Reference standards for stress radiography measurements in knee ligament injury and instability: a systematic review.

PURPOSE: Stress radiographs are an easily accessible, cost-effective tool in the evaluation of acute and chronic ligament knee injuries. Stress radiographs provide an objective, quantifiable, and functional assessment of the injured ligament and can be a useful adjunct when planning surgical management and to objectively assess postoperative outcomes. This study aimed to review the literature reporting on stress radiographic techniques in evaluating knee ligament injury and instability and propose thresholds for interpreting stress radiography techniques. METHODS: The following three databases, OVID MEDLINE, the EMBASE library, and the Cochrane Controlled Trials Register, were systematically searched on January 23, 2023, for studies published from January 1970 to January 2023. The search extended to the reference lists of all relevant studies and orthopedic journals. Included studies were those that described a stress technique for the diagnosis of knee ligament injury; studies that reported a description or comparison of the accuracy and/or reliability of one or several stress radiography techniques, or studies that reported a comparison with alternative diagnostic modalities. RESULTS: Sixteen stress radiography techniques were reported for assessing the ACL with stress applied in the anterior plane, 10 techniques for assessing the PCL with stress applied in the posterior plane, 3 techniques for valgus stress, and 4 techniques for varus stress. The Telos device was the most commonly used stress device in the ACL and PCL studies. There was no consensus on the accuracy and reliability of stress radiography techniques for the diagnosis of any knee ligament injury. Stress radiography techniques were compared with alternative diagnostic techniques including instrumented arthrometry, MRI, and physical examination in 18 studies, with variability in the advantages and disadvantages of stress radiography techniques and alternatives. Analysis of results pooled from different studies demonstrated average delta gapping in knees with a completely injured ligament compared to the normal contralateral knee as per the following: for the ACL 4.9 ± 1.4 mm; PCL 8.1 ± 2.5 mm; MCL 2.3 ± 0.05 mm; and the FCL 3.4 ± 0.2 mm. CONCLUSION: Despite heterogeneity in the available literature with regard to stress examination techniques and device utilization, the data support that stress radiography techniques were accurate and reliable when compared to numerous alternatives in the diagnosis of acute and chronic knee ligament injuries. The present study also provides average increased ipsilateral compartment gapping/translation for specific knee ligament injuries based on the best available data. These values provide a reference standard for the interpretation of stress radiography techniques, help to guide surgical decision-making, and provide benchmark values for future investigations. LEVEL OF EVIDENCE: III.

Case Report of AdAPT-001-Mediated Sensitization to a Previously Failed Checkpoint Inhibitor in a Metastatic Chordoma Patient.

Chordoma is a rare, but aggressive bone tumor with a high recurrence rate that primarily arises at the cranial and caudal ends of the axial skeleton. Systemic chemotherapies are not effective against the tumor, and outside of surgical resection and radiation, no approved options are available. Prognosis depends on the extent of surgical resection, with the more the better, and adjuvant radiotherapy. Herein is presented the first-ever case of a recurrent chordoma patient that responded to the combination of one dose of an experimental TGF-beta trap carrying oncolytic adenovirus, known as AdAPT-001, followed by immune checkpoint inhibitor therapy, despite prior progression on an anti-PD-1. This case report highlights the potential of AdAPT-001 as a treatment modality in combination with checkpoint inhibition for recurrent chordoma.

Locally advanced rectal cancer: The past, present, and future.

From a series of clinical trials in the last several decades, current treatment paradigms for locally advanced rectal cancer include: (1) preoperative long-course radiotherapy (RT) combined with radiosensitizing chemotherapy; (2) preoperative short-course RT alone followed by adjuvant postoperative chemotherapy; and (3) total neoadjuvant therapy with induction chemotherapy followed by chemoradiotherapy. Other strategies under active investigation in both institutional and cooperative trials include neoadjuvant chemotherapy alone without RT in select patients, total neoadjuvant therapy, watchful waiting after a clinical complete response as an alternative to surgical resection, and the use of different chemotherapeutic and targeted agents. The focus of this review is on established and novel therapeutic strategies for locally advanced rectal cancer.

Extended treatment with MY-NEOVAX, personalized neoantigen-enhanced oncolytic viruses, for two end-stage cancer patients.

Neoantigen vaccines involving multi-peptides and poly-epitope-encoding RNA or DNA have undergone early phase clinical testing with modest reported antitumor effects [ 1]. The less-than-expected activity of these neoantigenic vaccines may correspond with the development of immune escape mechanisms. One permutation on neoantigen vaccines, which may counter or prevent these adaptive immune escape mechanisms, are 'personalized' oncolytic viruses that encode one or more tumor-specific transgenes. Herein, positive therapeutic effects for MY-NEOVAX™, personalized neoantigen-enhanced oncolytic adenoviruses, are described for two heavily pretreated end-stage patients, one with high-grade metastatic neuroendocrine carcinoma of the pancreas and the other with colorectal cancer metastatic to the brain, liver and lungs. To date, treatment benefit has exceeded 12 months without dose-limiting toxicities or related serious adverse events and with documented radiologic stabilization and improved performance status.

A Deformable Interface for Human Touch Recognition Using Stretchable Carbon Nanotube Dielectric Elastomer Sensors and Deep Neural Networks.

This article presents a machine learning approach to map outputs from an embedded array of sensors distributed throughout a deformable body to continuous and discrete virtual states, and its application to interpret human touch in soft interfaces. We integrate stretchable capacitors into a rubber membrane, and use a passive addressing scheme to probe sensor arrays in real time. To process the signals from this array, we feed capacitor measurements into convolutional neural networks that classify and localize touch events on the interface. We implement this concept with a device called OrbTouch. To modularize the system, we use a supervised learning approach wherein a user defines a set of touch inputs and trains the interface by giving it examples; we demonstrate this by using OrbTouch to play the popular game Tetris. Our regression model localizes touches with mean test error of 0.09 mm, whereas our classifier recognizes five gestures with a mean test error of 1.2%. In a separate demonstration, we show that OrbTouch can discriminate between 10 different users with a mean test error of 2.4%. At test time, we feed the outputs of these models into a debouncing algorithm to provide a nearly error-free experience.

Pursuing use of optimal formulations for paediatric HIV epidemic control - a look at the use of LPV/r oral pellets and oral granules.

INTRODUCTION: Despite a significant reduction in mother-to-child transmission of HIV, an estimated 180,000 children were infected with HIV in 2017, and only 52% of children under 15 years of age living with HIV (CLHIV) are on life-saving antiretroviral therapy (ART). Without effective treatment, half of CLHIV die before the age of two years and only one in five survives to five years of age. DISCUSSION: Over the past four years, the United States Food and Drug Administration tentatively approved new formulations of lopinavir/ritonavir (LPV/r) in the form of oral pellets and oral granules. However, the slow uptake of the aforementioned formulations in the low- and middle-income countries with the highest paediatric HIV burden is largely due to three challenges: limited manufacturing capacity; current unit cost of the pellets and granules; and slow uptake of these new formulations by policy makers and health care workers. CONCLUSIONS: Solutions to overcome these barriers include ensuring availability of an adequate supply of LPV/r oral pellets and oral granules, considering all programmatic and clinical factors when selecting paediatric ART formulations, and leveraging current resources to decrease paediatric HIV morbidity and mortality.

Untethered Stretchable Displays for Tactile Interaction.

Although physical buttons provide tactile sensations that allow them to be identified and pressed without visual focus, their static nature limits their use for dynamic interfaces. Conversely, touchscreens offer highly flexible, task-specific interfaces, but they do not provide the tactile qualities needed for vision-free interaction. Here, we present a stretchable display that can change shape from a flat sheet into a dome when pressurized. The vanishing interface we designed uses hyperelastic light-emitting capacitors (HLECs) that actively emit light, sense strain, and detect finger presses. We characterize the stretch and luminance of the device as the thin sheet is pressurized. Interestingly, but not unexpectedly, these HLEC panels show a pressure-dependent luminance, which we use to highlight where they are being pressed, a visual display of haptic information. We further demonstrate the co-located touch sensing and light-emitting capabilities by developing an interactive memory game.

Thoracic and paraspinal extramedullary hematopoiesis in a cat with chronic non-regenerative anemia.

CASE SUMMARY: A 6-year-old neutered male domestic shorthair cat presented with non-regenerative macrocytic anemia of 2 years' duration and minimally ambulatory paraparesis. Neurologic examination suggested an upper motor neuron paresis or T3-L3 myelopathy. The cat was positive for feline immunodeficiency virus (FIV), neutropenic, had polyclonal gammopathy and was euthanized following a hemolytic crisis. At autopsy, multifocal bilateral dark red masses were observed subpleurally around the costochondral junctions, extradurally and paraspinally in the spinal canal, and paravertebrally, on the lateral and ventral subpleural surfaces of the T4-11 vertebrae. Histologic examination of the masses revealed extramedullary hematopoietic tissue composed primarily of erythroid precursors and megakaryocytes, with occasional myeloid precursors and blood-filled sinuses. Bone marrow findings supported ineffective granulopoiesis, and decreased erythropoiesis and megakaryopoiesis, with probable myelodysplasia as the underlying cause of the hematologic abnormalities. RELEVANCE AND NOVEL INFORMATION: Thoracic, paraspinal and paravertebral extramedullary hematopoietis presenting as masses has not been described previously in cats with chronic anemia. This is a unique case of a thoracic-spinal-epidural extramedullary hematopoietic masses resulting in possible spinal cord compression and paraparesis in a cat.

Case Series: Abscopal Benefit of Surgery in 3 Immunotherapy-Treated Patients With Unresectable Cancer.

For all of the optimism that immunotherapy has engendered, the flip side is that 7/10 patients with susceptible tumor types do not respond, while in nonsusceptible tumor types the response rates are significantly lower. In contradiction of the current orthodoxy against surgery in the setting of unresectable disease, we present 3 examples of immunotherapy-treated patients with widespread recurrence who experienced dramatic clinical improvement following debulking/metastasectomy. Taken together with examples from the literature that correlate longer survival with surgical intervention during treatment with immunotherapy, these 3 cases suggest that a new paradigm involving a wider role for surgery in the management of these patients should be explored. Possible mechanisms by which surgery may synergize with immunotherapy and improve outcomes are also discussed.

A Stretchable Multicolor Display and Touch Interface Using Photopatterning and Transfer Printing.

An intrinsically soft and stretchable multicolor display and touch interface is reported. Red, green, and blue pixels are formed separately by photopatterning transition-metal-doped ZnS embedded in silicone gels and transfer printing onto an elastomeric dielectric sheet. The device shows stable illumination while being stretched up to 200% area strain or under different deformation modalities. It also introduces capabilities for dynamic colorations and multipoint capacitive touch sensing.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.

Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.

Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

TLR7 agonist 852A inhibition of tumor cell proliferation is dependent on plasmacytoid dendritic cells and type I IFN.

Antitumor effects of the toll-like receptor 7 (TLR7) agonist, 852A, were evaluated. Supernatants from human peripheral blood mononuclear cells (PBMC) stimulated with 852A inhibited the proliferation of tumor cell lines Hs294T and 769-P but had no effect on others (786-O and Caki-1). Because addition of 852A directly to the Hs294T cells did not inhibit their proliferation, the mechanism(s) of inhibition of tumor cell proliferation was investigated. Low nanomolar concentrations of 852A stimulated the production of interferon-alpha (IFN-alpha), IFN-inducible protein-10 (IP-10), interleukin-1 receptor antagonist (IL-1Ra), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from human PBMCs. Cytokines stimulated by submicromolar concentrations of 852A were sufficient to inhibit Hs294T proliferation. At higher concentrations (3-30 microM), 852A induced the production of IL-12p70, IL-18, and IFN-gamma. PBMC cultures depleted of plasmacytoid dendritic cells (pDC) did not produce IFN-alpha, and their conditioned medium did not inhibit Hs294T proliferation. Anti-IFN-alpha/beta receptor (IFNAR) and anti-IFN-alpha antibodies partially abrogated Hs294T proliferation inhibition by 852A-stimulated PBMC supernatants, whereas separate neutralization of TRAIL, tumor necrosis factor-alpha (TNF-alpha, IFN-gamma, IFN-beta, or IFN-omega had no effect. In vivo, six doses of 852A administration significantly delayed the onset of lung colonies in a B16 melanoma model. Thus, the results demonstrate that the TLR7 agonist 852A inhibits in vitro proliferation of some tumor cells in a pDC-dependent and IFN-alpha-dependent manner and can delay tumor growth in vivo.

The heat of formation of chlorine-isocyanate and the relative stability of isoelectronic molecules: an experimental and theoretical study.

Accurate thermochemical data of small molecules are invaluable to the progress of every aspect of chemistry, especially in the atmosphere, combustion and industry. In this work, photofragmentation translational spectroscopy and 1st principles electronic structure theory reveal the literature value of the heat of formation of chlorine-isocyanate to be in error by more than 40 kcalmol. We report a revised experimental value for D0(Cl-NCO) = 51+/-3 kcal/mol which leads to a Delta Hf (ClNCO) = 8.5+/-3 kcal/mol. High level ab initio (CCSD(T)) electronic structure calculations extrapolated to the complete basis set limit give D0(Cl-NCO) = 6.3 kcal/mol, in good agreement with experiment. In light of the present results, the destabilization of azides relative to isoelectronic isocyanates has been evaluated empirically for three pairs of related molecules. It is found to be 90-110 kcal/mol, and has been attributed mainly to the weakening of the N-NN bond relative to the N-CO bond. Electronic structure calculations employing decomposition analysis suggest that, compared to homopolar N2, the (+delta)CO(-delta) pi polarity provides better orbital interaction (charge transfer) and electrostatic attraction and results in a closer encounter and larger stabilization between the fragments and that this is the origin of isoelectronic destabilization of azides relative to the isocyanates.