Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.

This Perspective explores and explains the fundamental dogma of nanoparticle delivery to tumours and answers two central questions: ‘how many nanoparticles accumulate in a tumour?’ and ‘how does this number affect the clinical translation of nanomedicines?’

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Analysis of nanoparticle delivery to tumours

Executive Summary Introduction Methodology Used to Prepare the Guideline Epidemiology Incidence Etiology Major Epidemiologic Points Pathogenesis Major Points for Pathogenesis Modifiable Risk Factors Intubation and Mechanical Ventilation Aspiration, Body Position, and Enteral Feeding Modulation of Colonization: Oral Antiseptics and Antibiotics Stress Bleeding Prophylaxis, Transfusion, and Glucose Control Major Points and Recommendations for Modifiable Risk Factors Diagnostic Testing Major Points and Recommendations for Diagnosis Diagnostic Strategies and Approaches Clinical Strategy Bacteriologic Strategy Recommended Diagnostic Strategy Major Points and Recommendations for Comparing Diagnostic Strategies Antibiotic Treatment of Hospital-acquired Pneumonia General Approach Initial Empiric Antibiotic Therapy Appropriate Antibiotic Selection and Adequate Dosing Local Instillation and Aerosolized Antibiotics Combination versus Monotherapy Duration of Therapy Major Points and Recommendations for Optimal Antibiotic Therapy Specific Antibiotic Regimens Antibiotic Heterogeneity and Antibiotic Cycling Response to Therapy Modification of Empiric Antibiotic Regimens Defining the Normal Pattern of Resolution Reasons for Deterioration or Nonresolution Evaluation of the Nonresponding Patient Major Points and Recommendations for Assessing Response to Therapy Suggested Performance Indicators

Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia the official statement of the American Thoracic Society and the Infectious Disease Society of America (特集 救急診療ガイドライン) -- (海外のガイドライン)

Gene families are growing rapidly, but standard methods for inferring phylogenies do not scale to alignments with over 10,000 sequences. We present FastTree, a method for constructing large phylogenies and for estimating their reliability. Instead of storing a distance matrix, FastTree stores sequence profiles of internal nodes in the tree. FastTree uses these profiles to implement neighbor-joining and uses heuristics to quickly identify candidate joins. FastTree then uses nearest-neighbor interchanges to reduce the length of the tree. For an alignment with N sequences, L sites, and a different characters, a distance matrix requires O(N^2) space and O(N^2 L) time, but FastTree requires just O( NLa + N sqrt(N) ) memory and O( N sqrt(N) log(N) L a ) time. To estimate the tree's reliability, FastTree uses local bootstrapping, which gives another 100-fold speedup over a distance matrix. For example, FastTree computed a tree and support values for 158,022 distinct 16S ribosomal RNAs in 17 hours and 2.4 gigabytes of memory. Just computing pairwise Jukes-Cantor distances and storing them, without inferring a tree or bootstrapping, would require 17 hours and 50 gigabytes of memory. In simulations, FastTree was slightly more accurate than neighbor joining, BIONJ, or FastME; on genuine alignments, FastTree's topologies had higher likelihoods. FastTree is available at http://microbesonline.org/fasttree.

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Fast Tree: Computing Large Minimum-Evolution Trees with Profiles instead of a Distance Matrix

Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Defining the Appropriate PET Intensity Threshold and CT Threshold for Target Delineation in Early Stage Non-small Cell Lung Cancer: A Radiological and Pathological Correlation Study

identify the histologic features of AMR in allograft biopsies and correlate them with the presence of serologic alloantibodies in lung transplant patients. Methods: We reviewed a consecutive series of lung allograft biopsies stained with hematoxylin-eosin, anti-CD68, and anti-C4d, blinded to serologic data. Findings of ACR were classified by ISHLT criteria. Complement deposition was considered positive if there was capillary endothelial positivity, excluding stromal and larger vessel staining. Macrophages were considered increased if there was linear granular staining in capillary septa. Results: There were 628 biopsies from 111 patients. Panel reactive alloantibodies (PRA) and donor specific antibodies (DSA) were available in 103 and 100 patients, respectively. There were 73 men (64 ± 13 years) and 38 women (60 ± 12 years). PRA was positive in 38% of patients, and DSA in 30%. 24 patients had ≥ 1 biopsy with positive complement staining and 26 patients had increased macrophage density. 65 patients had ≥ 1 episode of ACR (31 A only, 25 AB, and 6 B; all were grade 1 or 2). There was a positive correlation between ACR and PRA to type II HLA antigens (p= .02), any DSA (p= .0016), the number of DSA (p= .0008) as well as the presence of DSA to type II HLA antigens (p= .003). Additionally, there was a positive correlation between increased macrophages and PRA to type II HLA antigens (p= .04), presence of DSA (p= .009) and the number of DSA type II HLA antibodies (p= .02). There was a positive correlation between complement staining and the presence of any DSA (p= .05). Other correlations were not significant. Conclusion: There is a correlation between multiple histologic findings suggestive of rejection and the serologic presence of donor specific alloantibodies, specifically against type II HLA antigens. The correlation is strongest for ACR, followed by the presence of increased capillary septal macrophages, and weakest for complement staining for C4d.

Acute Fibrinous and Organizing Pneumonia is a Common Histological Pattern of Acute Lung Injury in Patients Developing Restrictive Allograft Syndrome

e18027 Background: Histologic subtypes of non-small cell cancer (NSCLC) may have differential benefit with selected systemic treatments. Hence, histological differentiation of NSCLC is becoming inc...

David M. Hwang

Papers

Defining the Appropriate PET Intensity Threshold and CT Threshold for Target Delineation in Early Stage Non-small Cell Lung Cancer: A Radiological and Pathological Correlation Study

Acute Fibrinous and Organizing Pneumonia is a Common Histological Pattern of Acute Lung Injury in Patients Developing Restrictive Allograft Syndrome

Diagnostic patterns of non-small cell lung cancer at Princess Margaret Hospital.

Pulmonary Involvement in Inflammatory Bowel Disease

A Novel Nanoscale Formulation of Hydrophobic Src Tyrosine Kinase Inhibitor PP2 Prevents Pulmonary Ischemia Reperfusion Induced Acute Lung Injury