<A<em>b</em>stractText>Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed resu<em>lt</em>s. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.</A<em>b</em>stractText><A<em>b</em>stractText>To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.</A<em>b</em>stractText><A<em>b</em>stractText>MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), We<em>b</em> of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Num<em>b</em>er (ISRCTN) registry.</A<em>b</em>stractText><p><div>(<em>b</em>)STUDY SELECTION</<em>b</em>)</div>Randomised, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled trials of supplementation with vitamin D<su<em>b</em>)3</su<em>b</em>) or vitamin D<su<em>b</em>)2</su<em>b</em>) of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.</p><A<em>b</em>stractText>Study quality was assessed using the Cochrane Colla<em>b</em>oration Risk of Bias tool to assess sequence generation, allocation concealment, <em>b</em>linding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>We identified 25 eligi<em>b</em>le RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were o<em>b</em>tained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity <i>p</i> &<em>lt</em>; 0.001]. Su<em>b</em>group analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional <em>b</em>olus doses (aOR 0.81, 95% CI 0.72 to 0.91), <em>b</em>ut not in those receiving one or more <em>b</em>olus doses (aOR 0.97, 95% CI 0.86 to 1.10; <i>p</i> = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a <em>b</em>aseline 25-hydroxyvitamin D [25(OH)D] concentration of &<em>lt</em>; 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a <em>b</em>aseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; <i>p</i> = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; <i>p</i> = 0.83). The <em>b</em>ody of evidence contri<em>b</em>uting to these analyses was assessed as <em>b</em>eing of high quality.</p><A<em>b</em>stractText>Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.</A<em>b</em>stractText><A<em>b</em>stractText>Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving <em>b</em>olus doses experienced the <em>b</em>enefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.</A<em>b</em>stractText><A<em>b</em>stractText>This study is registered as PROSPERO CRD42014013953.</A<em>b</em>stractText><A<em>b</em>stractText>The National Institute for Hea<em>lt</em>h Research Hea<em>lt</em>h Technology Assessment programme.</A<em>b</em>stractText>

OBJECTIVE

In the new WHO-European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas three major groups of primary cutaneous B-cell lymphoma (CBCL) are distinguished: primary cutaneous marginal zone B-cell lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL) with a good prognosis, and primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT), with an intermediate-level prognosis. This study aimed to assess the clinical significance of the new classification compared with previous classification schemes (EORTC 1997; WHO 2001) and to define prognostic factors within the newly defined categories.

METHODS

In the present study clinical data and histologic sections of 300 patients with CBCL, formerly classified according to the EORTC classification, were reviewed and reclassified according to the WHO and the new WHO-EORTC classification schemes.

RESULTS

After reclassification, the study comprised 71 patients with PCMZL, 171 patients with PCFCL, and 58 patients with PCLBCL-LT, showing 5-year disease-specific survivals of 98%, 95%, and 50%, respectively. When compared with the EORTC and WHO schemes, 5.3% and 36.3% of patients with CBCL were reclassified into another prognostic category. Multivariate analysis of PCFCL revealed localization on the leg and expression of FOXP1 as independent parameters associated with a poor prognosis. Expression of Bcl-2 or MUM-1 had no significant effect on survival in this group. In PCLBCL-LT, no independent prognostic parameters were found.

CONCLUSIONS

These results emphasize the clinical significance of the WHO-EORTC classification, but suggest that within the group of PCFCL, distinction should be made between lymphomas presenting on the legs and lymphomas presenting at other sites.

Background: The COVID-19 pandemic outbreak might induce acute stress disorder (ASD) to people living in the epidemic regions. The current study aims to investigate the association of COVID-19-related stressful experiences with ASD and possible psychological mechanisms of the association among college students.

Methods: Data were collected from 7,800 college students via an online survey during the initial stage of the COVID-19 outbreak in China (from 31 January to 11 February 2020). Existing scales were adapted to measure stressful experiences, resilience, coping, social support, and ASD symptoms. Path analysis was employed to examine the research hypotheses.

Results: Among the 7,800 college students, 61.53% were women and their mean age was 20.54 years. Both direct and indirect effects from COVID-19-related stressful experiences to ASD symptoms were significant. The relationship between COVID-19-related stressful experiences and ASD could be mediated by resilience (β = 0.01, p &lt; .001), adaptive coping strategies (β = 0.02, p &lt; .001), and social support (β = 0.01, p &lt; .001); while not being significantly mediated by maladaptive coping strategies.

Conclusion: The findings presented the ASD symptoms related to the COVID-19 outbreak and the mediating role of interpersonal and intrapersonal factors in the association. Identifying the risk and protective factors is important to reduce acute psychological responses.

Keywords: COVID-19; acute stress disorder; coping strategies; resilience; social support.

The SARS-CoV-2 B.1.1.7 variant of concern (VOC) is increasing in prevalence across Europe. Accurate estimation of disease severity associated with this VOC is critical for pandemic planning. We found increased risk of death for VOC compared with non-VOC cases in England (hazard ratio: 1.67; 95% confidence interval: 1.34-2.09; p &lt; 0.0001). Absolute risk of death by 28 days increased with age and comorbidities. This VOC has potential to spread faster with higher mortality than the pandemic to date.

Keywords: CFR; COVID-19; Case fatality risk; Coronavirus; Mortality; SARS-CoV-2; Variant of concern.

The safety of nasal vaccines containing enterotoxin-based mucosal adjuvants has not been studied in detail. Previous studies have indicated that native cholera toxin (nCT) can alter antigen trafficking when applied nasally. In this study, we determined the enterotoxin-based variables that alter antigen trafficking. To measure the influence of enterotoxin-based mucosal adjuvants on antigen trafficking in the nasal tract, native and mutant enterotoxins were coadministered with radiolabeled tetanus toxoid (TT). The nCT and heat-labile enterotoxin type 1 (LTh-1) redirected TT into the olfactory neuroepithelium (ON/E). Antigen redirection occurred mainly across the nasal epithelium without subsequent transport along olfactory neurons into the olfactory bulbs (OB). Thus, no significant accumulation of the vaccine antigen TT was observed in the OB when coadministered with nCT. In contrast, neither mutant CT nor mutant LTh-1, which lack ADP-ribosyltransferase activity, redirected TT antigen into the ON/E. Thus, ADP-ribosyltransferase activity was essential for antigen trafficking across the olfactory epithelium. Accumulation of TT in the ON/E was also due to B-subunit binding to GM1 gangliosides, as was demonstrated (i) by redirection of TT by LTh-1 in a dose-dependent manner, (ii) by ganglioside inhibition of the antigen redirection by LTh-1 and nCT, and (iii) by the use of LT-IIb, a toxin that binds to gangliosides other than GM1. Redirection of TT into the ON/E coincided with elevated production of interleukin 6 (IL-6) but not IL-1beta or tumor necrosis factor alpha in the nasal mucosa. Thus, redirection of TT is dependent on ADP-ribosyltransferase activity and GM1 binding and is associated with production of the inflammatory cytokine IL-6.

The role of receptor binding in the toxicity, immunogenicity, and adjuvanticity of the heat-labile enterotoxin of Escherichia coli (LT) was examined by comparing native LT and LT(G33D), a B-subunit receptor binding mutant, with respect to the ability to bind to galactose and to GM1, toxicity on mouse Y-1 adrenal tumor cells, the ability to stimulate adenylate cyclase in Caco-2 cells, enterotoxicity in the patent mouse model, and oral immunogenicity and adjuvanticity. In contrast to native LT, LT(G33D) was unable to bind to the galactosyl moiety of Sepharose 4B or GM1 but did retain the lectin-like ability to bind to immobilized galactose on 6% agarose beads. LT(G33D) had no enterotoxicity in the patent mouse model but exhibited residual toxicity on mouse Y-1 adrenal tumor cells and had an ability equivalent to that of native LT to stimulate adenylate cyclase in Caco-2 cells (5,000 versus 6,900 pmol per mg of protein). In addition, LT(G33D) was unable to serve as an effective oral adjuvant for induction of immunoglobulin G or A directed against a coadministered antigen. Furthermore, LT(G33D) elicited negligible serum and mucosal antibody responses against itself. These data indicate that the toxicity, immunogenicity, and oral adjuvanticity of LT are dependent upon binding of the B subunit to ganglioside GM1.

Although they share approximately 88% of their genome with NOD mice including the H2g7 haplotype, NOR mice remain free of T cell-mediated autoimmune diabetes (IDDM), due to non-MHC genes of C57BLKS/J (BKS) origin. NOR IDDM resistance was previously found to be largely controlled by the Idd13 locus within an approximately 24 cM segment on Chromosome 2 encompassing BKS-derived alleles for H3a, B2m, Il1, and Pcna. NOD stocks carrying subcongenic intervals of NOR Chromosome 2 were utilized to more finely map and determine possible functions of Idd13. NOR- derived H3a-Il1 (approximately 6.0 cM) and Il1-Pcna (approximately 1.2 cM) intervals both contribute components of IDDM resistance. Hence, the Idd13 locus is more complex than originally thought, since it consists of at least two genes. B2m variants within the H3a-Il1 interval may represent one of these. Monoclonal Ab binding demonstrated that dimerizing with the beta 2m(a) (NOD type) vs beta 2m(b) isoform (NOR type) alters the structural conformation, but not total expression levels of H2g7 class I molecules (e.g. Kd, Db). Beta 2m-induced alterations in H2g7 class I conformation may partially explain findings from bone marrow chimera analyses that Idd13 modulates IDDM development at the level of non-hematopoietically derived cell types controlling selection of diabetogenic T cells and/or pancreatic beta cells targeted by these effectors. Since trans-interactions between relatively common and functionally normal allelic variants may contribute to IDDM in NOD mice, the search for Idd genes in humans should not be limited to functionally defective variants.

Lymphotoxin (LT) provides a critical signal for the genesis of lymph nodes (LN) in mice. Here we show that mice treated in utero with LT beta-R-Ig, which binds to the membrane LT alpha 1 beta 2 heterotrimer, lacked most LN, yet retained a set of mucosal surface draining LN. Since mice genetically deficient in LT alpha lack all LN, including the mucosal set, we hypothesize that a novel LT alpha-dependent pathway controls their genesis. This novel set of mucosal LN cannot be discriminated on the basis of addressin expression. The discovery of LN in mice treated with LT beta-R-Ig fusion protein in utero allowed us to compare the roles of membrane LT alpha beta or soluble LT alpha/tumor necrosis factor (TNF) in the development of cellular organization in LN and spleen. Our results indicate that both membrane LT alpha beta and soluble LT alpha/TNF mediate T-B cell segregation and the organization of B cell follicles in spleen and LN. Interestingly, while antagonism of membrane LT alpha beta or soluble LT alpha/TNF prevented germinal center (GC) formation in spleen, antagonism of soluble LT alpha/TNF had no effect on LN formation. The data suggest that multiple LT/TNF ligands control B cell follicle organization in the spleen and LN of adult mice, and that the requirements for LT/TNF ligands in GC formation are distinct in the different lymphoid organs.

<A<em>b</em>stractText>To estimate and compare progression rates to type 2 dia<em>b</em>etes mellitus (T2DM) in women with gestational dia<em>b</em>etes mellitus (GDM) and hea<em>lt</em>hy controls.</A<em>b</em>stractText><A<em>b</em>stractText>Systematic review and meta-analysis.</A<em>b</em>stractText><A<em>b</em>stractText>Medline and Em<em>b</em>ase <em>b</em>etween January 2000 and Decem<em>b</em>er 2019, studies pu<em>b</em>lished in English and conducted on humans.</A<em>b</em>stractText><A<em>b</em>stractText>O<em>b</em>servational studies investigating progression to T2DM. Inclusion criteria were postpartum follow-up for at least 12 months, incident physician <em>b</em>ased diagnosis of dia<em>b</em>etes, T2DM reported as a separate outcome rather than com<em>b</em>ined with impaired fasting glucose or impaired glucose tolerance, and studies with <em>b</em>oth a group of patients with GDM and a control group.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>This meta-analysis of 20 studies assessed a total of 1 332 373 individuals (67 956 women with GDM and 1 264 417 controls). Data were pooled <em>b</em>y random effects meta-analysis models, and heterogeneity was assessed <em>b</em>y use of the I² statistic. The pooled relative risk for the incidence of T2DM <em>b</em>etween participants with GDM and controls was estimated. Reasons for heterogeneity <em>b</em>etween studies were investigated <em>b</em>y prespecified su<em>b</em>group and meta-regression analyses. Pu<em>b</em>lication <em>b</em>ias was assessed <em>b</em>y funnel plots and, overall, studies were deemed to have a low risk of <em>b</em>ias (P=0.58 and P=0.90). The overall relative risk for T2DM was almost 10 times higher in women with previous GDM than in hea<em>lt</em>hy controls (9.51, 95% confidence interval 7.14 to 12.67, P&<em>lt</em>;0.001). In populations of women with previous GDM, the cumulative incidence of T2DM was 16.46% (95% confidence interval 16.16% to 16.77%) in women of mixed ethnicity, 15.58% (13.30% to 17.86%) in a predominantly non-white population, and 9.91% (9.39% to 10.42%) in a white population. These differences were not statistically significant <em>b</em>etween su<em>b</em>groups (white <i>v</i> mixed populations, P=0.26; white <i>v</i> non-white populations, P=0.54). Meta-regression analyses showed that the study effect size was not significantly associated with mean study age, <em>b</em>ody mass index, pu<em>b</em>lication year, and length of follow-up.</p><A<em>b</em>stractText>Women with a history of GDM appear to have a nearly 10-fold higher risk of developing T2DM than those with a normoglycaemic pregnancy. The magnitude of this risk highlights the importance of intervening to prevent the onset of T2DM, particularly in the early years after pregnancy.</A<em>b</em>stractText><A<em>b</em>stractText>PROSPERO CRD42019123079.</A<em>b</em>stractText>

The proinflammatory mediators leukotriene (LT) B(4) and LTC(4) must be transported out of cells before they can interact with LT receptors. Previously, we identified the multidrug resistance protein ABCC1 (MRP1) as an efflux pump for LTC(4). However, the molecular basis for the efflux of LTB(4) was unknown. Here, we demonstrate that human ABCC4 mediates the ATP-dependent efflux of LTB(4) in the presence of reduced glutathione (GSH), whereby the latter can be replaced by S-methyl GSH. Transport studies were performed with inside-out membrane vesicles from V79 fibroblasts and Sf9 insect cells that contained recombinant ABCC4, with vesicles from human platelets and myelomonocytic U937 cells, which were rich in endogenous ABCC4, but ABCC1 was below detectability. Moreover, human polymorphonuclear leukocytes contained ABCC4. K(m) values for LTB(4) were 5.2 muM with vesicles from fibroblasts and 5.6 muM with vesicles from platelets. ABCC4, with its broad substrate specificity, also functioned as an ATP-dependent efflux pump for LTC(4) with a K(m) of 0.13 muM in vesicles from fibroblasts and 0.32 muM in vesicles from platelets. However, GSH was not required for the transport of this glutathionylated leukotriene. The transport of LTC(4) by ABCC4 explains its release from platelets during transcellular synthesis. ATP-dependent transport of LTB(4) and LTC(4) by ABCC4 was inhibited by several organic anions, including S-decyl GSH, sulindac sulfide, and by the LTD(4) receptor antagonists montelukast and 3-(((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-((3-dimethyl-amino-3-oxopropyl)-thio)-methyl)thio)propanoic acid (MK571). Thus, as an efflux pump for the proinflammatory mediators LTB(4) and LTC(4), ABCC4 may represent a novel target for anti-inflammatory therapies.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. As over 90% of HCCs arise in cirrhotic livers preventive methods and surveillance policies have been adopted in most countries with high prevalence of hepatitis B or C infected people. Poor prognosis of HCC has shown some improvement during the last years. Targeted therapy with radiofrequency ablation (RFA), hepatic resection (HR), liver transplantation (LT), and transcatheter arterial chemoembolisation (TACE) seems to have an influence on this development. The heterogeneity of cirrhotic patients with HCC is still a big challenge. A patient with a small tumour in a cirrhotic liver may have a worse prognosis than a patient with a large tumor in a relatively preserved liver after "curative" HR. The choice of the treatment modality depends on the size and the number of tumours, the stage and the cause of cirrhosis and finally on the availability of various modalities in each centre.

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values&lt;0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Keywords: B-cell depleting therapies; COVID-19; DMTs; Multiple Sclerosis.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Familial chylomicronemia syndrome is a rare genetic disorder that is caused <em>b</em>y loss of lipoprotein lipase activity and characterized <em>b</em>y chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-la<em>b</em>el study of three patients with this syndrome, antisense-mediated inhi<em>b</em>ition of hepatic <i>APOC3</i> mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.</p><A<em>b</em>stractText>We conducted a phase 3, dou<em>b</em>le-<em>b</em>lind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or place<em>b</em>o. The primary end point was the percentage change in fasting triglyceride levels from <em>b</em>aseline to 3 months.</A<em>b</em>stractText><A<em>b</em>stractText>Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from <em>b</em>aseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving place<em>b</em>o had an increase in mean plasma apolipoprotein C-III levels from <em>b</em>aseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P&<em>lt</em>;0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving place<em>b</em>o had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P&<em>lt</em>;0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the place<em>b</em>o group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received place<em>b</em>o had such reactions. No patients in the place<em>b</em>o group had platelet counts <em>b</em>elow 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels <em>b</em>elow 25,000 per microliter. No patient had platelet counts <em>b</em>elow 50,000 per microliter after enhanced platelet-monitoring <em>b</em>egan.</A<em>b</em>stractText><A<em>b</em>stractText>Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Throm<em>b</em>ocytopenia and injection-site reactions were common adverse events. (Funded <em>b</em>y Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov num<em>b</em>er, NCT02211209.).</A<em>b</em>stractText>

<A<em>b</em>stractText>To report the epidemiological, clinical, and radiological characteristics of patients with COVID-19 in Xiaogan, Hu<em>b</em>ei, China.</A<em>b</em>stractText><p><div>(<em>b</em>)MATERIALS AND METHODS</<em>b</em>)</div>The complete clinical and imaging data of 114 confirmed COVID-19 patients treated in Xiaogan Hospital were analysed retrospectively. Data were gathered regarding the presence of chest computed tomography (CT) a<em>b</em>normalities; the distri<em>b</em>ution, morphology, density, location, and stage of a<em>b</em>normal shadows on chest CT; and o<em>b</em>serving the correlation <em>b</em>etween the severity of chest infection and lymphocyte ratio and <em>b</em>lood oxygen saturation (SPO<su<em>b</em>)2</su<em>b</em>)) in patients.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Chest CT revealed a<em>b</em>normal lung shadows in 110 patients. Regarding lesion distri<em>b</em>ution, mu<em>lt</em>i-lo<em>b</em>e lesions in <em>b</em>oth lungs were present in most patients (80 cases; 72.7%). Lesions most frequently involved <em>b</em>oth the peripheral zone and the central zone (62 cases; 56.4%). Regarding lesion morphology, 56 cases (50.1%) demonstrated patchy shadows that were partially fused into large areas. Thirty cases showed ground-glass opacity (27.3%), 30 cases showed the consolidation change (27.3%), and the remaining 50 cases showed <em>b</em>oth types of changes (45.4%). The progressing stage was the most common stage (54 cases; 49.1%). CT resu<em>lt</em>s showed a negative correlation with SPO<su<em>b</em>)2</su<em>b</em>) and lymphocyte num<em>b</em>ers (p&<em>lt</em>;0.05), with r-values of -0.446 and -0.780, respectively.</p><A<em>b</em>stractText>Spiral CT is a sensitive examination method, which can <em>b</em>e applied to make an early diagnosis and for evaluation of progression, with a diagnostic sensitivity and accuracy <em>b</em>etter than that of nucleic acid detection.</A<em>b</em>stractText>

Background: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β₂-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking.

Methods: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only.

Results: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group.

Conclusions: Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).

Clinical descriptions about influenza-like illnesses (ILI) in COVID-19 seem non-specific. We aimed to compare the clinical features of COVID-19 and influenza. We retrospectively investigated the clinical features and outcomes of confirmed cases of COVID-19 and influenza in Nord Franche-Comté Hospital between February 26th and March 14th 2020. We used SARS-CoV-2 RT-PCR and influenza virus A/B RT-PCR in respiratory samples to confirm the diagnosis. We included 124 patients. The mean age was 59 (±19 [19-98]) years with 69% female. 70 patients with COVID-19 and 54 patients with influenza A/B. Regarding age, sex and comorbidities, no differences were found between the two groups except a lower Charlson index in COVID-19 group (2 [±2.5] vs 3 [±2.4],p = 0.003). Anosmia (53% vs 17%,p &lt; 0.001), dysgeusia (49% vs 20%,p = 0.001), diarrhea (40% vs 20%,p = 0.021), frontal headache (26% vs 9%,p = 0.021) and bilateral cracklings sounds (24% vs 9%,p = 0.034) were statistically more frequent in COVID-19. Sputum production (52% vs 29%,p = 0.010), dyspnea (59% vs 34%,p = 0.007), sore throat (44% vs 20%,p = 0.006), conjunctival hyperhemia (30% vs 4%,p &lt; 0.001), tearing (24% vs 6%,p = 0.004), vomiting (22% vs 3%,p = 0.001) and rhonchi sounds (17% vs 1%,p = 0.002) were more frequent with influenza infection. We described several clinical differences which can help the clinicians during the co-circulation of influenza and SARS-CoV-2.

Keywords: COVID- 19; Clinical feature; Influenza; Influenza-like-illness; SARS-CoV-2.

Activation of the classical and noncanonical NF-kappaB pathways by ligation of the lymphotoxin (LT)-beta receptor (LTbetaR) plays a crucial role in lymphoid organogenesis and in the generation of ectopic lymphoid tissue at sites of chronic inflammation. Within these microenvironments, LTbetaR signaling regulates the phenotype of the specialized high endothelial cells. However, the direct effects of LTbetaR ligation on endothelial cells remain unclear. We therefore questioned whether LTbetaR ligation could directly activate endothelial cells and regulate classical and noncanonical NF-kappaB-dependent gene expression. We demonstrate that the LTbetaR ligands LIGHT and LTalpha1betaLTalpha1betaLTalpha1betaLTbetaR ligation up-regulated T cell adhesion to HUVEC. Furthermore, the homeostatic chemokine CXCL12 was up-regulated by LIGHT and LTalpha1betaLTbetaR ligation regulates gene expression in endothelial cells via both NF-kappaB pathways and we identify CXCL12 as a bona fide noncanonical NF-kappaB-regulated gene in these cells.

<p><div>(<em>b</em>)PURPOSE</<em>b</em>)</div>Standard first-line therapy for <i>EGFR</i>-mutant advanced non-small-cell lung cancer (NSCLC) is an epidermal growth factor receptor (EGFR)-directed oral tyrosine kinase inhi<em>b</em>itor. Adding pemetrexed and car<em>b</em>oplatin chemotherapy to an oral tyrosine kinase inhi<em>b</em>itor may improve outcomes.</p><p><div>(<em>b</em>)PATIENTS AND METHODS</<em>b</em>)</div>This was a phase III randomized trial in patients with advanced NSCLC har<em>b</em>oring an <i>EGFR</i>-sensitizing mutation and a performance status of 0 to 2 who were planned to receive first-line palliative therapy. Random assignment was 1:1 to gefitini<em>b</em> 250 mg orally per day (Gef) or gefitini<em>b</em> 250 mg orally per day plus pemetrexed 500 mg/m² and car<em>b</em>oplatin area under curve 5 intravenously every 3 weeks for four cycles, followed <em>b</em>y maintenance pemetrexed (gefitini<em>b</em> plus chemotherapy [Gef+C]). The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), response rate, and toxicity.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Between 2016 and 2018, 350 patients were randomly assigned to Gef (n = 176) and Gef+C (n = 174). Twenty-one percent of patients had a performance status of 2, and 18% of patients had <em>b</em>rain metastases. Median follow-up time was 17 months (range, 7 to 30 months). Radiologic response rates were 75% and 63% in the Gef+C and Gef arms, respectively (<i>P</i> = .01). Estimated median PFS was significantly longer with Gef+C than Gef (16 months [95% CI, 13.5 to 18.5 months] <i>v</i> 8 months [95% CI, 7.0 to 9.0 months], respectively; hazard ratio for disease progression or death, 0.51 [95% CI, 0.39 to 0.66]; <i>P</i> &<em>lt</em>; .001). Estimated median OS was significantly longer with Gef+C than Gef (not reached <i>v</i> 17 months [95% CI, 13.5 to 20.5 months]; hazard ratio for death, 0.45 [95% CI, 0.31 to 0.65]; <i>P</i> &<em>lt</em>; .001). Clinically relevant grade 3 or greater toxicities occurred in 51% and 25% of patients in the Gef+C and Gef arms, respectively (<i>P</i> &<em>lt</em>; .001).</p><A<em>b</em>stractText>Adding pemetrexed and car<em>b</em>oplatin chemotherapy to gefitini<em>b</em> significantly prolonged PFS and OS <em>b</em>ut increased toxicity in patients with NSCLC.</A<em>b</em>stractText>

The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates.

574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model.

24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs. >2 in the whole population (13.2±1.8% vs. 49.8±8.7%, p<0.001, HR=4.98), in patients within Milan criteria (12.8±2.0% vs. 32.4±12.1%, p=0.009, HR=3.51), beyond Milan criteria (14.9±4.2% vs. 58.9±11.5%, p<0.001, HR=4.26), HCV patients (14.9±2.5% vs. 67.6±14.7%, p<0.001, HR=6.56) and HBV patients (11.6±3.4% vs. 34.3±12.5%, p=0.012, HR=3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7±2.2% vs. 42.2±8.3% (p<0.001, HR=2.14).

The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis.

Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis.

<A<em>b</em>stractText>Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 dia<em>b</em>etes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.</A<em>b</em>stractText><A<em>b</em>stractText>REWIND was a mu<em>lt</em>icentre, randomised, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 dia<em>b</em>etes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly su<em>b</em>cutaneous injection of dulaglutide (1·5 mg) or place<em>b</em>o and followed up at least every 6 months for outcomes. Urinary al<em>b</em>umin-to-creatinine ratios (UACRs) and estimated glomerular fi<em>lt</em>ration rates (eGFRs) were estimated from urine and serum values measured in local la<em>b</em>oratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have <em>b</em>een reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroal<em>b</em>uminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from <em>b</em>aseline, or chronic renal replacement therapy. Analyses were <em>b</em>y intention to treat. This trial is registered with ClinicalTrials.gov, num<em>b</em>er NCT01394952.</A<em>b</em>stractText><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or place<em>b</em>o (n=4952). At <em>b</em>aseline, 791 (7·9%) had macroal<em>b</em>uminuria and mean eGFR was 76·9 mL/min per 1·73 m² (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the place<em>b</em>o group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroal<em>b</em>uminuria (HR 0·77, 95% CI 0·68-0·87; p&<em>lt</em>;0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy.</p><A<em>b</em>stractText>Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 dia<em>b</em>etes.</A<em>b</em>stractText><A<em>b</em>stractText>Eli Lilly and Company.</A<em>b</em>stractText>

Previously described GM1 ganglioside enzyme-linked immunosorbent assays (GM1-ELISA) for the detection of Escherichia coli heat-labile enterotoxin (LT) showed sensitivity equal to the Y-1 adrenal cell assay when anti-LT (a reagent not commercially available) was used. However, when antitoxin to immunologically related (commercially available) cholera toxin was substituted, a marked loss in sensitivity occurred. We modified the GM1-ELISA that employed anti-cholera toxin to make it comparable in sensitivity to the Y-1 adrenal cell assay. When five media commonly used for LT production were compared, Mundell's Casamino Acids medium was shown to be significantly superior. Lincomycin (45 micrograms/ml) added to E. coli cultures significantly increased net optical densities in the GM1-ELISA, a direct measure of the amount of LT. Treatment of broth cultures or bacterial cell pellets with polymyxin B or extension of culture time to 48 h also significantly increased net optical density by allowing enhanced release of periplasmic LT. A major innovation involved the direct culture of E. coli strains in GM1-coated wells of microtiter plates followed by ELISA. This direct culture method GM1-ELISA (DCM-GM1-ELISA) saved not only assay time, but also materials and reagents. The net optical densities that result from this assay allow the test to be read visually without a spectrophotometer. Three independent observers read plates with E. coli tested by DCM-GM1-ELISA. Thirty-four of 35 adrenal cell-positive strains (97% sensitivity) and 30 of 30 LT-negative control E. coli strains (100% specificity) were identified by all three observers reading coded plates. The DCM-GM1-ELISA provides a simple, practical and efficient assay for LT for less sophisticated laboratories.

This study analyzes stroke phases and arm and leg coordination during front crawl swimming as a function of swim velocity and performance level. Forty-three swimmers constituted three groups based on performance level. All swam at three different swim velocities, corresponding to the paces appropriate for the 800 m, 100 m, and 50 m. The different stroke phases and the arm and leg coordination were identified by video analysis. Arm coordination was quantified using a new index of coordination (IdC), which expresses the three major modalities opposition, catch-up and superposition. Opposition, where one arm begins the pull phase when the other is finishing the push phase; catch up, which has a lag time (LT) between propulsive phases of the two arms; and superposition, which describes an overlap in the propulsive phases. The IdC is an index which characterizes coordination patterns by measure of LT between propulsive phases of each arm. The most important results showed that duration of the propulsive phases (B + C) increased significantly with increasing velocity: 43.1 +/- 3.3% for V800; 46.5 +/- 3% for V100 and 49 +/- 3% for V50. The arm and leg synchronization was modified in the sense of an increase in six-beat kick. The IdC increased significantly with velocity: IdCV800 = -7.6 +/- 6.4%; IdCV100 = -3.2 +/- 5.1% and IdCV50 = -0.9 +/- 5.6%. IdC increased also significantly with performance level: IdCG3 = -6.07 +/- 5.3%; IdCG2 = -3.9 +/- 4.2% and IdCG1 = -1.76 +/- 5.6% for the mean of the 3 velocity. The two extreme IdC were IdCG3V800 = -9.4 +/- 5.4% and IdCG1V50 = +2.53 +/- 4.4%.

Lymphotoxin (<em>LT</em>, <em>LT</em> alpha, TNF <em>beta</em>) is a member of the immediate TNF family that also includes TNF-alpha and lymphotoxin-<em>beta</em> (<em>LT</em> <em>beta</em>). <em>LT</em> is produced by activated lymphocytes and functions as either a secreted homotrimer or a membrane-associated heterotrimer that includes the transmembrane protein <em>LT</em> <em>beta</em>. Secreted <em>LT</em> alpha3 can bind to two cell surface receptors, TNFR1 and TNFR2, while the membrane-bound heterotrimer <em>LT</em> alpha1<em>beta</em>2 has been shown to interact with a distinct receptor, <em>LT</em> <em>beta</em>R. <em>LT</em> alpha induces inflammation at the sites of expression of a rat insulin promoter-driven lymphotoxin (RIP<em>LT</em>) transgene in the pancreas and kidney. To determine the role of the various ligands and their receptors in <em>LT</em>-induced inflammation, mice deficient in either TNFR1, TNFR2, or <em>LT</em> <em>beta</em> were crossed to RIP<em>LT</em>-transgenic mice. Our results indicate that <em>LT</em> alpha-induced inflammation is dependent on the interaction of <em>LT</em> alpha3 with TNFR1, and there is no obvious role for TNFR2, since in its absence, <em>LT</em> alpha-induced inflammation is quantitatively and qualitatively similar to that seen in the wild type. However, the absence of <em>LT</em> <em>beta</em> results in accentuated infiltration of the kidney with an increase in the proportion of memory cells in the infiltrate. These data show a crucial role for the secreted <em>LT</em> alpha3 signaling via TNFR1 in <em>LT</em> alpha-induced inflammation, and a separate and distinct role for the membrane <em>LT</em> alpha1<em>beta</em>2 form in this inflammatory process.

Cytotoxic necrotizing factor 1 (CNF1), a 110-kDa protein toxin from pathogenic Escherichia coli induces actin reorganization into stress fibers and retraction fibers in human epithelial cultured cells allowing them to spread. CNF1 is acting in the cytosol since microinjection of the toxin into HEp-2 cells mimics the effects of the externally applied CNF1. Incubation in vitro of CNF1 with recombinant small GTPases induces a modification of Rho (but not of Rac, Cdc42, Ras, or Rab6) as demonstrated by a discrete increase in the apparent molecular weight of the molecule. Preincubation of cells with CNF1 impairs the cytotoxic effects of Clostridium difficile toxin B, which inactivates Rho but not those of Clostridium sordellii LT toxin, which inhibits Ras and Rac. As shown for Rho-GTP, CNF1 activates, in a time- and dose-dependent manner, a cytoskeleton-associated phosphatidylinositol 4-phosphate 5-kinase. However, neither the phosphatidylinositol 4,5-bisphosphate (PIP2) nor the phosphatidylinositol 3,4-bisphosphate (PI 3,4-P2) or 3,4,5-trisphosphate (PIP3) cellular content were found increased in CNF1 treated HEp-2 cells. Cellular effects of CNF1 were not blocked by LY294002, a stable inhibitor of the phosphoinositide 3-kinase. Incubation of HEp-2 cells with CNF1 induces relocalization of myosin 2 in stress fibers but not in retraction fibers. Altogether, our data indicate that CNF1 is a toxin that selectively activates the Rho GTP-binding protein, thus inducing contractility and cell spreading.