of a recently described subset of CXCR3-expressing T cells that localize to the lung parenchyma. Intranasal delivery results in superior protection compared with BCG, significantly boosts BCG-based immunity, and elicits both Th1 and Th17 immune responses, the latter of which correlates with enhanced protection. Thus, a CDN-adjuvanted protein subunit vaccine has the capability of eliciting a multi-faceted immune response that results in protection from infection by an intracellular pathogen.

Interactive Exploration, Analysis, and Visualization of Complex Phenome-Genome Datasets with ASPIREdb.

Identifying variants causal for complex genetic disorders is challenging. With the advent of whole-exome and whole-genome sequencing, computational tools are needed to explore and analyze the list of variants for further validation. Correlating genetic variants with subject phenotype is crucial for the interpretation of the disease-causing mutations. Often such work is done by teams of researchers who need to share information and coordinate activities. To this end, we have developed a powerful, easy to use Web application, ASPIREdb, which allows researchers to search, organize, analyze, and visualize variants and phenotypes associated with a set of human subjects. Investigators can annotate variants using publicly available reference databases and build powerful queries to identify subjects or variants of interest. Functional information and phenotypic associations of these genes are made accessible as well. Burden analysis and additional reporting tools allow investigation of variant properties and phenotype characteristics. Projects can be shared, allowing researchers to work collaboratively to build queries and annotate the data. We demonstrate ASPIREdb's functionality using publicly available data sets, showing how the software can be used to accomplish goals that might otherwise require specialized bioinformatics expertise. ASPIREdb is available at http://aspiredb.chibi.ubc.ca.

Wikidata as a semantic framework for the Gene Wiki initiative.

Open biological data are distributed over many resources making them challenging to integrate, to update and to disseminate quickly. Wikidata is a growing, open community database which can serve this purpose and also provides tight integration with Wikipedia. In order to improve the state of biological data, facilitate data management and dissemination, we imported all human and mouse genes, and all human and mouse proteins into Wikidata. In total, 59,721 human genes and 73,355 mouse genes have been imported from NCBI and 27,306 human proteins and 16,728 mouse proteins have been imported from the Swissprot subset of UniProt. As Wikidata is open and can be edited by anybody, our corpus of imported data serves as the starting point for integration of further data by scientists, the Wikidata community and citizen scientists alike. The first use case for these data is to populate Wikipedia Gene Wiki infoboxes directly from Wikidata with the data integrated above. This enables immediate updates of the Gene Wiki infoboxes as soon as the data in Wikidata are modified. Although Gene Wiki pages are currently only on the English language version of Wikipedia, the multilingual nature of Wikidata allows for usage of the data we imported in all 280 different language Wikipedias. Apart from the Gene Wiki infobox use case, a SPARQL endpoint and exporting functionality to several standard formats (e.g. JSON, XML) enable use of the data by scientists. In summary, we created a fully open and extensible data resource for human and mouse molecular biology and biochemistry data. This resource enriches all the Wikipedias with structured information and serves as a new linking hub for the biological semantic web. Database URL: https://www.wikidata.org/.

Stereochemical Outcomes in Reductive Cyclizations To Form Spirocyclic Heterocycles.

Reductive lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product.

Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity.

Spontaneous tumor-initiated T cell priming is dependent on IFN-ß production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-ß expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.

STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade.

Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.