Diagnostic validation of vertebral heart score machine learning algorithm for canine lateral chest radiographs.

OBJECTIVES: The vertebral heart score is a measurement used to index heart size relative to thoracic vertebra. Vertebral heart score can be a useful tool for identifying and staging heart disease and providing prognostic information. The purpose of this study is to validate the use of a vertebral heart score algorithm compared to manual vertebral heart scoring by three board-certified veterinary cardiologists. MATERIALS AND METHODS: A convolutional neural network centred around semantic segmentation of relevant anatomical features was developed to predict heart size and vertebral bodies. These predictions were used to calculate the vertebral heart score. An external validation study consisting of 1200 canine lateral radiographs was randomly selected to match the underlying distribution of vertebral heart scores. Three American College of Veterinary Internal Medicine board-certified cardiologists were enrolled to manually score 400 images each using the traditional Buchanan method. Post-scoring, the cardiologists evaluated the algorithm for misaligned anatomic landmarks and overall image quality. RESULTS: The 95th percentile absolute difference between the cardiologist vertebral heart score and the algorithm vertebral heart score was 1.05 vertebrae (95% confidence interval: 0.97 to 1.20 vertebrae) with a mean bias of -0.09 vertebrae (95% confidence interval: -0.12 to -0.05 vertebrae). In addition, the model was observed to be well calibrated across the predictive range. CLINICAL SIGNIFICANCE: We have found the performance of the vertebral heart score algorithm comparable to three board-certified cardiologists. While validation of this vertebral heart score algorithm has shown strong performance compared to veterinarians, further external validation in other clinical settings is warranted before use in those settings.

A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

BACKGROUND: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. PATIENTS AND METHODS: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. CONCLUSIONS: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Controlled local release of PPARγ agonists from biomaterials to treat peripheral nerve injury.

OBJECTIVE: Poor clinical outcomes following peripheral nerve injury (PNI) are partly attributable to the limited rate of neuronal regeneration. Despite numerous potential drug candidates demonstrating positive effects on nerve regeneration rate in preclinical models, no drugs are routinely used to improve restoration of function in clinical practice. A key challenge associated with clinical adoption of drug treatments in nerve injured patients is the requirement for sustained administration of doses associated with undesirable systemic sideeffects. Local controlled-release drug delivery systems could potentially address this challenge, particularly through the use of biomaterials that can be implanted at the repair site during the microsurgical repair procedure. APPROACH: In order to test this concept, this study used various biomaterials to deliver ibuprofen sodium or sulindac sulfide locally in a controlled manner in a rat sciatic nerve injury model. Following characterisation of release parameters in vitro, ethylene vinyl acetate tubes or polylactic-co-glycolic acid wraps, loaded with ibuprofen sodium or sulindac sulfide, were placed around directly-repaired nerve transection or nerve crush injuries in rats. MAIN RESULTS: Ibuprofen sodium, but not sulindac sulfide caused an increase in neurites in distal nerve segments and improvements in functional recovery in comparison to controls with no drug treatment. SIGNIFICANCE: This study showed for the first time that local delivery of ibuprofen sodium using biomaterials improves neurite growth and functional recovery following PNI and provides the basis for future development of drug-loaded biomaterials suitable for clinical translation.

A Population Pharmacokinetic Model for Vancomycin in Adult Patients Receiving Extracorporeal Membrane Oxygenation Therapy.

The literature on the pharmacokinetics of vancomycin in patients undergoing extracorporeal membrane oxygenation (ECMO) therapy is sparse. A population pharmacokinetic (PK) model for vancomycin in ECMO patients was developed using a nonlinear mixed effects modeling on the concentration-time profiles of 14 ECMO patients who received intravenous vancomycin. Model selection was based on log-likelihood criterion, goodness of fit plots, and scientific plausibility. Identification of covariates was done using a full covariate model approach. The pharmacokinetics of vancomycin was adequately described with a two-compartment model. Parameters included clearance of 2.83 L/hr, limited central volume of distribution 24.2 L, and low residual variability 0.67%. Findings from the analysis suggest that standard dosing recommendations for vancomycin in non-ECMO patients are adequate to achieve therapeutic trough concentrations in ECMO patients. This further shows that ECMO minimally affects the PK of vancomycin in adults including in higher-weight patients.

Impact-induced muscle damage and urinary pterins in professional rugby: 7,8-dihydroneopterin oxidation by myoglobin.

Muscle damage caused through impacts in rugby union is known to increase oxidative stress and inflammation. Pterins have been used clinically as markers of oxidative stress, inflammation, and neurotransmitter synthesis. This study investigates the release of myoglobin from muscle tissue due to force-related impacts and how it is related to the subsequent oxidation of 7,8-dihydroneopterin to specific pterins. Effects of iron and myoglobin on 7,8-dihydroneopterin oxidation were examined in vitro via strong cation-exchange high-performance liquid chromatography (SCX-HPLC) analysis of neopterin, xanthopterin, and 7,8-dihydroxanthopterin. Urine samples were collected from 25 professional rugby players pre and post four games and analyzed for myoglobin by enzyme-linked immunosorbent assay, and 7,8-dihydroneopterin oxidation products by HPLC. Iron and myoglobin oxidized 7,8-dihydroneopterin to neopterin, xanthopterin, and 7,8-dihydroxanthopterin at concentrations at or above 10 µM and 50 µg/mL, respectively. All four games showed significant increases in myoglobin, neopterin, total neopterin, biopterin, and total biopterin, which correlated between each variable (P < 0.05). Myoglobin and iron facilitate 7,8-dihydroneopterin oxidation to neopterin and xanthopterin. In vivo delocalization of myoglobin due to muscle damage may contribute to oxidative stress and inflammation after rugby. Increased concentrations of biopterin and total biopterin may indicate production of nitric oxide and monoamine neurotransmitters in response to the physical stress.

Building-related health symptoms and classroom indoor air quality: a survey of school teachers in New York State.

UNLABELLED: Most previous research on indoor environments and health has studied school children or occupants in non-school settings. This investigation assessed building-related health symptoms and classroom characteristics via telephone survey of New York State school teachers. Participants were asked about 14 building-related symptoms and 23 classroom characteristics potentially related to poor indoor air quality (IAQ). Poisson regression analysis was used to assess the relationship between these symptoms and each classroom characteristic, controlling for potential confounders. About 500 teachers completed the survey. The most frequently reported classroom characteristics included open shelving (70.7%), food eaten in class (65.5%), dust (59.1%), and carpeting (46.9%). The most commonly reported symptoms included sinus problems (16.8%), headache (15.0%), allergies/congestion (14.8%), and throat irritation (14.6%). Experiencing one or more symptoms was associated most strongly with reported dust (relative risk (RR) = 3.67; 95% confidence interval (CI): 2.62-5.13), dust reservoirs (RR = 2.13; 95% CI: 1.72-2.65), paint odors (RR = 1.73; 95% CI: 1.40-2.13), mold (RR = 1.71; 95% CI: 1.39-2.11), and moldy odors (RR = 1.65 95% CI: 1.30-2.10). Stronger associations were found with increasing numbers of reported IAQ-related classroom characteristics. Similar results were found with having any building-related allergic/respiratory symptom. This research adds to the body of evidence underscoring the importance to occupant health of school IAQ. PRACTICAL IMPLICATIONS: Teachers play an important role in educating children, and teacher well-being is important to this role. Health symptoms among New York teachers while at work are common and appear to be associated with numerous characteristics related to poor classroom IAQ. Improving school Indoor Air Quality may reduce sickness and absenteeism and improve teacher performance.

MRI findings in the lumbar spines of asymptomatic elite junior tennis players.

OBJECTIVE: To evaluate the MRI findings in the lumbar spines of asymptomatic elite junior tennis players. MATERIALS AND METHODS: The lumbar spine MRI studies of 98 asymptomatic junior elite tennis players (51 male, 47 female) with a mean age of 18 years (age range 11.2-26.3 years; standard deviation 3.1) was reviewed by two consultant musculoskeletal radiologists using consensus opinion. Images were assessed using accepted classification systems. RESULTS: Four players (4%) had no abnormality. Facet joint arthropathy occurred in 89.7% of the players, being mild in 84.5% of cases. There were 41 synovial cysts in 22.4% of the cohort all occurring in the presence of facet arthropathy. Disc degeneration was noted in 62.2 % of players, being mild in 76.2% of those affected. Disc herniation was noted in 30.6% of players, with 86.1% of these being broad based and 13.9% being focal. There was nerve root compression in 2%. There were 41 pars interarticularis abnormalities in 29.6% of patients, 63.4% of these being grades 1-3. There was grade 1 spondylolisthesis in 5.1% of players. The prevalence of facet joint arthropathy, disc degeneration, disc herniation and pars interarticularis fracture was lower in female players than in male and lower in the under 16-year-olds compared with the over 20-year-olds. CONCLUSION: There is a significant amount of underlying pathology that would normally go undetected in this group of asymptomatic elite athletes. Whilst these findings cannot be detected clinically, their relevance is in facilitating appropriate prehabilitation to prevent loss of playing time and potentially career-ending injuries.

Versatile multi-functionalization of protein nanofibrils for biosensor applications.

Protein nanofibrils offer advantages over other nanostructures due to the ease in their self-assembly and the versatility of surface chemistry available. Yet, an efficient and general methodology for their post-assembly functionalization remains a significant challenge. We introduce a generic approach, based on biotinylation and thiolation, for the multi-functionalization of protein nanofibrils self-assembled from whey proteins. Biochemical characterization shows the effects of the functionalization onto the nanofibrils' surface, giving insights into the changes in surface chemistry of the nanostructures. We show how these methods can be used to decorate whey protein nanofibrils with several components such as fluorescent quantum dots, enzymes, and metal nanoparticles. A multi-functionalization approach is used, as a proof of principle, for the development of a glucose biosensor platform, where the protein nanofibrils act as nanoscaffolds for glucose oxidase. Biotinylation is used for enzyme attachment and thiolation for nanoscaffold anchoring onto a gold electrode surface. Characterization via cyclic voltammetry shows an increase in glucose-oxidase mediated current response due to thiol-metal interactions with the gold electrode. The presented approach for protein nanofibril multi-functionalization is novel and has the potential of being applied to other protein nanostructures with similar surface chemistry.

Imaging of muscle injury in the elite athlete.

Injuries to muscle in the elite athlete are common and may be responsible for prolonged periods of loss of competitive activity. The implications for the athlete and his/her coach and team may be catastrophic if the injury occurs at a critical time in the athlete's diary. Imaging now plays a crucial role in diagnosis, prognostication and management of athletes with muscle injuries. This article discusses the methods available to clinicians and radiologists that are used to assess skeletal muscle injury. The spectrum of muscle injuries sustained in the elite athlete population is both discussed and illustrated.

Paediatric nasopharyngeal rhabdomyosarcoma: A case series and literature review.

Rhabdomyosarcoma (RMS) is the most common soft tissue tumour in children, with the head and neck region accounting for 35-40% of cases. Nasopharyngeal RMSs tend to grow rapidly and invade adjacent structures. Both the Intergroup Rhabdomyosarcoma Studies and the European Studies have established that the ideal management of this disease is multimodal, using a combination of surgery, chemotherapy and radiotherapy. This case series examines the role of radiotherapy in the management of paediatric nasopharyngeal RMSs, with particular reference to long-term morbidity and disease-free survival. The cases of five children with nasopharyngeal RMS were reviewed and a systematic review of the literature contained in the PubMed databases was conducted to establish 24 individually detailed cases. Management in all patients was multimodal, using a combination of chemotherapy, radiotherapy as well as surgery. External beam radiotherapy is an integral component of treatment for nasopharyngeal RMSs. With more patients surviving for longer periods, more long-term sequelae of radiotherapy have been reported. Complications include sensorineural deafness, endocrine manifestations following radiation of the pituitary gland, cranial nerve palsies, second malignancies within the radiation field, cataract formation, retinopathy and growth disturbance. Morbidity from radiotherapy may be considerable and depends on the field and dose of radiation. Current advances in radiotherapy are aimed at improving the rate of tumour control and reducing such complications. Recent improvements in imaging and conformal techniques have the potential to reduce the morbidity associated with radiotherapy in this cohort.

Musculoskeletal sonography of the normal foot.

Traumatic, degenerative and rheumatological injuries of the foot are common and can be managed by an ever increasing number of treatments and surgical interventions. High-frequency sonography is inexpensive, portable and is unique in allowing true dynamic assessment of the ligamentous, muscular and tendinous structures. The ultrasound technique demonstrates a steep learning curve and requires detailed knowledge of the foot anatomy. Ultrasound assessment plays an important role in the diagnosis and management of injuries of these structures by guiding rehabilitation and surgical intervention without delay. However, intimate knowledge of the ultrasound appearances of the foot anatomy and normal variants is paramount to correctly identify pathological conditions. We describe the normal sonographic appearances of the foot musculoskeletal structures with MR correlation including joints and their ligaments, dorsal and plantar surfaces of the foot, and the arches of the foot and their supporting structures.

The use of ultrasound in the assessment and treatment of Achilles tendinosis.

The use of ultrasound in the diagnosis and management of disorders of the tendo Achillis is discussed. Some of the pathological processes which occur in Achilles tendinopathy can be identified by ultrasound, which may also be used to direct local treatment.

The use of MRI to detect occult fractures of the proximal femur: a study of 102 consecutive cases over a ten-year period.

An MR scan was performed on all patients who presented to our hospital with a clinical diagnosis of a fracture of the proximal femur, but who had no abnormality on plain radiographs. This was a prospective study of 102 consecutive patients over a ten-year period. There were 98 patients who fulfilled our inclusion criteria, of whom 75 were scanned within 48 hours of admission, with an overall mean time between admission and scanning of 2.4 days (0 to 10). A total of 81 patients (83%) had abnormalities detected on MRI; 23 (23%) required operative management. The use of MRI led to the early diagnosis and treatment of occult hip pathology. We recommend that incomplete intertrochanteric fractures are managed non-operatively with protected weight-bearing. The study illustrates the high incidence of fractures which are not apparent on plain radiographs, and shows that MRI is useful when diagnosing other pathology such as malignancy, which may not be apparent on plain films.

Extensor pollicis longus tendon rupture following avulsion fracture of the third metacarpal.

Extensor pollicis longus (EPL) tendon rupture is a recognised complication of distal radial fractures and their fixation with dorsal radial plates and pins. A number of other conditions including internal fixation of wrist fractures and inflammatory arthropathies have also been reported as aetiological factors of EPL tendon rupture. We report a case of extensor pollicis longus tendon rupture following avulsion fracture of the third metacarpal and review the radiographic and sonographic features.

Medium-to-long term DEXA analysis of an uncemented (AML) femoral component.

We present medium-to-long-term bone mineral density studies assessing bone resorption and remodelling around the cementless femoral component of a total hip arthroplasty (Depuy AML prosthesis). Bone mineral densities were compared with the unoperated side at a time interval of eight years between scans using dual energy X-ray absorptiometry. Initial proximal stress shielding is known but we show that this response continues into the medium to long term in relative terms. We have also found an overall trend for bone mineral density to increase around the prosthesis with the greatest changes occurring distally. The greatest real increase in bone mineral density occurred in Gruen zones 2, 3 and 5 with smaller increases in zones 1, 4, 6 and 7. However, when compared with the contralateral unoperated femur (thus considering systemic changes in bone mineral density), we found these changes only reached statistical significance in Gruen zones 5, 6 and 7.