A novel entity of HIPK2::YAP1 pulmonary fibromatosis.

BACKGROUND: Pulmonary fibromatosis (PF) is a specific variant of fibromatosis, which is rarely reported occurring in the lung. PF with HIPK2-YAP1 fusion was a novel entity. CASE PRESENTATION: In this report, a 66-year-old male with PF had been smoking over 40 years. Multiple cords and small nodules in both lungs had been detected in a health examination two years earlier at our hospital. But approximately twofold enlarged in the lingual segment of the upper lobe in the left lung were disclosed in this year. Immunohistochemical analysis demonstrated that the vimentin and ß-Catenin were positive in the largest nodule. After underwent a DNA/RNA panel next-generation sequencing (NGS), missense mutations and HIPK2-YAP1 fusion were found in this sample. Ultimately, the case diagnosis as PF with HIPK2-YAP1 fusion after multidisciplinary treatment. Currently, the patient is doing well and recurrence-free at 14 months post-surgery. CONCLUSIONS: It's difficult for patients with complex morphology to make accurate diagnosis solely based on morphology and immunohistochemistry. But molecular detection is an effective method for further determining pathological subtypes.

Outcomes of Hospitalised COVID-19 Patients Arriving With Hypoxic Respiratory Failure.

BACKGROUND: Hypoxia is a common complication seen in people with COVID-19 and can often be the presenting symptom. METHODS: Using a multi-centre observational database, we analysed 3,624 hospitalised COVID-19 PCR-positive patients at Methodist Health System, Dallas, Texas, USA from March 2020 to December 2020. We compared in-hospital death or hospice referral rates and major adverse cardiovascular events (MACE) between patients with four levels of oxygen (O2) requirements (0-1 L/min, 2-10 L/min, 11-20 L/min, 21-100 L/min). MACE included congestive heart failure (CHF) exacerbations, myocardial infarctions (MI), strokes, pulmonary embolism (PE) / deep venous thrombosis (DVT), and shock. Logistic regression analysis was used to determine comorbidities and demographics associated with mortality. Multinomial regression analysis was used to find which of these variables were associated with hypoxia. RESULTS: Patients who arrived needing 0-1 L/min of O2 had reduced risk of mortality compared to those requiring 2-10 L/min (OR=1.54, 95% CI=1.207-1.976, p<0.0001), 11-20 L/min (OR=4.55, 95% CI=3.169-6.547, p<0.0001), or 21-100 L/min (OR=12.06, 95% CI=8.548-17.016, p<0.0001). In addition, patients who arrived needing 0-1 L/min of O2 showed reduced risk of MACE compared to those requiring 2-10 L/min (OR=1.20, 95% CI=1.029-1.409, p<0.0001), 11-20 L/min (OR=2.76, 95% CI 2.06-3.696, p<0.0001), or 21-100 L/min (OR=6.74, 95% CI 4.966-9.155, p<0.0001). CONCLUSION: Hypoxia on arrival is associated with a significantly increased risk of mortality and MACE among hospitalised patients with COVID-19. This data will promote better prognostication and help reduce negative outcomes in an inpatient setting.

Antitumor Efficacy of Liposome-Encapsulated NVP-BEZ235 Combined with Irreversible Electroporation for Head and Neck Cancer.

Irreversible electroporation (IRE) kills tumor cells by the delivery of short pulses of strong electric fields. However, the field strength decreases with distance from the treatment center. When IRE cannot eradicate the entire tumor mass, the surviving tumor cells can regrow. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that has been administered orally in clinical trials. However, its hydrophobicity and poor water solubility make NVP-BEZ235 difficult to deliver to target areas. To improve its pharmacokinetics and therapeutic efficacy, we have encapsulated NVP-BEZ235 in a liposome (termed as L-BEZ). Our current study focuses on the long-term antitumor efficacy of IRE and intratumoral injection of L-BEZ in HN5 head and neck cancer xenografts in nude mice. We compared in vitro efficacy, as well as the effect on tumor size and growth rate in vivo, between IRE alone, IRE + oral BEZ, and IRE + L-BEZ over the course of two months. All animals in the control group were sacrificed by day 36, due to excess tumor burden. Tumors treated with IRE alone grew faster and larger than those in the control group. IRE + oral BEZ suppressed tumor growth, but the growth rate increased to that of the controls toward the end of 21 days. Only IRE + L-BEZ eradicated the tumor masses, with no palpable or extractable tumor mass observed after two months. The combination of IRE and L-BEZ could effectively eradicate tumors and prevent recurrence.

Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection.

Herpesviruses are DNA viruses harboring the capacity to establish lifelong latent-recurrent infections. There is limited knowledge about viruses targeting the innate DNA-sensing pathway, as well as how the innate system impacts on the latent reservoir of herpesvirus infections. In this article, we report that murine gammaherpesvirus 68 (MHV68), in contrast to α- and ß-herpesviruses, induces very limited innate immune responses through DNA-stimulated pathways, which correspondingly played only a minor role in the control of MHV68 infections in vivo. Similarly, Kaposi's sarcoma-associated herpesvirus also did not stimulate immune signaling through the DNA-sensing pathways. Interestingly, an MHV68 mutant lacking deubiquitinase (DUB) activity, embedded within the large tegument protein open reading frame (ORF)64, gained the capacity to stimulate the DNA-activated stimulator of IFN genes (STING) pathway. We found that ORF64 targeted a step in the DNA-activated pathways upstream of the bifurcation into the STING and absent in melanoma 2 pathways, and lack of the ORF64 DUB was associated with impaired delivery of viral DNA to the nucleus, which, instead, localized to the cytoplasm. Correspondingly, the ORF64 DUB active site mutant virus exhibited impaired ability to establish latent infection in wild-type, but not STING-deficient, mice. Thus, gammaherpesviruses evade immune activation by the cytosolic DNA-sensing pathway, which, in the MHV68 model, facilitates establishment of infections.

Case report: Adult NTRK-rearranged spindle cell neoplasms with TPM3-NTRK1 fusion in the pelvic.

NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) are rare soft tissue tumor molecularly characterized by NTRK gene rearrangement, which occurs mostly in children and young adults, and rarely in adults. The abnormal tumor located in superficial or deep soft tissues of human extremities and trunk mostly, and rarely also involves abdominal organs. In this case, we report a malignant NTRK-RSCN that occurred in the pelvic region of an adult. The patient was found to have a large tumor in the pelvic region with a pathological diagnosis of infiltrative growth of short spindle-shaped tumor cells with marked heterogeneity. Immunohistochemistry of this patient showed positive vimentin, pan-TRK and Ki67 (approximately 60%) indicators with negative S100, Desmin and DOG1. Molecular diagnosis revealed c-KIT and PDGFRα wild type with TPM3-NTRK1 fusion, unfortunately this patient had a rapidly progressive disease and passed away. This case highlights the gene mutation in the molecular characteristics of NTRK-RSCNs, and the significance of accurate molecular typing for the diagnosis of difficult cases.

Mortality and Major Adverse Cardiovascular Events in Hospitalized Patients With Atrial Fibrillation With COVID-19.

COVID-19 results in increased incidence of cardiac arrhythmias, including atrial fibrillation (AF). However, little is known about the combined effect of AF and COVID-19 on patient outcomes. This study aimed to determine if AF, specifically new-onset AF (NOAF), is associated with increased risk of mortality and major adverse cardiovascular events (MACEs) in hospitalized patients with COVID-19. This multicenter retrospective analysis identified 2,732 patients with COVID-19 admitted between March and December 2020. Data points were manually reviewed in the patients' electronic health records. Multivariate logistic regression was used to assess if AF was associated with death or MACE. Patients with AF (6.4%) had an increased risk of mortality (risk ratio 2.249, 95% confidence interval [CI] 1.766 to 2.864, p <0.001) and MACE (risk ratio 1.753, 95% CI 1.473 to 2.085, p <0.001) compared with those with sinus rhythm. Patients with NOAF had an increased risk of mortality compared with those with existing AF (odds ratio 19.30, 95% CI 5.39 to 69.30, p <0.001); the risk of MACE was comparable between NOAF and patients with existing AF (p = 1). AF during hospitalization with COVID-19 is associated with a higher risk of mortality and MACE. NOAF in patients with COVID-19 is associated with a higher risk of mortality but a similar risk of MACE compared with patients with existing AF.

Coronary Artery Disease as an Independent Predictor of Cardiovascular Mortality in COVID-19 Patients.

Background: Coronavirus disease 2019 (COVID-19) is associated with increased risk of cardiovascular mortality. However, little is known about the combined effect of coronary artery disease (CAD) and COVID-19 on mortality. We aimed to investigate the incidence of cardiovascular and all-cause mortality in COVID-19 patients with CAD. Methods: This multicenter retrospective study identified 3,336 COVID-19 patients admitted between March and December 2020. Data points were manually reviewed in the patients' electronic health records. Multivariate logistic regression was used to assess whether CAD and its subtypes were associated with mortality. Results: This study shows that CAD was not an independent predictor of all-cause mortality (odds ratio (OR): 1.512, 95% confidence interval (CI): 0.1529 - 14.95, P = 0.723). However, there was a significant increase in cardiovascular mortality in patients with CAD compared to those without (OR: 6.89, 95% CI: 2.706 - 17.53, P < 0.001). There was no significant difference in all-cause mortality in patients with left main artery and left anterior descending artery disease (OR: 1.29, 95% CI: 0.80 - 2.08, P = 0.29). However, CAD patients with a history of interventions (e.g., coronary stenting or coronary artery bypass graft) showed increased mortality compared to those solely treated by medical management (OR: 1.93, 95% CI: 1.12 - 3.33, P = 0.017). Conclusions: CAD is associated with a higher incidence of cardiovascular mortality but not all-cause mortality in COVID-19 patients. Overall, this study will help clinicians identify characteristics of COVID-19 patients with increased risk of mortality in the setting of CAD.

A cross-sectional study of knowledge, attitude, and practice toward COVID-19 in solid organ transplant recipients at a transplant center in the United States.

Objectives: Knowledge, attitude, and practices (KAP) have been widely used during times of pandemic to quantify and locate gaps of care during pandemics. Using this tool, we can identify and target populations who underwent solid organ transplant (SOT) to bolster preventative practices in these patients during COVID-19. Materials and methods: An institution-based cross-sectional study was conducted between June 1, 2020 and June 30, 2021 on patients who underwent a liver and/or kidney transplant at Methodist Dallas Medical Center in Dallas, Texas, USA. A KAP questionnaire of 26 questions about COVID-19 was designed based on the clinical and community management guidelines published by the WHO. The participant's overall KAP was categorized using Bloom's cut-off point. A KAP domain was considered sufficient if the score was between 60 and 100% and insufficient if the score was <60%. The strength of association was assessed by using odds ratio (OR); only significant independent factors in each tested area were assessed. Results: Respondents with children in the household were less likely to have sufficient practices than those who did not [OR = 0.2491, 95% Confidence Interval (0.0893-0.6120), p = 0.001]. We also found that sufficient levels of knowledge correlated with higher likelihood of sufficient levels of practices [OR = 4.94, 95% CI (1.646-14.2159), p < 0.005]. Interestingly, we found that sufficient levels of attitude did not correlate with sufficient levels of practice (p = 0.201). Conclusion: Our study found that knowledge and having children in the household correlated with higher levels of practice.

Balloons for kids: Anatomic candidacy and optimal catheter size for pediatric resuscitative endovascular balloon occlusion of the aorta.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potential adjunct in pediatric trauma patients with noncompressible truncal and pelvic hemorrhage; however, there are little data evaluating the anatomic considerations of REBOA in children. We evaluated the vascular dimensions and anatomic limitations of using REBOA in children. METHODS: Computed tomography scans of pediatric patients performed between February 2016 and October 2019 were retrospectively reviewed by two investigators. Vascular measurements included diameters of aorta zones I and III, common iliac arteries, external iliac arteries, and common femoral arteries (CFAs), and distances between access site (CFA) and aorta zones I and III. Measurements were grouped within Broselow categories, based upon patient height. Interrater reliability for measurements was determined using intraclass correlation coefficients. Vascular dimensions were correlated with the patient's height, weight, and body mass index using linear regression analysis. RESULTS: A total of 557 computed tomography scans met the inclusion criteria and were reviewed. Measurements of vessel diameter and distance from the CFA to aorta zones I and III were determined and grouped by Broselow category. Patient age ranged from 0 to 18 years, with a male to female ratio of 1:1. Overall interrater reliability of vessel measurements was good (average intraclass correlation coefficient, 0.90). Vessel diameter had greatest correlation with height (R2 = 0.665, aorta zone I; R2 = 0.611, aorta zone III) and poorly correlated with body mass index (R2 = 0.318 and R2 = 0.290, respectively). CONCLUSION: This study represents the largest compilation of REBOA-related pediatric vessel diameter measurements and the first to provide data on distance between access site and balloon deployment zones. Based on our findings, the 7-Fr REBOA catheter would be appropriate for the Black, Green, and Orange Broselow categories, and a 4-Fr REBOA catheter would be warranted for Yellow, White, and Blue Broselow categories. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.

Internal Built-In Electric Fields at Organic-Inorganic Interfaces of Two-Dimensional Ruddlesden-Popper Perovskite Single Crystals.

Two-dimensional (2D) organic-inorganic hybrid Ruddlesden-Popper perovskites (OIRPPs), which consist of naturally formed "multiple quantum well (MQW)-like" structure, have received considerable interest in optoelectronic applications, owing to their outstanding optical properties and tailorable functionalities. While the quantum-confined electrons and holes at an MQW structure are under an applied electric field, the tilt of the energy bands may cause a significant influence on their optical properties. This work demonstrates the presence of internal built-in electric fields (BIEFs) at the as-synthesized 2D OIRPP single crystals. Spontaneous Franz-Keldysh oscillations, which usually act as the fingerprint to account for the presence of BIEFs in the MQW-like structures, are observed at 2D OIRPPs by the highly sensitive differential technique of modulated thermoreflectance spectroscopy. The strength of BIEFs at 2D OIRPP single crystals reduces with increased n values due to the increased width of the quantum well. The origin of the presence of BIEFs at 2D OIRPPs is further unveiled by atomically resolved scanning tunneling microscopy on their electronic band structures at organic-inorganic interfaces. Unlike the conventional III-V MQW semiconductors with the BIEFs, which are dominated by the spatial concentration gradients at heterointerfaces, the presence of BIEFs at the 2D OIRPP single crystals is attributed to the molecular dipoles within organic spacers pointing to the organic-inorganic interfaces. The discovery of internal BIEFs at the 2D OIRPPs may provide deep insight into understanding the fundamental optical properties for the future design of large-area and low-cost perovskite optoelectronic devices.

Something Out of Nothing: A Rare Case of Pulmonary Renal Syndrome With Pauci-Immune Glomerulonephritis and Diffuse Alveolar Hemorrhage With Negative Serologies.

BACKGROUND: Pauci-immune crescentic glomerulonephritis (CrGN) is one of the most common etiologies of rapidly progressive glomerulonephritis. This condition presents with crescentic glomerulonephritis with little or no immunoglobulin staining and negative serological workup aside from a positive antineutrophil cytoplasmic autoantibody (ANCA). Typically, patients with pauci-immune CrGN have an underlying systemic small vessel vasculitis, but in rare cases, it presents without any known vasculitis or ANCA. Pauci-immune ANCA negative CrGN is often strictly isolated to the kidneys. In this case, we present a patient with ANCA negative, pauci-immune CrGN with severe diffuse alveolar hemorrhage. CASE PRESENTATION: A 66-year-old Hispanic woman with a past medical history of controlled hypertension presented with fatigue and dysphagia. On admission, her vital signs were significant for hypoxia on room air, and her physical exam was remarkable for crackles bilaterally. The initial laboratory results revealed anemia (hemoglobin 5.2 g/dL), hyperkalemia (6.3 mmol/L), elevated creatinine (4.50 mg/dL, with a baseline of 0.9mg/dL). Urinalysis showed moderate blood and urine protein (200 mg/dL). Urine microscopic examination showed 25-50 RBCs seen/high power field. The patient was admitted to ICU due to hypoxia, a computed tomography scan of the chest/abdomen/pelvis was obtained and revealed multifocal pulmonary consolidations. A blood transfusion was ordered. The patient began to have hemoptysis and subsequent bronchoscopy showed diffuse alveolar hemorrhage. ICU team proceeded to intubate her as the hemorrhage continued to worsen. Further workup revealed a positive anti-nuclear antibodies (ANA) of 1:40, but otherwise negative serologies including myeloperoxidase (MPO)-ANCA, glomerular basement membrane antibody, and anti-double stranded DNA. Kidney biopsy showed necrotizing glomerulonephritis with crescents and negative immunofluorescence. She was diagnosed with pauci-immune ANCA-negative vasculitis with associated diffuse alveolar hemorrhage and nephritis based on these results and was started on pulse-dose steroids. The patient was started on intravenous (IV) high-dose cyclophosphamide, which helped improved the overall clinical condition significantly. After creatinine began trending down and urine output improved, the patient was discharged on a regimen of daily oral cyclophosphamide and steroid taper. Patient oxygen requirements decreased and she was sent home with supplemental oxygen while requiring 3L/min of oxygen. CONCLUSION: Pauci-immune and ANCA-negative glomerulonephritis with concurrent diffuse alveolar hemorrhage is exceptionally rare. In this situation, medical management relied on clinical evidence from similar populations in the use of steroids and cyclophosphamide. This case report aims to shed more light on the clinical progression and management of this condition. Here we present a case of pulmonary-renal syndrome with biopsy-proven glomerulonephritis but without ANCA positive serologies.

Antitumor efficacy of liposome-encapsulated NVP-BEZ 235 in combination with irreversible electroporation.

Irreversible electroporation (IRE) is an emerging minimally invasive tumor ablation technique that delivers short pulses of strong electric fields and kills cancer cells by disrupting their cell membranes with the electric pulses. However, clinical studies report that more than 10% of local tumor recurrences occur at the original ablated site. NVP BEZ-235 (BEZ) is a dual PI3K/mTOR inhibitor that has substantial anticancer effects. However, the clinical trials of BEZ was not satisfactory because of its low bioavailability and high toxicity, which stemmed from the use of oral administration of high doses over a long period of time. In this research, we prepared a liposomal formulation of BEZ (L-BEZ) for intratumoral injection and studied its antitumor efficacy alone and in combination with IRE. We hypothesized that IRE could release BEZ from the liposomes and that the combination could decrease tumor viability. Our results show that IRE released BEZ from its liposomal encapsulation. The combination of L-BEZ and IRE killed more Hep3B tumor cells in vitro than did L-BEZ or IRE alone and also inhibited cancer cell proliferation in nude mice bearing Hep3B xenografts. Combination of chemotherapeutic agent loaded nanoparticles could enhance the antitumor efficacy of IRE.