Citations

Abstract Objective . Estimation of the probability density of the microdosimetric quantities in macroscopic matter is indispensable for applying the concept of microdosimetry to medical physics and radiological protection. The Particle and Heavy Ion Transport code System (PHITS) enables estimating the microdosimetric probability densities due to its unique hybrid modality between the Monte Carlo and analytical approaches called the microdosimetric function. It can convert the deposition energies calculated by the macroscopic Monte Carlo radiation transport simulation to microdosimetric probability densities in water using an analytical function based on the track-structure simulations. Approach . In this study, we improved this function using the latest track-structure simulation codes implemented in PHITS. The improved function is capable of calculating the probability densities of not only the conventional microdosimetric quantities such as lineal energy but also the number of ionization events occurring in a target site, the so-called ionization cluster size distribution, for arbitrary site diameters from 3 nm to 1 μ m. Main results . The accuracy of the improved function was well verified by comparing the microdosimetric probability densities measured by tissue-equivalent proportional counters with the corresponding data calculated in this study. Test calculations for clonogenic cell survival using the improved function coupled with the modified microdosimetric kinetic model suggested a slight increase of its relative biological effectiveness compared with our previous estimations. As a new application of the improved function, we calculated the relative biological effectiveness of the single-strand break and double-strand break yields for proton irradiations using the updated PHITS coupled with the simplified DNA damage estimation model, and confirmed its equivalence in accuracy and its superiority in computational time compared to our previously proposed method based on the track-structure simulation. Significance . From these features, we concluded that the improved function could expand the application fields of PHITS by bridging the gap between microdosimetry and macrodosimetry.

Abstract Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Introduction: Patients with acute heart failure (AHF) exacerbation are susceptible to complications in the setting of COVID-19 infection. Data regarding the clinical outcomes of COVID-19 in patients admitted with AHF is limited. Methods: We used the national inpatient sample database by utilizing ICD-10 codes to identify all hospitalizations with a diagnosis of AHF in 2020. We classified the sample into AHF with COVID-19 infection versus those without COVID-19. Primary outcome was in-hospital mortality. Secondary outcomes were acute myocardial infarction, need for pressors, mechanical cardiac support, cardiogenic shock, and cardiac arrest. Also, we evaluated for acute pulmonary embolism (PE), bacterial pneumonia, need for a ventilator, and acute kidney injury (AKI). Results: We identified a total of 694,920 of AHF hospitalizations, 660,463 (95.04%) patients without COVID-19 and 34,457 (4.96%) with COVID-19 infection. For baseline comorbidities, diabetes mellitus, chronic heart failure, ESRD, and coagulopathy were significantly higher among AHF patients with COVID-19 ( P < .01). While CAD, prior MI, percutaneous coronary intervention, and coronary artery bypass graft, atrial fibrillation, chronic obstructive pulmonary disease, and peripheral vascular disease were higher among those without COVID-19. After adjustment for baseline comorbidities, in-hospital mortality (aOR 5.08 [4.81 to 5.36]), septic shock (aOR 2.54 [2.40 to 2.70]), PE (aOR 1.75 [1.57 to 1.94]), and AKI (aOR 1.33 [1.30 to 1.37]) were significantly higher among AHF with COVID-19 patients. The mean length of stay (5 vs 7 days, P < .01) and costs of hospitalization ($42,143 vs $60,251, P < .01) were higher among AHF patients with COVID-19 infection. Conclusion: COVID-19 infection in patients with AHF is associated with significantly higher in-hospital mortality, need for mechanical ventilation, septic shock, and AKI along with higher resource utilization. Predictors for mortality in AHF patients during the COVID-19 pandemic, COVID-19 infection, patients with end-stage heart failure, and atrial fibrillation. Studies on the impact of vaccination against COVID-19 in AHF patients are needed

Background: All-suture anchors and knotless anchors are increasingly used in the repair of anteroinferior labral tears in patients with shoulder instability. Optimal repair constructs may limit recurrent instability. Purpose: To perform a quantitative biomechanical comparison of 3 labral fixation devices for soft tissue Bankart lesions: knotless soft-body tensionable anchor (SB knotless), knotted soft-body anchor (SB knotted), and knotless hard-body PEEK (polyether ether ketone) interference anchor (HB knotless). Study Design: Controlled laboratory study. Methods: A total of 21 glenoid specimens were randomized into 3 groups: SB knotless, SB knotted, and HB knotless. Artificial Bankart lesions were created at the anteroinferior labrum. Anchors were placed at the 3:30, 4:30, and 5:30 clockface positions, and sutures were passed through 1 cm of tissue. Anchors were tested simultaneously as one construct by pulling capsular tissue connected to the anteroinferior quadrant. Cyclic loading (5-25 N, 100 cycles) was followed by load-to-failure testing (15 mm/min). Biomechanical testing variables were collected, and failure mechanisms were recorded per individual anchor. Results: There were no differences in baseline specimen characteristics. There was no difference in elongation during cyclic loading ( P = .40). The ultimate load to failure between SB knotless (309.7 ± 125.6 N), SB knotted (226.4 ± 34.8 N), and HB knotless (256.5 ± 90.5 N) did not significantly differ ( P = .25). Failure mechanisms differed among groups ( P = .008); mechanisms included anchor pullout (SB knotless: 33.3%; SB knotted: 23.8%; HB knotless: 28.6%), suture pull-through (SB knotless: 66.7%; SB knotted: 38.1%; HB knotless: 33.3%), and anchor fixation method failure, defined as knot failure for knotted anchors or locking mechanism failure for knotless anchors (SB knotless: 0.0%; SB knotted: 38.1%; HB knotless: 38.1%).) Conclusion: The SB knotless, SB knotted, and HB knotless labral fixation anchors studied exhibited comparable elongation during cyclic loading, stiffness, and ultimate loads to failure in a cadaveric model. However, the failure mechanisms significantly differed, as SB knotless anchors failed primarily from suture pull-through, while SB knotted and HB knotless anchors were subject to knot failure and locking mechanism failure, respectively. Clinical Relevance: These data support the benefit of SB knotless anchors for anteroinferior labral repair in limiting knot failure typically seen with knotted anchors, perhaps demonstrating that all-suture anchors may have better locking mechanism quality than their PEEK counterparts.

Abstract Cancer stem cells (CSCs) defined as a small fraction of cells within malignancies have been isolated from tumors with different histological origins with stem related characteristics such as self-replicating potential, tumorigenesis, and therapy resistance. The dynamic communication between CSCs and tumor microenvironment particularly immune cells orchestrates their fate and plasticity as well as the patient outcome. According to recent evidence, it has been reported that they harness different immunological pathways to escape immunosurveillance and express aberrantly immunomodulatory agents or decreased levels of factors forming antigen presenting machinery (APM), subsequently followed by impaired antigen presentation and suppressed immune detection. As effective therapies are expected to be able to eradicate CSCs, mechanistic understanding of such interactions can provide insights into causes of therapy failure particularly in immunotherapy. Also, it can contribute to enhance the practical interventions against CSCs and their immunomodulatory features resulting in CSCs eradication and improving patient clinical outcome. The aim of this review is to explain the present knowledge regarding the immunobiology of CSCs and the immunoevasion mechanisms they use.

Introduction Rapidly increasing costs of medication acquisition can pose a challenge for health-system pharmacy budgets. The impact of dose-rounding in a pediatric oncology population has not previously been well documented and a retrospective review was undertaken to quantify the potential cost benefits. Methods A retrospective chart review of patients with an oncologic diagnosis was performed for cytotoxic agents, asparaginase products, and biotherapy administered between January 1, 2014, and December 31, 2017. In the analysis, orders that could be rounded down to the nearest vial size by 5 or 10% were included. Medication pricing information was based on wholesale acquisition cost (WAC) and was provided by the Department of Pharmacy. Cost savings per medication were determined by multiplying the WAC of the medication by the number of vials saved. Results Over a 4-year span, 347 patients were evaluated and 552 out of a possible 3110 orders (17.7%) met criteria for a theoretical cost savings of approximately $1,126,000 (∼$3200 per patient). Rounding down doses by up to 5% resulted in a potential savings of about $529,000. When rounding was extended to 5–10% of the originally ordered dose, an additional $597,000 of approximate cost savings could have been realized. The medications with the largest impact on cost savings were rituximab, pegaspargase, and erwinia asparaginase. Conclusions For pediatric oncology patients, there exists a unique potential cost savings opportunity if doses are rounded down within 5 or 10% of the originally ordered weight-based or body surface area-calculated dose.

TB remains a leading cause of morbidity and mortality worldwide. However, most infected immunocompetent individuals are asymptomatic and only 5–10% of these will eventually develop active TB during their lifetime (typically within 2 years after exposure). Therefore, rapid diagnosis and efficient management of asymptomatic infected individuals who are at the highest risk of progression and transmission remain major clinical and public health challenges. In recent years, there has been important scientific progress in our understanding of the spectrum of asymptomatic Mycobacterium tuberculosis (Mtb) infections that not only includes the dynamic state of latent TB infection (LTBI), but also the preclinical state of incipient and subclinical TB. The latter is possibly as prevalent as symptomatically active TB and potentially contributes to global Mtb transmission in various settings. We summarize the latest developments and current challenges of the existing testing tools for LTBI and describe promising biomarkers and diagnostics for the spectrum of asymptomatic TB. Following the negative results of a recent clinical trial for a biomarker-guided preventive therapy approach, we also suggest some treatment options for incipient TB.

Key message Diffuse pulmonary meningotheliomatosis (DPM) is an ultra‐rare pulmonary disease characterized by innumerable bilateral minute meningothelial‐like nodules, sometimes presenting a characteristic ‘cheerio‐sign’ on imaging. Most patients with DPM are asymptomatic and experience no disease progression. Although little is known about its nature, DPM may be associated with pulmonary malignancies, mostly lung adenocarcinoma.

An elderly man with COPD and heart failure was admitted to the Family Medicine Inpatient Service from the Emergency Department (ED) after experiencing acute onset of shortness of breath at home. He had recently been briefly hospitalized with COVID pneumonia. Upon arrival in the ED, he was requiring continuous positive airway pressure to maintain oxygen saturations. Overall, physical exam was notable for mild respiratory distress. Lab evaluation was unremarkable, but chest x-ray showed a right sided pneumothorax. Spontaneous pneumothoraces have been described in post-COVID cases, with COPD and mechanical ventilation thought to be risk factors. Treatment consists of supportive cares, needle decompression and thoracostomy if necessary. Providers should be aware of this rare albeit serious complication and monitor higher risk patients appropriately.