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Abstract Introduction Current literature suggests that axial skeleton magnetic resonance imaging (AS‐MRI) is more sensitive than Tc 99m bone scintigraphy (BS) for detecting bone metastases (BM) in high‐risk prostate cancer (PCa). However, BS is still widely performed. Its diagnostic accuracy has been studied; however, its feasibility and cost implications are yet to be examined. Methods We reviewed all patients with high risk PCa undergoing AS‐MRI over a 5‐year period. AS‐MRI was performed on patients with histologically confirmed PCa and either PSA > 20 ng/ml, Gleason ≥8, or TNM Stage ≥T3 or N1 disease. All AS‐MRI studies were obtained using a 1.5‐T AchievaPhilips™MRI scanner. We compared the AS‐MRI positivity and equivocal rate with that of BS. Data were analysed according to Gleason score, T‐stage and PSA. Multivariate logistic regression analyses were used to quantify the strength of association between positive scans and clinical variables. Feasibility and burden of expenditure was also evaluated. Results Five hundred three patients with a median age of 72 and a mean PSA of 34.8 ng/ml were analysed. Eighty‐eight patients (17.5%) were positive for BM on AS‐MRI (mean PSA 99 [95% CI 69.1–129.9]). Comparatively 409 patients (81.3%) were negative for BM on AS‐MRI (mean PSA 24.7 (95% CI [21.7–27.7]) (p = 0.007); 1.2% (n = 6) of patients had equivocal results (mean PSA 33.4 [95% CI 10.5–56.3]). There was no significant difference in age (p = 0.122) between this group and patients with a positive scan, but there was a significant difference in PSA (p = 0.028), T stage (p = 0.006) and Gleason score (p = 0.023). In comparison with BS, AS‐MRI detection rate was equivalent or higher compared with the literature. Based on NHS tariff calculations, there would be a minimum cost saving of £8406.89. All patients underwent AS‐MRI within 14 days. Conclusion The use of AS‐MRI to stage BM in high‐risk PCa is both feasible and results in a reduced burden of expenditure.

BACKGROUND Electrocardiography (ECG) may be performed as part of preparticipation sports screening. Recommendations on screening of athletes to identify individuals with previously unrecognized cardiac disease are robust; however, data guiding the preparticipation screening of unselected populations are scarce. T wave inversion (TWI) on ECG may suggest an undiagnosed cardiomyopathy. This study aims to describe the prevalence of abnormal TWI in an unselected young male cohort and the outcomes of an echocardiography‐guided approach to investigating these individuals for structural heart diseases, focusing on the yield for cardiomyopathies. METHODS AND RESULTS Consecutive young male individuals undergoing a national preparticipation cardiac screening program for 39 months were studied. All underwent resting supine 12‐lead ECG. Those manifesting abnormal TWI, defined as negatively deflected T waves of at least 0.1 mV amplitude in any 2 contiguous leads, underwent echocardiography. A total of 69 714 male individuals with a mean age of 17.9±1.1 years were studied. Of the individuals, 562 (0.8%) displayed abnormal TWI. This was most frequently observed in the anterior territory and least so in the lateral territory. A total of 12 individuals (2.1%) were diagnosed with a cardiomyopathy. Cardiomyopathy diagnoses were significantly associated with deeper maximum TWI depth and the presence of abnormal TWI in the lateral territory, but not with abnormal TWI in the anterior and inferior territories. No individual presenting with TWI restricted to solely leads V1 to V2, 2 inferior leads or both was diagnosed with a cardiomyopathy. CONCLUSIONS Cardiomyopathy diagnoses were more strongly associated with certain patterns of abnormal TWI. Our findings may support decisions to prioritize echocardiography in these individuals.

Abstract Introduction Immune checkpoint inhibitor (ICI) therapy is an established treatment for advanced non‐small‐cell lung cancer (NSCLC) and programmed death ligand‐1 (PD‐L1) expression is a recognized biomarker to determine response to therapy. We retrospectively analyzed NSCLC patients in the Malaysia Lung Cancer Registry (MLCR) and report on the clinical characteristics associated with PD‐L1 expression and ICI use in Malaysia, a low‐ to middle‐income country. Methods All 901 NSCLC patients in the MLCR who were diagnosed from January 1, 2017 to December 31, 2020 from 14 hospitals across the country were analyzed. Results Out of 901 patients, 505 had PDL‐1 testing done with complete data available only in 489 patients. The most common histology was adenocarcinoma (84.7%) followed by squamous cell carcinoma (10.2%). The majority (95%) presented with stage 3 or 4. The number and percentage of patients with PDL‐1 tumor proportion scores of ≥50%, 1–49%, and

Abstract Extracting energy from ocean waves has become a heated topic since the energy crisis of the 2000s. Among all the different concepts and designs of Wave Energy Converter (WEC), point absorber is a widely adopted type with great potential, and various configurations and constraints are applicable to it. Here, the point absorber WECs with four different set‐up configurations are explored: single body heaving WEC, two‐body heaving WEC, two‐body WEC with a flat plate (Reference Model 3), and a two‐body WEC with a cylinder‐shaped second body. Dynamic models are established for each case and wave tank tests are conducted for verification. The results show that the power capture of a point absorber can benefit from several aspects: the two‐body WEC with a streamlined shape can double the wave capture width ratio (up to 66.5%) over the single‐body WEC or Reference Model 3, while coupling other motion or mooring dynamics can further improve the capture width ratio by 12% by increasing the relative motion stroke.

Background Left atrial (LA) decompression on extracorporeal membrane oxygenation (ECMO) can reduce left ventricular distension, allowing myocardial rest and recovery, and protect from lung injury secondary to cardiogenic pulmonary edema. However, clinical benefits remain unknown. We sought to evaluate the association between LA decompression and in‐hospital adverse outcome (mortality, transplant on ECMO, or conversion to ventricular assist device) in patients who failed to wean from cardiopulmonary bypass using a propensity score to adjust for baseline differences. Methods and Results Children (aged

Abstract A quantitative systems pharmacology model for metastatic melanoma was developed for immuno‐oncology with the goal of predicting efficacy of combination checkpoint therapy with pembrolizumab and ipilimumab. This literature‐based model is developed at multiple scales: (i) tumor and immune cell interactions at a lesion level; (ii) multiple heterogeneous target lesions, nontarget lesion growth, and appearance of new metastatic lesion at a patient level; and (iii) interpatient differences at a population level. The model was calibrated to pembrolizumab and ipilimumab monotherapy in patients with melanoma from Robert et al., specifically, waterfall plot showing target lesion response and overall response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), which additionally considers nontarget lesion growth and appearance of new metastatic lesions. We then used the model to predict waterfall and RECIST version 1.1 for combination treatment reported in Long et al. A key insight from this work was that nontarget lesions growth and appearance of new metastatic lesion contributed significantly to disease progression, despite reduction in target lesions. Further, the lesion level simulations of combination therapy show substantial efficacy in warm lesions (intermediary immunogenicity) but limited advantage of combination in both cold and hot lesions (low and high immunogenicity). Because many patients with metastatic disease are expected to have a mixture of these lesions, disease progression in such patients may be driven by a subset of cold lesions that are unresponsive to checkpoint inhibitors. These patients may benefit more from the combinations which include therapies to target cold lesions than double checkpoint inhibitors.

Objective Immunoglobulin M antibodies against phosphorylcholine (anti‐PCs) may be protective in atherosclerosis, cardiovascular disease (CVD), and systemic lupus erythematosus (SLE). We study immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti‐PCs, with a focus on atherosclerosis and SLE. Methods We determined anti‐PCs by using the enzyme‐linked immunosorbent assay in 116 patients with SLE and 110 age‐ and sex‐matched controls. For functional studies, we used three in‐house–generated, fully human monoclonal IgG1 anti‐PCs (A01, D05, and E01). Apoptosis was induced in Jurkat T cells and preincubated with A01, D05, E01, or IgG1 isotype control, and effects on efferocytosis by human macrophages were studied. Anti‐PC peptide/protein characterization was determined using a proteomics de novo sequencing approach. Results IgG1, but not IgG2, anti‐PC levels were higher among patients with SLE (P = 0.02). IgG1 anti‐PCs were negatively associated with Systemic Lupus International Collaborating Clinics (SLICC) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (odds ratio [OR]: 2.978 [confidence interval (CI): 0.876‐10.098] and OR: 5.108 [CI 1.3‐20.067], respectively) and negatively associated with CVD, atherosclerotic plaques, and echolucent plaques (potentially vulnerable plaques), but the association for the two former was not significant after controlling for confounders. D05 had a maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC‐associated neoepitopes. A peptide analysis showed a difference in the complementarity‐determining region 3 of the three IgG1 anti‐PC clones that are crucial for recognition of PC on apoptotic cell surfaces and other neoepitopes. Conclusion IgG1 anti‐PCs are negatively associated with disease activity and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.

Objective: To evaluate the survival outcomes for a cohort of nasopharyngeal cancer with intracranial extension (ICE) treated with induction chemotherapy (ICT) followed by chemo-intensity-modulated radiotherapy (CTRT) at a tertiary cancer center. Methods: We retrospectively analyzed 45 patients with histologically proven, non-metastatic NPC with ICE treated at our institute between October 2008 and October 2016. Patients were classified as minor ICE or major ICE, based on the extent of ICE. All the patients received 2–3 cycles of a taxane-based ICT regimen followed by CTRT. Radiotherapy was delivered with “risk-adapted” intensity-modulated radiotherapy (IMRT) technique in all patients. Results: After a median follow up of 45 months (range: 8–113 months), the estimated 5-year DFS, LRFS, DMFS, and OS of the entire cohort was 58%, 82%, 67% and 74% respectively. On multivariate analysis, histological subtype was an independent predictor of LRFS, and age was an independent predictor of DFS. The extent of ICE showed only a trend towards worse DFS (P = 0.06). None of the factors significantly predicted for DMFS or OS. Gender, N-stage, and response to ICT did not significantly affect any of the outcomes. Grade 2 or worse subcutaneous fibrosis was seen in 22% of patients and grade 2 or worse xerostomia was seen in 24% of patients at last follow up. Thirty-three percent of the patients developed clinical hypothyroidism at last follow up. None of the patients experienced any neurological or vascular complications. Conclusions: Taxane-based induction chemotherapy followed by chemo-intensity modulated radiotherapy resulted in excellent locoregional control and survival with acceptable toxicities in patients of nasopharyngeal cancer with intracranial extension. Distant metastasis continues to be the predominant problem in these patients.

Background Previous studies suggest that infant heart transplant (HT) recipients are at higher risk of developing severe primary graft dysfunction (PGD) than older children. We sought to identify risk factors for developing severe PGD in infant HT recipients. Methods and Results We identified all HT recipients aged

BACKGROUND Outcomes from extracorporeal cardiopulmonary resuscitation (ECPR) are felt to be influenced by selective use, but the characteristics of those receiving ECPR are undefined. We demonstrate the relationship between individual patient and hospital characteristics and the probability of ECPR use. METHODS AND RESULTS We performed an observational analysis of adult inpatient cardiac arrests in the United States from 2000 to 2018 reported to the American Heart Association's Get With The Guidelines—Resuscitation registry restricted to hospitals that provided ECPR. We calculated case mix adjusted relative risk (RR) of receiving ECPR for individual characteristics. From 2000 to 2018, 129 736 patients had a cardiac arrest (128 654 conventional cardiopulmonary resuscitation and 1082 ECPR) in 224 hospitals that offered ECPR. ECPR use was associated with younger age (RR, 1.5 for

Abstract Treatment with dasatinib, a tyrosine kinase inhibitor, is associated with edema, pleural effusion, and pulmonary edema. We investigated the effect of dasatinib on the barrier function of human microvascular endothelial cells‐1 (HMEC‐1) in vitro and in vivo. The permeability of HMEC‐1 to fluorescein isothiocyante (FITC)‐dextran increased in Transwell chambers within 5 min following the addition of therapeutic concentrations of dasatinib. The change in permeability was associated with increased activation of RhoA GTPase and its effector Rho‐associated coiled‐coil kinase 1(ROCK1). RhoA inhibitor C3 transferase almost completely inhibited dasatinib‐induced increase in permeability. Under similar conditions, imatinib had no effect on permeability or activation of RhoA. Since integrin‐induced cell spreading suppresses RhoA activation, we examined the effect of dasatinib on cell spreading on fibronectin substrate. Dasatinib impaired endothelial cell spreading in a concentration‐dependent manner and induced disorganization of actin fibers. Tyrosine kinases play an essential role in transmitting signals from integrins to RhoA and we examined tyrosine phosphorylation of several cytoskeletal proteins. Dasatinib markedly inhibited tyrosine phosphorylation of p130 Crk‐associated substrate (p130cas), paxillin and vinculin. These results suggest that the inhibition of tyrosine phosphorylation of the focal adhesion plaque components by dasatinib may alter the assembly of actin fibers resulting in the activation of RhoA/ROCK pathway. Consistent with these findings, dasatinib‐induced increase in the permeability was blocked by ROCK inhibitor y27632. In vivo administration of y27632, significantly inhibited the dasatinib‐induced extravasation of Evans blue in mice and dasatinib‐induced increase in microvascular permeability was attenuated in ROCK1‐deficient mice. These findings suggest that ROCK inhibitors could serve as therapeutic modalities to ameliorate the dasatinib‐induced pulmonary changes.

BackgroundMalondialdehyde (MDA) is generated during lipid peroxidation as in oxidized low‐density lipoprotein, but antibodies against oxidized low‐density lipoprotein show variable results in clinical studies. We therefore studied the risk of cardiovascular disease (CVD) associated with IgM antibodies against MDA conjugated with human albumin (anti‐MDA). Methods and ResultsIn a 5‐ to 7‐year follow‐up of 60‐year‐old men and women from Stockholm County previously screened for cardiovascular risk factors (2039 men, 2193 women), 209 incident CVD cases (defined as new events of coronary heart disease, fatal and nonfatal myocardial infarction, ischemic stroke, and hospitalization for angina pectoris) and 620 age‐ and sex‐matched controls were tested for IgM anti‐MDA by ELISA. Antibody peptide/protein characterization was done using a proteomics de novo sequencing approach. After adjustment for smoking, body‐mass index, type 2 diabetes mellitus, hyperlipidemia, and hypertension, an increased CVD risk was observed in the low IgM anti‐MDA percentiles (below 10th and 25th) (odds ratio and 95% CI: 2.0; 1.19–3.36 and 1.67; 1.16–2.41, respectively). Anti‐MDA above the 66th percentile was associated with a decreased CVD risk (odds ratio 0.68; CI: 0.48–0.98). After stratification by sex, associations were only present among men. IgM anti‐MDA levels were lower among cases (median [interquartile range]: 141.0 [112.7–164.3] versus 147.4 [123.5–169.6]; P=0.0177), even more so among men (130.6 [107.7–155.3] versus 143.0 [120.1–165.2]; P=0.001). The IgM anti‐MDA variable region profiles are distinctly different and also more homologous in their content (correlates strongly with fewer peptides) than control antibodies (not binding MDA). ConclusionsIgM anti‐MDA is a protection marker for CVD. This finding could have diagnostic and therapeutic implications.

BackgroundSystemic vasodilation using α‐receptor blockade has been shown to decrease the incidence of postoperative cardiac arrest following stage 1 palliation (S1P), primarily when utilizing the modified Blalock‐Taussig shunt. We studied the effects of a protocol in which milrinone was primarily used to lower systemic vascular resistance (SVR) following S1P using the right ventricular to pulmonary artery shunt, measuring its effects on oxygen delivery (DO2) profiles and clinical outcomes. We also correlated Fick‐based assessments of DO2 with commonly used surrogate measures. Methods and ResultsNeonates undergoing S1P were treated according to best clinical judgment prior to (n=32) and following (n=24) implementation of a protocol that guided operative, anesthetic, and postoperative management, particularly as it related to SVR. A majority of the subjects (n=51) received a modified right ventricular to pulmonary artery shunt. In a subset of these patients (n=21), oxygen consumption (VO2) was measured and used to calculate SVR, DO2, and oxygen debt. Neonates treated with the protocol had significantly lower SVR (P=0.02), serum lactate (P