A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.

<A<em>b</em>stractText>The Bergamo province, which is extensively affected <em>b</em>y the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural o<em>b</em>servatory of virus manifestations in the general population. In the past month we recorded an out<em>b</em>reak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic.</A<em>b</em>stractText><A<em>b</em>stractText>All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation <em>b</em>efore (group 1) or after (group 2) the <em>b</em>eginning of the SARS-CoV-2 epidemic. Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined <em>b</em>y presence of circulatory dysfunction, and macrophage activation syndrome (MAS) <em>b</em>y the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought <em>b</em>y reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swa<em>b</em>s, and <em>b</em>y serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.</A<em>b</em>stractText><p><div>(<em>b</em>)Findings</<em>b</em>)</div>Group 1 comprised 19 patients (seven <em>b</em>oys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed <em>b</em>etween Jan 1, 2015, and Fe<em>b</em> 17, 2020. Group 2 included ten patients (seven <em>b</em>oys, three girls; aged 7·5 years [SD 3·5]) diagnosed <em>b</em>etween Fe<em>b</em> 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or <em>b</em>oth. The two groups differed in disease incidence (group 1 <i>vs</i> group 2, 0·3 <i>vs</i> ten per month), mean age (3·0 <i>vs</i> 7·5 years), cardiac involvement (two of 19 <i>vs</i> six of ten), KDSS (zero of 19 <i>vs</i> five of ten), MAS (zero of 19 <i>vs</i> five of ten), and need for adjunctive steroid treatment (three of 19 <i>vs</i> eight of ten; all p&<em>lt</em>;0·01).</p><A<em>b</em>stractText>In the past month we found a 30-fold increased incidence of Kawasaki-like disease. Children diagnosed after the SARS-CoV-2 epidemic <em>b</em>egan showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease. A similar out<em>b</em>reak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic.</A<em>b</em>stractText><A<em>b</em>stractText>None.</A<em>b</em>stractText>

<A<em>b</em>stractText>Type 2 dia<em>b</em>etes mellitus is the leading cause of kidney failure worldwide, <em>b</em>ut few effective long-term treatments are availa<em>b</em>le. In cardiovascular trials of inhi<em>b</em>itors of sodium-glucose cotransporter 2 (SGLT2), exploratory resu<em>lt</em>s have suggested that such drugs may improve renal outcomes in patients with type 2 dia<em>b</em>etes.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this dou<em>b</em>le-<em>b</em>lind, randomized trial, we assigned patients with type 2 dia<em>b</em>etes and al<em>b</em>uminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhi<em>b</em>itor, at a dose of 100 mg daily or place<em>b</em>o. All the patients had an estimated glomerular fi<em>lt</em>ration rate (GFR) of 30 to &<em>lt</em>;90 ml per minute per 1.73 m² of <em>b</em>ody-surface area and al<em>b</em>uminuria (ratio of al<em>b</em>umin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system <em>b</em>lockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &<em>lt</em>;15 ml per minute per 1.73 m²), a dou<em>b</em>ling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.</p><A<em>b</em>stractText>The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the place<em>b</em>o group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a dou<em>b</em>ling of the creatinine level, or death from renal causes was lower <em>b</em>y 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&<em>lt</em>;0.001), and the relative risk of end-stage kidney disease was lower <em>b</em>y 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&<em>lt</em>;0.001). There were no significant differences in rates of amputation or fracture.</A<em>b</em>stractText><A<em>b</em>stractText>In patients with type 2 dia<em>b</em>etes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the place<em>b</em>o group at a median follow-up of 2.62 years. (Funded <em>b</em>y Janssen Research and Development; CREDENCE ClinicalTrials.gov num<em>b</em>er, NCT02065791.).</A<em>b</em>stractText>

In the exercising human, maximal oxygen uptake (VO2max) is limited by the ability of the cardiorespiratory system to deliver oxygen to the exercising muscles. This is shown by three major lines of evidence: 1) when oxygen delivery is altered (by blood doping, hypoxia, or beta-blockade), VO2max changes accordingly; 2) the increase in VO2max with training results primarily from an increase in maximal cardiac output (not an increase in the a-v O2 difference); and 3) when a small muscle mass is overperfused during exercise, it has an extremely high capacity for consuming oxygen. Thus, O2 delivery, not skeletal muscle O2 extraction, is viewed as the primary limiting factor for VO2max in exercising humans. Metabolic adaptations in skeletal muscle are, however, critical for improving submaximal endurance performance. Endurance training causes an increase in mitochondrial enzyme activities, which improves performance by enhancing fat oxidation and decreasing lactic acid accumulation at a given VO2. VO2max is an important variable that sets the upper limit for endurance performance (an athlete cannot operate above 100% VO2max, for extended periods). Running economy and fractional utilization of VO2max also affect endurance performance. The speed at lactate threshold (LT) integrates all three of these variables and is the best physiological predictor of distance running performance.

Mice rendered deficient in lymphotoxin (LT) by gene targeting in embryonic stem cells have no morphologically detectable lymph nodes or Peyer's patches, although development of the thymus appears normal. Within the white pulp of the spleen, there is failure of normal segregation of B and T cells. Spleen and peripheral blood contain CD4+CD8- and CD4-CD8+ T cells in a normal ratio, and both T cells subsets have an apparently normal lytic function. Lymphocytes positive for immunoglobulin M are present in increased numbers in both the spleen and peripheral blood. These data suggest an essential role for LT in the normal development of peripheral lymphoid organs.

TGF-beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-kappaB and AP-1 and, therefore, plays a crucial role in regulating the genes that mediate inflammation. Although in vitro biochemical studies have revealed the existence of a TAK1 complex, which includes TAK1 and the adapter proteins TAB1 and TAB2, it remains unclear which members of this complex are essential for signaling. To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality. Using embryonic fibroblasts lacking TAK1, TAB1, or TAB2, we have found that TNFR1, IL-1R, TLR3, and TLR4-mediated NF-kappaB and AP-1 activation are severely impaired in Tak1(m/m) cells, but they are normal in Tab1(-/-) and Tab2(-/-) cells. In addition, Tak1(m/m) cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-alpha and IL-1 signaling pathways, where it functions downstream of RIP1-TRAF2 and MyD88-IRAK1-TRAF6, respectively. However, TAK1 is not required for NF-kappaB activation through the alternative pathway following LT-beta signaling. In the TGF-beta signaling pathway, TAK1 deletion leads to impaired NF-kappaB and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF-beta-induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKKbeta and JNK, but not IKKalpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.

<A<em>b</em>stractText>An epidemic of Coronavirus Disease 2019 (COVID-19) <em>b</em>egan in Decem<em>b</em>er 2019 and triggered a Pu<em>b</em>lic Hea<em>lt</em>h Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help.</A<em>b</em>stractText><A<em>b</em>stractText>The data of COVID-19 patients until March 20, 2020 were retrieved from four data<em>b</em>ases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Thirteen studies were included in Meta-analysis, including a total num<em>b</em>er of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P &<em>lt</em>; 0.00001; age over 65 years old: OR =6.06, 95% CI(3.98, 9.22), P &<em>lt</em>; 0.00001; current smoking: OR =2.51, 95% CI(1.39, 3.32), P = 0.0006). The proportion of underlying diseases such as hypertension, dia<em>b</em>etes, cardiovascular disease, and respiratory disease were statistically significant higher in critical/mortal patients compared to the non-critical patients (dia<em>b</em>etes: OR=3.68, 95% CI (2.68, 5.03), P &<em>lt</em>; 0.00001; hypertension: OR = 2.72, 95% CI (1.60,4.64), P = 0.0002; cardiovascular disease: OR = 5.19, 95% CI(3.25, 8.29), P &<em>lt</em>; 0.00001; respiratory disease: OR = 5.15, 95% CI(2.51, 10.57), P &<em>lt</em>; 0.00001). Clinical manifestations such as fever, shortness of <em>b</em>reath or dyspnea were associated with the progression of disease [fever: 0R = 0.56, 95% CI (0.38, 0.82), P = 0.003;shortness of <em>b</em>reath or dyspnea: 0R=4.16, 95% CI (3.13, 5.53), P &<em>lt</em>; 0.00001]. La<em>b</em>oratory examination such as aspartate amino transferase(AST) > 40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI) > 28pg/mL, procalcitonin(PCT) > 0.5ng/mL, lactatede hydrogenase(LDH) > 245U/L, and D-dimer > 0.5mg/L predicted the deterioration of disease while white <em>b</em>lood cells(WBC)&<em>lt</em>;4 × 10⁹/L meant a <em>b</em>etter clinical status[AST > 40U/L:OR=4.00, 95% CI (2.46, 6.52), P &<em>lt</em>; 0.00001; Cr ≥ 133μmol/L: OR = 5.30, 95% CI (2.19, 12.83), P = 0.0002; hs-cTnI > 28 pg/mL: OR = 43.24, 95% CI (9.92, 188.49), P &<em>lt</em>; 0.00001; PCT > 0.5 ng/mL: OR = 43.24, 95% CI (9.92, 188.49), P &<em>lt</em>; 0.00001;LDH > 245U/L: OR = 43.24, 95% CI (9.92, 188.49), P &<em>lt</em>; 0.00001; D-dimer > 0.5mg/L: OR = 43.24, 95% CI (9.92, 188.49), P &<em>lt</em>; 0.00001; WBC &<em>lt</em>; 4 × 10⁹/L: OR = 0.30, 95% CI (0.17, 0.51), P &<em>lt</em>; 0.00001].</p><A<em>b</em>stractText>Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comor<em>b</em>idities such as hypertension, dia<em>b</em>etes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of <em>b</em>reath or dyspnea and la<em>b</em>oratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19.</A<em>b</em>stractText>

Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT-alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LT beta R), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far--caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-kappa B activation cascade--mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.

The regulation of the subclass of immunoglobulin secreted by B cells has been studied in vitro in polyclonal systems using mitogens, such as lipopolysaccharide (LPS), to bypass the requirement for cognate interaction between antigen-specific T and B cells. In these systems, interleukin-(IL)-4 induces the secretion of IgG1 (ref. 1) and IgE (ref. 2); IL-5 enhances the secretion of IgA, and interferon-gamma (IFN-gamma) enhances the secretion of IgG2a (ref. 5). Clones of murine TH cells can be divided into two subsets, TH1 and TH2 (ref. 6). Both subsets synthesize IL-3 and granulocyte-monocyte colony-stimulating factor (GM-CSF), but only TH1 clones produce IL-2, IFN-gamma, and lymphotoxin (LT) and TH2 clones produce IL-4 and IL-5 (ref. 7). We have examined the role of clones of antigen-specific TH1 and TH2 cells in the regulation of the subclasses of IgG antibody secreted by antigen-specific B cells. Our results show that both types of TH cells induce the secretion of IgM and IgG3, whereas clones of TH1 and TH2 cells specifically induce antigen-specific B cells to secrete IgG2a and IgG1, respectively. We also demonstrate that regulation of commitment to the secretion of a particular IgG isotype occurs in two distinct stages: cognate interaction between T and B cells and interaction between T-cell-derived lymphokines and B cells.

In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arranged in sophisticated organizations that resemble microstructures usually formed in secondary lymphoid organs. Molecular pathways and host risk factors involved in this process of lymphoid neogenesis remain to be defined. In a series of 64 synovial tissue biopsies, lymphoid follicles with germinal centers (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the recruitment or in situ maturation of FDCs is a critical factor for GC formation in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lymphoid organogenesis. Multivariate logistic regression analysis of tissue cytokines and chemokines identified two parameters, in situ transcription of lymphotoxin (LT)-beta and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), that were predictors for FDC recruitment and synovial GC formation. LT-beta and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each other to facilitate GC formation. Prediction models incorporating in situ transcription of LT-beta and BLC/CXCL13 had high negative yet moderate positive predictive values, suggesting that LT-beta and BLC/CXCL13 are necessary but not sufficient. LT-beta protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular structures. BLC/CXCL13 was produced by FDCs in follicular centers, but was predominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrating lymphocytes in regulating extranodal lymphoid neogenesis.

<A<em>b</em>stractText>The 2019 novel coronavirus (SARS-CoV-2) is a new human coronavirus which is spreading with epidemic features in China and other Asian countries with cases reported worldwide. This novel Coronavirus Disease (COVID-19) is associated with a respiratory illness that may cause severe pneumonia and acute respiratory distress syndrome (ARDS). A<em>lt</em>hough related to the Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), COVID-19 shows some peculiar pathogenetic, epidemiological and clinical features which have not <em>b</em>een completely understood to date.</A<em>b</em>stractText><A<em>b</em>stractText>We provide a review of the differences in terms of pathogenesis, epidemiology and clinical features <em>b</em>etween COVID-19, SARS and MERS.</A<em>b</em>stractText><A<em>b</em>stractText>The most recent literature in English language regarding COVID-19 has <em>b</em>een reviewed and extracted data have <em>b</em>een compared with the current scientific evidence a<em>b</em>out SARS and MERS epidemics.</A<em>b</em>stractText><p><div>(<em>b</em>)CONTENT</<em>b</em>)</div>COVID-19 seems not to <em>b</em>e very different from SARS regarding its clinical features. However, it has a fatality rate of 2.3%, lower than SARS (9.5%) and much lower than MERS (34.4%). It cannot <em>b</em>e excluded that <em>b</em>ecause of the COVID-19 less severe clinical picture it can spread in the community more easily than MERS and SARS. The actual <em>b</em>asic reproductive num<em>b</em>er (R<su<em>b</em>)0</su<em>b</em>)) of COVID-19 (2-2.5) is still controversial. It is pro<em>b</em>a<em>b</em>ly slightly higher than the R<su<em>b</em>)0</su<em>b</em>) of SARS (1.7-1.9) and higher than MERS (&<em>lt</em>;1),. The gastrointestinal route of transmission of SARS-CoV-2, which has <em>b</em>een also assumed for SARS-CoV and MERS-CoV, cannot <em>b</em>e ruled out and needs to <em>b</em>e further investigated.</p><A<em>b</em>stractText>There is still much more to know a<em>b</em>out COVID-19, especially as concerns mortality and capacity of spreading on a pandemic level. Nonetheless, all of the lessons we learned in the past from SARS and MERS epidemics are the <em>b</em>est cu<em>lt</em>ural weapons to face this new glo<em>b</em>al threat.</A<em>b</em>stractText>

Immunoglobulin A (IgA) is generated in the gut by both T cell-dependent and T cell-independent processes. The sites and the mechanisms for T cell-independent IgA synthesis remain elusive. Here we show that isolated lymphoid follicles (ILFs) were sites where induction of activation-induced cytidine deaminase (AID) and IgA class switching of B cells took place in the absence of T cells. We also show that formation of ILFs was regulated by interactions between lymphoid tissue-inducer cells expressing the nuclear receptor ROR gamma t (ROR gamma t(+)LTi cells) and stromal cells (SCs). Activation of SCs by ROR gamma t(+)LTi cells through lymphotoxin (LT)-beta receptor (LT beta R) and simultaneously by bacteria through TLRs induced recruitment of dendritic cells (DCs) and B cells and formation of ILFs. These findings provide insight into the crosstalk between bacteria, ROR gamma t(+)LTi cells, SCs, DCs, and B cells required for ILF formation and establish a critical role of ILFs in T cell-independent IgA synthesis in gut.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div><i>PIK3CA</i> mutations occur in approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative <em>b</em>reast cancer. The PI3Kα-specific inhi<em>b</em>itor alpelisi<em>b</em> has shown antitumor activity in early studies.</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In a randomized, phase 3 trial, we compared alpelisi<em>b</em> (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with place<em>b</em>o plus fulvestrant in patients with HR-positive, HER2-negative advanced <em>b</em>reast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the <em>b</em>asis of tumor-tissue <i>PIK3CA</i> mutation status. The primary end point was progression-free survival, as assessed <em>b</em>y the investigator, in the cohort with <i>PIK3CA</i>-mutated cancer; progression-free survival was also analyzed in the cohort without <i>PIK3CA</i>-mutated cancer. Secondary end points included overall response and safety.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue <i>PIK3CA</i> mutations. In the cohort of patients with <i>PIK3CA</i>-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisi<em>b</em>-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the place<em>b</em>o-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P&<em>lt</em>;0.001); in the cohort without <i>PIK3CA</i>-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior pro<em>b</em>a<em>b</em>ility of hazard ratio &<em>lt</em>;1.00, 79.4%). Overall response among all the patients in the cohort without <i>PIK3CA</i>-mutated cancer was greater with alpelisi<em>b</em>-fulvestrant than with place<em>b</em>o-fulvestrant (26.6% vs. 12.8%); among patients with measura<em>b</em>le disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisi<em>b</em>-fulvestrant group vs. 0.7% in the place<em>b</em>o-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisi<em>b</em>-fulvestrant group, as compared with 0.3% of those in the place<em>b</em>o-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisi<em>b</em> and place<em>b</em>o owing to adverse events were 25.0% and 4.2%, respectively.</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>Treatment with alpelisi<em>b</em>-fulvestrant prolonged progression-free survival among patients with <i>PIK3CA</i>-mutated, HR-positive, HER2-negative advanced <em>b</em>reast cancer who had received endocrine therapy previously. (Funded <em>b</em>y Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov num<em>b</em>er, NCT02437318.).</p>

Lymphotoxin alpha (LT alpha)-deficient mice revealed critical roles for LT alpha in lymphoid organogenesis, but it is not clear whether LT alpha functions through an LT alpha homotrimer (LT alpha3) or LT alpha/beta heterotrimers. We generated LTbeta-deficient mice and found them to lack Peyer's patches, peripheral lymph nodes, splenic germinal centers, and follicular dendritic cells. Unlike LT alpha-deficient mice, LT beta-deficient mice had cervical and mesenteric lymph nodes. Furthermore, the mesenteric lymph nodes had germinal center-like regions, although these structures appeared to lack follicular dendritic cells. The absence of cervical and mesenteric lymph nodes in LT alpha-deficient mice, and yet their presence in LT beta-deficient mice and in mice deficient in tumor necrosis factor receptor types I and II, suggest that LT alpha3 may signal via an as yet unidentified receptor.

Mice deficient in the cytokines tumor necrosis factor (TNF) or lymphotoxin (LT) alpha/beta lack polarized B cell follicles in the spleen. Deficiency in CXC chemokine receptor 5 (CXCR5), a receptor for B lymphocyte chemoattractant (BLC), also causes loss of splenic follicles. Here we report that BLC expression by follicular stromal cells is defective in TNF-, TNF receptor 1 (TNFR1)-, LTalpha- and LTbeta-deficient mice. Treatment of adult mice with antagonists of LTalpha1betaBLC expression. These findings indicate that LTalpha1betaBLC/CXCR5 in the process of follicle formation. In addition to disrupted follicles, LT-deficient animals have disorganized T zones. Expression of the T cell attractant, secondary lymphoid tissue chemokine (SLC), by T zone stromal cells is found to be markedly depressed in LTalpha-, and LTbeta-deficient mice. Expression of the SLC-related chemokine, Epstein Barr virus-induced molecule 1 ligand chemokine (ELC), is also reduced. Exploring the basis for the reduced SLC expression led to identification of further disruptions in T zone stromal cells. Together these findings indicate that LTalpha1betaB and T zone stromal cells that make chemokines necessary for lymphocyte compartmentalization in the spleen.

(<em>b</em>)Background:</<em>b</em>) Cardiac injury and myocarditis have <em>b</em>een descri<em>b</em>ed in adu<em>lt</em>s with COVID-19. SARS-CoV-2 infection in children is typically minimally symptomatic. We report a series of fe<em>b</em>rile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the mu<em>lt</em>isystem inflammatory syndrome in children (MIS-C) as defined <em>b</em>y the US Centers for Disease Control. (<em>b</em>)Methods:</<em>b</em>) Over a two-month period contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, <em>b</em>iological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction and severe inflammatory state. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) Thirty-five children were identified and included in the study. Median age at admission was 10 years (range 2-16 years). Co-mor<em>b</em>idities were present in 28% including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was &<em>lt</em>;30% in one third; 80% required inotropic support with 28% treated with ECMO. Inflammation markers were suggestive of cytokine storm (interleukin 6 median 135 pg/mL) and macrophage activation (D-dimer median 5284 ng/mL). Mean <em>b</em>rain natriuretic peptide was elevated (5743 pg/mL). Thirty-one/35 (88%) patients tested positive for SARS-CoV-2 infection <em>b</em>y PCR of nasopharyngeal swa<em>b</em> or serology. All patients received intravenous immune glo<em>b</em>ulin, with adjunctive steroid therapy used in one third. Left ventricular function was restored in the 25/35 of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned. (<em>b</em>)Conclusion:</<em>b</em>) Children may experience an acute cardiac decompensation due to severe inflammatory state following SARS-CoV-2 infection (mu<em>lt</em>isystem inflammatory syndrome in children - MIS-C). Treatment with immune glo<em>b</em>ulin appears to <em>b</em>e associated with recovery of left ventricular systolic function.

Keywords: COVID-19; SARS-CoV-2; myocardial stunning.

<A<em>b</em>stractText>The prevalence and prognosis of digestive system involvement, including gastrointestinal symptoms and liver injury, in patients with COVID-19 remains largely unknown. We aimed to quantify the effects of COVID-19 on the digestive system.</A<em>b</em>stractText><A<em>b</em>stractText>In this systematic review and meta-analysis, we systematically searched Pu<em>b</em>Med, Em<em>b</em>ase, and We<em>b</em> of Science for studies pu<em>b</em>lished <em>b</em>etween Jan 1, 2020, and April 4, 2020. The we<em>b</em>sites of WHO, CDC, and major journals were also searched. We included studies that reported the epidemiological and clinical features of COVID-19 and the prevalence of gastrointestinal findings in infected patients, and excluded preprints, duplicate pu<em>b</em>lications, reviews, editorials, single case reports, studies pertaining to other coronavirus-related illnesses, and small case series (&<em>lt</em>;10 cases). Extracted data included author; date; study design; country; patient demographics; num<em>b</em>er of participants in severe and non-severe disease groups; prevalence of clinical gastrointestinal symptoms such as vomiting, nausea, diarrhoea, loss of appetite, a<em>b</em>dominal pain, and <em>b</em>elching; and digestive system comor<em>b</em>idities including liver disease and gastrointestinal diseases. Raw data from studies were pooled to determine effect estimates.</A<em>b</em>stractText><p><div>(<em>b</em>)Findings</<em>b</em>)</div>We analysed findings from 35 studies, including 6686 patients with COVID-19, that met inclusion criteria. 29 studies (n=6064) reported gastrointestinal symptoms in patients with COVID-19 at diagnosis, and the pooled prevalence of digestive system comor<em>b</em>idities was 4% (95% CI 2-5; range 0-15; <i>I</i>²=74%). The pooled prevalence of digestive symptoms was 15% (10-21; range: 2-57; <i>I</i>²=96%) with nausea or vomiting, diarrhoea, and loss of appetite <em>b</em>eing the three most common symptoms. The pooled prevalence of a<em>b</em>normal liver functions (12 studies, n=1267) was 19% (9-32; range 1-53; <i>I</i>²=96%). Su<em>b</em>group analysis showed patients with severe COVID-19 had higher rates of gastrointestinal symptoms (odds ratio [OR] 1·60 [95% CI 1·09-2·36]; p=0·0020; <i>I</i>²=44%) and liver injury (2·20 [1·60-3·02]; p&<em>lt</em>;0·00001; <i>I</i>²=36%) compared with those with non-severe disease. Patients in Hu<em>b</em>ei province, where the initial COVID-19 out<em>b</em>reak occurred, were more likely to present with a<em>b</em>normal liver functions (p&<em>lt</em>;0·0001) compared with those outside of Hu<em>b</em>ei. Paediatric patients with COVID-19 had a similar prevalence of gastrointestinal symptoms to those of adu<em>lt</em> patients. 10% (95% CI 4-19; range 3-23; <i>I</i>²=97%) of patients presented with gastrointestinal symptoms alone without respiratory features. Patients who presented with gastrointestinal system involvement had delayed diagnosis (standardised mean difference 2·85 [95% CI 0·22-5·48]; p=0·030; <i>I</i>²=73%). Patients with gastrointestinal involvement had a higher prevalence of complication (OR 2·51 [95% CI 1·62-3·89]; p&<em>lt</em>;0·0001; <i>I</i>²=0%).</p><A<em>b</em>stractText>Our study showed that digestive symptoms and liver injury are not uncommon in patients with COVID-19. Increased attention should <em>b</em>e paid to the care of this unique group of patients.</A<em>b</em>stractText><A<em>b</em>stractText>None.</A<em>b</em>stractText>

BACKGROUND

Liver transplantation (LT) has been the treatment of choice for patients with hepatocellular carcinoma (HCC). This study was designed to summarize our experience in LT for HCC patients and establish a new set of criteria for patient selection and prognosis prediction.

METHODS

Data of 195 patients with HCC were retrospectively analyzed and various clinical and pathological factors for survival and tumor-free survival were examined by univariate and multivariate analyses.

RESULTS

Macrovascular invasion, preoperative serum alpha fetoprotein (AFP) level, tumor size, multifocality, histopathologic grading, distribution, and cirrhosis background were significant factors for survival and tumor-free survival by univariate analysis. Multivariate analysis identified macrovascular invasion, tumor size, preoperative AFP level, and histopathologic grading were prognostic factors independently associated with patient survival or tumor-free survival (RR=1.688-2.779, P=0.000-0.034). Based on the prognostic stratification of different risk groups of patients without macrovascular invasion, Hangzhou criteria was established, containing one of the two following items: (a) Total tumor diameter less than or equal to 8 cm; (b) total tumor diameter more than 8 cm, with histopathologic grade I or II and preoperative AFP level less than or equal to 400 ng/mL, simultaneously. The difference between survival curves of patients fulfilling Milan criteria (n=72) and patients fulfilling Hangzhou criteria (n=99) did not achieve statistical significance (5-year survival rates: 78.3% vs. 72.3%, P>0.05). Of the patients exceeding Milan criteria (n=123), those who fulfilled Hangzhou criteria (n=26) also had better prognosis than the others (n=97) (P=0.000).

CONCLUSIONS

The results of this study show a reliable and feasible candidates selection and prognostic criteria of LT in HCC patients.

<A<em>b</em>stractText>Docetaxel-<em>b</em>ased chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-<em>b</em>ased triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resecta<em>b</em>le tumours.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this controlled, open-la<em>b</em>el, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or <em>b</em>oth, resecta<em>b</em>le tumours, with no evidence of distant metastases, via central interactive we<em>b</em>-<em>b</em>ased-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m² epiru<em>b</em>icin and 60 mg/m² cisplatin on day 1 plus either 200 mg/m² fluorouracil as continuous intravenous infusion or 1250 mg/m² capecita<em>b</em>ine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m² docetaxel, 85 mg/m² oxaliplatin, 200 mg/m² leucovorin and 2600 mg/m² fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, num<em>b</em>er NCT01216644.</p><A<em>b</em>stractText>Between Aug 8, 2010, and Fe<em>b</em> 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-<em>b</em>ased oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The num<em>b</em>er of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the num<em>b</em>er of toxic deaths (two [&<em>lt</em>;1%] in <em>b</em>oth groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.</A<em>b</em>stractText><A<em>b</em>stractText>In locally advanced, resecta<em>b</em>le gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX.</A<em>b</em>stractText><A<em>b</em>stractText>The German Cancer Aid (Deutsche Kre<em>b</em>shilfe), Sanofi-Aventis, Chugai, and Stiftung Le<em>b</em>en mit Kre<em>b</em>s Foundation.</A<em>b</em>stractText>

<A<em>b</em>stractText>Dia<em>b</em>etes Mellitus (DM) is chronic conditions with devastating mu<em>lt</em>i-systemic complication and may <em>b</em>e associated with severe form of Coronavirus Disease 2019 (COVID-19). We conducted a systematic review and meta-analysis in order to investigate the association <em>b</em>etween DM and poor outcome in patients with COVID-19 pneumonia.</A<em>b</em>stractText><A<em>b</em>stractText>Systematic literature search was performed from several electronic data<em>b</em>ases on su<em>b</em>jects that assess DM and outcome in COVID-19 pneumonia. The outcome of interest was composite poor outcome, including mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care, and disease progression.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>There were a total of 6452 patients from 30 studies. Meta-analysis showed that DM was associated with composite poor outcome (RR 2.38 [1.88, 3.03], p &<em>lt</em>; 0.001; I²: 62%) and its su<em>b</em>group which comprised of mortality (RR 2.12 [1.44, 3.11], p &<em>lt</em>; 0.001; I²: 72%), severe COVID-19 (RR 2.45 [1.79, 3.35], p &<em>lt</em>; 0.001; I²: 45%), ARDS (RR 4.64 [1.86, 11.58], p = 0.001; I²: 9%), and disease progression (RR 3.31 [1.08, 10.14], p = 0.04; I²: 0%). Meta-regression showed that the association with composite poor outcome was influenced <em>b</em>y age (p = 0.003) and hypertension (p &<em>lt</em>; 0.001). Su<em>b</em>group analysis showed that the association was weaker in studies with median age ≥55 years-old (RR 1.92) compared to &<em>lt</em>;55 years-old (RR 3.48), and in prevalence of hypertension ≥25% (RR 1.93) compared to &<em>lt</em>;25% (RR 3.06). Su<em>b</em>group analysis on median age &<em>lt</em>;55 years-old and prevalence of hypertension &<em>lt</em>;25% showed strong association (RR 3.33) CONCLUSION: DM was associated with mortality, severe COVID-19, ARDS, and disease progression in patients with COVID-19.</p>

To better understand population phenomena in thalamocortical neuronal ensembles, we have constructed a preliminary network model with 3,560 multicompartment neurons (containing soma, branching dendrites, and a portion of axon). Types of neurons included superficial pyramids (with regular spiking [RS] and fast rhythmic bursting [FRB] firing behaviors); RS spiny stellates; fast spiking (FS) interneurons, with basket-type and axoaxonic types of connectivity, and located in superficial and deep cortical layers; low threshold spiking (LTS) interneurons, which contacted principal cell dendrites; deep pyramids, which could have RS or intrinsic bursting (IB) firing behaviors, and endowed either with nontufted apical dendrites or with long tufted apical dendrites; thalamocortical relay (TCR) cells; and nucleus reticularis (nRT) cells. To the extent possible, both electrophysiology and synaptic connectivity were based on published data, although many arbitrary choices were necessary. In addition to synaptic connectivity (by AMPA/kainate, NMDA, and GABA(A) receptors), we also included electrical coupling between dendrites of interneurons, nRT cells, and TCR cells, and--in various combinations--electrical coupling between the proximal axons of certain cortical principal neurons. Our network model replicates several observed population phenomena, including 1) persistent gamma oscillations; 2) thalamocortical sleep spindles; 3) series of synchronized population bursts, resembling electrographic seizures; 4) isolated double population bursts with superimposed very fast oscillations (>100 Hz, "VFO"); 5) spike-wave, polyspike-wave, and fast runs (about 10 Hz). We show that epileptiform bursts, including double and multiple bursts, containing VFO occur in rat auditory cortex in vitro, in the presence of kainate, when both GABA(A) and GABA(B) receptors are blocked. Electrical coupling between axons appears necessary (as reported previously) for persistent gamma and additionally plays a role in the detailed shaping of epileptogenic events. The degree of recurrent synaptic excitation between spiny stellate cells, and their tendency to fire throughout multiple bursts, also appears critical in shaping epileptogenic events.