tbuckley/cabot-search huggingface dataset:
Detection of cell-free microbial DNA using a contaminant-controlled analysis framework
Authors: Enrique Zozaya-Valdés, Stephen Q. Wong, Jeanette Raleigh, Athena Hatzimihalis, Sarah Ftouni, Anthony T. Papenfuss, Shahneen Sandhu, Mark A. Dawson, Sarah-Jane Dawson
Journal: Genome biology (2021)

Abstract Background The human microbiome plays an important role in cancer. Accumulating evidence indicates that commensal microbiome-derived DNA may be represented in minute quantities in the cell-free DNA of human blood and could possibly be harnessed as a new cancer biomarker. However, there has been limited use of rigorous experimental controls to account for contamination, which invariably affects low-biomass microbiome studies. Results We apply a combination of 16S-rRNA-gene sequencing and droplet digital PCR to determine if the specific detection of cell-free microbial DNA (cfmDNA) is possible in metastatic melanoma patients. Compared to matched stool and saliva samples, the absolute concentration of cfmDNA is low but significantly above the levels detected from negative controls. The microbial community of plasma is strongly influenced by laboratory and reagent contaminants introduced during the DNA extraction and sequencing processes. Through the application of an in silico decontamination strategy including the filtering of amplicon sequence variants (ASVs) with batch dependent abundances and those with a higher prevalence in negative controls, we identify known gut commensal bacteria, such as Faecalibacterium , Bacteroides and Ruminococcus , and also other uncharacterised ASVs. We analyse additional plasma samples, highlighting the potential of this framework to identify differences in cfmDNA between healthy and cancer patients. Conclusions Together, these observations indicate that plasma can harbour a low yet detectable level of cfmDNA. The results highlight the importance of accounting for contamination and provide an analytical decontamination framework to allow the accurate detection of cfmDNA for future biomarker studies in cancer and other diseases.
In a world of horses, don't miss zebras: A case of e-cigarette or vaping use-associated lung injury (EVALI) in the COVID-19 era
Authors: R. Abdelmaseih, R. Abdelmasih, S. Hasan, J. J. Chacko, R. R. De Oleo
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

INTRODUCTION: E-Cigarette use or vaping has rapidly become the most common alternative to traditional tobacco smoking among youth. The use of e-cigarettes is still highly controversial from medical, scientific and psychological standpoints because of the insufficient formal research available on the effects of vaping on the public health. Moreover, as of September 2019;CDC and FDA started a wide investigation after a multistate outbreak of lung injury associated with e-cigarette products use (EVALI). Here, we present a case report of EVALI in the COVID-19 era that was initially isolated for a high suspicion of COVID-19 pneumonia due to its similarities. CASE PRESENTATION: 20-year-old female presented to the hospital with worsening dysnea, productive cough with gray/yellow sputum, nausea, vomiting, and fever for 1 week. She was in severe respiratory distress and was subsequently sedated and intubated. Lung examination was consistent with diffuse rhonchi throughout the lungs. Chest radiograph showed bilateral extensive areas of parenchymal infiltrates concerning for atypical infectious process. Computed Tomography (CT) scan of chest showed bilateral lower lobe consolidation with air bronchograms and reticulations. Laboratory workup was remarkable for leukocytosis with lymphopenia, and elevated inflammatory markers and transaminases. Due to high suspicion of COVID-19, nasopharyngeal specimen was sent for PCR analysis, and isolation precautions were initiated. Patient was started on empiric antibiotics and steroids. Influenza antigen, streptococcus pneumonia, legionella and mycoplasma were all negative. Upon further questioning, her mother reported that the patient has recently started vaping and uses orange juice in her vape. COVID-19, MRSA screen, and sputum culture were all negative. Pro-calcitonin was negative. Patient was extubated and showed significant improvement. She was discharged home with supplemental oxygen. DISCUSSION: According to CDC statistics in 2018, more than 3.6 million U.S middle and high school students used e-cigarettes in 30 days. Among current users aged 18-24 years, 40% had never been regular cigarette smokers. E-cigarettes use has been linked to hazardous adverse effects, most importantly EVALI, through triggering cytokine expression, airway hyper-reactivity, altered mucin secretion, oxidative stress and lung tissue destruction. A wide range of imagining discrepancies has been described in EVALI, including acute lung injury, organizing pneumonia, hypersensitivity pneumonitis and diffuse alveolar hemorrhage. COVID- 19 pandemic has made diagnosing EVALI even more challenging due to the overlap of their clinical, laboratory and radiological features, necessitating a high index of suspicion and a thorough history and physical examination. More data is needed to increase our knowledge of this disorder.
Multiparametric Photoacoustic Analysis of Human Thyroid Cancers <i>In Vivo</i>
Authors: Jeesu Kim, Byullee Park, Jeonghoon Ha, Idan Steinberg, Sarah M. Hooper, Chaiho Jeong, Eun-Yeong Park, Wonseok Choi, Tie Liang, Ja Seong Bae, Ravi Managuli, Yongmin Kim, Sanjiv S. Gambhir, Dong-Jun Lim, Chulhong Kim
Journal: Cancer Research (2021)

Abstract Thyroid cancer is one of the most common cancers, with a global increase in incidence rate for both genders. Ultrasound-guided fine-needle aspiration is the current gold standard to diagnose thyroid cancers, but the results are inaccurate, leading to repeated biopsies and unnecessary surgeries. To reduce the number of unnecessary biopsies, we explored the use of multiparametric photoacoustic (PA) analysis in combination with the American Thyroid Association (ATA) Guideline (ATAP). In this study, we performed in vivo multispectral PA imaging on thyroid nodules from 52 patients, comprising 23 papillary thyroid cancer (PTC) and 29 benign cases. From the multispectral PA data, we calculated hemoglobin oxygen saturation level in the nodule area, then classified the PTC and benign nodules with multiparametric analysis. Statistical analyses showed that this multiparametric analysis of multispectral PA responses could classify PTC nodules. Combining the photoacoustically indicated probability of PTC and the ATAP led to a new scoring method that achieved a sensitivity of 83% and a specificity of 93%. This study is the first multiparametric analysis of multispectral PA data of thyroid nodules with statistical significance. As a proof of concept, the results show that the proposed new ATAP scoring can help physicians examine thyroid nodules for fine-needle aspiration biopsy, thus reducing unnecessary biopsies. Significance: This report highlights a novel photoacoustic scoring method for risk stratification of thyroid nodules, where malignancy of the nodules can be diagnosed with 83% sensitivity and 93% specificity.
Safety of tocilizumab in patients with COVID-19
Authors: S. Gundling, A. Popa, C. Tumbush, R. B. Hejal, O. K. Giddings, C. Teba, A. R. John
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale Severe acute respiratory syndrome coronavirus 2 can cause an uncontrolled release of proinflammatory cytokines, such as interleukin-6 (IL-6), leading to cytokine release syndrome. Tocilizumab, a humanized monoclonal antibody that inhibits the IL-6 receptor, has been proposed as a treatment option to prevent clinical worsening in coronavirus disease 2019 (Covid-19). There is limited data regarding the safety of using tocilizumab in patients with Covid-19. The objective of this study was to evaluate the pneumonia at University Hospitals Cleveland Medical Center. Methods This was an institutional review board approved, singlecenter, retrospective chart review of all patients who received tocilizumab for Covid-19 between March 1, 2020 and October 31, 2020. Patients less than 18 years old were excluded. The primary outcome was incidence of secondary infection within 28 days or until end of hospitalization. Secondary outcomes included incidence of adverse events, length of stay in the intensive care unit, length of hospitalization, progression to invasive mechanical ventilation, duration of mechanical ventilation, and death. Results There were eighteen patients who received tocilizumab for the treatment of Covid-19. Within the first 28 days after receiving tocilizumab, nine (50%) patients developed a secondary infection and ten (55.6%) patients were given antibiotics. Liver enzyme elevations also occurred in nine (50%) of the patients who received tocilizumab. At 28 days, seven (38.9%) patients were discharged from the hospital, four (22.2%) were mechanically ventilated, two (11.1%) were receiving oxygen via nasal cannula, and five (27.8%) were dead. Median ICU and hospital length of stay were 10.5 and 14 days, respectively. Five (27.8%) patients received a second dose of tocilizumab and all five patients were alive at 28 days after receiving first dose of tocilizumab. Conclusion In this retrospective chart review of patients with Covid-19 who received tocilizumab as part of their management, half developed secondary infections and half developed transient liver enzyme elevations. These adverse events may be associated with the use of tocilizumab in these patients. As of now, there is a lack of consensus on the role of tocilizumab in the treatment of Covid-19.
Effect of Clonally Expanded <scp>PD‐1<sup>high</sup>CXCR5</scp>–<scp>CD4</scp>+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis
Authors: Jonas Fischer, Johannes Dirks, Julia Klaussner, Gabriele Haase, Annette Holl‐Wieden, Christine Hofmann, Stephan Hackenberg, Hermann Girschick, Henner Morbach
Journal: Arthritis & Rheumatology (2021)

Objective Antinuclear antibody (ANA)–positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA. Methods Flow cytometry was performed to compare the phenotype and cytokine patterns of PD‐1 high CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next‐generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro. Results Multidimensional flow cytometry revealed the expansion of interleukin‐21 (IL‐21) and interferon‐γ (IFNγ)–coexpressing PD‐1 high CXCR5–HLA–DR+CD4+ T cells that accumulate in the joints of ANA‐positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T‐bet and B lymphocyte–induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL‐21 and IFNy, skewed B cell differentiation toward a CD21 low/– CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21 low/– CD11c+CD27–IgM– double‐negative (DN) B cells in situ. Conclusion Clonally expanded CD4+ Tph cells accumulate in the joints of ANA‐positive JIA patients and, in particular, promote CD21 low/– CD11c+ DN B cell differentiation. The expansion of Tph cells and DN B cells might reflect the autoimmune response in the joints of ANA‐positive JIA patients.
Methods matter: clinical prediction models will benefit sports medicine practice, but only if they are properly developed and validated
Authors: Garrett S Bullock, Tom Hughes, Jamie C Sergeant, Michael J Callaghan, Richard Riley, Gary Collins
Journal: British Journal of Sports Medicine (2021)

Sports medicine clinicians are expected to make accurate diagnoses, estimate prognoses and identify athletes at risk of sustaining an injury.1 These complex decisions are dependent on clinical reasoning, which is informed by, and often biased toward, a practitioner’s scientific knowledge and experience. Clinical prediction models are developed by researchers to help facilitate such decisions in practice2; data for multiple predictor variables are combined to estimate an individual’s risk of a health outcome either being present (diagnosis) or whether it will occur in future (prognosis).3 Despite being employed widely in clinical medicine, clinical prediction models are uncommon in sports medicine. Clinical prediction models can offer benefits to both practitioners and athletes, but only if they are developed and validated using rigorous methods and transparently reported so that potential users can judge their accuracy and usefulness.

Therefore, the purpose of this editorial is to describe the recommended steps for clinical prediction development and validation and to guide practitioners using and interpreting prediction models in sports medicine.

The first step in developing a prediction model is to identify its clinical need, the target population and how and when it would fit into the clinical workflow. Models should predict outcomes that are relevant to sport stakeholders, and be clearly defined, including how and when assessed.4 

Next is to identify any existing models that could be evaluated or updated. If not, …
Taskforce report on the diagnosis and clinical management of COVID-19 associated pulmonary aspergillosis
Authors: Paul E. Verweij, Roger J. M. Brüggemann, Elie Azoulay, Matteo Bassetti, Stijn Blot, Jochem B. Buil, Thierry Calandra, Tom Chiller, Cornelius J. Clancy, Oliver A. Cornely, Pieter Depuydt, Philipp Koehler, Katrien Lagrou, Dylan de Lange, Cornelia Lass-Flörl, Russell E. Lewis, Olivier Lortholary, Peter-Wei Lun Liu, Johan Maertens, M. Hong Nguyen, Thomas F. Patterson, Bart J. A. Rijnders, Alejandro Rodriguez, Thomas R. Rogers, Jeroen A. Schouten, Joost Wauters, Frank L. van de Veerdonk, Ignacio Martin-Loeches
Journal: Intensive Care Medicine (2021)

Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance.A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology.The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients' clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients.CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.
Respiratory disease, and treatment / thematic poster session comparison of tracheostomy timing and outcomes between COVID-19 and non-COVID-19 patients
Authors: D. Geriani, J. Egan
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Background: Evidence regarding timing of tracheostomy in adult patients with COVID-19 is unknown. Intensive care unit(ICU) mortality as high as 42-78% has been reported in critically ill COVID-19 patients. Medical literature has not shown mortality benefit in early tracheostomy, with exceptions in traumatic brain injury and neurological injury. There is some evidence to support shorter ICU length of stay and reduced ventilator-free days with early tracheostomy. This study aims to compare tracheostomy outcomes at day 28 between COVID-19 and non- COVID-19 patients, and to assess if timing of tracheostomy from intubation impacts outcomes. Methods: A prospective single-system multi-center observational cohort study will be performed on patients who underwent percutaneous dilatational tracheostomy(PDT) for prolonged mechanical ventilation. Results: Thus far, thirty patients have undergone PDT due to respiratory failure from COVID-19 and 28 for non-COVID-19 patients. We will evaluate 28-day mortality between the two groups, as well as times to decannulation. Secondary outcomes will aim to compare ICU length of stay between the two groups, incidence of ventilator-associated pneumonia(VAP) in the two groups, sequential organ failure assessment scores between the two groups, and to compare the impact of positive end expiratory pressure(PEEP) and fraction of inspired oxygen(FiO2) at the time of tracheostomy on outcomes in the two groups. We will continue to follow these patients beyond 28 days to assess any change in outcomes.Conclusions: Our study will attempt to analyze primary and secondary outcomes between COVID-19 patients and non-COVID-19 patients undergoing PDT in ICU. We anticipate a higher 28-day mortality and poorer outcomes in COVID-19 patients as compared to non-COVID-19 patients. This outcome is expected on the basis of higher complication rate being reported in COVID-19 in terms of severity of acute respiratory distress syndrome(ARDS) requiring prolonged prone positioning, higher PEEP and FiO2 for longer duration, thromboembolic complications, renal failure and heart failure among many others. Given longer duration required for prone positioning in COVID-19 patients, our study also anticipates later timing of tracheostomy in these patients as compared to non-COVID-19 patients. Knowing the difficulty in predicting duration of mechanical ventilation in ARDS, our study will help answer important questions like the factors that should be considered in decision-making at the time of offering PDT to these critically ill COVID-19 patients. With recent literature showing benefit of dexamethasone in COVID-19, our study will also help establish if there is a difference in the incidence of VAP between the two groups. .
COVID-19 and Type 1 Diabetes: Addressing Concerns and Maintaining Control
Authors: Linda A. DiMeglio
Journal: Diabetes Care (2021)

The worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an unprecedented pandemic. Early on, even as the signs and symptoms of coronavirus disease 2019 (COVID-19) were first characterized, significant concerns were articulated regarding its potential impact on people with chronic disease, including type 1 diabetes. Information about the basic and clinical interrelationships between COVID-19 and diabetes has rapidly emerged. Initial rapid reports were useful to provide alerts and guide health care responses and initial policies. Some of these have proven subsequently to have durable findings, whereas others lacked scientific rigor/reproducibility. Many publications that report on COVID-19 and “diabetes” also have not distinguished between type 1 and type 2 (1). Available evidence now demonstrates that people with type 1 diabetes have been acutely affected by COVID-19 in multiple ways. This includes effects from limited access to health care, particularly during lockdown periods, and increased morbidity/mortality in infected adults with type 1 diabetes compared with peers without diabetes.
ユビキチン蛋白質分解系の変化の系統的解析は,癌におけるドライバー変異への寄与を明らかにする【JST・京大機械翻訳】
Authors: Martinez-Jimenez Francisco, Muinos Ferran, Lopez-Arribillaga Erika, Lopez-Bigas Nuria, Gonzalez-Perez Abel
Journal: Nature Cancer (2020)
Abstract 73: Yap Plays a Crucial Role in the Development of Cardiomyopathy in Lysosomal Storage Diseases
Authors: SHOHEI IKEDA, Akihiro Shirakabe, Sebastiano Sciarretta, Junichi Sadoshima
Journal: Circulation Research (2016)

Rag proteins play a critical role in regulating lysosomal functions. Muscle-specific deletion of RagA and RagB (Rag A/B) results in lysosomal dysfunction, suppression of autophagy, and development of cardiomyopathy, reminiscent of lysosomal storage diseases (LSDs). We investigated the molecular mechanism by which cardiomyopathy is developed in RagA/B knockout (KO) mice. We generated cardiac-specific Rag A/BKO (RagA/BcKO) mice using αMHC-Cre. Similar to the muscle-specific KO mice, RagA/BcKO mice showed prominent cardiac hypertrophy (heart weight (HW)/ tibial length (TL): 12.35 ± 0.41 vs. 7.12 ± 0.15, p&lt; 0.01) at 3 months of age. RagA/BcKO mice exhibited significantly greater phospho-histone H3-positive cardiomyocytes than control mice, suggesting that cardiomyocyte proliferation is stimulated in RagA/BcKO mice. However, RagA/BcKO mice exhibited a significantly smaller percentage of fractional shortening (%FS: 23.0 ± 0.82 vs. 45.8 ± 1.06, p&lt; 0.01) and significantly greater mortality than control mice (50% vs. 0%, p&lt;0.01). RagA/BcKO mouse hearts showed upregulation of β-MHC and α-smooth muscle actin, indicating de-differentiation. Yes-associated protein (YAP) is a transcription co-factor that controls growth and survival and is a key downstream target of the Hippo pathway. YAP associates with p62/SQSTM1 and is degraded through autophagy. YAP is significantly more accumulated (5.9-fold, p&lt;0.05) in RagA/BcKO mouse hearts, where autophagy is inhibited and p62/SQSTM1 is accumulated, than in control hearts. In order to elucidate the role of YAP in mediating cardiomyopathy, we crossed RagA/BcKO mice with cardiac-specific heterozygous YAPKO mice. Heterozygous deletion of YAP in RagA/BcKO mice reduced the heart size (HW/ TL: 9.12 ± 0.10 vs. 11.9 ± 0.27, p&lt; 0.05) and improved cardiac function (%FS: 35.0 ± 2.89 vs. 24.0 ± 0.58, p&lt; 0.05) in RagA/BcKO mice. Pharmacological inhibition of YAP by verteporfin treatment also suppressed cardiac hypertrophy (HW/ TL: 8.92 ± 0.11 vs. 12.09 ± 0.30, p&lt; 0.05) and heart failure (%FS: 33.3 ± 2.29 vs. 23.3 ± 0.63, p&lt; 0.05) in RagA/BcKO mice. These results indicate that YAP plays a crucial role in the development of cardiomyopathy in RagA/BcKO mice, a mouse model of LSDs.