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OBJECTIVE To evaluate the short- and long-term outcomes of dogs undergoing surgical ligation for a left-to-right shunting patent ductus arteriosus (PDA), identify risk factors for intraoperative hemorrhage and intra- and postoperative complications, and report overall mortality rates. ANIMALS 417 client-owned dogs undergoing surgical ligation for a left-to-right shunting PDA between January 2010 and January 2020. PROCEDURES Data recorded included patient signalment, echocardiogram findings, intraoperative complications and mortality, postoperative complications, and short- and long-term outcomes. RESULTS There was no association between age and risk of intraoperative hemorrhage (P = .7), weight and intraoperative hemorrhage (P = .96), or increasing left atrium-to-aortic (LA:Ao) ratio and intraoperative hemorrhage (P = .08). Intraoperative hemorrhage occurred in 10.8% of patients. Intraoperative mortality was 2%. Ninety-five percent of dogs experiencing intraoperative hemorrhage survived to discharge. Survival to discharge was 97%. One- and 5-year survival rates were 96.4% and 87%, respectively. CLINICAL RELEVANCE Surgical ligation for a left-to-right shunting PDA is recommended due to the good long-term prognosis. Certain preoperative factors such as age, weight, and the presence and degree of mitral valve regurgitation had no detectable association with risks of intraoperative hemorrhage and, therefore, should not preclude surgical treatment for a left-to-right shunting PDA. Future studies are needed to further assess the association between increasing LA:Ao ratio and risk of intraoperative hemorrhage.

Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm2 elliptical field with a dose rate of ~120 Gy/s was provided by a 228 MeV proton pencil beam. Partial abdominal irradiation was delivered to C57BL/6j and immunodeficient Rag1−/−/C57 mice. Proliferating crypt cells were counted at 2 days post exposure, and the thickness of the muscularis externa was measured at 280 days following irradiation. FLASH irradiation did not reduce the morbidity or mortality of conventional irradiation in either strain of mice; in fact, a tendency for worse survival in FLASH-irradiated mice was observed. There were no significant differences in lymphocyte numbers between FLASH and conventional-dose-rate mice. A similar number of proliferating crypt cells and a similar thickness of the muscularis externa following FLASH and conventional dose rate irradiation were observed. Partial abdominal FLASH proton irradiation at 120 Gy/s did not spare normal intestinal tissue, and no difference in lymphocyte depletion was observed. This study suggests that the effect of FLASH irradiation may depend on multiple factors, and in some cases dose rates of over 100 Gy/s do not induce a FLASH effect and can even result in worse outcomes.

Supplementary Table 1 from Sunitinib Prolongs Survival in Genetically Engineered Mouse Models of Multistep Lung Carcinogenesis

Perspective on this Article from Sunitinib Prolongs Survival in Genetically Engineered Mouse Models of Multistep Lung Carcinogenesis

Aims Atrial fibrillation (AF) is associated with atrial enlargement, mitral annulus (MA) and tricuspid annulus (TA) dilation, and atrial functional regurgitation (AFR). However, less is known about the impact of AF on both atrioventricular valves in those with normal and abnormal ventricular function. We aimed to compare the remodelling of the TA and MA in patients with non-valvular AF without significant AFR. Methods and results Ninety-two patients referred for transoesophageal echocardiography were included and categorized into three groups: (i) AF with normal left ventricular (LV) function (Normal LV-AF), n = 36; (ii) AF with LV systolic dysfunction (LVSD-AF), n = 29; and (iii) Controls in sinus rhythm, n = 27. Three-dimensional MA and TA geometry were analysed using automated software. In patients with AF regardless of LV function, the MA and TA areas were larger compared with controls (LVSD-AF vs. Normal LV-AF vs. Controls, end-systolic MA: 5.2 ± 1.1 vs. 4.5 ± 0.7 vs. 3.9 ± 0.7 cm2/m2; end-systolic TA: 5.6 ± 1.3 vs. 5.3 ± 1.3 vs. 4.1 ± 0.7 cm2/m2; P < 0.05 for each comparison with Controls). TA and MA areas were not statistically different between the two AF groups. The TA increase over controls was greater than that of the MA in the Normal LV-AF group (27.7% vs. 15.6%, P = 0.041). Conversely, in the LVSD-AF group, MA and TA increased similarly (35.9% vs. 32.4%, P = 0.660). Conclusion Patients with AF showed dilation of both TA and MA compared with patients in sinus rhythm. In patients with normal LV function, AF was associated with greater TA dilation than MA dilation whereas in patients with LVSD the TA and MA were equally dilated.

Purpose: Percutaneous left atrial appendage (LAA) occlusion is increasingly performed in patients with atrial fibrillation and long-term contraindications for anticoagulation. Our aim was to evaluate the effects of LAA occlusion with the Watchman device on the geometry of the LAA orifice and assess its impact on the adjacent left upper pulmonary vein (LUPV) hemodynamics.Methods: We included 50 consecutive patients who underwent percutaneous LAA occlusion with the Watchman device. Three-dimensional images of LAA pre- and post-device placement were analyzed offline. We measured the LAA orifice diameters in the long axis, and the minimum and maximum diameters, circumference, and area in the short axis view. Eccentricity index was calculated as maximum/minimum diameter ratio. The LUPV peak S and D velocities pre- and post-procedure were also measured.Results: Patients were elderly (mean age 76±8 years years), 30 (60%) were men. There was a significant increase of all LAA orifice dimensions following LAA occlusion: diameter 1 (pre-device 18.1±3.2 vs. post-device 21.5±3.4 mm, p2, pConclusion: LAA orifice stretches significantly and it becomes more circular following LAA occlusion without causing a significant impact on the LUPV hemodynamics.

Background Standardization of risk is critical in benchmarking and quality improvement efforts for percutaneous coronary interventions (PCIs). In 2018, the CathPCI Registry was updated to include additional variables to better classify higher-risk patients. Objectives This study sought to develop a model for predicting in-hospital mortality risk following PCI incorporating these additional variables. Methods Data from 706,263 PCIs performed between July 2018 and June 2019 at 1,608 sites were used to develop and validate a new full and pre-catheterization model to predict in-hospital mortality, and a simplified bedside risk score. The sample was randomly split into a development cohort (70%, n = 495,005) and a validation cohort (30%, n = 211,258). The authors created 1,000 bootstrapped samples of the development cohort and used stepwise selection logistic regression on each sample. The final model included variables that were selected in at least 70% of the bootstrapped samples and those identified a priori due to clinical relevance. Results In-hospital mortality following PCI varied based on clinical presentation. Procedural urgency, cardiovascular instability, and level of consciousness after cardiac arrest were most predictive of in-hospital mortality. The full model performed well, with excellent discrimination (C-index: 0.943) in the validation cohort and good calibration across different clinical and procedural risk cohorts. The median hospital risk-standardized mortality rate was 1.9% and ranged from 1.1% to 3.3% (interquartile range: 1.7% to 2.1%). Conclusions The risk of mortality following PCI can be predicted in contemporary practice by incorporating variables that reflect clinical acuity. This model, which includes data previously not captured, is a valid instrument for risk stratification and for quality improvement efforts.

Resume L’annonce du diagnostic de handicap aux parents de jeunes enfants est un moment difficile pour les parents comme pour le medecin, mais le faire est un imperatif autant moral que medical. La methodologie comme la maniere de le faire sont cependant importantes. Un defaut de communication entre les parents et les medecins peut affecter la sante psychologique des parents. Cet article constitue une adaptation et une explication de la maniere d’utiliser le protocole SPIKES pour annoncer la « mauvaise nouvelle » d’un diagnostic de trouble du developpement a des familles d’enfants de moins de douze mois, la paralysie cerebrale servant d’exemple. Dans un deuxieme temps, il decrit et explique l’eventail des reponses des parents a l’annonce de cette mauvaise nouvelle, depuis « attente vigilante » jusqu’a « acceptation ». Le besoin de connaissances des parents va des causes et pronostics aux traitements et leurs resultats. Les questions frequemment posees et les suggestions de reponses sont presentees en utilisant les scenarios cliniques d’enfants diagnostiques recemment.

Background and AimsEarly diagnosis of aortic stenosis (AS) is critical to prevent morbidity and mortality but requires skilled examination with Doppler imaging. This study reports the development and validation of a novel deep learning model that relies on 2-dimensional parasternal long axis (PLAX) videos from transthoracic echocardiography (TTE) without Doppler imaging to identify severe AS, suitable for point-of-care ultrasonography.MethodsIn a training set of 5,257 studies (17,570 videos) from 2016-2020 (Yale-New Haven Hospital [YNHH], Connecticut), an ensemble of 3-dimensional convolutional neural networks was developed to detect severe AS, leveraging self-supervised contrastive pretraining for label-efficient model development. This deep learning model was validated in a temporally distinct set of 2,040 consecutive studies from 2021 from YNHH as well as two geographically distinct cohorts of 5,572 and 865 studies, from California and other hospitals in New England, respectively.ResultsThe deep learning model achieved an AUROC of 0.978 (95% CI: 0.966, 0.988) for detecting severe AS with 95.4% specificity and 90% sensitivity in the temporally distinct test set, maintaining its diagnostic performance in both geographically distinct cohorts (AUROC 0.972 [95% CI: 0.969, 0.975] in California and 0.915 [95% CI: 0.896, 0.933] in New England, respectively). The model was interpretable with saliency maps identifying the aortic valve as the predictive region. Among non-severe AS cases, predicted probabilities were associated with worse quantitative metrics of AS suggesting association with various stages of AS severity.ConclusionsThis study developed and externally validated an automated approach for severe AS detection using single-view 2D echocardiography, with implications for point-of-care screening.STRUCTURED GRAPHICAL ABSTRACTKey QuestionIs it feasible to automatically screen for the presence of severe aortic stenosis (AS) using single-view echocardiographic videos without the use of Doppler imaging?Key FindingUsing self-supervised pretraining and ensemble learning, we trained a deep learning model to detect severe AS using single-view echocardiography without Doppler imaging. The model maintained its high performance in multiple geographically and temporally distinct cohorts.Take-home MessageWe present an automated method to detect severe AS using single-view TTE videos, with implications for point-of-care ultrasound screening as part of routine clinic visits and in limited resource settings by individuals with minimal training.An automated deep learning approach for severe aortic stenosis detection from single-view echocardiography evaluated across geographically and temporally distinct cohorts.

Atrial cardiomyopathy has been recognized as having important consequences for cardiac performance and clinical outcomes. The pathophysiological role of the left atrial (LA) appendage and the effect of percutaneous left atrial appendage occlusion (LAAO) upon LA mechanics is incompletely understood. We evaluated if changes in LA stiffness due to endocardial LAAO can be detected by LA pressure-volume (PV) analysis and whether stiffness parameters are associated with baseline characteristics. Patients undergoing percutaneous endocardial LAAO (

To describe the transoral endoscopic arytenopexy (TEA) and evaluate its effects on the rima glottis area (RGA) and laryngeal epiglottic-glottic seal (LEGS). We hypothesize the TEA will be a feasible surgical technique and the TEA will provide a significant increase in RGA with minimal change to the LEGS.Canine cadaveric model.Fifteen medium- to large-breed canine cadavers.Endoscopic photos of the larynx were taken with the epiglottis open for baseline RGA measurement and closed for baseline measurement of exposed RGA and LEGS. A custom endoscopic gag port (EGP) facilitated the TEA, performed by suturing the lateral aspect of the left arytenoid soft tissues to adjacent pharyngeal wall across the piriform recess. Endoscopic photos were repeated to measure changes in RGA and LEGS. A computerized planimetric analysis program was used to calculate baseline RGA and LEGS. The RGA was reported in % change from baseline. The LEGS was reported as intact or altered. A nonparametric Wilcoxon signed-rank test was used to compare baseline to post-TEA RGA.The mean baseline RGA was 0.52 ± 0.28 cmThe TEA was technically feasible and resulted in an increase in RGA while maintaining the LEGS.The TEA may provide a minimally invasive addition to the established techniques for reducing airway resistance while minimizing the impact on the LEGS.

Background Many obstacles exist for adequate hypertension control, including low individual awareness and clinical inertia (CI). In this study, we aimed to determine hypertension prevalence, awareness, treatment, and control among community residents of rural areas of Peravia in Dominican Republic (DR), followed by an assessment of CI in their primary care clinics (PCCs). Methods We interviewed 827 adults from 8 rural communities of Peravia. Demographics, medical history, health care information, and blood pressure (BP) were obtained. We reviewed the community PCC visits of patients with known hypertension or a BP ≥140/90, abstracting medical history and the physician’s action toward uncontrolled BP. Results Of those interviewed, 57% (95% CI: 53%–60%) had hypertension, with 63% (95% CI: 59%–68%) of those aware of their diagnosis. Among individuals with hypertension, 60% (95% CI: 56%–65%) were receiving pharmacological treatment, and only 35% (95% CI: 31%–40%) were controlled. Characteristics associated with awareness were female sex, age >55 years, diabetes, private insurance, and having at least 1 health care visit within the past year. Of the 507 PCC patients reviewed, 340 (67%) had uncontrolled BP. Of these, 220 had no clinical action to address the uncontrolled BP, corresponding to a CI rate of 65%. Conclusions Among rural communities in the DR, undiagnosed hypertension remains common, especially in individuals who are younger, uninsured, or with limited access to health care. For those seen in PCCs, therapeutic intensification to achieve controlled BP is infrequently done. Strategies to address population awareness and CI are needed to improve hypertension control.

Supervisees’ experiences in supervision vary remarkably. To capture such variability, Ellis and colleagues offered a framework for understanding and assessing inadequate, harmful, and exceptional supervision. Although their framework was supported, it did not offer a nuanced understanding of these supervision experiences. Using consensual qualitative research–modified, this study sought to obtain a rich description of inadequate, harmful, and exceptional supervision. Participants ( N = 135) were presented with definitions and provided responses ( n = 156) to open-ended questions describing their inadequate ( n = 63), harmful ( n = 30), and/or exceptional ( n = 63) supervision experiences. Supervisees reporting harmful experiences described supervisors as neglectful and callous, whereas inadequate supervision reflected inappropriate feedback, unavailability, and unresponsiveness. Conversely, exceptional supervision involved safety, clinical paradigm shifts, and modeling specific techniques or theories. Implications for supervision research, theory, and practice are discussed.

Background Social inequalities in non-communicable diseases (NCDs) are evident across all European regions. Employment and working conditions are important determinants of NCDs, however, few comparative studies have examined how these conditions contribute to health inequalities. This study therefore examines the association of non-standard employment and poor working conditions with occupational inequalities in multiple NCDs and whether there are differences by gender and across European regions. Methods We used cross-sectional data from 20 European countries for women and men aged 25–75 (n = 19 876), from round 7 of the European Social Survey. Data were analyzed for self-rated health (SRH) and 9 NCDs: heart/circulatory problems, high blood pressure, arm/hand pain, breathing problems, diabetes, severe headaches, cancer, obesity and depression. We used logistic regression models, stratified by gender, and adjusted rate ratios to examine whether occupational inequalities in NCDs were reduced after adjusting for non-standard employment and poor working conditions, across European regions. Results After adjustment, occupational inequalities were significantly reduced across all regions of Europe. Reductions were particularly large among the lowest occupational group and for poor-SRH, depression and obesity. For these conditions, reductions were in the range of 60–99%. Conclusions Employment and working conditions are important determinants of occupational inequalities in NCDs. Labour market regulations should therefore be considered in the formulation of NCD prevention strategies.

Background: The association of weight change and short-term readmission in patients hospitalized for heart failure (HF) has not been well studied. Methods: We collected clinical and weight data from patients admitted with decompensated HF to a single center (2012−2013). We performed logistic regression to determine the association between weight change and two outcomes: a total of 30-day HF-specific readmission and 30-day all-cause readmission. Results: Admission and discharge weights were documented in 479/658 patients (73%). Weight loss >2 kg was not associated with 30-day all-cause or HF-specific readmission when compared with more modest inpatient weight change (-2 kg to +2 kg; all-cause readmission odds ratio: 0.86; CI: 0.56−1.37; HF-specific readmission odds ratio: 1.15; CI: 0.61−2.16). Conclusion: Among HF inpatients, in-hospital weight loss was not associated with 30-day all-cause or HF-specific readmission.

Purpose A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the cause. Methods and Materials We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cm3 of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy3(RBE). Results Thirteen of 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 ± 2.0 keV/μm, mean ± standard deviation), suggesting possible end-of-range radiobiological effects with increased RBE. The D0.5 of the fractured ribs is 80.3 ± 9.4 Gy3(RBE) with a generic factor of 1.1 and is relatively low compared with historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 ± 12.5 Gy3(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data. Conclusions The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.

Purpose The goal of this study was to assess whether a model-based approach applied retrospectively to a completed randomized controlled trial (RCT) would have significantly altered the selection of patients of the original trial, using the same selection criteria and endpoint for testing the potential clinical benefit of protons compared to photons. Methods and materials A model-based approach, based on three widely used normal tissue complication probability (NTCP) models for radiation pneumonitis (RP), was applied retrospectively to a completed non-small cell lung cancer RCT (NCT00915005). It was assumed that patients were selected by the model-based approach if their expected Δ N T C P value was above a threshold of 5%. The endpoint chosen matched that of the original trial, the first occurrence of severe (grade ≥3) RP. Results Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for lung cancer using RP as the normal tissue endpoint. The analyzed lung trial showed that less than 19% (32/165) of patients enrolled in the completed trial would have been enrolled in a model-based trial, prescribing photon therapy to all other patients. The number of patients enrolled was also found to be dependent on the type of NTCP model used for evaluating RP, with the three models enrolling 3%, 13% or 19% of patients. This result does show limitations in NTCP models which would affect the success of a model-based trial approach. No conclusion regarding the development of RP in patients randomized by the model-based approach could statistically be made. Conclusions Uncertainties in the outcome models to predict NTCP are the inherent drawback of a model-based approach to clinical trials. The impact of these uncertainties on enrollment in model-based trials depends on the predicted difference between the two treatment arms and on the set threshold for patient stratification. Our analysis demonstrates that NTCP differences between proton and photon therapy treatments may be too small to support a model-based trial approach for specific treatment sites, such as lung cancer, depending on the chosen normal tissue endpoint.

The USMCA (NAFTA 2.0), although signed over a year ago, went through several months of renegotiation of certain of its new rules that the Democrat-controlled US Congress wanted altered or strengthened. In December a ‘Protocol of Amendment’ was agreed upon and signed by the three Parties (the USA, Mexico, and Canada). A number of tough, new measures governing pharmaceuticals were revised or deleted, making it potentially easier for generic competition and lower drug costs in all three countries. Rules on protection of labour rights were also strengthened, lowering the threshold at which a complaint of unfair labour practices could be initiated. Procedures for investigating such a complaint or resolving a formal dispute were also improved. Similar procedural improvements were made on measures affecting environmental protection. These Protocol agreements are more health-positive than health-negative, and in the case of pharmaceuticals are of significant impact. Overall, however, these amendments are simply a political fine-tuning of the agreement. Concerns raised in our earlier health impact assessment of the USMCA, notably how the agreement’s regulatory reforms reduce public health policy flexibilities, remain. The agreement continues to subordinate known or potential health costs of many of its measures to dubious claims of aggregate economic gains. Moreover, these gains, if materialized, are likely to accrue to those atop the income/wealth hierarchies in all three nations.

Purpose This paper covers recent developments and applications of the TOPAS TOol for PArticle Simulation and presents the approaches used to disseminate TOPAS. Materials and methods Fundamental understanding of radiotherapy and imaging is greatly facilitated through accurate and detailed simulation of the passage of ionizing radiation through apparatus and into a patient using Monte Carlo (MC). TOPAS brings Geant4, a reliable, experimentally validated MC tool mainly developed for high energy physics, within easy reach of medical physicists, radiobiologists and clinicians. Requiring no programming knowledge, TOPAS provides all of the flexibility of Geant4. Results After 5 years of development followed by its initial release, TOPAS was subsequently expanded from its focus on proton therapy physics to incorporate radiobiology modeling. Next, in 2018, the developers expanded their user support and code maintenance as well as the scope of TOPAS towards supporting X-ray and electron therapy and medical imaging. Improvements have been achieved in user enhancement through software engineering and a graphical user interface, calculational efficiency, validation through experimental benchmarks and QA measurements, and either newly available or recently published applications. A large and rapidly increasing user base demonstrates success in our approach to dissemination of this uniquely accessible and flexible MC research tool. Conclusions The TOPAS developers continue to make strides in addressing the needs of the medical community in applications of ionizing radiation to medicine, creating the only fully integrated platform for four-dimensional simulation of all forms of radiotherapy and imaging with ionizing radiation, with a design that promotes inter-institutional collaboration.

MRI-Linacs couple magnetic resonance imaging (MRI) with a linear accelerator (Linac) to enable MR-guided radiotherapy. The magnetic field is known to cause inhomogeneities in the pattern of dose deposition at centimeter-scale air-tissue interfaces such as pockets of digestive gas but has not been studied at the micrometer scale of lung alveoli. Nanoparticle radio-enhancement is a novel therapy enhancing the dose deposition pattern where nanoparticles are delivered to the radiation target, with proposed application to lung cancer treatment through inhalation of nebulized nanoparticles. This study reports the first investigation of the effect of a magnetic field on the pattern of dose deposition at the micrometer air-tissue interfaces of alveoli in the lung, and the impact of incorporating nanoparticles. Monte Carlo simulations investigated a single alveolus model irradiated with mono-energetic, uni-directional electrons and a multi-alveoli model irradiated with a realistic beam at depth. The magnetic field was found to produce field-strength dependent hot- and cold-spot dose inhomogeneities in the tissue surrounding a micrometer air cavity irradiated with low energy (100 keV) electrons. The most affected regions exhibited a dose increase of 37.30 ± 1.29% and a decrease of 31.58 ± 1.01% with the application of a 1.5 T magnetic field. The addition of nanoparticles to the interior surface layer of the alveolus air cavity increased energy deposit by a constant ratio dependent on the nanoparticle concentration regardless of magnetic field strength. A similar but less pronounced effect was observed for a multi-alveolus model irradiated at depth by a 6 MV photon beam. This result warrants further investigation into the biological impact of micrometer-scale dose inhomogeneity on tumor response and normal tissue complication probability.

The effects of complex, mixed-ion radiation fields on neuronal function remain largely unexplored. Here, we present a complete analysis of the nano-scale physics associated with broad-spectrum galactic cosmic ray (GCR) irradiation in a realistic cornu ammonis 1 (CA1) pyramidal neuron geometry. We simulate the entire 33 ion-energy beam fluence distribution currently in use at the NASA Space Radiation Laboratory galactic cosmic ray simulator (GCRSim). We use the TOol for PArticle Simulation (TOPAS) and TOPAS-nBio Monte Carlo-based track structure simulation toolkits to assess the dosimetry, physics processes, and fluence statistics of different neuronal compartments at the nanometer scale. We also make comparisons between the full GCRSim distribution and a simplified 6 ion-energy spectrum (SimGCRSim). We show that across all physics processes, ionizations mediate the majority of the energy deposition $(68 \pm 1\%)$, though vibrational excitations are the most abundant ($70 \pm 2\%$ of all energy deposition events). We report that neuronal energy deposition by proton and $\alpha$-particle tracks declines approximately hyperbolically with increasing primary particle energy at mission-relevant energies. We also demonstrate an inverted exponential relationship between dendritic segment irradiation probability and neuronal absorbed dose. Finally, we find that there are no significant differences in the average physical responses between the GCRSim and SimGCRSim fluence distributions. To our knowledge, this is the first nano-scale simulation study of a realistic neuron geometry using the GCRSim and SimGCRSim fluence distributions. The results presented here are expected to aid in the interpretation of future experimental results and help guide future study designs., Comment: 37 pages, 16 figures

Recently, a number of clinical studies have explored links between possible Relative Biological Effectiveness (RBE) elevations and patient toxicities and/or image changes following proton therapy. Our objective was to perform a systematic review of such studies. We applied a “Problem [RBE], Intervention [Protons], Population [Patients], Outcome [Side effect]” search strategy to the PubMed database. From our search, we retrieved studies which: (a) performed novel voxel-wise analyses of patient effects versus physical dose and LET (n = 13), and (b) compared image changes between proton and photon cohorts with regard to proton RBE (n = 9). For each retrieved study, we extracted data regarding: primary tumour type; size of patient cohort; type of image change studied; image-registration method (deformable or rigid); LET calculation method, and statistical methodology. We compared and contrasted their methods in order to discuss the weight of clinical evidence for variable proton RBE. We concluded that clinical evidence for variable proton RBE remains statistically weak at present. Our principal recommendation is that proton centres and clinical trial teams collaborate to standardize follow-up protocols and statistical analysis methods, so that larger patient cohorts can ultimately be considered for RBE analyses.

This experimental study compared leak pressures and completion time of intestinal anastomoses performed by novice veterinarians and a Board-certified surgeon using simple interrupted and simple continuous suture patterns. Grossly normal jejunal segments (n = 108) from 6 fresh canine cadavers were used to harvest 8-cm cooled canine cadaveric jejunal segments that were randomly assigned to a control group (12 segments) and 4 treatment groups (24 segments/group, 12 constructs/group): i) simple interrupted anastomoses performed by a Board-certified surgeon (BSI); ii) simple continuous anastomoses performed by a Board-certified surgeon (BSC); iii) simple interrupted anastomoses performed by novice veterinarians (NSI); and iv) simple continuous anastomoses performed by novice veterinarians (NSC). Median (range) initial leak pressure (ILP) for control was 400.2 mmHg (226.0 to 500.0 mmHg), BSI 37.4 (14.4 to 124.0), BSC 32.5 (13.4 to 91.0), NSI 36.5 (22.9 to 62.0), and NSC 47.5 (8.9 to 120.0). No difference was noted between experience (P = 0.73, P = 0.53), suture technique (P = 0.07, P = 0.38), or across treatment groups (P = 0.17, P = 0.94), for ILP or MIP (maximum intraluminal pressure), respectively. Time to construct completion differed based on suture technique (P < 0.0001) and experience (P < 0.0001). The median and mean ILP of all anastomoses exceeded physiologic intraluminal peristaltic pressures. Simple continuous anastomoses were faster to complete overall. Both handsewn anastomosis techniques are appropriate for intestinal anastomoses.

Background There are widespread concerns that workers in precarious employment have suffered the most in the COVID-19 pandemic and merit special attention. The aim of this rapid scoping umbrella review was to examine what evidence exists about how COVID-19 has affected the health of this highly vulnerable group, and what gaps remain to be investigated. Methods Five databases were searched for systematic or scoping reviews from January 2020 to May 2021. The quality of the included reviews was determined using A MeaSurement Tool to Assess systematic Reviews. Results We identified 6 reviews that reported 30 unique relevant primary studies. The included studies indicate that essential (non-health) workers are at greater risk of COVID-19 infection and case fatality than others in their surrounding community. The occupational risk of exposure to COVID-19 also seems to be greater among more precarious categories of workers, including younger workers and workers in low-income and low-skilled occupations. Further, hazardous working conditions faced by many essential workers appear to have amplified the pandemic, as several occupational sites became ‘super-spreaders’, due to an inability to socially distance at work and high contact rates among workers. Finally, employment and financial insecurity generated by the pandemic appears to be associated with negative mental health outcomes. The quality of the included reviews however, and their primary studies, were generally weak and many gaps remain in the evidence base. Conclusions Our study highlights that COVID-19 is creating new health risks for precarious workers as well as exacerbating the pre-existing health risks of precarious employment.

Mechanical stimulation (mechanotherapy) can promote skeletal muscle repair, but a lack of reproducible protocols and mechanistic understanding of the relation between mechanical cues and tissue regeneration limit progress in this field. To address these gaps, we developed a robotic device equipped with real-time force control and compatible with ultrasound imaging for tissue strain analysis. We investigated the hypothesis that specific mechanical loading improves tissue repair by modulating inflammatory responses that regulate skeletal muscle regeneration. We report that cyclic compressive loading within a specific range of forces substantially improves functional recovery of severely injured muscle in mice. This improvement is attributable in part to rapid clearance of neutrophil populations and neutrophil-mediated factors, which otherwise may impede myogenesis. Insights from this work will help advance therapeutic strategies for tissue regeneration broadly.

Background Hepatitis B virus (HBV) serum markers during typical acute self-limited infection are usually depicted as a composite of traditional HBV markers. The current study updates and expands our knowledge of acute hepatitis B with quantitative molecular and serological data on longitudinal samples from five plasmapheresis donors with acute HBV. Methods 137 longitudinal samples from five plasmapheresis donors with acute HBV were tested, four with self-limited infection and one who developed persistent infection. Testing included quantitative hepatitis B surface antigen (HBsAg), antibodies to HBV antigens, quantitative HBV e antigen (HBeAg), HBV DNA, quantitative HBV core-related antigen (HBcrAg), the highly sensitive ARCHITECT HBsAg NEXT (HBsAgNx) assay, and a quantitative research assay for HBV pregenomic RNA (pg RNA). Results Peak levels of HBV DNA and HBsAg differed by several orders of magnitude among the panels (2.2 × 105–2.7 × 109 IU/ml for HBV DNA and 7.9–1.1 × 105 IU/ml for HBsAg). HBsAg levels peaked an average of 2.8 days after the HBV DNA peak. The overall duration of observed HBsAg positivity was increased by the more sensitive HBsAgNx assay compared to the quantitative assay in four panels. Intermittently detectable low-level HBV DNA was observed after HBsAg loss in three panels. Peak HBeAg levels occurred 2–20 days after the DNA peak and ranged from 1.1 to 4.5 × 103 IU/ml. In four panels with resolution of infection, anti-HBs levels indicating immunity (≥ 10 mIU/ml) were detected 19–317 days after the HBV DNA peak. Maximum HBcrAg concentrations ranged from 1 × 105 to > 6.4 × 106 U/ml and correlated with HBeAg values (R2 = 0.9495) and with HBV DNA values (R2 = 0.8828). Peak pgRNA values ranged from 1.6 × 103 to 1.4 × 108 U/ml and correlated with HBV DNA (R2 = 0.9013). Conclusion Traditional and new/novel HBV biomarkers were used to generate molecular and serological profiles for seroconversion panels spanning the early to late phases of acute HBV. Seroconversion profiles were heterogeneous and may be instructive in appreciating the spectrum of acute profiles relative to the typical composite representation.

Background Coronavirus disease 2019 (COVID-19) can cause cardiac injury resulting in abnormal right or left ventricular function (RV/LV) with worse outcomes. We hypothesized that two-dimensional (2D) speckle-tracking assessment of LV global longitudinal strain (GLS) and RV free wall strain (FWS) by transthoracic echocardiography can assist as markers for subclinical cardiac injury predicting increased mortality. Methods We performed 2D strain analysis via proprietary software in 48 patients hospitalized with COVID-19. Clinical information, demographics, comorbidities, and lab values were collected via retrospective chart review. The primary outcome was in-hospital mortality based on an optimized abnormal LV GLS value via ROC analysis and RV FWS. Results The optimal LV GLS cutoff to predict death was −13.8%, with a sensitivity of 85% (95% CI 55–98%) and specificity of 54% (95% CI 36–71%). Abnormal LV GLS > −13.8% was associated with a higher risk of death [unadjusted hazard ratio 5.15 (95% CI 1.13–23.45), p = 0.034], which persisted after adjustment for clinical variables. Among patients with LV ejection fraction (LVEF) >50%, those with LV GLS > −13.8% had higher mortality compared to those with LV GLS −13.8% (−13.7 ± 5.9 vs. −19.6 ± 6.7, p = 0.003), but not associated with decreased survival. Conclusion Abnormal LV strain with a cutoff of >−13.8% in patients with COVID-19 is associated with significantly higher risk of death. Despite normal LVEF, abnormal LV GLS predicted worse outcomes in patients hospitalized with COVID-19. There was no mortality difference based on RV strain.

Purpose Endocardial involvement documented by echocardiography is a major criterion of the modified Duke criteria (MDC) for infective endocarditis (IE). Though transesophageal echocardiography (TEE) is sensitive in the diagnosis of IE, it can be inappropriately used. Methods This retrospective study included all patients who underwent TEE due to bacteremia, fever, and/or endocarditis in a single, tertiary academic medical center in 2013. Data collected from electronic medical charts were as follows: demographics, history, physical examination, blood cultures, and transthoracic (TTE) and TEE findings. Cases were categorized based on appropriate use criteria (AUC) and MDC. An infectious disease (ID) specialist reviewed cases with rarely appropriate TEE use. Results In the 194 patients included, 147 (75.8%) were rated as appropriate, 36 (18.6%) rarely appropriate, and 11 (5.6%) uncertain. Of the 36 with rarely appropriate TEEs, using MDC 31 (86%) were rejected and 5 (14%) were possible for IE. Retrospective chart review by an ID specialist determined that 10 of these patients warranted TEE due to compelling issues, including immunosuppression or complicated infection. Conclusions In this retrospective cohort, almost one fifth of cases were rated as rarely appropriate. However, a review of these cases showed that TEE was often pursued when the clinical situation involved immunosuppression or complex infectious process. There remains room for improvement to our screening process for TEE and a need to implement a nuanced educational plan to better precisely identify appropriate cases for TEE usage.

Background Hepatitis B surface antigen (HBsAg) is the primary marker for diagnosis of acute and chronic hepatitis B. Although HBsAg assays have undergone continuous improvement, gaps remain in the detection of early and late acute infection and occult hepatitis B infection (OBI). Objectives The performance of a prototype, improved sensitivity HBsAg assay run on the ARCHITECT and Alinity instruments was evaluated for detection of early and late acute infection and OBI. Study design Seventy seven early acute samples [positive only for hepatitis B viral DNA (HBV DNA)], twelve seroconversion panels spanning late acute infection, and 101 occult samples (HBsAg negative, positive for HBV DNA and anti-HBc) were tested with the prototype assay and ARCHITECT HBsAg Qualitative II. HBsAg gene sequencing was performed to determine genotype and mutations in the immunodominant region. Results Compared with ARCHITECT HBsAg Qualitative II, the prototype assay showed increased detection of NAT yield samples (28/77, 36.4%,), late acute samples (≥13 days longer detection of HBsAg for 6/12 panels), and OBI samples (11/101, 10.9%). HBsAg sequence data were obtained for 62 samples. Genotypes represented were A1, A2, B2, B4, C1, C2, C5, D3, E, and H. HBsAg escape mutations were found in 4.8% of NAT yield and 38.9% of OBI samples sequenced. Prototype assay values for 188 samples were equivalent on the ARCHITECT and Alinity instruments. Conclusions The new prototype HBsAg assay will be of diagnostic value in providing improved detection of early acute, late acute, and occult HBV infections.

The accurate identification of thrombus in the left atrial appendage with transesophageal echocardiogram (TEE) in patients with atrial fibrillation (AF) before cardioversion is essential. Most of these patients have some grade of spontaneous echo contrast (SEC). Severe SEC is often called "sludge," and its prognosis and treatment are still controversial. Current guidelines suggest the use of ultrasound enhancing agents (UEAs) when significant SEC is present. However, little is known about the utility of the UEAs in the differentiation between sludge and less severe SEC.

Background Endocardial Fibroelastosis is diffuse, accentuated proliferation of ventricular endocardium causing a rare form of restrictive cardiomyopathy in both children and adults. It is an incompletely understood cause of heart failure predominantly in Sub-Saharan Africa associated with high morbidity and mortality. Atrial fibrillation and thrombus formation are common accompanying complications and portend a poor prognosis. Due to rarity of the condition in the developed countries and lack of evidence based options, the optimal strategy for anticoagulation is unclear. Case presentation Herein, we describe a relatively asymptomatic patient with endocardial fibroelastosis who has been found to have atrial fibrillation and a large thrombus in the right atrium. Currently, there is no evidence-based strategy in the management of endocardial fibroelastosis-associated intracardiac thrombus. This case report illustrates a scenario by which the use of apixaban potentially benefited or prevented the thrombus formation compared with warfarin as demonstrated by imaging findings. Conclusions The patients with endocardial fibroelastosis are at risk of developing intracardiac thrombus due to sticky substrate lining cardiac chambers while being relatively asymptomatic. No directed therapy is known for the management of heart failure and any complications of subsequent arrhythmias. The general recommendations follow those of same conditions in other hosts. Novel oral anticoagulant agents can be considered in the treatment of atrial thrombus in the appropriate settings.

Background Although vaccines for hepatitis B virus (HBV) are highly effective, HBV infections in vaccinees occur. Index samples of breakthrough infections are typically anti-HBc negative but HBV DNA positive with protective anti-HBs levels while HBsAg detection may be delayed or absent. HBsAg mutations have been associated with some vaccine breakthrough cases. Methods This research characterizes the serological and molecular profiles of vaccine breakthrough infections in serial samples from two commercially available plasma donor panels. Samples were tested with commercially available assays for HBV antigens and antibodies: HBsAg, HBeAg, anti-HBc, anti-HBc IgM, anti-HBe, and anti-HBs. Different immunoassay approaches for earlier detection of breakthrough infection were explored including hepatitis B core-related antigen (HBcrAg), a research assay for preS2 antigen, and a new prototype ARCHITECT HBsAg assay with improved sensitivity. The prototype HBsAg assay is fully automated and involves no sample pre-treatment. Molecular testing included HBV DNA quantitation and sequencing of preS1, preS2, surface, and basal core promoter/core promoter genes. Results Although the research preS2 antigen assay allowed earlier detection of the breakthrough infections than current HBsAg assays and HBcrAg, the new prototype ARCHITECT HBsAg assay provided the earliest serologic detection. The ability of the new prototype HBsAg assay to detect HBsAg in the presence of anti-HBs was investigated using known concentrations of native HBsAg mixed with anti-HBs from a vaccinee. The results demonstrated that the prototype ARCHITECT assay is more sensitive in detecting HBsAg in the presence of anti-HBs than current HBsAg assays. Sequencing revealed multiple substitutions in preS1, preS2, and S regions for one panel including a rare D144N substitution associated with vaccine breakthrough that emerged with increasing frequency as the breakthrough infection developed. Conclusions When compared with other immunoassay approaches, the new prototype ARCHITECT HBsAg assay allows earlier detection of vaccine breakthrough infections and more sensitive detection of HBsAg in the presence of anti-HBs. Molecular characterization of longitudinal samples demonstrated the progressive appearance of a rare HBsAg mutation associated with vaccine breakthrough.

High atomic number nanoparticles (NPs) have been shown to enhance the effects of radiation in vitro and in vivo. However, NPs are often observed to cluster together, leading to inhomogeneous distribution within the tissue and within cells themselves. The effect of this clustering on the capability of NPs to enhance radiation dose has not yet been fully investigated. In this Monte Carlo simulation study, the dependence of radio-enhancement on a separation parameter characterising NP clustering was investigated. A target water cube of side length 100 μm was simulated containing gold NPs constituting ~1% by mass. The NPs were placed in a cubic grid pattern and the separation distance between nanoparticles was varied. For NPs of 100 nm radius widely separated 2 μm apart, 91% of the total energy deposit was found to occur in the surrounding water, compared to only 56% when the NPs were moved closer together to 0.2 μm. The remaining energy deposit was absorbed by the NPs themselves. A similar trend was observed for NPs of radius 50 nm. The clustering effect was found to persist to greater separations for the larger NPs. The proportion of energy deposit in the available water of the target impacts the potential for cellular damage. Energy deposited within nanoparticles is unlikely to cause biological damage, as ionisations in the surrounding water are required to create radical oxygen species which then progress to cause the biological response to radiation. Clustering of nanoparticles is therefore expected to decrease their effectiveness for enhancing radiotherapy.