NF-κB mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages.

Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. Whereas most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that 1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, 2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, 3) MyD88 splicing is regulated by the NF-κB transcription factor, and 4) NF-κB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled.

Characteristics of an Outbreak of E-cigarette, or Vaping, Product Use-Associated Lung Injury-North Carolina, 2019.

BACKGROUND In August 2019, the North Carolina Division of Public Health (NCDPH) began investigating e-cigarette, or vaping, product use-associated lung injury (EVALI) cases as part of a national response. We describe clinical, epidemiologic, and laboratory findings of North Carolina EVALI patients.METHODS NCDPH requested that physicians report cases of respiratory illness or bilateral pulmonary infiltrates or opacities in patients who reported using e-cigarette, or vaping, products and had no infection or alternative plausible diagnoses. We reviewed medical records, interviewed patients, and tested vaping products for substances.RESULTS During August 13, 2019-February 18, 2020, 78 EVALI cases were reported in North Carolina. Median age of cases was 24 years (range: 13-72 years); 49 (63%) patients were male. Symptoms included cough (n = 70; 90%), shortness of breath (n = 66; 85%), and gastrointestinal symptoms (n = 63; 81%). Seventy-five patients (96%) were hospitalized, 32 (41%) required intensive care, and 12 (16%) required mechanical ventilation; none died. Among 20 patients interviewed, most reported using tetrahydrocannabinol (THC) (n = 16; 80%) or nicotine-containing products (n = 14; 70%). All obtained THC-containing products from informal sources, such as family, friends, or dealers, as THC is illegal in North Carolina. Among 82 products tested, 74 (90%) contained THC, cannabidiol, or cannabinol; 54 (66%) contained vitamin E acetate.LIMITATIONS In North Carolina, EVALI is not reportable by law, and THC is illegal. Thus, cases and exposures are likely underreported.CONCLUSIONS THC-containing products, particularly those containing vitamin E acetate, are associated with EVALI. Persons should not use these products, particularly from informal sources. Continued communication of health risks to persons who use e-cigarette, or vaping, products is essential.

Outbreak of Electronic-Cigarette-Associated Acute Lipoid Pneumonia - North Carolina, July-August 2019.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). Electronic cigarettes (e-cigarettes) produce an aerosol by heating a liquid that usually contains nicotine, flavorings, and other chemicals that users inhale, a behavior commonly referred to as "vaping." E-cigarettes can also be used to deliver marijuana and other drugs. In recent months, more than 200 possible cases of acute lung injury potentially associated with vaping were reported from 25 states (1). During July and August 2019, five patients were identified at two hospitals in North Carolina with acute lung injury potentially associated with e-cigarette use. Patients were adults aged 18-35 years and all experienced several days of worsening dyspnea, nausea, vomiting, abdominal discomfort and fever. All patients demonstrated tachypnea with increased work of breathing on examination, hypoxemia (pulse oximetry <90% on room air), and bilateral lung infiltrates on chest x-ray. All five patients shared a history of recent use of marijuana oils or concentrates in e-cigarettes. All of the products used were electronic vaping pens/e-cigarettes that had refillable chambers or interchangeable cartridges with tetrahydrocannabinol (THC) vaping concentrates or oils, which were all purchased on the street. Three of the patients also used nicotine-containing e-cigarettes, and two of the patients smoked marijuana or conventional cigarettes, although none used other illicit drugs. All five patients were hospitalized for hypoxemic respiratory failure; three required intensive care for acute respiratory distress syndrome, one of whom required intubation and mechanical ventilation. All of the patients survived.

Baseline characteristics in the Israel refraction, environment, and devices (iREAD) study.

The purpose of this study is to present baseline data from a longitudinal study assessing behavioral factors in three groups of boys in Israel with varying myopia prevalence. Ultra-Orthodox (N = 57), religious (N = 67), and secular (N = 44) Jewish boys (age 8.6 ± 1.4 years) underwent cycloplegic autorefraction and axial-length measurement. Time-outdoors and physical-activity were assessed objectively using an Actiwatch. Ocular history, educational factors, and near-work were assessed with a questionnaire. Group effects were tested and mixed effects logistic and linear regression were used to evaluate behaviors and their relationship to myopia. The prevalence of myopia (≤ - 0.50D) varied by group (ultra-Orthodox: 46%, religious: 25%, secular: 20%, P < 0.021). Refraction was more myopic in the ultra-Orthodox group (P = 0.001). Ultra-Orthodox boys learned to read at a younger age (P < 0.001), spent more hours in school (P < 0.001), spent less time using electronic devices (P < 0.001), and on weekdays, spent less time outdoors (P = 0.02). Increased hours in school (OR 1.70) and near-work (OR 1.22), increased the odds of myopia. Being ultra-Orthodox (P < 0.05) and increased near-work (P = 0.007) were associated with a more negative refraction. Several factors were associated with the prevalence and degree of myopia in young boys in Israel, including being ultra-Orthodox, learning to read at a younger age, and spending more hours in school.

Carinal Compression from Primary Mediastinal Germ Cell Tumor.

Mediastinal masses can present as a medical emergency when there is central airway obstruction, superior vena cava (SVC) syndrome, direct mediastinal extension of tumor, or obstruction of the central pulmonary vasculature. Diagnostic evaluation may include the need for invasive tissue biopsy under anesthesia, which can pose several distinct risks for patients. Among the many etiologies of mediastinal tumors, primary mediastinal germ cell tumors are a rare form with a favorable prognosis.

Pleural effusions associated with squamous cell lung carcinoma have a low diagnostic yield and a poor prognosis.

BACKGROUND: Malignant pleural effusion (MPE) portends a poor prognosis in non-small cell lung cancer (NSCLC). However, the yield of pleural fluid cytology as well as survival of patients with MPE associated with squamous cell carcinoma versus adenocarcinoma is not well understood. We conducted this study to assess the diagnostic yield of pleural cytology and survival of patients with NSCLC related MPE. METHODS: We performed a single-center, retrospective analysis of patients with NSCLC related MPE between 2010 and 2017. Kaplan-Meier method was used to compare survival and Cox proportional hazards analysis to assess if squamous cell cytopathology was associated with mortality. RESULTS: We identified 277 patients, 29 with squamous cell and 248 with adenocarcinoma MPE. Pleural fluid cytology from initial thoracentesis was diagnostic in 13.8% (4/29) patients with squamous cell and 80.2% (199/248) with adenocarcinoma (P<0.001). Cytology from second thoracentesis was diagnostic in 13.3% (2/15) patients with squamous cell carcinoma, compared to 37.5% (12/32) with adenocarcinoma (P=0.17). There was no statistically significant difference in the pleural biopsy yield from medical pleuroscopy or video-assisted thoracoscopic surgery (VATS) in the two groups. The median survival of patients with squamous cell MPE was 112 [interquartile range (IQR): 44-220] days versus 194 (IQR: 54-523) days in adenocarcinoma (Log-rank test P=0.04). Multivariate Cox proportional hazards analysis showed that squamous cell cytopathology was independent predictor of mortality (hazard ratio for death of 1.73, 95% CI: 1.1-2.6; P=0.01). CONCLUSIONS: Pleural fluid cytology has a low diagnostic yield in squamous cell carcinoma MPE, and these patients have a poor survival compared to lung adenocarcinoma.

Pilot Study of the Performance of 19-G Needle in Endobronchial Ultrasound-guided Transbronchial Aspiration for the Diagnosis and Testing of Molecular Markers in Lung Cancer.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become the standard for diagnosis and staging of lung cancer. Historically, 21- and 22-G needles have been paired with EBUS. We evaluated the performance of EBUS-TBNA using a larger 19-G needle in the assessment of tumor tissue obtained and success of testing for molecular markers. METHODS: We prospectively enrolled adult patients with lymphadenopathy concerning for metastatic lung cancer. Patients underwent diagnostic EBUS-TBNA utilizing 19-G needles. Cases of non-small cell lung cancer (NSCLC) were evaluated for programmed cell death receptor ligand (PD-L1) expression. Cases of adenocarcinoma or undifferentiated NSCLC were further evaluated for 3 molecular markers for driver mutations: epidermal growth factor receptor (EGFR), c-ros oncogene 1 (ROS-1), and anaplastic lymphoma kinase (ALK). RESULTS: Fifty patients were enrolled and underwent EBUS-TBNA using 19-G needles. PD-L1 assay was successfully performed in 90% of NSCLC cases. In adenocarcinoma or undifferentiated NSCLC cases, the success rate in testing was 90% for EGFR and 86% for ALK. ROS-1 testing had a success rate of 67%; 24% of these specimens had adequate tumor cells but there was technical difficulty with the assay. Block quality was judged by total number of tumor cells per hematoxylin and eosin-stained slide of each cell block (58% of specimens had >500 cells and 22% had 200 to 500 cells). There were no adverse events. CONCLUSION: EBUS-TBNA using 19-G needles can obtain a high number of tumor cells and has a high rate of success in performing assays for PD-L1, EGFR, and ALK in NSCLC patients without an increase in adverse events. The success rate of ROS-1 testing was lower.

Association between Tunneled Pleural Catheter Use and Infection in Patients Immunosuppressed from Antineoplastic Therapy. A Multicenter Study.

Rationale: Patients with malignant or paramalignant pleural effusions (MPEs or PMPEs) may have tunneled pleural catheter (TPC) management withheld because of infection concerns from immunosuppression associated with antineoplastic therapy.Objectives: To determine the rate of infections related to TPC use and to determine the relationship to antineoplastic therapy, immune system competency, and overall survival (OS).Methods: We performed an international, multiinstitutional study of patients with MPEs or PMPEs undergoing TPC management from 2008 to 2016. Patients were stratified by whether or not they underwent antineoplastic therapy and/or whether or not they were immunocompromised. Cumulative incidence functions and multivariable competing risk regression analyses were performed to identify independent predictors of TPC-related infection. Kaplan-Meier method and multivariable Cox proportional hazards modeling were performed to examine for independent effects on OS.Results: A total of 1,408 TPCs were placed in 1,318 patients. Patients had a high frequency of overlap between antineoplastic therapy and an immunocompromised state (75-83%). No difference in the overall (6-7%), deep pleural (3-5%), or superficial (3-4%) TPC-related infection rates between subsets of patients stratified by antineoplastic therapy or immune status was observed. The median time to infection was 41 (interquartile range, 19-87) days after TPC insertion. Multivariable competing risk analyses demonstrated that longer TPC duration was associated with a higher risk of TPC-related infection (subdistribution hazard ratio, 1.03; 95% confidence interval [CI], 1.00-1.06; P = 0.028). Cox proportional hazards analysis showed antineoplastic therapy was associated with better OS (hazard ratio, 0.84; 95% CI, 0.73-0.97; P = 0.015).Conclusions: The risk of TPC-related infection does not appear to be increased by antineoplastic therapy use or an immunocompromised state. The overall rates of infection are low and comparable with those of immunocompetent patients with no relevant antineoplastic therapy. These results support TPC palliation for MPE or PMPEs regardless of plans for antineoplastic therapy.

Managing Massive Hemoptysis.

Massive hemoptysis is a medical emergency with high mortality presenting several difficult diagnostic and therapeutic challenges. The origin of bleeding and underlying etiology often is not immediately apparent, and techniques for management of this dangerous condition necessitate an expedient response. Unlike hemorrhage in other circumstances, a small amount of blood can rapidly flood the airways, thereby impairing oxygenation and ventilation, leading to asphyxia and consequent cardiovascular collapse. Of paramount importance is early control of the patient's airway and immediate isolation of hemorrhage in an attempt to localize and control bleeding. A coordinated team response is essential to guarantee the best chances of patient survival. Prompt control of the airway and steps to limit the spread of hemorrhage take precedence. Bronchial artery embolization, rigid and flexible bronchoscopy, and surgery all serve as potential treatment options to provide definitive control of hemorrhage. Several adjunctive therapies described in recent years may also assist in the control of bleeding; however, their role is less defined in life-threatening hemoptysis and warrants additional studies. In this concise review, we emphasize the steps necessary for a systematic approach in the management of life-threatening hemoptysis.

Bronchoalveolar lavage as a diagnostic procedure: a review of known cellular and molecular findings in various lung diseases.

Bronchoalveolar lavage (BAL) is a commonly used procedure in the evaluation of lung disease as it allows for sampling of the lower respiratory tract. In many circumstances, BAL differential cell counts have been reported to be typical of specific lung disorders. In addition, more specific diagnostic tests including molecular assays such as polymerase chain reaction (PCR) or enzyme-linked immunosorbent assay, special cytopathologic stains, or particular microscopic findings have been described as part of BAL fluid analysis. This review focuses on common cellular and molecular findings of BAL in a wide range of lung diseases. Since the performance of the first lung irrigation in 1927, BAL has become a common and important diagnostic tool. While some pulmonary disorders have a highly characteristic signature of BAL findings, BAL results alone often lack specificity and require interpretation along with other clinical and radiographic details. Development of new diagnostic assays is certain to reinforce the utility of BAL in the future. Our review of the BAL literature is intended to serve as a resource to assist clinicians in the care of patients with lung disorders.

The Link between Fusobacteria and Colon Cancer: a Fulminant Example and Review of the Evidence.

Systemic infections due to Fusobacterium may originate in the tonsillar/internal jugular veins or from the abdomen. We encountered a patient who presented with bacteremia, fulminant septic shock, and extensive soft tissue pyogenic infection due to Fusobacterium necrophorum. In addition, there was widespread metastatic colon cancer with the unique finding of pre-mortem co-localization of F. necrophorum and cancer cells at a site distant from the colon. We reviewed the literature of the association of F. necrophorum and colon cancer, and discuss the evidence of how each of these 2 distinct entities may mutually augment the development or progression of the other.

The Impact of Gravity vs Suction-driven Therapeutic Thoracentesis on Pressure-related Complications: The GRAVITAS Multicenter Randomized Controlled Trial.

BACKGROUND: Thoracentesis can be accomplished by active aspiration or drainage with gravity. This trial investigated whether gravity drainage could protect against negative pressure-related complications such as chest discomfort, re-expansion pulmonary edema, or pneumothorax compared with active aspiration. METHODS: This prospective, multicenter, single-blind, randomized controlled trial allocated patients with large free-flowing effusions estimated ≥ 500 mL 1:1 to undergo active aspiration or gravity drainage. Patients rated chest discomfort on 100-mm visual analog scales prior to, during, and following drainage. Thoracentesis was halted at complete evacuation or for persistent chest discomfort, intractable cough, or other complication. The primary outcome was overall procedural chest discomfort scored 5 min following the procedure. Secondary outcomes included measures of discomfort and breathlessness through 48 h postprocedure. RESULTS: A total of 142 patients were randomized to undergo treatment, with 140 in the final analysis. Groups did not differ for the primary outcome (mean visual analog scale score difference, 5.3 mm; 95% CI, -2.4 to 13.0; P = .17). Secondary outcomes of discomfort and dyspnea did not differ between groups. Comparable volumes were drained in both groups, but the procedure duration was significantly longer in the gravity arm (mean difference, 7.4 min; 95% CI, 10.2 to 4.6; P < .001). There were no serious complications. CONCLUSIONS: Thoracentesis via active aspiration and gravity drainage are both safe and result in comparable levels of procedural comfort and dyspnea improvement. Active aspiration requires less total procedural time. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03591952; URL: www.clinicaltrials.gov.

The Impact of the Spanish-to-English Proficiency Shift on the Grammaticality of English Learners.

Purpose The general aim of this study is to enhance our understanding of the patterns of language growth in Spanish and English during the school years. In this study, we used a longitudinal retrospective approach to explore the growth of the percentage of grammatical utterances (PGU) in both Spanish and English in 2 groups of English learners (ELs): ELs attending English-only instruction and ELs attending Spanish-English bilingual instruction. Method The participants included 1,080 ELs. ELs produced at least 3 story retells in both Spanish and English between kindergarten and 2nd grade. All stories were transcribed and coded for errors, and PGU was calculated for each story. Results At the onset of the study, children showed higher PGU in Spanish and lower PGU in English. Growth curve analysis indicated that PGU in English improved over time, whereas PGU in Spanish declined in both instructional groups. However, those children who were in bilingual programs showed a slower rate of decline in Spanish PGU and a slower rate of improvement in English PGU. By the age of 9 years, children in English-only programs had approximately a Spanish PGU of 65% in Spanish, whereas children in bilingual instruction had an average Spanish PGU of 80%. The improvement in English PGU was steady with a small difference in the rate of growth benefiting children in English-only programs. Conclusion The results of this study document a shift in language proficiency from Spanish to English during the school years. This study offers evidence of a temporary period of relatively low grammaticality in both languages that seems to be the result of a shift in proficiency from Spanish to English.

Management of Lung Transplant Bronchial Stenosis With Mitomycin C.

BACKGROUND: Bronchial stenosis is a significant source of morbidity among lung transplant recipients, with etiologies including infection and ischemia of the airways. Current management with balloon bronchoplasty and stents is imperfect and a subset of patients requires multiple procedures to maintain airway patency. Mitomycin C (MMC) has been utilized for its antifibrotic properties in nonmalignant tracheobronchial stenosis but its application is not well studied in post-lung transplant stenosis. We performed this study to assess if MMC application decreases the need for repeated balloon bronchoplasty in lung transplant-related airway stenosis. METHODS: This is a retrospective cohort study of all lung transplant recipients who developed airway stenosis and who were treated with MMC over 4 years. MMC was injected submucosally into the stenotic airway. We compared the rate of bronchoscopic dilation at intervals of 3 and 6 months before and after MMC therapy. RESULTS: Eleven lung transplant recipients, with airway stenosis were included in our study, who required recurrent balloon dilation, despite airway stents in place in 73% of these patients. At 3 months after MMC treatment the median number of dilations decreased from 3 to 1 (P=0.023), and at 6 months from 3 to 2 dilations (P=0.004). There was a trend toward improvement in forced expiratory volume in one second and forced vital capacity, although it was not statistically significant. No adverse events related to MMC therapy was observed CONCLUSION:: Application of MMC is safe and is associated with a reduction in frequency of bronchoscopic balloon dilation in patients with post-lung transplant airway stenosis.

Discovery of Tetrahydropyridopyrimidines as Irreversible Covalent Inhibitors of KRAS-G12C with In Vivo Activity.

KRAS is the most frequently mutated driver oncogene in human cancer, and KRAS mutations are commonly associated with poor prognosis and resistance to standard treatment. The ability to effectively target and block the function of mutated KRAS has remained elusive despite decades of research. Recent findings have demonstrated that directly targeting KRAS-G12C with electrophilic small molecules that covalently modify the mutated codon 12 cysteine is feasible. We have discovered a series of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. The PK/PD and efficacy of compound 13 will be highlighted.

Levothyroxine and prednisone causing generalized weakness in a middle-aged man.

Thyrotoxic induced hypokalemic periodic paralysis is a rare disorder that had been described in middle-aged men, predominantly Asians and Hispanics. This case presented with generalized weakness and hypokalemia after changing prescription for levothyroxine and starting prednisone to treat upper respiratory infection in a previously asymptomatic middle-aged Hispanic male. In this paper, we will go over the clinical presentation, mechanisms, and treatment of thyrotoxic induced hypokalemic periodic paralysis. Our objectives are to identify the classic constellation of findings in thyrotoxic periodic paralysis and to recognize the importance of considering thyrotoxic periodic paralysis among patients with hypokalemia.