Citations

Mutations provide an enduring record Somatic mutations pepper our cells with change, but because they are not in the germline, they do not propagate to the next generation. Bizzotto et al. leveraged data on the distribution of somatic mutations in adults to take a backward look at the earliest moments of human development. Calculation of cellular lineages on the basis of shared somatic mutations shows the number of cells from which the body will develop when the human embryo gastrulates. The lineage for forebrain cells is identifiable, as are the asymmetrical fates spun out of many of the gastrula cells. Science , this issue p. 1249

BackgroundA recent analysis suggested potential narrowing of the gender gap in research productivity in the field of rhinology. This analysis did not, however, provide insight into how the genders are represented in the rhinologic literature. This study aimed to evaluate 11 years of literature to evaluate for gender differences in authorship position, collaborations, category and content of research, citations, and funding to gain perspective on how gender and authorship has changed over time.MethodsAuthorship data for all articles on rhinologic subject matter published between January 1, 2008 and December 31, 2018 in four otolaryngology journals was collected. The gender of authors was determined by protocol. Category and content of research and funding status/source were additionally obtained.ResultsData were collected from 2666 articles. Gender of 14,510 authors was determined. Female authors accounted for 23% of the overall authors and male authors accounted for 77%. Female first authorship increased significantly over time, but there was no change in female senior authorship. The percentage of female authors steadily increased over time, whereas male authorship decreased slightly. Mixed gender teams were shown to be increasing in frequency. Women published more than expected in basic science and allergy and less than expected in skull base. On funded studies, women were significantly underrepresented as senior authors.ConclusionThis study represents the first assessment of gender differences in the rhinology literature. Areas where female representation can improve include senior authorship, increased involvement in skull base publications, and increased funding.

Abstract GLP-1 agonists have become increasingly interesting as a new Parkinson’s disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. “Motivated” behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.

Preclinical testing platforms have been instrumental in the research and development of thrombectomy devices. However, there is no single model which fully captures the complexity of cerebrovascular anatomy, physiology, and the dynamic artery-clot-device interaction. This article provides a critical review of phantoms, in-vivo animal, and human cadaveric models used for thrombectomy testing and provides insights into the strengths and limitations of each platform. Articles published in the past 10 years that reported thrombectomy testing platforms were identified. Characteristics of each test platform, such as intracranial anatomy, artery tortuosity, vessel friction, flow conditions, device-vessel interaction, and visualization, were captured and benchmarked against human cerebral vessels involved in large-vessel occlusion stroke. Thrombectomy phantoms have been constructed from silicone, direct 3D-printed polymers, and glass. These phantoms represent oversimplified patient-specific cerebrovascular geometry but enable adequate visualization of devices and clots under appropriate flow conditions. They do not realistically mimic the artery-clot interaction. For the animal models, arteries from swine, canines, and rabbits have been reported. These models can reasonably replicate the artery-clot-device interaction and have the unique value of evaluating the safety of thrombectomy devices. However, the vasculature geometries are substantially less complex and flow conditions are different from human cerebral arteries. Cadaveric models are the most accurate vascular representations but with limited access and challenges in reproducibility of testing conditions. Multiple test platforms should be likely used for comprehensive evaluation of thrombectomy devices. Interpretation of the testing results should take into consideration platform-specific limitations.

Abstract Background & Aims The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non‐Asians, but little is known regarding the effect of ethnicity on outcomes of HBV‐related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non‐Asian patients with HBV‐related HCC. Methods We analyzed the baseline characteristics and long‐term survival of 613 Asian and 410 non‐Asian patients with HBV‐related HCC from three US and one Spanish centre. Results Overall, non‐Asian patients were more likely to have HIV or hepatitis C co‐infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤ .04). Compared with Asians, non‐Asians were more likely to be listed for transplantation ( P < .0001) and undergo HCC treatment with curative intent ( P = .003). Propensity‐score matching on HCC diagnosis year, gender and age was performed to balance the two groups for survival analysis and yielded 370 pairs of patients. There was no significant difference in survival overall ( P = .43) and among patients with cirrhosis ( P = .57). Among patients without cirrhosis, non‐Asians had poorer 5‐year survival compared with Asians (37.6% vs 53.7%, P = .01), and was associated with poorer survival after adjusting for age, gender, diabetes, alcohol, co‐infections, diagnosis date, antiviral therapy, BCLC stage and HCC treatment (adjusted HR 2.01 [95% CI 1.07‐3.74], P = .03). Conclusion Among HBV‐related HCC patients, non‐Asians presented with more advanced BCLC stage compared to Asians. Non‐Asian ethnicity was independently associated with twice the risk of mortality among patients without cirrhosis, but not among those with cirrhosis. Additional studies are needed to clarify this disparity.

Abstract The role of thoracic CT (computerized tomography) in monitoring disease course of COVID-19 is controversial. The purpose of this study is to investigate the risk factors and predictive value of deterioration on repeatedly performed CT scan during hospitalization. All COVID-19 patients treated in our isolation ward, from January 22, 2020 to February 7, 2020, were reviewed. Patients included were categorized into RD (Radiological Deterioration) group or NRD (No Radiological Deterioration) group according to the manifestation on the CT routinely performed during the hospitalization. All clinical data and CT images were analyzed. Forty three patients were included in our study. All are moderate cases with at least 4 CT scans each. Eighteen (42.9%) patients had radiological deteriorations which were all identified in CT2 (the first CT after admission). Patients in RD group had lower leukocyte count (P = .003), lymphocyte count (P = .030), and higher prevalence (P = .012) of elevated C-reactive protein (CRP) at admission. NRD patients had a lower prevalence of reticulations (P = .034) on baseline CT (CT1, performed within 2 days before admission) and a longer duration between symptom onset and the time of CT2 (P < .01). There was no significant difference in hospital stay or fibrotic change on CT4 (follow-up CT scan performed 4 weeks after discharge) between 2 groups. Shorter duration between symptom onset and CT2 time (odds ratio [OR], 0.436; 95% confidence interval: 0.233–0.816; P < .01) and lower leukocyte count in baseline evaluation (OR, 0.316; 95% CI: 0.116–0.859; P < .05) were associated with increased odds of radiological deterioration on CT image during hospitalization. For moderate COVID-19 patients, the value of routinely performed CT during the treatment is limited. We recommend avoiding using CT as a routine monitor in moderate COVID-19 patients.

Abstract TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer that has no standard treatment for advanced disease. We described comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion, certain fusion isoforms and high somatic copy number alteration burdens were associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibited low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis revealed five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which showed association with fusion patterns and prognosis. Specifically, the high angiogenesis/stroma/proliferation cluster exclusively consisted of tumors with ASPSCR1-TFE3 fusion, which was likely to benefit from combination of immune checkpoint and anti-angiogenesis inhibitors. Our findings reveal the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.

Introduction: Recent studies suggest that suction based thrombectomy leads to better recanalization with RBC-rich clots while stent-retrievers perform better with fibrin-rich clots. The ability to determine real-time histology of clots, in the setting of large vessel occlusion (LVO), could potentially lead to improved recanalization and better clinical outcomes while simultaneously reducing procedural costs. There is an unmet need for technology that would allow for accurate assessment of real-time clot histology in LVOs. Hypothesis: Bioimpedance measurements can be used to predict real-time clot histology. Methods: We constructed an in vitro test bed to measure the bioimpedance of clot analogs with different RBC percentages. The test bed includes a cylindrical chamber with a gold electrode embedded at the bottom. A mixture of human RBCs and plasma was injected into the chamber and coagulation was induced by adding calcium chloride solution. After coagulation, another gold electrode was used to sandwich the clot. Both electrodes were connected to an inductance, capacitance, and resistance (LCR) meter and a low-voltage (10 mV) excitation was sent to the clot at 1 to 201 kHz. We fabricated 5 types of clot analogs by mixing human RBCs and plasma with different RBC percentages (10%, 30%, 50%, 70%, and 90%). Clot types were measured 3 times. The Pearson correlation coefficient was calculated and used to evaluate the relationship between clot bioimpedance and RBC percentage. Results and Conclusions: Clot impedance decreases with the excitation frequency and clots with higher RBC percentages had higher impedance at all excitation frequencies (Fig. 1). The impedance was strongly and positively related to the RBC percentage ( r = .996, p = .0004). By minimizing the electrode size and integrating them into catheters, stents, or wires, such technology could inform clinicians of clot composition and guide device selection for optimum recanalization.

Introduction: Suction catheters and stent retrievers are based on the classical paradigm of “en bloc” removal of emboli by generation of tensile forces by vacuum or device withdrawal. However, in this process emboli elongate and fracture leading to fragmentation. Fragments can migrate downstream or remain impacted in the arterial wall resulting in a residual occlusion. Hypothesis: Clot ingestion is biomechanically superior to “en bloc” removal and leads to higher recanalization rates with less complications. Methods: To test this hypothesis, we present a hybrid test bed consisting of pressurized human brains which was developed and validated for large vessel occlusion (LVO) and revascularization. We fabricated 3 types of representative embolus analogs (EAs) (elastic, fragment-prone and stiff) and recreated 105 LVO in twenty-four fresh human brains with the vasculature connected to an hydraulic system to mimic physiological flow and pressures. Recanalization was attempted in 61 LVO cases by Direct Aspiration (DA) using an 068 catheter and in 44 LVO cases combining Stent Retriever with Aspiration (SR+A). Rates of successful recanalization (SR, Grade 2b or higher) and complete recanalization (CR, Grade 2c or higher) were measured. Up to 4 attempts were done before declaring a failure (Grade 2a or lower). Results: DA resulted in 90% of SR, 79% of CR, 61% of first pass SR and 49% of first pass CR. SR+A resulted in 34% of SR, 34% of CR, 23% of first pass SR and 14% of first pass CR. Elastic EA were associated with 88% of SR, 85% of CR, 61% of first pass SR and 52% of first pass CR. Stiff EAs were associated with 64% of SR, 64% of CR, 36% of first pass SR and 36% of first pass CR. Fragment-prone EAs were associated with 64% of SR, 40% of CR, 38% of first pass SR and 21% of first pass CR. Conclusion: Clot ingestion is biomechanically superior to “en bloc” removal and leads to the highest rates of SR, CR and first pass recanalization. DA achieves higher recanalization rates than SR+A. Elastic clots are associated with the highest rates or recanalization, followed by stiff clots and finally by fragment-prone clots.