Joint Segmentation and Uncertainty Visualization of Retinal Layers in Optical Coherence Tomography Images using Bayesian Deep Learning

Optical coherence tomography (OCT) is commonly used to analyze retinal layers for assessment of ocular diseases. In this paper, we propose a method for retinal layer segmentation and quantification of uncertainty based on Bayesian deep learning. Our method not only performs end-to-end segmentation of retinal layers, but also gives the pixel wise uncertainty measure of the segmentation output. The generated uncertainty map can be used to identify erroneously segmented image regions which is useful in downstream analysis. We have validated our method on a dataset of 1487 images obtained from 15 subjects (OCT volumes) and compared it against the state-of-the-art segmentation algorithms that does not take uncertainty into account. The proposed uncertainty based segmentation method results in comparable or improved performance, and most importantly is more robust against noise

Daratumumab With Cetrelimab, an Anti-PD-1 Monoclonal Antibody, in Relapsed/Refractory Multiple Myeloma

Patients with relapsed or refractory multiple myeloma have an immunosuppressive state with upregulation of programmed death receptor-1 on immune effector cells. Treatment with daratumumab plus cetrelimab, which targets the programmed death receptor-1, was evaluated in 9 patients with relapsed or refractory multiple myeloma. No new safety concerns were identified for the combination. The potential clinical benefit of daratumumab plus cetrelimab remains uncertain. Background: Daratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM. Patients and Methods: This open-label, multiphase study enrolled adults with RRMM with >= 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses. Results: Nine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee's global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had >= 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had > 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%. Conclusions: No new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination. (C) 2020 The Author(s). Published by Elsevier Inc

Treatment of Infected Hip Arthroplasty

The clinical outcomes of a consecutive series of deep total joint infections treated with a prosthesis retaining protocol were reviewed. The treatment of deep periprosthetic joint infections is challenging. In recent years, two-stage exchange arthroplasty has emerged as the gold standard for successful elimination of infection. With success rates averaging 82% to 96%, this treatment method has both the highest and most consistent rate of infection eradication. Another alternative in the treatment of the deep periprosthetic infection is the single-stage exchange arthroplasty. Successful eradication of infection after single-stage exchange arthroplasty has been reported to average from 60% to 83% after total hip infections. While both the single and two-stage exchange arthroplasty are viable treatment options, they are associated with negative factors such as they are time consuming, expensive, and may entail a 6- to 12-week period with a minimally functioning extremity after prosthesis removal. This paper reports the general principles of management, the treatment of acute infection occurring in the postoperative period or later, and the treatment of chronic infection by exchange arthroplasty or resection arthroplasty

Force Generation upon T Cell Receptor Engagement

T cells are major players of adaptive immune response in mammals. Recognition of an antigenic peptide in association with the major histocompatibility complex at the surface of an antigen presenting cell (APC) is a specific and sensitive process whose mechanism is not fully understood. The potential contribution of mechanical forces in the T cell activation process is increasingly debated, although these forces are scarcely defined and hold only limited experimental evidence. In this work, we have implemented a biomembrane force probe (BFP) setup and a model APC to explore the nature and the characteristics of the mechanical forces potentially generated upon engagement of the T cell receptor (TCR) and/or lymphocyte function-associated antigen-1 (LFA-1). We show that upon contact with a model APC coated with antibodies towards TCR-CD3, after a short latency, the T cell developed a timed sequence of pushing and pulling forces against its target. These processes were defined by their initial constant growth velocity and loading rate (force increase per unit of time). LFA-1 engagement together with TCR-CD3 reduced the growing speed during the pushing phase without triggering the same mechanical behavior when engaged alone. Intracellular Ca2+ concentration ([Ca2+]i) was monitored simultaneously to verify the cell commitment in the activation process. [Ca2+]i increased a few tens of seconds after the beginning of the pushing phase although no strong correlation appeared between the two events. The pushing phase was driven by actin polymerization. Tuning the BFP mechanical properties, we could show that the loading rate during the pulling phase increased with the target stiffness. This indicated that a mechanosensing mechanism is implemented in the early steps of the activation process. We provide here the first quantified description of force generation sequence upon local bidimensional engagement of TCR-CD3 and discuss its potential role in a T cell mechanically-regulated activation process

Tension-Compression Loading with Chemical Stimulation Results in Additive Increases to Functional Properties of Anatomic Meniscal Constructs

Objective: This study aimed to improve the functional properties of anatomically-shaped meniscus constructs through simultaneous tension and compression mechanical stimulation in conjunction with chemical stimulation. Methods: Scaffoldless meniscal constructs were subjected to simultaneous tension and compressive stimulation and chemical stimulation. The temporal aspect of mechanical loadingwas studied by employing two separate five day stimulation periods. Chemical stimulation consisted of the application of a catabolic GAG-depleting enzyme, chondroitinase ABC (C-ABC), and an anabolic growth factor, TGF-b1. Mechanical and chemical stimulation combinations were studied through a full-factorial experimental design and assessed for histological, biochemical, and biomechanical properties following 4 wks of culture. Results: Mechanical loading applied from days 10–14 resulted in significant increases in compressive, tensile, and biochemical properties of meniscal constructs. When mechanical and chemical stimuliwere combined significant additive increases in collagen per wet weight (4-fold), compressive instantaneous (3-fold) and relaxation (2-fold) moduli, and tensile moduli in the circumferential (4-fold) and radial (6-fold) directions were obtained. Conclusions: This study demonstrates that a stimulation regimen of simultaneous tension and compression mechanical stimulation, C-ABC, and TGF-b1 is able to create anatomic meniscus constructs replicating the compressive mechanica

Mechanics rules cell biology

Cells in the musculoskeletal system are subjected to various mechanical forces in vivo. Years of research have shown that these mechanical forces, including tension and compression, greatly influence various cellular functions such as gene expression, cell proliferation and differentiation, and secretion of matrix proteins. Cells also use mechanotransduction mechanisms to convert mechanical signals into a cascade of cellular and molecular events. This mini-review provides an overview of cell mechanobiology to highlight the notion that mechanics, mainly in the form of mechanical forces, dictates cell behaviors in terms of both cellular mechanobiological responses and mechanotransduction

Novel strategies in tendon and ligament tissue engineering: Advanced biomaterials and regeneration motifs

Tendon and ligaments have poor healing capacity and when injured often require surgical intervention. Tissue replacement via autografts and allografts are non-ideal strategies that can lead to future problems. As an alternative, scaffold-based tissue engineering strategies are being pursued. In this review, we describe design considerations and major recent advancements of scaffolds for tendon/ligament engineering. Specifically, we outline native tendon/ligament characteristics critical for design parameters and outcome measures, and introduce synthetic and naturally-derived biomaterials used in tendon/ligament scaffolds. We will describe applications of these biomaterials in advanced tendon/ligament engineering strategies including the utility of scaffold functionalization, cyclic strain, growth factors, and interface considerations. The goal of this review is to compile and interpret the important findings of recent tendon/ligament engineering research in an effort towards the advancement of regenerative strategies

TILLING - a shortcut in functional genomics

Recent advances in large-scale genome sequencing projects have opened up new possibilities for the application of conventional mutation techniques in not only forward but also reverse genetics strategies. TILLING (Targeting Induced Local Lesions IN Genomes) was developed a decade ago as an alternative to insertional mutagenesis. It takes advantage of classical mutagenesis, sequence availability and high-throughput screening for nucleotide polymorphisms in a targeted sequence. The main advantage of TILLING as a reverse genetics strategy is that it can be applied to any species, regardless of its genome size and ploidy level. The TILLING protocol provides a high frequency of point mutations distributed randomly in the genome. The great mutagenic potential of chemical agents to generate a high rate of nucleotide substitutions has been proven by the high density of mutations reported for TILLING populations in various plant species. For most of them, the analysis of several genes revealed 1 mutation/200–500 kb screened and much higher densities were observed for polyploid species, such as wheat. High-throughput TILLING permits the rapid and low-cost discovery of new alleles that are induced in plants. Several research centres have established a TILLING public service for various plant species. The recent trends in TILLING procedures rely on the diversification of bioinformatic tools, new methods of mutation detection, including mismatch-specific and sensitive endonucleases, but also various alternatives for LI-COR screening and single nucleotide polymorphism (SNP) discovery using next-generation sequencing technologies. The TILLING strategy has found numerous applications in functional genomics. Additionally, wide applications of this throughput method in basic and applied research have already been implemented through modifications of the original TILLING strategy, such as Ecotilling or Deletion TILLING

Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption

To prevent dehydration, terrestrial animals and humans have developed a sensitive and versatile system to maintain their water homeostasis. In states of hypernatremia or hypovolemia, the antidiuretic hormone vasopressin (AVP) is released from the pituitary and binds its type-2 receptor in renal principal cells. This triggers an intracellular cAMP signaling cascade, which phosphorylates aquaporin-2 (AQP2) and targets the channel to the apical plasma membrane. Driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels. When water homeostasis is restored, AVP levels decline, and AQP2 is internalized from the plasma membrane, leaving the plasma membrane watertight again. The action of AVP is counterbalanced by several hormones like prostaglandin E2, bradykinin, dopamine, endothelin-1, acetylcholine, epidermal growth factor, and purines. Moreover, AQP2 is strongly involved in the pathophysiology of disorders characterized by renal concentrating defects, as well as conditions associated with severe water retention. This review focuses on our recent increase in understanding of the molecular mechanisms underlying AVP-regulated renal water transport in both health and disease