BACKGROUND

In the background of availability of better treatments for specific liver diseases and listing of nonalcoholic steatohepatitis (NASH) as an etiology for liver transplantation (LT), data are unclear on the impact of disease etiology on the frequency of LT and liver posttransplantation outcomes.

METHODS

The United Network for Organ Sharing database (1994-2009) was queried for adults receiving first LT for primary biliary cirrhosis (PBC; n=3052), primary sclerosing cholangitis (PSC; n=3854), hepatitis C virus (HCV; n=15,147), alcoholic cirrhosis (AC; n=8940), HCV+alcohol (n=6066), NASH (n=1368), cryptogenic cirrhosis (CC; n=5856), hepatitis B virus (HBV; n=1816), and hepatocellular carcinoma (HCC; n=8588). Graft and patient survival were compared and Cox models were built to determine independent prediction of outcomes by disease etiology.

RESULTS

The frequency of LT increased for NASH, HCC, and HCV+alcohol, remained stable for AC, and decreased for PBC, PSC, HCV, CC, and HBV. The proportion of simultaneous liver-kidney transplants increased from approximately 3% in 2001 to 10% in 2009. Compared with PBC, 5-year graft and patient survival were (a) similar for PSC, NASH, and HBV (80-85%), (b) poorer for AC and CC (hazard ratio, 1-1.5), and (c) worst for HCV, HCV+alcohol, and HCC (hazard ratio, 1.5-2.4). Five-year outcomes for HCV-associated HCC were poorer compared with HCC due to other etiologies.

CONCLUSIONS

LT performed for NASH and HCC are increasing. Potent treatment options resulted in a decrease in number of transplants for HBV, HCV, and PBC. Better treatment modalities for HCV are expected to further reduce the number of LT for HCV. Excellent posttransplantation outcomes for NASH and AC are encouraging, resulting in wider acceptance of transplants for these etiologies.

A genetically engineered Vibrio cholerae strain from which the cholera toxin genes had previously been deleted was used as a host in which to study the expression and secretion of related toxins and their subunits. Recombinant plasmids encoding heat-labile enterotoxins (LTs) from Escherichia coli of human and porcine origin were expressed in the V. cholerae host, and this resulted in the secretion of the LTs into the extracellular milieu. The secreted LTs were isolated and it was found that the A subunits of human and porcine LT were "unnicked" polypeptides, which indicates that nicking is not obligatory for toxin secretion. V. cholerae strains were also constructed that harbored plasmids encoding either the A or the B subunits of human LT (A+B-, or A-B+). Approximately 90% of the B subunits were secreted from the A-B+ strain, while all of the A subunits expressed by the A+B- strain remained cell associated. This implies that strains synthesizing both subunits assemble the A and B subunits prior to their secretion. We propose that the entry of the toxin into the secretory step of the export pathway is mediated by a secretory apparatus that recognizes structural domains within the B subunit of LT.

The transfer of lymphocytes into severe combined immunodeficiency (SCID) mice induces a series of histological changes in the spleen, including the appearance of mature follicular dendritic cells (FDCs). Studies were undertaken to clarify the role of lymphotoxin (LT) in this process. The results show that SCID mice have a small and partially differentiated white pulp containing marginal zone and interdigitating dendritic cells, but lacking FDCs. Transferred spleen cells can segregate into T and B cell areas shortly after their injection to SCID mice. This ability is dependent on signaling through LT-beta receptor (LT-betaR), since blocking ligand-receptor interaction in recipient SCID mice ablates the capacity of the transferred cells to segregate. A week after lymphocyte transfer, host-derived FDCs appeared in the reconstituted SCID mice. This induction of FDCs is dependent on LT-betaR signaling by B cells since LT-alpha-/- B cells are incapable of inducing development of FDCs in SCID mice, even after cotransfer of LT-alpha+/+ T cells. Therefore, LT plays at least two discrete roles in splenic organization. First, it appears that LT induces the differentiation of the white pulp to create sites for lymphocyte segregation. Second, LT expression by B cells drives the maturation of FDCs and the organization of B cell follicles.

The authors have designed and constructed a plant-optimize synthetic gene encoding the Escherichia coli heat-labile enterotoxin B subunit (LT-B), for use in transgenic plants as an edible vaccine against enterotoxigenic E. coli. Expression of the synthetic LT-B gene in potato plants under the control of a constitutive promoter yielded increased accumulation of LT-B in leaves and tubers, as compared to the bacterial LT-B gene. The plant-derived LT-B assembled into native pentameric structures as evidenced by its ability to bind ganglioside. The authors demonstrated immunogenicity by feeding mice the raw tubers and comparing the anti-LT-B serum IgG and faecal IgA to that produced in mice gavaged with bacterial LT-B. Mice were fed three weekly doses of 5 g tuber tissue containing either 20 or 50 micrograms LT-B, or gavaged weekly with 5 micrograms of LT-B from recombinant E. coli. One week after the third dose, mice immunized with potato LT-B had higher levels of serum and mucosal anti-LT-B than those gavaged with bacterial LT-B. Mice were challenged by oral administration of 25 micrograms LT, and protection assessed by comparing the gut/carcass mass ratios. Although none of the mice were completely protected, the higher dose potato vaccine compared favourably with the bacterial vaccine. These findings show that an edible vaccine against E. coli LT-B is feasible.

<A<em>b</em>stractText>To investigate the association <em>b</em>etween hypertension and outcome in patients with Coronavirus Disease 2019 (COVID-19) pneumonia.</A<em>b</em>stractText><A<em>b</em>stractText>We performed a systematic literature search from several data<em>b</em>ases on studies that assess hypertension and outcome in COVID-19. Composite of poor outcome, comprising of mortality, severe COVID-19, acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) care and disease progression were the outcomes of interest.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 6560 patients were pooled from 30 studies. Hypertension was associated with increased composite poor outcome (risk ratio (RR) 2.11 (95% confidence interval (CI) 1.85, 2.40), <i>p</i> &<em>lt</em>; 0.001; <i>I</i>², 44%) and its su<em>b</em>-group, including mortality (RR 2.21 (1.74, 2.81), <i>p</i> &<em>lt</em>; 0.001; <i>I</i>², 66%), severe COVID-19 (RR 2.04 (1.69, 2.47), <i>p</i> &<em>lt</em>; 0.001; <i>I</i>² 31%), ARDS (RR 1.64 (1.11, 2.43), <i>p</i> = 0.01; <i>I</i>²,0%, <i>p</i> = 0.35), ICU care (RR 2.11 (1.34, 3.33), <i>p</i> = 0.001; <i>I</i>² 18%, <i>p</i> = 0.30), and disease progression (RR 3.01 (1.51, 5.99), <i>p</i> = 0.002; <i>I</i>² 0%, <i>p</i> = 0.55). Meta-regression analysis showed that gender (<i>p</i> = 0.013) was a covariate that affects the association. The association was stronger in studies with a percentage of males &<em>lt</em>; 55% compared to ⩾ 55% (RR 2.32 v. RR 1.79).</p><A<em>b</em>stractText>Hypertension was associated with increased composite poor outcome, including mortality, severe COVID-19, ARDS, need for ICU care and disease progression in patients with COVID-19.</A<em>b</em>stractText>

<A<em>b</em>stractText>The effect of corticosteroids on clinical outcomes in patients with influenza pneumonia remains controversial. We aimed to further evaluate the influence of corticosteroids on mortality in adu<em>lt</em> patients with influenza pneumonia <em>b</em>y comparing corticosteroid-treated and place<em>b</em>o-treated patients.</A<em>b</em>stractText><A<em>b</em>stractText>The Pu<em>b</em>Med, Em<em>b</em>ase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and Information Sciences Institute (ISI) We<em>b</em> of Science data<em>b</em>ases were searched for all controlled studies that compared the effects of corticosteroids and place<em>b</em>o in adu<em>lt</em> patients with influenza pneumonia. The primary outcome was mortality, and the secondary outcomes were mechanical ventilation (MV) days, length of stay in the intensive care unit (ICU LOS), and the rate of secondary infection.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Ten trials involving 6548 patients were pooled in our final analysis. Significant heterogeneity was found in all outcome measures except for ICU LOS (I² = 38%, P = 0.21). Compared with place<em>b</em>o, corticosteroids were associated with higher mortality (risk ratio [RR] 1.75, 95% confidence interval [CI] 1.30 ~ 2.36, Z = 3.71, P = 0.0002), longer ICU LOS (mean difference [MD] 2.14, 95% CI 1.17 ~ 3.10, Z = 4.35, P &<em>lt</em>; 0.0001), and a higher rate of secondary infection (RR 1.98, 95% CI 1.04 ~ 3.78, Z = 2.08, P = 0.04) <em>b</em>ut not MV days (MD 0.81, 95% CI - 1.23 ~ 2.84, Z = 0.78, P = 0.44) in patients with influenza pneumonia.</p><A<em>b</em>stractText>In patients with influenza pneumonia, corticosteroid use is associated with higher mortality.</A<em>b</em>stractText><A<em>b</em>stractText>PROSPERO (ID: CRD42018112384 ).</A<em>b</em>stractText>

<A<em>b</em>stractText>Dia<em>b</em>etes is common in COVID-19 patients and associated with unfavora<em>b</em>le outcomes. We aimed to descri<em>b</em>e the characteristics and outcomes and to analyze the risk factors for in-hospital mortality of COVID-19 patients with dia<em>b</em>etes.</A<em>b</em>stractText><p><div>(<em>b</em>)RESEARCH DESIGN AND METHODS</<em>b</em>)</div>This two-center retrospective study was performed at two tertiary hospitals in Wuhan, China. Confirmed COVID-19 patients with dia<em>b</em>etes (<i>N</i> = 153) who were discharged or died from 1 January 2020 to 8 March 2020 were identified. One sex- and age-matched COVID-19 patient without dia<em>b</em>etes was randomly selected for each patient with dia<em>b</em>etes. Demographic, clinical, and la<em>b</em>oratory data were a<em>b</em>stracted. Cox proportional hazards regression analyses were performed to identify the risk factors associated with the mortality in these patients.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Of 1,561 COVID-19 patients, 153 (9.8%) had dia<em>b</em>etes, with a median age of 64.0 (interquartile range 56.0-72.0) years. A higher proportion of intensive care unit admission (17.6% vs. 7.8%, <i>P</i> = 0.01) and more fatal cases (20.3% vs. 10.5%, <i>P</i> = 0.017) were identified in COVID-19 patients with dia<em>b</em>etes than in the matched patients. Mu<em>lt</em>ivaria<em>b</em>le Cox regression analyses of these 306 patients showed that hypertension (hazard ratio [HR] 2.50, 95% CI 1.30-4.78), cardiovascular disease (HR 2.24, 95% CI 1.19-4.23), and chronic pulmonary disease (HR 2.51, 95% CI 1.07-5.90) were independently associated with in-hospital death. Dia<em>b</em>etes (HR 1.58, 95% CI 0.84-2.99) was not statistically significantly associated with in-hospital death after adjustment. Among patients with dia<em>b</em>etes, nonsurvivors were older (76.0 vs. 63.0 years), most were male (71.0% vs. 29.0%), and were more likely to have underlying hypertension (83.9% vs. 50.0%) and cardiovascular disease (45.2% vs. 14.8%) (all <i>P</i> values &<em>lt</em>;0.05). Age ≥70 years (HR 2.39, 95% CI 1.03-5.56) and hypertension (HR 3.10, 95% CI 1.14-8.44) were independent risk factors for in-hospital death of patients with dia<em>b</em>etes.</p><A<em>b</em>stractText>COVID-19 patients with dia<em>b</em>etes had worse outcomes compared with the sex- and age-matched patients without dia<em>b</em>etes. Older age and comor<em>b</em>id hypertension independently contri<em>b</em>uted to in-hospital death of patients with dia<em>b</em>etes.</A<em>b</em>stractText>

Amyloid-beta (Abeta) immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with Abetabeta. Nevertheless, beneficial effects were reported in antibody responders. Consequently, alternatives are required for a safer vaccine. The Abetabetabetabetabetabetabetabetabeta antibody titers were observed in wild-type mice after intranasal immunization with R-2xAbetabetaLT(R192G) adjuvant. Moderate antibody levels were induced after immunization with T1-R-AbetabetaLT(R192G). Restimulation of splenocytes with the corresponding immunogens resulted in moderate proliferative responses, whereas proliferation was absent after restimulation with full-length Abeta or Abetabetabetabeta titers of noninflammatory T-helper 2 isotypes (IgG1 and IgG2b), a lack of splenocyte proliferation against full-length Abeta, significantly reduced Abeta plaque load, and lower cerebral Abeta levels. In addition, 2xAbetabeta titers. Thus, our novel immunogens show promise for future AD vaccines.

<A<em>b</em>stractText>Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed mu<em>lt</em>iple myeloma who are ineligi<em>b</em>le for autologous stem-cell transplantation. We sought to determine whether the addition of daratumuma<em>b</em> would significantly reduce the risk of disease progression or death in this population.</A<em>b</em>stractText><A<em>b</em>stractText>We randomly assigned 737 patients with newly diagnosed mu<em>lt</em>iple myeloma who were ineligi<em>b</em>le for autologous stem-cell transplantation to receive daratumuma<em>b</em> plus lenalidomide and dexamethasone (daratumuma<em>b</em> group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unaccepta<em>b</em>le side effects. The primary end point was progression-free survival.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumuma<em>b</em> group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumuma<em>b</em> group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P&<em>lt</em>;0.001). The percentage of patients with a complete response or <em>b</em>etter was 47.6% in the daratumuma<em>b</em> group and 24.9% in the control group (P&<em>lt</em>;0.001). A total of 24.2% of the patients in the daratumuma<em>b</em> group, as compared with 7.3% of the patients in the control group, had resu<em>lt</em>s <em>b</em>elow the threshold for minimal residual disease (1 tumor cell per 10⁵ white cells) (P&<em>lt</em>;0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumuma<em>b</em> group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).</p><A<em>b</em>stractText>Among patients with newly diagnosed mu<em>lt</em>iple myeloma who were ineligi<em>b</em>le for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumuma<em>b</em> plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was o<em>b</em>served in the daratumuma<em>b</em> group. (Funded <em>b</em>y Janssen Research and Development; MAIA ClinicalTrials.gov num<em>b</em>er, NCT02252172.).</A<em>b</em>stractText>

<A<em>b</em>stractText>Appropriate antithrom<em>b</em>otic regimens for patients with atrial fi<em>b</em>rillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In an international trial with a two-<em>b</em>y-two factorial design, we randomly assigned patients with atrial fi<em>b</em>rillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y<su<em>b</em>)12</su<em>b</em>) inhi<em>b</em>itor to receive apixa<em>b</em>an or a vitamin K antagonist and to receive aspirin or matching place<em>b</em>o for 6 months. The primary outcome was major or clinically relevant nonmajor <em>b</em>leeding. Secondary outcomes included death or hospitalization and a composite of ischemic events.</p><A<em>b</em>stractText>Enrollment included 4614 patients from 33 countries. There were no significant interactions <em>b</em>etween the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor <em>b</em>leeding was noted in 10.5% of the patients receiving apixa<em>b</em>an, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P&<em>lt</em>;0.001 for <em>b</em>oth noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving place<em>b</em>o (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P&<em>lt</em>;0.001). Patients in the apixa<em>b</em>an group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the place<em>b</em>o group.</A<em>b</em>stractText><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>In patients with atrial fi<em>b</em>rillation and a recent acute coronary syndrome or PCI treated with a P2Y<su<em>b</em>)12</su<em>b</em>) inhi<em>b</em>itor, an antithrom<em>b</em>otic regimen that included apixa<em>b</em>an, without aspirin, resu<em>lt</em>ed in less <em>b</em>leeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or <em>b</em>oth. (Funded <em>b</em>y Bristol-Myers Squi<em>b</em><em>b</em> and Pfizer; AUGUSTUS ClinicalTrials.gov num<em>b</em>er, NCT02415400.).</p>

OBJECTIVE

After liver transplantation (LT) infection of the graft with the hepatitis C virus (HCV) is almost universal and chronic hepatitis and cirrhosis develop in a significant proportion of patients. One of the possible strategies to prevent HCV infection recurrence is to eradicate HCV before LT.

METHODS

We evaluated the efficacy and safety of antiviral therapy to prevent HCV recurrence in 30 HCV-cirrhotic patients awaiting LT. At the time of inclusion 15 patients were Child-Pugh A and 15 Child-Pugh B/C. The infecting genotype was 1b in 25 patients. Treatment with interferon alpha-2b 3 MU/day and ribavirin 800 mg/day was initiated when the expected time for LT was less than 4 months and continued until LT. The median duration of treatment was 12 weeks.

RESULTS

Nine patients (30%) achieved a virological response and 21 did not respond to therapy. In nine (43%) of the 21 non-responders viral load decreased>> or =2 log10 during treatment. A viral load decrease>> or = 2 log10 at week 4 of treatment was the strongest predictor of virological response. All nine virological responders have already undergone LT; six patients remain free of infection after a median follow-up of 46 weeks and HCV infection recurred in three patients after LT. In one of these patients HCV-RNA was still detectable in the explanted liver. Side effects were frequent and dose reduction was necessary in 19 (63%) of the 30 patients; no patient died while on therapy.

CONCLUSIONS

Our data support the utilization of antiviral therapy in HCV-infected patients awaiting LT as one of the strategies to prevent hepatitis C recurrence after transplantation.

<A<em>b</em>stractText>An increased risk of venous throm<em>b</em>oem<em>b</em>olism (VTE) in patients with COVID-19 pneumonia admitted to intensive care unit (ICU) has <em>b</em>een reported. Whether COVID-19 increases the risk of VTE in non-ICU wards remains unknown. We aimed to evaluate the <em>b</em>urden of asymptomatic deep vein throm<em>b</em>osis (DVT) in COVID-19 patients with elevated D-dimer levels.</A<em>b</em>stractText><A<em>b</em>stractText>In this prospective study consecutive patients hospitalized in non-intensive care units with diagnosis of COVID-19 pneumonia and D-dimer > 1000 ng/mL were screened for asymptomatic DVT with complete compression doppler u<em>lt</em>rasound (CCUS). The study was approved <em>b</em>y the Institutional Ethics Committee.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>The study comprised 156 patients (65.4% male). All <em>b</em>ut three patients received standard doses of throm<em>b</em>oprophylaxis. Median days of hospitalization until CCUS was 9 (IQR 5-17). CCUS was positive for DVT in 23 patients (14.7%), of whom only one was proximal DVT. Seven patients (4.5%) had <em>b</em>ilateral distal DVT. Patients with DVT had higher median D-dimer levels: 4527 (IQR 1925-9144) ng/ml vs 2050 (IQR 1428-3235) ng/ml; <i>p</i> &<em>lt</em>; 0.001. D-dimer levels > 1570 ng/mL were associated with asymptomatic DVT (OR 9.1; CI 95% 1.1-70.1). D-dimer showed an accepta<em>b</em>le discriminative capacity (area under the ROC curve 0.72, 95% CI 0.61-0.84).</p><A<em>b</em>stractText>In patients admitted with COVID-19 pneumonia and elevated D-dimer levels, the incidence of asymptomatic DVT is similar to that descri<em>b</em>ed in other series. Higher cut-off levels for D-dimer might <em>b</em>e necessary for the diagnosis of DVT in COVID-19 patients.</A<em>b</em>stractText>

We report a retrospective clinicopathologic study of 108 primary thyroid gland lymphomas (PTLs), classified using the REAL and proposed WHO classification schemes. The patients included 79 women and 29 men, with an average age of 64.3 years. All patients presented with a thyroid mass. The PTLs were classified as marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MZBL (n = 30), diffuse large B-cell lymphoma (DLBCL) with MZBL (n = 36), DLBCL without MZBL (n = 41), and follicle center lymphoma (FCL; n = 1). Excluding the FCL, features of lymphomas of MALT-type were identified in all groups, despite a follicular architecture in 23% of cases. Lymphocytic thyroiditis (LT) was identified in 94%. Ninety-one percent of patients presented with stage IE or IIE disease, whereas 69% had perithyroidal soft tissue infiltration. All patients were treated with surgical excision followed by adjuvant therapy (76%): chemotherapy (15%), radiation (19%), or a combination of radiation and chemotherapy (42%). Disease-specific survival was 82% at last follow up (mean, 82.8 mos) and 79% at 5 years. Statistically, stages greater than IE, presence of DLBCL, rapid clinical growth, abundant apoptosis, presence of vascular invasion, high mitotic rate, and infiltration of the perithyroidal soft tissue were significantly associated with death with disease. No patients with MZBL or stage IE disease died with disease. In summary, PTLs typically occur in middle- to older-aged individuals as a thyroid mass, with a predilection for females. Despite their histologic heterogeneity and frequent simulation of other lymphoma subtypes, virtually all PTLs are lymphomas of MALT-type arising in the setting of LT. Mixed DLBCL and MZBL are common. Overall, PTLs have a favorable outcome with appropriate therapy, but prognosis depends on both clinical stage and histology. MZBL and stage IE tumors have an excellent prognosis, whereas tumors with a large cell component or DLBCL or stage greater than IE have the greatest potential for a poor outcome.

<A<em>b</em>stractText>The prognostic significance of dia<em>b</em>etes mellitus (DM) in patients with coronavirus 2019 disease (COVID-19) remains unknown.</A<em>b</em>stractText><A<em>b</em>stractText>To assess the risk of ICU admission and morality risk in dia<em>b</em>etic COVID-19 patients.</A<em>b</em>stractText><p><div>(<em>b</em>)STUDY DESING</<em>b</em>)</div>A data<em>b</em>ase search was conducted to identify studies comparing dia<em>b</em>etic COVID-19 patients hospitalized in intensive care unit (ICU) and those reporting the overall mortality of these patients pu<em>b</em>lished up to March 25, 2020 within MEDLINE, Scopus and We<em>b</em> of Science. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in a<em>b</em>stracting data and assessing validity. Quality assessment was performed using the Newcastle-Ottawa quality assessment scale. The main outcome was the risk of ICU admission in dia<em>b</em>etic patients with COVID-19 infection while the second was the mortality risk in overall dia<em>b</em>etic COVID-19 patients. Data were pooled using the Mantel-Haenszel random effects models with odds ratio (OR) as the effect measure with the related 95 % confidence interval (CI). Statistical heterogeneity <em>b</em>etween groups was measured using the Higgins I² statistic.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Among 1382 patients (mean age 51.5 years, 798 males), DM resu<em>lt</em>ed to <em>b</em>e the second more frequent comor<em>b</em>idities. Dia<em>b</em>etic patients resu<em>lt</em>ed to have a significant increased risk of ICU admission (OR: 2.79, 95 % CI 1.85-4.22, p &<em>lt</em>; 0.0001, I² = 46 %). In 471 patients (mean age 56.6 years, 294 males) analysed for the secondary outcome dia<em>b</em>etic su<em>b</em>jects resu<em>lt</em>ed to <em>b</em>e at higher mortality risk (OR 3.21, 95 % CI 1.82-5.64, p &<em>lt</em>; 0.0001, I² = 16 %).</p><A<em>b</em>stractText>Dia<em>b</em>etic patients with COVID-19 patients are at higher risk of ICU admission and show an higher mortality risk.</A<em>b</em>stractText>

Vibrio cholerae and Escherichia coli heat labile toxins (CT and LT) elicit a secretory response from intestinal epithelia by binding apical receptors (ganglioside GM1) and subsequently activating basolateral effectors (adenylate cyclase). We have recently proposed that signal transduction in polarized cells may require transcytosis of toxin-containing membranes (Lencer, W. I., G. Strohmeier, S. Moe, S. L. Carlson, C. T. Constable, and J. L. Madara. 1995. Proc. Natl. Acad. Sci. USA. 92:10094-10098). Targeting of CT into this pathway depends initially on binding of toxin B subunits to GM1 at the cell surface. The anatomical compartments in which subsequent steps of CT processing occur are less clearly defined. However, the enzymatically active A subunit of CT contains the ER retention signal KDEL (RDEL in LT). Thus if the KDEL motif were required for normal CT trafficking, movement of CT from the Golgi to ER would be implied. To test this idea, recombinant wild-type (wt) and mutant CT and LT were prepared. The COOH-terminal KDEL sequence in CT was replaced by seven unrelated amino acids: LEDERAS. In LT, a single point mutation replacing leucine with valine in RDEL was made. Wt and mutant toxins displayed similar enzymatic activities and binding affinities to GM1 immobilized on plastic. Biologic activity of recombinant toxins was assessed as a Cl- secretory response elicited from the polarized human epithelial cell line T84 using standard electrophysiologic techniques. Mutations in K(R)DEL of both CT and LT delayed the time course of toxin-induced Cl- secretion. At T1/2, dose dependencies for K(R)DEL-mutant toxins were increased>> or = 10-fold. KDEL-mutants displayed differentially greater temperature sensitivity. In direct concordance with a slower rate of signal transduction. KDEL-mutants were trafficked to the basolateral membrane more slowly than wt CT (assessed by selective cell surface biotinylation as transcytosis of B subunit). Mutation in K(R)DEL had no effect on the rate of toxin endocytosis. These data provide evidence that CT and LT interact directly with endogenous KDEL-receptors and imply that both toxins may require retrograde movement through Golgi cisternae and ER for efficient and maximal biologic activity.

Neutralizing antibodies have been thought to be required for protection against acutely cytopathic viruses, such as the neurotropic vesicular stomatitis virus (VSV). Utilizing mice that possess B cells but lack antibodies, we show here that survival upon subcutaneous (s.c.) VSV challenge was independent of neutralizing antibody production or cell-mediated adaptive immunity. However, B cells were absolutely required to provide lymphotoxin (LT) α1β2, which maintained a protective subcapsular sinus (SCS) macrophage phenotype within virus draining lymph nodes (LNs). Macrophages within the SCS of B cell-deficient LNs, or of mice that lack LTα1β2 selectively in B cells, displayed an aberrant phenotype, failed to replicate VSV, and therefore did not produce type I interferons, which were required to prevent fatal VSV invasion of intranodal nerves. Thus, although B cells are essential for survival during VSV infection, their contribution involves the provision of innate differentiation and maintenance signals to macrophages, rather than adaptive immune mechanisms.

<A<em>b</em>stractText>Bortezomi<em>b</em>, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligi<em>b</em>le patients with newly diagnosed mu<em>lt</em>iple myeloma. We evaluated whether the addition of daratumuma<em>b</em> to VTd <em>b</em>efore and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed mu<em>lt</em>iple myeloma.</A<em>b</em>stractText><A<em>b</em>stractText>In this two-part, randomised, open-la<em>b</em>el, phase 3 CASSIOPEIA trial, we recruited transplant-eligi<em>b</em>le patients with newly diagnosed mu<em>lt</em>iple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in com<em>b</em>ination with daratumuma<em>b</em> (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, num<em>b</em>er NCT02541383.</A<em>b</em>stractText><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or <em>b</em>etter, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10^-5 sensitivity threshold, assessed <em>b</em>y mu<em>lt</em>iparametric flow cytometry; <em>b</em>oth p&<em>lt</em>;0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p&<em>lt</em>;0·0001). 46 deaths on study were o<em>b</em>served (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%).</p><A<em>b</em>stractText>D-VTd <em>b</em>efore and after autologous stem-cell transplantation improved depth of response and progression-free survival with accepta<em>b</em>le safety. CASSIOPEIA is the first study showing the clinical <em>b</em>enefit of daratumuma<em>b</em> plus standard of care in transplant-eligi<em>b</em>le patients with newly diagnosed mu<em>lt</em>iple myeloma.</A<em>b</em>stractText><A<em>b</em>stractText>The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.</A<em>b</em>stractText>

Epithelial cells provide the first line of defense against mucosal pathogens; however, their coordination with innate and adaptive immune cells is not well understood. Using mice with conditional gene deficiencies, we found that lymphotoxin (LT) from innate cells expressing transcription factor RORgammat, but not from adaptive T and B cells, was essential for the control of mucosal C. rodentium infection. We demonstrate that the LTbetaR signaling was required for the regulation of the early innate response against infection. Furthermore, we have revealed that LTbetaR signals in gut epithelial cells and hematopoietic-derived cells coordinate to protect the host from infection. We further determined that LTbetaR signaling in intestinal epithelial cells was required for recruitment of neutrophils to the infection site early during infection via production of CXCL1 and CXCL2 chemokines. These results support a model wherein LT from RORgammat(+) cells orchestrates the innate immune response against mucosal microbial infection.

Background: There is major concern about the impact of the global COVID-19 outbreak on mental health. Several studies suggest that mental health deteriorated in many countries before and during enforced isolation (ie, lockdown), but it remains unknown how mental health has changed week by week over the course of the COVID-19 pandemic. This study aimed to explore the trajectories of anxiety and depression over the 20 weeks after lockdown was announced in England, and compare the growth trajectories by individual characteristics.

Methods: In this prospective longitudinal observational study, we analysed data from the UCL COVID-19 Social Study, a panel study weighted to population proportions, which collects information on anxiety (using the Generalised Anxiety Disorder assessment) and depressive symptoms (using the Patient Health Questionnaire) weekly in the UK since March 21, 2020. We included data from adults living in England who had at least three repeated measures between March 23 and Aug 9, 2020. Analyses were done using latent growth models, which were fitted to account for sociodemographic and health covariates.

Findings: Between March 23, and Aug 9, data from over 70 000 adults were collected in the UCL COVID-19 Social Study. When including participants living in England with three follow-up measures and no missing values, our analytic sample consisted of 36 520 participants. The average depression score was 6·6 (SD=6·0, range 0-27) and the average anxiety score 5·7 (SD=5·6, range 0-21) in week 1. Anxiety and depression levels both declined across the first 20 weeks following the introduction of lockdown in England (b=-1·93, SE=0·26, p&lt;0·0001 for anxiety; b=-2·52, SE=0·28, p&lt;0·0001 for depressive symptoms). The fastest decreases were seen across the strict lockdown period (between weeks 2 and 5), with symptoms plateauing as further lockdown easing measures were introduced (between weeks 16 and 20). Being a woman or younger, having lower educational attainment, lower income, or pre-existing mental health conditions, and living alone or with children were all risk factors for higher levels of anxiety and depression at the start of lockdown. Many of these inequalities in experiences were reduced as lockdown continued, but differences were still evident 20 weeks after the start of lockdown.

Interpretation: These data suggest that the highest levels of depression and anxiety occurred in the early stages of lockdown but declined fairly rapidly, possibly because individuals adapted to circumstances. Our findings emphasise the importance of supporting individuals in the lead-up to future lockdowns to try to reduce distress, and highlight that groups already at risk for poor mental health before the pandemic have remained at risk throughout lockdown and its aftermath.

Funding: Nuffield Foundation, UK Research and Innovation, Wellcome Trust.

Diabetes susceptibility in non-obese diabetic (NOD) mice may entail faulty activation of immunoregulatory cells resulting from cytokine deficiencies. Depletion of T cells prevents disease onset in these mice. Since we had previously shown that IL-2 treatment in vivo restored the ability of NOD/Lt mice to produce self-restricted suppressor T cells (Ts) in a syngeneic mixed lymphocyte reaction (SMLR), we investigated the possibility that diabetes could be circumvented by treatment with immunostimulatory agents that increase cytokine production. By 20 weeks of age, 75% of vehicle-treated NOD/Lt female controls had become glycosuric, while glycosuria developed in only 17% of NOD/Lt females injected with human recombinant interleukin-2 (rIL-2, 250 U twice weekly) beginning at 6 weeks of age. Treatment of mice with Poly [I:C] alone [50 micrograms twice weekly, an inducer of Interferon (IFN) alpha/beta] or in conjunction with rIL-2 was even more effective, completely preventing glycosuria for 20 weeks. However, therapeutic effects required continuous administration of the immunostimulants since pancreatic insulin content declined and severity of insulitis increased following cessation of treatment. IL-2 treatment increased transcription of interleukin-1 (IL-1) mRNA in peritoneal macrophages and increased lipopolysaccharide (LPS)-stimulated IL-1 secretion in comparison to controls. In the presence of stimulators from IL-2-treated mice, T lymphocytes isolated from both controls and IL-2-treated NOD/Lt mice proliferated in a SMLR and acquired Ts function. Peritoneal macrophages from Poly [I:C]-treated mice exhibited increased IFN alpha gene transcription and LPS-stimulated IL-1 secretion. T cells isolated from Poly [I:C]-treated mice were capable of suppressing NOD-Lt T cell responses to alloantigens in a mixed lymphocyte culture without prior activation in a SMLR. Thus, Poly [I:C] treatment may recruit a different population of regulatory cells than those elicited by treatment with IL-2. However, the mechanisms by which autoreactive T-cell clones may be regulated by these two treatments in NOD/Lt mice may be synergistic. These results indicate that in addition to T-cell depletion protocols, diabetes in NOD mice can be prevented by treatment with immunostimulatory agents.

<A<em>b</em>stractText>Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ri<em>b</em>ose) polymerase inhi<em>b</em>itors, such as velipari<em>b</em>, in com<em>b</em>ination with chemotherapy followed <em>b</em>y maintenance as initial treatment in patients with high-grade serous ovarian carcinoma.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In an international, phase 3, place<em>b</em>o-controlled trial, we assessed the efficacy of velipari<em>b</em> added to first-line induction chemotherapy with car<em>b</em>oplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus place<em>b</em>o followed <em>b</em>y place<em>b</em>o maintenance (control), chemotherapy plus velipari<em>b</em> followed <em>b</em>y place<em>b</em>o maintenance (velipari<em>b</em> com<em>b</em>ination only), or chemotherapy plus velipari<em>b</em> followed <em>b</em>y velipari<em>b</em> maintenance (velipari<em>b</em> throughout). Cytoreductive surgery could <em>b</em>e performed <em>b</em>efore initiation or after 3 cycles of trial treatment. Com<em>b</em>ination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the velipari<em>b</em>-throughout group as compared with the control group, analyzed sequentially in the <i>BRCA</i>-mutation cohort, the cohort with homologous-recom<em>b</em>ination deficiency (HRD) (which included the <i>BRCA</i>-mutation cohort), and the intention-to-treat population.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 1140 patients underwent randomization. In the <i>BRCA</i>-mutation cohort, the median progression-free survival was 34.7 months in the velipari<em>b</em>-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P&<em>lt</em>;0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P&<em>lt</em>;0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P&<em>lt</em>;0.001). Velipari<em>b</em> led to a higher incidence of anemia and throm<em>b</em>ocytopenia when com<em>b</em>ined with chemotherapy as well as of nausea and fatigue overall.</p><A<em>b</em>stractText>Across all trial populations, a regimen of car<em>b</em>oplatin, paclitaxel, and velipari<em>b</em> induction therapy followed <em>b</em>y velipari<em>b</em> maintenance therapy led to significantly longer progression-free survival than car<em>b</em>oplatin plus paclitaxel induction therapy alone. The independent value of adding velipari<em>b</em> during induction therapy without velipari<em>b</em> maintenance was less clear. (Funded <em>b</em>y A<em>b</em><em>b</em>Vie; VELIA/GOG-3005 ClinicalTrials.gov num<em>b</em>er, NCT02470585.).</A<em>b</em>stractText>