<A<em>b</em>stractText>The purpose of this article was to perform a systematic review and meta-analysis regarding the diagnostic test accuracy of chest CT for detecting coronavirus disease 2019 (COVID-19).</A<em>b</em>stractText><A<em>b</em>stractText>Pu<em>b</em>Med, Em<em>b</em>ase, We<em>b</em> of Science, and CNKI were searched up to March 12, 2020. We included studies providing information regarding diagnostic test accuracy of chest CT for COVID-19 detection. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity and specificity were pooled.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Sixteen studies (n = 3186 patients) were included. The risks of <em>b</em>ias in all studies were moderate in general. Pooled sensitivity was 92% (95% CI = 86-96%), and two studies reported specificity (25% [95% CI = 22-30%] and 33% [95% CI = 23-44%], respectively). There was su<em>b</em>stantial heterogeneity according to Cochran's Q test (p &<em>lt</em>; 0.01) and Higgins I² heterogeneity index (96% for sensitivity). After dividing the studies into two groups <em>b</em>ased on the study site, we found that the sensitivity of chest CT was great in Wuhan (the most affected city <em>b</em>y the epidemic) and the sensitivity values were very close to each other (97%, 96%, and 99%, respectively). In the regions other than Wuhan, the sensitivity varied from 61 to 98%.</p><A<em>b</em>stractText>Chest CT offers the great sensitivity for detecting COVID-19, especially in a region with severe epidemic situation. However, the specificity is low. In the context of emergency disease control, chest CT provides a fast, convenient, and effective method to early recognize suspicious cases and might contri<em>b</em>ute to confine epidemic.</A<em>b</em>stractText><A<em>b</em>stractText>• Chest CT has a high sensitivity for detecting COVID-19, especially in a region with severe epidemic, which is helpful to early recognize suspicious cases and might contri<em>b</em>ute to confine epidemic.</A<em>b</em>stractText>

<A<em>b</em>stractText>Epidermal growth factor receptor (EGFR) tyrosine kinase inhi<em>b</em>itor com<em>b</em>ined with cytotoxic chemotherapy is highly effective for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, little is known a<em>b</em>out the efficacy and safety of this com<em>b</em>ination compared with that of standard therapy with EGFR- tyrosine kinase inhi<em>b</em>itors alone.</A<em>b</em>stractText><A<em>b</em>stractText>We randomly assigned 345 patients with newly diagnosed metastatic NSCLC with EGFR mutations to gefitini<em>b</em> com<em>b</em>ined with car<em>b</em>oplatin plus pemetrexed or gefitini<em>b</em> alone. Progression-free survival (PFS), PFS2, and overall survival (OS) were sequentially analyzed as primary end points according to a hierarchical sequential testing method. Secondary end points were o<em>b</em>jective response rate (ORR), safety, and quality of life.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The com<em>b</em>ination group demonstrated a <em>b</em>etter ORR and PFS than the gefitini<em>b</em> group (ORR, 84% <i>v</i> 67% [<i>P</i> &<em>lt</em>; .001]; PFS, 20.9 <i>v</i> 11.9 months; hazard ratio for death or disease progression, 0.490 [<i>P</i> &<em>lt</em>; .001]), a<em>lt</em>hough PFS2 was not significantly different (20.9 <i>v</i> 18.0 months; <i>P</i> = .092). Median OS in the com<em>b</em>ination group was also significantly longer than in the gefitini<em>b</em> group (50.9 <i>v</i> 38.8 months; hazard ratio for death, 0.722; <i>P</i> = .021). The rate of grade ≥ 3 treatment-related adverse events, such as hematologic toxicities, in the com<em>b</em>ination group was higher than in the gefitini<em>b</em> group (65.3% <i>v</i> 31.0%); there were no differences in quality of life. One treatment-related death was o<em>b</em>served in the com<em>b</em>ination group.</p><A<em>b</em>stractText>Compared with gefitini<em>b</em> alone, gefitini<em>b</em> com<em>b</em>ined with car<em>b</em>oplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations with an accepta<em>b</em>le toxicity profile, a<em>lt</em>hough its OS <em>b</em>enefit requires further validation.</A<em>b</em>stractText>

<A<em>b</em>stractText>At the prior data cutoff (Fe<em>b</em>ruary 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectini<em>b</em> versus crizotini<em>b</em> in untreated, anaplastic lymphoma kinase (ALK)-positive, advanced NSCLC (hazard ratio = 0.47, 95% confidence interval: 0.34-0.65, p &<em>lt</em>; 0.001). The median PFS in the alectini<em>b</em> arm was not reached versus 11.1 months with crizotini<em>b</em>. Retrospective analyses suggest that the echinoderm microtu<em>b</em>ule-associated protein-like 4 gene-ALK variant (EML4-ALK) may influence ALK-inhi<em>b</em>itor treatment <em>b</em>enefit. We present updated analyses, including exploratory su<em>b</em>group analysis <em>b</em>y EML4-ALK variant, after an additional 10 months' follow-up (cutoff Decem<em>b</em>er 1, 2017).</A<em>b</em>stractText><A<em>b</em>stractText>Patients were randomized to receive twice-daily alectini<em>b</em>, 600 mg, or crizotini<em>b</em>, 250 mg, until disease progression, toxicity, death, or withdrawal. PFS was determined <em>b</em>y the investigators. Baseline plasma and tissue <em>b</em>iomarker samples were analyzed <em>b</em>y using hy<em>b</em>rid-capture, next-generation sequencing to determine EML4-ALK variant.</A<em>b</em>stractText><A<em>b</em>stractText>Baseline characteristics were <em>b</em>alanced. Investigator-assessed PFS was prolonged with alectini<em>b</em> (stratified hazard ratio = 0.43, 95% confidence interval: 0.32-0.58). The median PFS times were 34.8 months with alectini<em>b</em> and 10.9 months with crizotini<em>b</em>. EML4-ALK fusions were detecta<em>b</em>le in 129 patient plasma samples and 124 tissue samples; variants 1, 2, and 3/a<em>b</em> did not affect PFS, o<em>b</em>jective response rate, or duration of response. Investigator-assessed PFS was longer for alectini<em>b</em> than for crizotini<em>b</em> across EML4-ALK variants 1, 2, and 3a/<em>b</em> in plasma and tissue. Despite longer treatment duration (27.0 months in the case of alectini<em>b</em> versus 10.8 months in the case of crizotini<em>b</em>), the safety of alectini<em>b</em> compared favora<em>b</em>ly with that of crizotini<em>b</em>.</A<em>b</em>stractText><A<em>b</em>stractText>Alectini<em>b</em> continues to demonstrate superior investigator-assessed PFS versus crizotini<em>b</em> in untreated ALK-positive NSCLC, irrespective of EML4-ALK variant.</A<em>b</em>stractText>

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P &lt; 0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment.

Not all asthma can be adequately controlled, despite the use of high-dose inhaled corticosteroids. Because cysteinyl-leukotrienes (Cys-LT) have been implicated in the pathogenesis of asthma, we hypothesized that the leukotriene receptor antagonist zafirlukast, in combination with high-doses of inhaled corticosteroids, might be efficacious in severe asthma. In a double-blind, parallel group study, 368 chronic adult asthmatic patients treated with inhaled corticosteroids (1,000 to 4,000 microgram/d), who had a predefined level of asthma symptoms during the run in period of the study, were randomly assigned to receive additional treatment with a high dose of zafirlukast (80 mg twice daily) (n = 180) or placebo (n = 188) for 6 wk. Compared with placebo, zafirlukast produced a significant improvement over baseline in the primary study endpoint of mean morning peak expiratory flow rate (PEFR) (18.7 L/min versus 1.5 L/min, p < 0.001), as well as in evening PEFR (p < 0.01), FEV(1) (p < 0.05), daytime symptom score (p < 0.001), and beta(2)-agonist use (p < 0.001). Furthermore, zafirlukast significantly reduced the risk of an exacerbation of asthma (odds ratio [OR]: 0.61; 95% confidence interval [CI]: 0.38 to 0.99) and the risk of patients requiring a further increase in asthma controller therapy (OR: 0.4; 95% CI: 0.2 to 0.8). In conclusion, in patients taking high-dose inhaled corticosteroids, zafirlukast improves pulmonary function and asthma symptoms, and reduces the risk of an asthma exacerbation, suggesting that the contribution of leukotrienes to asthma symptoms and exacerbations is not adequately controlled by high-dose inhaled corticosteroids.

Immunodiffusion experiments were conducted to associate a precipitin line with Escherichia coli heat-labile enterotoxin (LT). Wild strains of porcine and of human enteropathogenic E. coli as well as laboratory-derived enterotoxigenic variants of E. coli K-12 were used for LT antigen preparations. These were produced mainly by ultrafiltration and ammonium sulfate precipitation of broth culture supernatants. When antisera with anti-LT activity were reacted with antigen preparations from Ent(+) and Ent(-) variants of E. coli K-12, a line "a" was given by Ent(+) but not by Ent(-) preparations. Line "a" was removed by absorption of anti-LT serum with antigen preparation from an Ent(+)E. coli K-12, but was unaffected when the antigen preparation used to absorb the serum was from an Ent(-)E. coli K-12. A line identical to "a" was given by antigen preparations from wild strains of porcine enteropathogenic E. coli reacted with homologous or heterologous anti-LT sera. One human strain of enteropathogenic E. coli was shown to possess an antigen identical to that which gave rise to line "a." To demonstrate this line it was necessary to use high concentrations of gammaglobulin and high concentrations of the crude antigen preparations. LT preparations reacted with anticholera toxin to give a line "c," which showed a reaction of partial identity with line "b" produced by reaction of pure choleragenoid and anticholera toxin. Lines "a" and "c" gave reactions of identity.

Reperfusion of ischemic vascular beds may lead to recruitment and activation of leukocytes, release of mediators of the inflammatory process and further injury to the affected vascular bed and to remote sites. Neutrophils appear to play a major role in the pathophysiology of reperfusion injury. Amongst inflammatory mediators shown to activate neutrophils and induce their recruitment in vivo, much interest has been placed on the role of leukotriene (LT)B(4). Here, we have assessed the effects of the BLT receptor antagonist (+)-1-(3S, 4R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl]-cyclopentane carboxylic acid (CP 105,696) in a model of neutrophil-dependent ischemia and reperfusion injury in the rat. The superior mesenteric artery was isolated and ischemia was induced by its total occlusion for 30 min. After 30 min of reperfusion, injury was assessed by evaluating the extravasation of Evans blue, an index of vascular permeability, and the levels of myeloperoxidase, an index of neutrophil accumulation, in the intestine, mesentery and lung. The neutrophil-dependence of the local (intestine and mesentery) and remote (lung) injury was confirmed by using fucoidin, a selectin blocker, and WT-3, an anti-CD18 monoclonal antibody. Post-ischemic treatment with CP 105,696 dose-dependently inhibited vascular permeability and neutrophil accumulation in the intestine and mesentery. CP 105,696 also blocked the vascular permeability changes, but not neutrophil accumulation, in the lungs after reperfusion injury. Virtually identical results were obtained with another BLT receptor antagonist, 1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)-heptoxy++ +)-phenyl )ethanone (LY255283). Our results suggest that post-ischemic treatment with BLT receptor antagonists may inhibit local and remote ischemia and reperfusion injury by blocking both the accumulation and/or activation of neutrophils.

TNF-alpha and lymphotoxin (LT, TNF-beta) genes are tandemly arranged and map within the MHC centromeric to HLA-B and telomeric to the class III genes. Both cytokines encoded by these genes are potent immunomodulators. On the other hand, some MHC-linked autoimmune diseases are characterized by abnormal levels of their expression or inducibility. A search for the putative disease-associated TNF/LT alleles depends on the informative genetic markers at the TNF locus. Previously, a low degree of genetic polymorphism at the human TNF locus has been reported, mostly bi-allelic RFLP. To localize and define additional polymorphic markers, we probed the collection of genomic clones with synthetic tandemly repeated dinucleotides, corresponding to the sequences known as microsatellites. We mapped and characterized three (TC/GA) and one (AC/GT) repeats within cloned 40-kb DNA comprising the human TNF locus. Using a polymerase chain reaction-based technique, we analyzed three of these four microsatellites and observed their length of polymorphism. Using DNA samples from blood donors, two families, and three human cell lines, we detected 13 distinct alleles of the AC/GT microsatellite neighboring human TNF genes. The variability was further increased by simultaneous analysis of the second linked microsatellite. This linked TC/GA repeat showed at least five alleles, whereas the least polymorphic TC/GA repeat located in the first intron of LT (TNF-beta) gene had two alleles. TNF alleles defined by microsatellites were stably inherited and segregated in the Mendelian way. Therefore, we describe thus far the most informative level of DNA sequence polymorphism in this part of human MHC. We propose a nomenclature for microsatellite tagged LT/TNF alleles based on their size and variability, which could also be extended to include RFLP and other not yet identified polymorphic markers. Microsatellite tagged polymorphism described here can be used in systematic linkage studies of HLA-associated diseases.

The aim of our study was to determine the outcomes of liver transplant recipients receiving either lamivudine (LAM) monotherapy or LAM combined with low-dose intramuscular (IM) hepatitis B Immunoglobulin (HBIG) therapy. We performed a retrospective review of the medical records of patients that had had liver transplantation in a single center for HBV-related liver diseases from December 1999 to June 2004. A total of 165 patients received LAM monotherapy (51 patients) or combined prophylaxis (114 patients) post-liver transplantation (LT) with a mean follow-up of 20.13 months. Hepatitis B relapsed in 21 patients of the hepatitis B surface antigen (HBsAg) carriers who received LAM monotherapy, with a 1- and 2-yr actuarial risk of 27.4% and 39.7%. Recurrence occurred in 16 patients of 114 patients receiving the combined prophylaxis, with a 1- and 2-yr recurrence rate of 13.5% and 15.2% (P = 0.024). A total of 25 cases (67.6%) with YMDD mutants were detected in all the 37 patients, 14 cases (66.7%) in the monotherapy group and 11 cases (68.8%) in the combination group. In conclusion, LAM and low-dose intramuscular HBIG treatment demonstrates a better result than LAM monotherapy, as prophylaxis against post-LT reinfection of the graft, but the safety and efficacy as a substitution for high-dose intravenous HBIG with LAM needs to be investigated further.

The lethal toxin (LT) from Clostridium sordellii belongs to the family of large clostridial cytotoxins causing morphological alterations in cultured cell lines accompanied by destruction of the actin cytoskeleton. C. sordellii LT exhibits 90% homology to Clostridium difficile toxin B, which has been recently identified as a monoglucosyltransferase (Just, I., Selzer, J., Wilm, M., von Eichel-Streiber, C., Mann, M., and Aktories, K. (1995) Nature 375, 500-503). We report here that LT too is a glucosyltransferase, which uses UDP-glucose as cosubstrate to modify low molecular mass GTPases. LT selectively modifies Rac and Ras, whereas the substrate specificity of toxin B is confined to the Rho subfamily proteins Rho, Rac, and Cdc42, which participate in the regulation of the actin cytoskeleton. In Rac, both toxin B and LT share the same acceptor amino acid, threonine 35. Glucosylation of Ras by LT results in inhibition of the epidermal growth factor-stimulated p42/p44 MAP-kinase signal pathway. LT is the first bacterial toxin to inactivate Ras in intact cells.

Transcription of the human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest events that occurs after stimulation of B or T cells via their antigen receptors. Antibody directed at surface immunoglobulin (anti-Ig) on B cells has previously been shown to induce a rapid burst of TNF-alpha gene transcription, which can be blocked by the immunosuppressants cyclosporin A (CsA) and FK506. Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity. Endogenous TNF-alpha produced after stimulation was involved in B-cell proliferation since anti-TNF-alpha monoclonal antibody inhibited both anti-Ig- and anti-CD40-induced B-cell proliferative responses. Moreover, addition of TNF-alpha during stimulation resulted in augmentation of B-cell proliferation, which was also inhibited by anti-TNF-alpha monoclonal antibody. Although lymphotoxin alpha (LT-alpha) mRNA is induced by both pathways, it is not blocked by CsA, whereas LT-beta mRNA is constitutively expressed in B cells. Thus, TNF-alpha is a necessary autocrine growth factor for human B cells stimulated via two independent CsA-sensitive pathways and plays a role similar to that of interleukin 2 in T-cell proliferation. The autocrine nature of TNF-alpha in activated B cells implies a potential role for this cytokine in infection-related polyclonal B-cell expansion and in B-cell malignancies.

Introduction: Because of their inability to access adequate medical care, transportation, and nutrition, socially vulnerable populations are at an increased risk of health challenges during disasters. This study estimates the association between case counts of COVID-19 infection and social vulnerability in the U.S., identifying counties at increased vulnerability to the pandemic.

Methods: Using Social Vulnerability Index and COVID-19 case count data, an ordinary least squares regression model was fitted to assess the global relationship between COVID-19 case counts and social vulnerability. Local relationships were assessed using a geographically weighted regression model, which is effective in exploring spatial nonstationarity.

Results: As of May 12, 2020, a total of 1,320,909 people had been diagnosed with COVID-19 in the U.S. Of the counties included in this study (91.5%, 2,844 of 3,108), the highest case count was recorded in Trousdale, Tennessee (16,525.22 per 100,000) and the lowest in Tehama, California (1.54 per 100,000). At the global level, overall Social Vulnerability Index (e^β=1.65, p=0.03) and minority status and language (e^β=6.69, p&lt;0.001) were associated with increased COVID-19 case counts. However, on the basis of the local geographically weighted model, the association between social vulnerability and COVID-19 varied among counties. Overall, minority status and language, household composition and transportation, and housing and disability predicted COVID-19 infection.

Conclusions: Large-scale disasters differentially affect the health of marginalized communities. In this study, minority status and language, household composition and transportation, and housing and disability predicted COVID-19 case counts in the U.S. Addressing the social factors that create poor health is essential to reducing inequities in the health impacts of disasters.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>National Comprehensive Cancer Network guidelines consider ¹⁸F-fluciclovine PET-CT for prostate cancer <em>b</em>iochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific mem<em>b</em>rane antigen (PSMA) PET-CT. To the <em>b</em>est of our knowledge, no prospective head-to-head comparison <em>b</em>etween these tests has <em>b</em>een done so far. The aim of this study was to compare prospectively paired ¹⁸F-fluciclovine and PSMA PET-CT scans for localising <em>b</em>iochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (&<em>lt</em>;2·0 ng/mL).</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This was a prospective, single-centre, open-la<em>b</em>el, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer <em>b</em>iochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligi<em>b</em>le. Patients underwent ¹⁸F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of <em>b</em>iochemical recurrence at the patient level and <em>b</em>y anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted <em>b</em>y three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, num<em>b</em>er NCT02940262, and is complete.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between Fe<em>b</em> 26, 2018, and Sept 20, 2018, 143 patients were screened for eligi<em>b</em>ility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with ¹⁸F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the su<em>b</em>analysis of the pelvic nodes region (four [8%; 2-19] with ¹⁸F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the su<em>b</em>analysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estima<em>b</em>le [95% CI non-estima<em>b</em>le], p=0·0078).</p><A<em>b</em>stractText>With higher detection rates, PSMA should <em>b</em>e the PET tracer of choice when PET-CT imaging is considered for su<em>b</em>sequent treatment management decisions in patients with prostate cancer and <em>b</em>iochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes.</A<em>b</em>stractText><A<em>b</em>stractText>None.</A<em>b</em>stractText>

<A<em>b</em>stractText>Canna<em>b</em>is use is associated with increased risk of later psychotic disorder <em>b</em>ut whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of canna<em>b</em>is use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contri<em>b</em>ute to variations in the incidence rates of psychotic disorder.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We included patients aged 18-64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of canna<em>b</em>is use carried the highest odds for psychotic disorder. Using Europe-wide and national data on the expected concentration of Δ⁹-tetrahydrocanna<em>b</em>inol (THC) in the different types of canna<em>b</em>is availa<em>b</em>le across the sites, we divided the types of canna<em>b</em>is used <em>b</em>y participants into two categories: low potency (THC &<em>lt</em>;10%) and high potency (THC ≥10%). Assuming causality, we calculated the population attri<em>b</em>uta<em>b</em>le fractions (PAFs) for the patterns of canna<em>b</em>is use associated with the highest odds of psychosis and the correlation <em>b</em>etween such patterns and the incidence rates for psychotic disorder across the study sites.</p><A<em>b</em>stractText>Between May 1, 2010, and April 1, 2015, we o<em>b</em>tained data from 901 patients with first-episode psychosis across 11 sites and 1237 population controls from those same sites. Daily canna<em>b</em>is use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3·2, 95% CI 2·2-4·1), increasing to nearly five-times increased odds for daily use of high-potency types of canna<em>b</em>is (4·8, 2·5-6·3). The PAFs calculated indicated that if high-potency canna<em>b</em>is were no longer availa<em>b</em>le, 12·2% (95% CI 3·0-16·1) of cases of first-episode psychosis could <em>b</em>e prevented across the 11 sites, rising to 30·3% (15·2-40·0) in London and 50·3% (27·4-66·0) in Amsterdam. The adjusted incident rates for psychotic disorder were positively correlated with the prevalence in controls across the 11 sites of use of high-potency canna<em>b</em>is (r = 0·7; p=0·0286) and daily use (r = 0·8; p=0·0109).</A<em>b</em>stractText><A<em>b</em>stractText>Differences in frequency of daily canna<em>b</em>is use and in use of high-potency canna<em>b</em>is contri<em>b</em>uted to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availa<em>b</em>ility of high-potency canna<em>b</em>is, this has important implications for pu<em>b</em>lic hea<em>lt</em>h.</A<em>b</em>stractText><A<em>b</em>stractText>Medical Research Council, the European Community's Seventh Framework Program grant, São Paulo Research Foundation, National Institute for Hea<em>lt</em>h Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR BRC at University College London, Wellcome Trust.</A<em>b</em>stractText>

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To analyze the clinical characteristics of 2019 novel coronavirus (2019-nCoV) pneumonia and to investigate the correlation <em>b</em>etween serum inflammatory cytokines and severity of the disease. (<em>b</em>)Methods:</<em>b</em>) 29 patients with 2019-ncov admitted to the isolation ward of Tongji hospital affiliated to Tongji medical college of Huazhong University of Science and Technology in January 2020 were selected as the study su<em>b</em>jects. Clinical data were collected and the general information, clinical symptoms, <em>b</em>lood test and CT imaging characteristics were analyzed. According to the relevant diagnostic criteria, the patients were divided into three groups: mild (15 cases), severe (9 cases) and critical (5 cases). The expression levels of inflammatory cytokines and other markers in the serum of each group were detected, and the changes of these indicators of the three groups were compared and analyzed, as well as their relationship with the clinical classification of the disease. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) (1) The main symptoms of 2019-nCoV pneumonia was fever (28/29) with or without respiratory and other systemic symptoms. Two patients died with underlying disease and co-<em>b</em>acterial infection, respectively. (2) The <em>b</em>lood test of the patients showed normal or decreased white <em>b</em>lood cell count (23/29), decreased lymphocyte count (20/29), increased hypersensitive C reactive protein (hs-CRP) (27/29), and normal procalcitonin. In most patients, serum lactate dehydrogenase (LDH) was significantly increased (20/29), while al<em>b</em>umin was decreased (15/29). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total <em>b</em>iliru<em>b</em>in (T<em>b</em>il), serum creatinine (Scr) and other items showed no significant changes. (3) CT findings of typical cases were single or mu<em>lt</em>iple patchy ground glass shadows accompanied <em>b</em>y septal thickening. When the disease progresses, the lesion increases and the scope expands, and the ground glass shadow coexists with the solid shadow or the stripe shadow. (4) There were statistically significant differences in the expression levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of the three groups (<i>P&<em>lt</em>;</i>0.05), among which the critical group was higher than the severe group and the severe group was higher than the mild group. However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-α), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (<i>P></i>0.05). (<em>b</em>)Conclusion:</<em>b</em>) The clinical characteristics of 2019-nCoV pneumonia are similar to those of common viral pneumonia. High resolution CT is of great value in the differential diagnosis of this disease. The increased expression of IL-2R and IL-6 in serum is expected to predict the severity of the 2019-nCoV pneumonia and the prognosis of patients.

<A<em>b</em>stractText>To assess the value of <em>b</em>lood neurofilament light chain (NfL) as a <em>b</em>iomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting mu<em>lt</em>iple sclerosis.</A<em>b</em>stractText><A<em>b</em>stractText>We measured NfL in <em>b</em>lood samples from 589 patients with relapsing-remitting mu<em>lt</em>iple sclerosis (from phase 3 studies of fingolimod vs place<em>b</em>o, FREEDOMS and interferon [IFN]-<em>β</em>-1a, TRANSFORMS) and 35 hea<em>lt</em>hy controls and compared NfL levels with clinical and MRI-related outcomes.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>At <em>b</em>aseline, NfL levels (pg/mL) were higher in patients than in hea<em>lt</em>hy controls (30.5 and 27.0 vs 16.9, <i>p</i> = 0.0001) and correlated with T2 lesion load and num<em>b</em>er of gadolinium-enhancing T1 lesions (<i>p</i> &<em>lt</em>; 0.0001, <em>b</em>oth). Baseline NfL levels, treatment, and num<em>b</em>er of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all <i>p</i> &<em>lt</em>; 0.01). High vs low <em>b</em>aseline NfL levels were associated (estimate [95% confidence interval]) with an increased num<em>b</em>er of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; <i>p</i> = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; <i>p</i> &<em>lt</em>; 0.0001), <em>b</em>rain volume loss (difference in means: -0.78% [-1.02 to -0.54]; <i>p</i> &<em>lt</em>; 0.0001), and risk of confirmed disa<em>b</em>ility worsening (hazard ratio: 1.94 [0.97-3.87]; <i>p</i> = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs place<em>b</em>o 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs place<em>b</em>o 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; <i>p</i> &<em>lt</em>; 0.001, <em>b</em>oth studies at all assessments).</p><A<em>b</em>stractText>Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our resu<em>lt</em>s support the utility of <em>b</em>lood NfL as an easily accessi<em>b</em>le <em>b</em>iomarker of disease evolution and treatment response.</A<em>b</em>stractText>

The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT beta R monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LT beta R caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LT beta R activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LT beta R with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers.

BACKGROUND

Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

METHODS

Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.

RESULTS

GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.

CONCLUSIONS

Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

<A<em>b</em>stractText>Stereotactic a<em>b</em>lative <em>b</em>ody radiotherapy (SABR) is widely used to treat inopera<em>b</em>le stage 1 non-small-cell lung cancer (NSCLC), despite the a<em>b</em>sence of prospective evidence that this type of treatment improves local control or prolongs overall survival compared with standard radiotherapy. We aimed to compare the two treatment techniques.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We did this mu<em>lt</em>icentre, phase 3, randomised, controlled trial in 11 hospitals in Australia and three hospitals in New Zealand. Patients were eligi<em>b</em>le if they were aged 18 years or older, had <em>b</em>iopsy-confirmed stage 1 (T1-T2aN0M0) NSCLC diagnosed on the <em>b</em>asis of ¹⁸F-fluorodeoxyglucose PET, and were medically inopera<em>b</em>le or had refused surgery. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and the tumour had to <em>b</em>e peripherally located. Patients were randomly assigned after stratification for T stage and opera<em>b</em>ility in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumour was &<em>lt</em>;2 cm from the chest wall) or standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5 Gy fractions, depending on institutional preference) using minimisation, so no sequence was pre-generated. Clinicians, patients, and data managers had no previous knowledge of the treatment group to which patients would <em>b</em>e assigned; however, the treatment assignment was su<em>b</em>sequently open la<em>b</em>el (<em>b</em>ecause of the nature of the interventions). The primary endpoint was time to local treatment failure (assessed according to Response Evaluation Criteria in Solid Tumors version 1.0), with the hypothesis that SABR would resu<em>lt</em> in superior local control compared with standard radiotherapy. All efficacy analyses were <em>b</em>ased on the intention-to-treat analysis. Safety analyses were done on a per-protocol <em>b</em>asis, according to treatment that the patients actually received. The trial is registered with ClinicalTrials.gov (NCT01014130) and the Australia and New Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to new participants.</p><A<em>b</em>stractText>Between Dec 31, 2009, and June 22, 2015, 101 eligi<em>b</em>le patients were enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy (n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard radiotherapy group did not receive treatment, and a further four in each group withdrew <em>b</em>efore study end. As of data cutoff (July 31, 2017), median follow-up for local treatment failure was 2·1 years (IQR 1·2-3·6) for patients randomly assigned to standard radiotherapy and 2·6 years (IQR 1·6-3·6) for patients assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of 66 patients in the SABR group and 11 (31%) of 35 patients in the standard radiotherapy group, and freedom from local treatment failure was improved in the SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95% CI 0·13-0·77, p=0·0077). Median time to local treatment failure was not reached in either group. In patients treated with SABR, there was one grade 4 adverse event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one lung infection, one weight loss, one dyspnoea, and one fatigue) related to treatment compared with two grade 3 events (chest pain) in the standard treatment group.</A<em>b</em>stractText><A<em>b</em>stractText>In patients with inopera<em>b</em>le peripherally located stage 1 NSCLC, compared with standard radiotherapy, SABR resu<em>lt</em>ed in superior local control of the primary disease without an increase in major toxicity. The findings of this trial suggest that SABR should <em>b</em>e the treatment of choice for this patient group.</A<em>b</em>stractText><A<em>b</em>stractText>The Radiation and Optometry Section of the Australian Government Department of Hea<em>lt</em>h with the assistance of Cancer Australia, and the Cancer Society of New Zealand and the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust).</A<em>b</em>stractText>

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 dia<em>b</em>etes, lowering glycated haemoglo<em>b</em>in (H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>)) and weight, <em>b</em>ut are currently only approved for use as su<em>b</em>cutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with su<em>b</em>cutaneous liraglutide and place<em>b</em>o in patients with type 2 dia<em>b</em>etes.</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this randomised, dou<em>b</em>le-<em>b</em>lind, dou<em>b</em>le-dummy, phase 3a trial, we recruited patients with type 2 dia<em>b</em>etes from 100 sites in 12 countries. Eligi<em>b</em>le patients were aged 18 years or older, with H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) of 7·0-9·5% (53-80·3 mmol/mol), on a sta<em>b</em>le dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhi<em>b</em>itor. Participants were randomly assigned (2:2:1) with an interactive we<em>b</em>-response system and stratified <em>b</em>y <em>b</em>ackground glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily su<em>b</em>cutaneous liraglutide (dose escalated to 1·8 mg), or place<em>b</em>o for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from <em>b</em>aseline to week 26 in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) (oral semaglutide superiority vs place<em>b</em>o and non-inferiority [margin: 0·4%] and superiority vs su<em>b</em>cutaneous liraglutide) and the confirmatory secondary endpoint was change from <em>b</em>aseline to week 26 in <em>b</em>odyweight (oral semaglutide superiority vs place<em>b</em>o and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinica<em>lt</em>rials.gov, num<em>b</em>er NCT02863419, and the European Clinical Trials registry, num<em>b</em>er EudraCT 2015-005210-30.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between Aug 10, 2016, and Fe<em>b</em> 7, 2017, 950 patients were screened, of whom 711 were eligi<em>b</em>le and randomly assigned to oral semaglutide (n=285), su<em>b</em>cutaneous liraglutide (n=284), or place<em>b</em>o (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the place<em>b</em>o group completed the 52-week trial period. Mean change from <em>b</em>aseline in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) at week 26 was -1·2% (SE 0·1) with oral semaglutide, -1·1% (SE 0·1) with su<em>b</em>cutaneous liraglutide, and -0·2% (SE 0·1) with place<em>b</em>o. Oral semaglutide was non-inferior to su<em>b</em>cutaneous liraglutide in decreasing H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) (estimated treatment difference [ETD] -0·1%, 95% CI -0·3 to 0·0; p&<em>lt</em>;0·0001) and superior to place<em>b</em>o (ETD -1·1%, -1·2 to -0·9; p&<em>lt</em>;0·0001) <em>b</em>y use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) than <em>b</em>oth su<em>b</em>cutaneous liraglutide (ETD -0·2%, 95% CI -0·3 to -0·1; p=0·0056) and place<em>b</em>o (ETD -1·2%, -1·4 to -1·0; p&<em>lt</em>;0·0001) at week 26. Oral semaglutide resu<em>lt</em>ed in superior weight loss (-4·4 kg [SE 0·2]) compared with liraglutide (-3·1 kg [SE 0·2]; ETD -1·2 kg, 95% CI -1·9 to -0·6; p=0·0003) and place<em>b</em>o (-0·5 kg [SE 0·3]; ETD -3·8 kg, -4·7 to -3·0; p&<em>lt</em>;0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with su<em>b</em>cutaneous liraglutide (-1·5 kg, 95% CI -2·2 to -0·9; p&<em>lt</em>;0·0001) and place<em>b</em>o (ETD -4·0 kg, -4·8 to -3·2; p&<em>lt</em>;0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and su<em>b</em>cutaneous liraglutide (n=211 [74%]) than with place<em>b</em>o (n=95 [67%]).</p><p><div>(<em>b</em>)INTERPRETATION</<em>b</em>)</div>Oral semaglutide was non-inferior to su<em>b</em>cutaneous liraglutide and superior to place<em>b</em>o in decreasing H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>), and superior in decreasing <em>b</em>odyweight compared with <em>b</em>oth liraglutide and place<em>b</em>o at week 26. Safety and tolera<em>b</em>ility of oral semaglutide were similar to su<em>b</em>cutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the dia<em>b</em>etes treatment continuum of care.</p><A<em>b</em>stractText>Novo Nordisk A/S.</A<em>b</em>stractText>

Islet-reactive T-cell clones from NOD mice provide an important approach to the investigation of antigens with relevance to type I diabetes. To identify a source of beta-cell antigen suitable for biochemical studies, we have used two islet-specific, diabetogenic T-cell clones to test beta-tumor cells. beta-tumor cell lines, maintained in continuous culture, were found to lose antigenicity rapidly. However, cells harvested directly from beta-tumors arising spontaneously in the transgenic NOD/Lt-Tg(RIPTag)1Lt mouse proved to be a potent source of beta-cell antigen for the T-cell clones. Subcellular fractionation of beta-tumor cells showed that the T-cell antigen was highly enriched in the beta-granule fraction and that this activity was associated with the granule membrane.

The heat-labile enterotoxins, such as cholera toxin (CT), and the labile toxins types I and II (LT-I and LT-II) of Escherichia coli have been extensively studied for their immunomodulatory properties, which result in the enhancement of immune responses. Despite superficial similarity in structure, in which a toxic A subunit is coupled to a pentameric binding B subunit, different toxins have different immunological properties. Administration of appropriate antigens admixed with or coupled to these toxins by oral, intranasal, or other routes in experimental animals induces mucosal IgA and circulating IgG antibodies that have protective potential against a variety of enteric, respiratory, or genital infections. These include the generation of salivary antibodies that may protect against colonization with mutans streptococci and the development of dental caries. However, exploitation of these adjuvants for human use requires an understanding of their mode of action and the separation of their desirable immunomodulatory properties from their toxicity. Recent findings have revealed that adjuvant action is not critically dependent upon the enzymic activity of the A subunits, and that the isolated B subunits may exert different effects on cells of the immune system than do the intact toxins. Interaction of the toxins with immunocompetent cells is not exclusively dependent upon their conventional ganglioside receptors. Immunomodulatory effects have been observed on dendritic cells, macrophages, CD4(+) and CD8(+) T-cells, and B-cells. Numerous factors-including the precise form of the toxin adjuvant, properties of the antigen, whether and how they are coupled, route of administration, and species of animal model-affect the outcome, whether this is enhanced humoral and cellular immunity, or specific induced tolerance toward the antigen.

Despite advances in understanding the pathophysiology of asthma, morbidity and mortality in pediatrics continue to rise. Little is known about the initiation and chronicity of inflammation resulting in asthma in this young population. We evaluated 20 "wheezing" children (WC) (median age 14.9 mo) with a minimum of two episodes of wheezing or prolonged wheezing>> or = 2 mo in a 6-mo period with bronchoscopy and bronchoalveolar lavage (BAL). Comparisons were made with six normal controls (NC) (median age 23.3 mo) undergoing general anesthesia for elective surgery. BAL fluid cell counts and differentials were determined. The eicosanoids, leukotriene (LT) B(4), LTE(4), prostaglandin (PG)E(2), and 15-hydroxyeicosatetraenoic acid (HETE) and the mast cell mediators, beta-tryptase and PGD(2), were evaluated by enzyme immunoassay (EIA). WC had significant elevations in total BAL cells/ml (p = 0.01), as well as, lymphocytes (LYMPH, p = 0.007), macrophages/monocytes (M&M, p = 0.02), polymorphonuclear cells (PMN, p = 0.02), epithelial cells (EPI, p = 0.03), and eosinophils (EOS, p = 0.04) compared with NC. Levels of PGE(2) (p = 0.0005), 15-HETE (p = 0.002), LTE(4) (p = 0.04), and LTB(4) (p = 0.05) were also increased in WC compared with NC, whereas PGD(2) and beta-tryptase were not. This study confirms that inflammation is present in the airways of very young WC and may differ from patterns seen in adults with asthma.

Interleukin (IL)-4-transgenic mice were used as a model system to study the consequences of low levels of IL-4 expression for the expression of other cytokines examined by quantitative polymerase chain reaction (PCR). For this purpose, a plasmid was constructed which contains, in tandem array, 5' and 3' primer sequences specific for the cytokine genes IL-1 to IL-6, tumor necrosis factor (TNF), lymphotoxin (LT), interferon (IFN)-gamma and beta-actin. During co-amplification, target and control DNA compete for the primers and the amount of PCR product is proportional to the amount of input DNA. Competitive PCR was performed first to adjust the cDNA to be compared to identical concentrations of beta-actin cDNA and subsequently to determine cytokine mRNA levels from spleen cells of normal and IL-4-transgenic animals. The sensitivity of this approach was demonstrated by the capability to detect a twofold difference in IL-4 mRNA levels between IL-4-transgenic heterozygous and homozygous animals. Upon lipopolysaccharide activation, the IL-4 transgene which is expressed essentially in B lymphocytes was induced approximately 50-fold. Several cytokine mRNA such as those coding for IL-5, IL-6, IFN-gamma and also the IL-4 receptor were found to be up-regulated in IL-4-transgenic mice, whereas IL-1, IL-2, IL-3, TNF and LT mRNA levels did not seemed to be influenced by IL-4. A possible functional significance of the elevated IFN-gamma mRNA was demonstrated by showing that (a) CD23 expression was not increased, and (b) Mac-1+ cells were markedly increased in the spleen of transgenic mice.