viSNE and Wanderlust, two algorithms for the visualization and analysis of high-dimensional single-cell data

The immune system presents a unique opportunity for studying development in mammals. White blood cells undergo differentiation and proliferation, a never-ending process throughout the life of the organism. Hematopoiesis, the development of cells in the immune system, depends upon the interaction between many different cell types (some of which comprise less than a tenth of a percent of the population), transient regulatory decisions, genomic rearrangement events, cell proliferation, and death. To capture these events we employ mass cytometry, a novel technology that measures fifty proteins simultaneously in single cells. Mass cytometry results in large quantities of high-dimensional data which challenges existing computational techniques. To address these challenges, we developed two dimensionality reduction algorithms for analyzing mass cytometry and other single-cell data. The first, viSNE, transforms high-dimensional data into an intuitive two-dimensional map, making it accessible to visual exploration. The second algorithm, Wanderlust, receives as input a static snapshot (where cells occupy different stages of their development) and constructs their developmental ordering: the developmental trajectory. viSNE maps healthy bone marrow into a canonical shape that separates cell subtypes. In leukemia, however, the shape is malformed: the maps of cancer samples are distinct from the healthy map and from each other. The algorithm highlights structure in the heterogeneity of surface phenotype expression in cancer, traverses the progression from diagnosis to relapse, and identifies a rare leukemia population in minimal residual disease settings. Wanderlust was applied to healthy B lineage cells, where the trajectory follows known marker expression trends and genetic recombination events. Using the Wanderlust trajectory we identified CD24 as an early marker of B cell development. The trajectory captures the coordination between several regulatory mechanisms (surface marker expression, signaling, proliferation and apoptosis) during crucial development checkpoints. As new technologies raise the number of simultaneously measured parameters in each cell to the hundreds, viSNE and Wanderlust will become a mainstay in analyzing and interpreting such experiments

The Realm of Oncological Lung Surgery: From Past to Present and Future Perspectives

In this chapter, a historical overview as well as an overview of state of the art of the surgical techniques for the treatment of lung cancer is outlined. The chapter focuses on the introduction of open surgery, video-assisted thoracic surgery (VATS), uniportal VATS (UVATS), and robotic-assisted thoracic surgery (RATS) techniques for lung resections. A short introduction on upcoming techniques and modalities is given. The currently available tools as three-dimensional (3D) computed tomography (CT), virtual reality, and endo-bronchial surgery will be discussed. Based on the current development, this chapter attempts to delineate the horizon of oncological lung surgery. The information is generated not only from the available literature, but also from the experiences of surgeons and other physicians as well as co-workers involved in lung cancer treatment around the world. This chapter can be seen as a general introduction to several aspects of oncological lung surgery

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

Preparing for the future of cardiothoracic surgery with virtual reality simulation and surgical planning:a narrative review

Background and Objective: Virtual reality (VR) technology in cardiothoracic surgery has been an area of interest for almost three decades, but computational limitations had restricted its implementation. Recent advances in computing power have facilitated the creation of high-fidelity VR simulations and anatomy visualisation tools. We undertook a non-systematic narrative review of literature on VR simulations and preoperative planning tools in cardiothoracic surgery and present the state-of-the-art, and a future outlook. Methods: A comprehensive search through MEDLINE database was performed in November 2022 for all publications that describe the use of VR in cardiothoracic surgery regarding training purposes, education, simulation, and procedural planning. We excluded papers that were not in English or Dutch, and that used two-dimensional (2D) screens, augmented, and simulated reality. Key Content and Findings: Results were categorised as simulators and preoperative planning tools. Current surgical simulators include the lobectomy module in the LapSim for video assisted thorascopic surgery which has been extensively validated, and the more recent robotic assisted lobectomy simulators from Robotix Mentor and Da Vinci SimNow, which are increasingly becoming integrated into the robotic surgery curriculum. Other perioperative simulators include the CardioPulmonary VR Resuscitation simulator for advanced life support after cardiac surgery, and the VR Extracorporeal Circulation (ECC) simulator for perfusionists to simulate the use of a heart-lung machine (HLM). For surgical planning, there are many small-scale tools available, and many case/pilot studies have been published utilising the visualisation possibilities provided by VR, including congenital cardiac, congenital thoracic, adult cardiac, and adult thoracic diseases. Conclusions: There are many promising tools becoming available to leverage the immersive power of VR in cardiothoracic surgery. The path to validate these simulators is well described, but large-scale trials producing high-level evidence for their efficacy are absent as of yet. Our view is that these tools will become increasingly integral parts of daily practice in this field in the coming decade.</p

Comment on: "Estimating the Hartree-Fock limit from finite basis set calculations" [Jensen F (2005) Theor Chem Acc 113:267]

We demonstrate that a minor modification of the extrapolation proposed by Jensen [(2005): Theor Chem Acc 113:267] yields very reliable estimates of the Hartree-Fock limit in conjunction with correlation consistent basis sets. Specifically, a two-point extrapolation of the form $E_{HF,L}=E_{HF,\infty}+A(L+1)\exp(-9\sqrt{L})$ yields HF limits $E_{HF,\infty}$ with an RMS error of 0.1 millihartree using aug-cc-pVQZ and aug-cc-pV5Z basis sets, and of 0.01 millihartree using aug-cc-pV5Z and aug-cc-pV6Z basis sets.Comment: Theoretical Chemistry Accounts, in pres

An unusual case of redo tricuspid valve replacement and repair of a previously unidentified anomalous pulmonary venous return in a patient with congenitally corrected transposition of the great arteries

Associated cardiovascular malformations in congenitally corrected transposition of the great arteries (CCTGA) should not be missed when a patient requires surgical correction. We present a case of an adult CCTGA patient who required redo surgery for recurrent tricuspid (left atrioventricular) valve regurgitation and previously unidentified partial anomalous pulmonary venous return

GPs' decision-making when prescribing medicines for breastfeeding women: Content analysis of a survey

<p>Abstract</p> <p>Background</p> <p>Many breastfeeding women seek medical care from general practitioners (GPs) for various health problems and GPs may consider prescribing medicines in these consultations. Prescribing medicines to a breastfeeding mother may lead to untimely cessation of breastfeeding or a breastfeeding mother may be denied medicines due to the possible risk to her infant, both of which may lead to unwanted consequences. Information on factors governing GPs' decision-making and their views in such situations is limited.</p> <p>Methods</p> <p>GPs providing shared maternity care at the Royal Women's Hospital, Melbourne were surveyed using an anonymous postal survey to determine their knowledge, attitudes and practices on medicines and breastfeeding, in 2007/2008 (n = 640). Content analysis of their response to a question concerning decision-making about the use of medicine for a breastfeeding woman was conducted. A thematic network was constructed with basic, organising and global themes.</p> <p>Results</p> <p>335 (52%) GPs responded to the survey, and 253 (76%) provided information on the last time they had to decide about the use of medicine for a breastfeeding woman. Conditions reported were mastitis (24%), other infections (24%) and depressive disorders (21%). The global theme that emerged was "<it>complexity of managing risk in prescribing for breastfeeding women"</it>. The organising themes were: <it>certainty around decision-making; uncertainty around decision-making; need for drug information to be available, consistent and reliable; joint decision-making; the vulnerable "third party" </it>and <it>infant feeding decision</it>. Decision-making is a spectrum from a straight forward decision, such as treatment of mastitis, to a complicated one requiring multiple inputs and consideration. GPs use more information seeking and collaboration in decision-making when they perceive the problem to be more complex, for example, in postnatal depression.</p> <p>Conclusion</p> <p>GPs feel that prescribing medicines for breastfeeding women is a contentious issue. They manage the risk of prescribing by gathering information and assessing the possible effects on the breastfed infant. Without evidence-based information, they sometimes recommend cessation of breastfeeding unnecessarily.</p

Optimized Preoperative Planning of Double Outlet Right Ventricle Patients by 3D Printing and Virtual Reality:A Pilot Study

OBJECTIVES: In complex double outlet right ventricle (DORV) patients, the optimal surgical approach may be difficult to assess based on conventional two-dimensional (2D) ultrasound (US) and computed tomography (CT) imaging. The aim of this study is to assess the added value of 3D printed and 3D Virtual Reality (VR) models of the heart used for surgical planning in DORV patients, supplementary to the gold standard 2D imaging modalities.METHODS: Five patients with different DORV-subtypes and high-quality CT scans were selected retrospectively. 3D prints and 3D-VR models were created. Twelve congenital cardiac surgeons and paediatric cardiologists, from three different hospitals, were shown 2D-CT first, after which they assessed the 3D print and 3D-VR models in random order. After each imaging method, a questionnaire was filled in on the visibility of essential structures and the surgical plan.RESULTS: Spatial relationships were generally better visualized using 3D methods (3D printing/3D-VR) than in 2D. The feasibility of VSD patch closure could be determined best using 3D-VR reconstructions (3D-VR 92%, 3D print 66%, and US/CT 46%, P &lt; 0.01). The percentage of proposed surgical plans corresponding to the performed surgical approach was 66% for plans based on US/CT, 78% for plans based on 3D printing, and 80% for plans based on 3D-VR visualization.CONCLUSIONS: This study shows that both 3D printing and 3D-VR have additional value for cardiac surgeons and cardiologists over 2D imaging, because of better visualization of spatial relationships. As a result, the proposed surgical plans based on the 3D visualizations matched the actual performed surgery to a greater extent.</p

Characteristics associated with quality of life among people with drug-resistant epilepsy

Quality of Life (QoL) is the preferred outcome in non-pharmacological trials, but there is little UK population evidence of QoL in epilepsy. In advance of evaluating an epilepsy self-management course we aimed to describe, among UK participants, what clinical and psycho-social characteristics are associated with QoL. We recruited 404 adults attending specialist clinics, with at least two seizures in the prior year and measured their self-reported seizure frequency, co-morbidity, psychological distress, social characteristics, including self-mastery and stigma, and epilepsy-specific QoL (QOLIE-31-P). Mean age was 42 years, 54% were female, and 75% white. Median time since diagnosis was 18 years, and 69% experienced ≥10 seizures in the prior year. Nearly half (46%) reported additional medical or psychiatric conditions, 54% reported current anxiety and 28% reported current depression symptoms at borderline or case level, with 63% reporting felt stigma. While a maximum QOLIE-31-P score is 100, participants’ mean score was 66, with a wide range (25–99). In order of large to small magnitude: depression, low self-mastery, anxiety, felt stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency were associated with low QOLIE-31-P scores. Despite specialist care, UK people with epilepsy and persistent seizures experience low QoL. If QoL is the main outcome in epilepsy trials, developing and evaluating ways to reduce psychological and social disadvantage are likely to be of primary importance. Educational courses may not change QoL, but be one component supporting self-management for people with long-term conditions, like epilepsy

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 &gt;= 98% of peripheral immune cells with &gt;= 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