This study determined the effects of altering the H(+) concentration during interval training, by ingesting NaHCO(3) (Alk-T) or a placebo (Pla-T), on changes in muscle buffer capacity (beta m), endurance performance, and muscle metabolites. Pre- and posttraining peak O(2) uptake (V(O2 peak)), lactate threshold (LT), and time to fatigue at 100% pretraining V(O2 peak) intensity were assessed in 16 recreationally active women. Subjects were matched on the LT, were randomly placed into the Alk-T (n = 8) or Pla-T (n = 8) groups, and performed 8 wk (3 days/wk) of six to twelve 2-min cycle intervals at 140-170% of their LT, ingesting NaHCO(3) or a placebo before each training session (work matched between groups). Both groups had improvements in beta m (19 vs. 9%; P < 0.05) and V(O2 peak) (22 vs. 17%; P < 0.05) after the training period, with no differences between groups. There was a significant correlation between pretraining beta m and percent change in beta m (r = -0.70, P < 0.05). There were greater improvements in both the LT (26 vs. 15%; P = 0.05) and time to fatigue (164 vs. 123%; P = 0.05) after Alk-T, compared with Pla-T. There were no changes to pre- or postexercise ATP, phosphocreatine, creatine, and intracellular lactate concentrations, or pH(i) after training. Our findings suggest that training intensity, rather than the accumulation of H(+) during training, may be more important to improvements in beta m. The group ingesting NaHCO(3) before each training session had larger improvements in the LT and endurance performance, possibly because of a reduced metabolic acidosis during training and a greater improvement in muscle oxidative capacity.

Adipose tissue is a heterogeneous organ with remarkable variations in fat cell metabolism depending on the anatomical location. However, the pattern and distribution of bioactive lipid mediators between different fat depots and their relationships in complex diseases have not been investigated. Using LC-MS/MS-based metabolo-lipidomics, here we report that human subcutaneous (SC) adipose tissues possess a range of specialized proresolving mediators (SPM) including resolvin (Rv) D1, RvD2, protectin (PD) 1, lipoxin (LX) A4, and the monohydroxy biosynthetic pathway markers of RvD1 and PD1 (17-HDHA), RvE1 (18-HEPE), and maresin 1 (14-HDHA). The "classic" eicosanoids prostaglandin (PG) E₂, PGD₂, PGF2α, leukotriene (LT) B₄, 5-hydroxyeicosatetraenoic acid (5-HETE), 12-HETE, and 15-HETE were also identified in SC fat. SC fat from patients with peripheral vascular disease (PVD) exhibited a marked deficit in PD1 and 17-HDHA levels. Compared with SC, perivascular adipose tissue displayed higher SPM levels, suggesting an enhanced resolution capacity in this fat depot. In addition, augmented levels of eicosanoids and SPM were observed in SC fat surrounding foot wounds. Notably, the profile of SC PGF2α differed significantly when patients were grouped by body mass index (BMI). In the case of peri-wound SC fat, BMI negatively correlated with PGE₂. In this tissue, proresolving mediators RvD2 and LXA₄ were identified in lower levels than the proinflammatory LTB₄. Collectively, these findings demonstrate a diverse distribution of bioactive lipid mediators depending on the localization of human fat depots and uncover a specific SPM pattern closely associated with PVD.

A lymphotoxin-beta (LTbeta) receptor-Ig fusion protein (LTbetaR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTbetaR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTbetaR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTbetaR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.

Lymphotoxin (LT) -alpha beta heterotrimer is a membrane-anchored ligand expressed by activated T cells which binds specifically to the LT beta receptor (LT beta R), a member of the TNFR family. The LT beta R is implicated as a critical element in controlling lymph node development and cellular immune reactions. To address this hypothesis we have isolated a mouse cDNA encoding a single transmembrane protein of 415 amino acids with 76% identity to human LT beta R. The receptor function of this molecule was demonstrated by the ability of the extracellular domain, constructed as a chimera with the Fc region of IgG7, to bind to LT alpha beta complexes expressed on the surface of activated T cells or insect cells infected with baculoviruses containing LT alpha and LT beta cDNAs. The gene encoding mouse LT beta R, Ltbr, contains 10 exons spanning 6.9 kb and maps to mouse chromosome 6, which is closely linked to Tnfr1, consistent with the tight linkage of the human homologue of these genes on chromosome 12p13. Mouse LT beta R mRNA is expressed by cell lines of monocytic and epithelial origin but not by a CTL line, and in vivo it is constitutively expressed in visceral and lymphoid tissues. The delineation of the structure of the mouse LT beta R will aid investigations into the role of this cytokine-receptor system in immune function and development.

Cytokines and chemokines govern leukocyte trafficking, thus regulating inflammatory responses. In this study, the anti-inflammatory effects of low dose 17 beta-estradiol were evaluated on chemokine, chemokine receptor, and cytokine expression in the spinal cords (SC) of BV8S2 transgenic female mice during acute and recovery phases of experimental autoimmune encephalomyelitis (EAE). In EAE protected mice, 17 beta-estradiol strongly inhibited mRNA expression of the chemokines RANTES, MIP-1 alpha, MIP-2, IP-10, and MCP-1, and of the chemokine receptors CCR1, CCR2 and CCR5 at both time points. Conversely, ovariectomy, which abrogated basal 17 beta-estradiol levels and increased the severity of EAE, enhanced the expression of MIP-1 alpha and MIP-2 that were over-expressed by inflammatory mononuclear cells in SC. 17 beta-estradiol inhibited expression of LT-beta, TNF-alpha, and IFN-gamma in SC, but had no effect on IL-4 or IL-10, indicating reduced inflammation but no deviation toward a Th2 response. Interestingly, elevated expression of CCR1 and CCR5 by lymph node cells was also inhibited in 17 beta-estradiol treated mice with EAE. Low doses of 17 beta-estradiol added in vitro to lymphocyte cultures had no direct effect on the activation of MBP-Ac1-11 specific T cells, and only at high doses diminished production of IFN-gamma, but not IL-12 or IL-10. These results suggest that the beneficial effects of 17 beta-estradiol are mediated in part by strong inhibition of recruited inflammatory cells, resulting in reduced production of inflammatory chemokines and cytokines in CNS, with modest effects on encephalitogenic T cells that seem to be relatively 17 beta-estradiol insensitive.

The combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues [NA(s)] is considered as the standard of care for prophylaxis against HBV recurrence after liver transplantation (LT), but the optimal protocol is controversial. We evaluated the efficacy of the newer NAs with high genetic barrier (hgbNA) [i.e. entecavir (ETV) or tenofovir (TDF)] with or without HBIG as prophylaxis against HBV recurrence after LT. In total, 519 HBV liver transplant recipients from 17 studies met the inclusion criteria and they were compared to those under lamivudine (LAM) and HBIG who had been selected in our previous review. Patients under HBIG and LAM developed HBV recurrence (115/1889 or 6.1%): (a) significantly more frequently compared to patients under HBIG and a hgbNA [1.0% (3/303), p < 0.001], and (b) numerically but not significantly more frequently compared to the patients who received a newer NA after discontinuation of HBIG [3.9% (4/102), p = 0.52]. The use of a hgbNA without any HBIG offered similar antiviral prophylaxis compared to HBIG and LAM combination, if the definition of HBV recurrence was based on HBV DNA detectability [0.9% vs. 3.8%, p = 0.11]. Our findings favor the use of HBIG and a hgbNA instead of HBIG and LAM combined prophylaxis against HBV recurrence after LT.

(<em>b</em>)Background</<em>b</em>): Throm<em>b</em>ocytopenia has <em>b</em>een implicated in patients infected with severe acute respiratory syndrome coronavirus 2, while the association of platelet count and changes with su<em>b</em>sequent mortality remains unclear.(<em>b</em>)Methods</<em>b</em>): The clinical and la<em>b</em>oratory data of 383 patients with the definite outcome <em>b</em>y March 1, 2020 in the Central Hospital of Wuhan were reviewed. The association <em>b</em>etween platelet parameters and mortality risk was estimated <em>b</em>y utilizing Cox proportional hazard regression models.(<em>b</em>)Resu<em>lt</em>s</<em>b</em>): Among the 383 patients, 334 (87.2%) were discharged and survived, and 49 (12.8%) died. Throm<em>b</em>ocytopenia at admission was associated with mortality of almost three times as high as that for those without throm<em>b</em>ocytopenia (<i>P</i> &<em>lt</em>; 0.05). Cox regression analyses revealed that platelet count was an independent risk factor associated with in-hospital mortality in a dose-dependent manner. An increment of per 50 × 10⁹/L in platelets was associated with a 40% decrease in mortality (hazard ratio: 0.60, 95%CI: 0.43, 0.84). Dynamic changes of platelets were also closely related to death during hospitalization.(<em>b</em>)Conclusions</<em>b</em>): Baseline platelet levels and changes were associated with su<em>b</em>sequent mortality. Monitoring platelets during hospitalization may <em>b</em>e important in the prognosis of patients with coronavirus disease in 2019.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Monotherapy with a P2Y<su<em>b</em>)12</su<em>b</em>) inhi<em>b</em>itor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of <em>b</em>leeding after percutaneous coronary intervention (PCI).</p><A<em>b</em>stractText>In a dou<em>b</em>le-<em>b</em>lind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant <em>b</em>leeding among patients who were at high risk for <em>b</em>leeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major <em>b</em>leeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or place<em>b</em>o for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 <em>b</em>leeding. We also evaluated the composite end point of death from any cause, nonfatal myocardial infarction, or nonfatal stroke, using a noninferiority hypothesis with an a<em>b</em>solute margin of 1.6 percentage points.</A<em>b</em>stractText><A<em>b</em>stractText>We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus place<em>b</em>o and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P&<em>lt</em>;0.001). The difference in risk <em>b</em>etween the groups was similar for BARC type 3 or 5 <em>b</em>leeding (incidence, 1.0% among patients receiving ticagrelor plus place<em>b</em>o and 2.0% among patients receiving ticagrelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in <em>b</em>oth groups (difference, -0.06 percentage points; 95% CI, -0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P&<em>lt</em>;0.001 for noninferiority).</A<em>b</em>stractText><A<em>b</em>stractText>Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant <em>b</em>leeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke. (Funded <em>b</em>y AstraZeneca; TWILIGHT ClinicalTrials.gov num<em>b</em>er, NCT02270242.).</A<em>b</em>stractText>

<A<em>b</em>stractText>Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Ara<em>b</em>ian Peninsula 7 years after it was first descri<em>b</em>ed in Saudi Ara<em>b</em>ia. MERS-CoV poses a significant risk to pu<em>b</em>lic hea<em>lt</em>h security <em>b</em>ecause of an a<em>b</em>sence of currently availa<em>b</em>le effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This dose-escalation, open-la<em>b</em>el, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included hea<em>lt</em>hy people aged 18-50 years with negative pre-vaccination tests for HIV anti<em>b</em>odies, hepatitis <em>B</em> surface antigen, and hepatitis C anti<em>b</em>odies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 10⁹ viral particles, the intermediate-dose group received 2·5 × 10¹⁰ viral particles, and the high-dose group received 5 × 10¹⁰ viral particles. The primary o<em>b</em>jective was to assess safety and tolera<em>b</em>ility of ChAdOx1 MERS, measured <em>b</em>y the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary o<em>b</em>jective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured <em>b</em>y interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div><em>B</em>etween March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were availa<em>b</em>le for follow-up at 6 months, <em>b</em>ut five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 10¹⁰ viral particles with no vaccine-related serious adverse events reported <em>b</em>y 12 months. One serious adverse event reported was deemed to <em>b</em>e not related to ChAdOx1 MERS. 92 (74% [95% CI 66-81]) of 124 solicited adverse events were mild, 31 (25% [18-33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to <em>b</em>e possi<em>b</em>ly, pro<em>b</em>a<em>b</em>ly, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11-17·42], p&<em>lt</em>;0·0001) La<em>b</em>oratory adverse events considered to <em>b</em>e at least possi<em>b</em>ly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from <em>b</em>aseline in T-cell (p&<em>lt</em>;0·003) and IgG (p&<em>lt</em>;0·0001) responses to the MERS-CoV spike antigen was o<em>b</em>served at all doses. Neutralising anti<em>b</em>odies against live MERS-CoV were o<em>b</em>served in four (44% [95% CI 19-73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58-93]) of 24 participants had anti<em>b</em>odies capa<em>b</em>le of neutralisation in a pseudotyped virus neutralisation assay.</p><A<em>b</em>stractText>ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was a<em>b</em>le to elicit <em>b</em>oth humoral and cellular responses against MERS-CoV. The resu<em>lt</em>s of this first-in-human clinical trial support clinical development progression into field phase 1<em>b</em> and 2 trials.</A<em>b</em>stractText><A<em>b</em>stractText>UK Department of Hea<em>lt</em>h and Social Care, using UK Aid funding, managed <em>b</em>y the UK National Institute for Hea<em>lt</em>h Research.</A<em>b</em>stractText>

<A<em>b</em>stractText>The COVID-19 pandemic has had an impact on hea<em>lt</em>hcare systems around the world with 3.0 million infected and 208,000 resu<em>lt</em>ant mortalities as of this writing. Information regarding infection in pregnancy is still limited.</A<em>b</em>stractText><A<em>b</em>stractText>To descri<em>b</em>e the clinical course of severe and critical infection in hospitalized pregnant women with positive la<em>b</em>oratory testing for SARS-CoV2.</A<em>b</em>stractText><A<em>b</em>stractText>This is a cohort study of pregnant women with severe or critical COVID-19 infection hospitalized at 12 US institutions <em>b</em>etween March 5, 2020 and April 20, 2020. Severe infection was defined according to pu<em>b</em>lished criteria <em>b</em>y patient reported dyspnea, respiratory rate > 30 per minute, <em>b</em>lood oxygen saturation ≤ 93% on room air, partial pressure of arterial oxygen to fraction of inspired oxygen &<em>lt</em>;300 and/or lung infi<em>lt</em>rates >50% within 24 to 48 hours on chest imaging. Critical disease was defined <em>b</em>y respiratory failure, septic shock, and/or mu<em>lt</em>iple organ dysfunction or failure. Women were excluded if they had presumed COVID-19 infection <em>b</em>ut la<em>b</em>oratory testing was negative. The primary outcome was median duration from hospital admission to discharge. Secondary outcomes included need for supplemental oxygen, intu<em>b</em>ation, cardiomyopathy, cardiac arrest, death, and timing of delivery. The clinical courses are descri<em>b</em>ed <em>b</em>y the median disease day on which these outcomes occurred after the onset of symptoms. Treatment and neonatal outcomes are also reported.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>Of 64 pregnant women hospitalized with COVID-19, 44 (69%) had severe and 20 (31%) critical disease. The following pre-existing comor<em>b</em>idities were o<em>b</em>served: 25% had a pulmonary condition, 17% had cardiac disease and the mean BMI was 34 kg/m². Gestational age at symptom onset was at a mean 29 ±6 weeks and at hospital admission a mean of 30 ±6 weeks, on a median day of disease 7 since first symptoms. Eighty-one percent of women were treated with hydroxychloroquine; 9% of women with severe disease and 65% of women with critical disease received remdesivir. All women with critical disease received either prophylactic or therapeutic anticoagulation during their admission. The median duration of hospital stay was 6 days (6 days for severe, 10.5 days for critical, <i>p</i>=0.01). For those who required it, intu<em>b</em>ation usually occurred around day 9, and peak respiratory support for women with severe disease occurred on day 8. In women with critical disease, prone positioning was performed in 20% of cases, the rate of ARDS was 70%, and re-intu<em>b</em>ation was necessary in 20%. There was one case of maternal cardiac arrest, <em>b</em>ut no cases of cardiomyopathy and no maternal deaths. Thirty-two (50%) women in this cohort delivered during their COVID-19 hospitalization (34% of severe and 85% of critical women). Eighty-eight percent (15/17) of pregnant women with critical COVID-19 who delivered during their disease course were delivered preterm, 94% of them via cesarean; in all, 75% (15/20) of critically ill women delivered preterm. There were no still<em>b</em>irths or neonatal deaths, or cases of vertical transmission.</p><A<em>b</em>stractText>In hospitalized pregnant women with severe or critical COVID-19 infection, admission typically occurred a<em>b</em>out 7 days after symptom onset, and the duration of hospitalization was 6 days (6 severe versus 12 critical). Critically ill women had a high rate of ARDS, and there was one case of cardiac arrest, <em>b</em>ut there were no cases of cardiomyopathy, or maternal mortality. Hospitalization for severe or critical COVID-19 infection resu<em>lt</em>ed in delivery during the course of infection in 50% of this cohort, usually in the third trimester. There were no perinatal deaths in this cohort.</A<em>b</em>stractText>

Mice deficient in LT alpha (LT alpha-/-) lack lymph nodes and Peyer's patches. This action of LT alpha in lymph node organogenesis appears to be mediated by the membrane form of LT using a mechanism independent of TNF receptor I (TNFR-I) or II (TNFR-II). In contrast, normal Peyer's patch development appears to require both LT alpha and TNFR-I, with TNFR-I-/- mice showing hypoplastic Peyer's patch structures. LT alpha-/- mice also fail to support the normal segregation of T-cell and B-cell zones within the splenic white pulp. Again, this occurs via a mechanism independent of TNFR-I or TNFR-II. Additionally, follicular dendritic cell (FDC) clusters or germinal centers fail to develop in the spleen of LT alpha-/- animals. Mice deficient in either TNF alpha or TNFR-I also fail to develop splenic FDC clusters and germinal centers, indicating that signaling by both LT alpha and TNF alpha is required for development of these specialized lymphoid tissue structures. Finally, the splenic white pulp areas in LT alpha-/- mice lack the marginal zone of monoclonal antibody MOMA-1-staining metallophilic macrophages, whereas TNFR-I-deficient mice have preserved MOMA-1 staining. Thus, certain actions of LT alpha to regulate spleen white pulp architecture are mediated by receptors other than TNFR-I, most likely by the LT beta R or a closely related receptor. We tested whether germinal centers are essential for maturation of T-cell-dependent antibody responses. When LT alpha-/- mice were immunized with low doses of NP-ovalbumin (NP-OVA) adsorbed to alum, there was dramatically impaired production of high affinity anti NP IgG; however, after immunization with high doses of NP-OVA adsorbed to alum, LT alpha-/- mice mounted a high affinity NP-specific serum IgG response similar to wild-type mice, all in the absence of germinal centers or clustered FDC. Thus, although germinal centers enhance the processes required for maturation of the humoral immune response, the mechanisms responsible for affinity maturation are not absolutely dependent on the presence of germinal centers.

Background: Perform a systematic review and meta-analysis of SARS-CoV-2 infection and pregnancy.

Methods: Databases (Medline, Embase, Clinicaltrials.gov, Cochrane Library) were searched electronically on 6th April and updated regularly until 8th June 2020. Reports of pregnant women with reverse transcription PCR (RT-PCR) confirmed COVID-19 were included. Meta-analytical proportion summaries and meta-regression analyses for key clinical outcomes are provided.

Findings: 86 studies were included, 17 studies (2567 pregnancies) in the quantitative synthesis; other small case series and case reports were used to extract rarely-reported events and outcome. Most women (73.9%) were in the third trimester; 52.4% have delivered, half by caesarean section (48.3%). The proportion of Black, Asian or minority ethnic group membership (50.8%); obesity (38.2%), and chronic co-morbidities (32.5%) were high. The most commonly reported clinical symptoms were fever (63.3%), cough (71.4%) and dyspnoea (34.4%). The commonest laboratory abnormalities were raised CRP or procalcitonin (54.0%), lymphopenia (34.2%) and elevated transaminases (16.0%). Preterm birth before 37 weeks' gestation was common (21.8%), usually medically-indicated (18.4%). Maternal intensive care unit admission was required in 7.0%, with intubation in 3.4%. Maternal mortality was uncommon (~1%). Maternal intensive care admission was higher in cohorts with higher rates of co-morbidities (beta=0.007, p&lt;0.05) and maternal age over 35 years (beta=0.007, p&lt;0.01). Maternal mortality was higher in cohorts with higher rates of antiviral drug use (beta=0.03, p&lt;0.001), likely due to residual confounding. Neonatal nasopharyngeal swab RT-PCR was positive in 1.4%.

Interpretation: The risk of iatrogenic preterm birth and caesarean delivery was increased. The available evidence is reassuring, suggesting that maternal morbidity is similar to that of women of reproductive age. Vertical transmission of the virus probably occurs, albeit in a small proportion of cases.

Funding: N/A.

Background: Medical mistrust, a result of systemic racism, is prevalent among Black Americans and may play a role in COVID-19 inequities. In a convenience sample of HIV-positive Black Americans, we examined associations of COVID-19 related medical mistrust with COVID-19 vaccine and COVID-19 treatment hesitancy, and negative impacts of COVID-19 on antiretroviral therapy (ART) adherence.

Methods: Participants were 101 HIV-positive Black Americans (age: M=50.3 years; SD=11.5; 86% cisgender male; 77% sexual minority) enrolled in a randomized controlled trial of a community-based ART adherence intervention in Los Angeles County, CA. From May to July 2020, participants completed telephone interviews on negative COVID-19 impacts, general COVID-19 mistrust (e.g., about the government withholding information), COVID-19 vaccine and treatment hesitancy, and trust in COVID-19 information sources. Adherence was monitored electronically with the Medication Events Monitoring System.

Results: Nearly all participants (97%) endorsed at least one general COVID-19 mistrust belief, and over half endorsed at least one COVID-19 vaccine or treatment hesitancy belief. Social service and healthcare providers were the most trusted sources. Greater COVID-19 mistrust was related to greater vaccine and treatment hesitancy [b (SE)=0.85 (0.14), p&lt;.0001 and b (SE)=0.88 (0.14), p&lt;.0001, respectively]. Participants experiencing more negative COVID-19 impacts showed lower ART adherence, assessed among a subset of 49 participants [b (SE) = -5.19 (2.08), p = .02].

Discussion: To prevent widening health inequities, healthcare providers should engage with communities to tailor strategies to overcome mistrust and deliver evidence-based information, in order to encourage COVID-19 vaccine and treatment uptake.

A combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NUCs) is currently recommended as prophylaxis against the recurrence of hepatitis B virus (HBV) after liver transplantation (LT), but the optimal protocol is a matter of controversy. The aim of this study was the identification of factors associated with post-LT HBV recurrence in patients receiving HBIG and NUCs. We searched MEDLINE and PubMed for studies in English about the effectiveness of HBIG and NUCs [lamivudine (LAM) and/or adefovir dipivoxil (ADV)] against post-LT HBV recurrence (January 1998 to June 2010). Forty-six studies, which included 2162 HBV LT recipients, met the selection criteria. Patients receiving HBIG and LAM experienced HBV recurrence more frequently than patients receiving HBIG and ADV with or without LAM [6.1% (115/1889) versus 2.0% (3/152), P = 0.024], although they also were more frequently treated with indefinite HBIG prophylaxis (90% versus 57%, P < 0.001). For patients receiving HBIG and LAM, a lower frequency of HBV recurrence was associated with a high HBIG dosage (≥10,000 IU/day) versus a low HBIG dosage (<10,000 IU/day) during the first week after LT [3.2% (14/440) versus 6.5% (80/1233), P = 0.016], but the HBIG protocol had no impact on HBV recurrence in patients receiving HBIG and ADV. In conclusion, in comparison with the combination of HBIG and LAM, the combination of HBIG and ADV is associated with a lower rate of HBV recurrence after LT. Patients receiving HBIG and LAM should be given a high dosage of HBIG during the first week after LT, but a lower dosage can be used safely in patients receiving HBIG and ADV. Further studies with newer and more potent anti-HBV agents are definitely required.

Given recent evidence suggesting that the heat-labile enterotoxin (LT) provides a colonization advantage for enterotoxigenic Escherichia coli (ETEC) in vivo, we hypothesized that LT preconditions the host intestinal epithelium for ETEC adherence. To test this hypothesis, we used an in vitro model of ETEC adherence to examine the role of LT in promoting bacterium-host interactions. We present data demonstrating that elaboration of LT promotes a significant increase in E. coli adherence. This phenotype is primarily dependent on the inherent ADP-ribosylation activity of this toxin, with a secondary role observed for the receptor-binding LT-B subunit. Rp-3',5'-cyclic AMP (cAMP), an inhibitor of protein kinase A, was sufficient to abrogate LT's ability to promote subsequent bacterial adherence. Increased adherence was not due to changes in the surface expression of the host receptor for the K88ac adhesin. Evidence is also presented for a role for bacterial sensing of host-derived cAMP in promoting adherence to host cells.

Hybridoma-derived monoclonal antibodies were raised to enterotoxins of the cholera family and to chimeric B-subunit proteins in which individual amino acid residues of a heat-labile, cholera-related enterotoxin from an Escherichia coli strain of porcine origin (P-LT) were substituted with corresponding residues from such an enterotoxin from an E. coli strain of human origin (H-LT). Single amino acid substitutions were found to have profound effects on the physicochemical behavior of the proteins and on their immunologic reactivity. With the use of enzyme-linked immunosorption assays (ELISAs) with and without the GM1 ganglioside receptor for these toxins, several distinct epitopes in GM1-binding domains were identified by different monoclonal antibodies. Polyclonal rabbit antisera to synthetic peptides of the cholera enterotoxin B subunit were cross-reactive to various degrees with the proteins in our library, which include two different cholera enterotoxins, two H-LTs, P-LT, and four chimeric proteins. Some of these reactions were blocked by GM1 ganglioside but not by the oligosaccharide of GM1, a finding suggesting that the peptides generated antibodies to epitopes near, but not in, a GM1-binding domain. A hypothetical evolutionary tree based on the reported amino acid sequences of the various enterotoxins is constructed. As additional enterotoxins are described, it will be interesting to determine if and where they fit in this scheme.

Further definition of the role of leukotrienes (LT) and prostaglandins (PG) in asthma would be helped by a noninvasive method for assessing airway production. The supernatant from sputum induced with hypertonic saline and dispersed using dithiotrietol has been successfully used to measure other molecular markers of airway inflammation and might be a useful method. We have measured induced sputum supernatant LTC(4)/D(4)/E(4) concentrations using enzyme immunoassay and PGE(2), PGD(2), TXB(2), and PGF(2alpha) using gas chromatography-negative ion chemical ionization-mass spectroscopy in 10 normal subjects and in 26 subjects with asthma of variable severity. Sputum cysteinyl-leukotrienes concentrations were significantly greater in subjects with asthma (median, 9.5 ng/ml) than in normal control subjects (6.4 ng/ml; p < 0.02) and greater in subjects with persistent asthma requiring inhaled corticosteroids (median, 11.4 ng/ml) or studied within 48 h of an acute severe exacerbation of asthma (13 ng/ml) than in subjects with episodic asthma treated with inhaled beta(2)-agonists only (7.2 ng/ml). There were no significant differences in the concentrations of other eicosanoids between groups, although there was a negative correlation between the percentage sputum eosinophil count and sputum PGE(2) concentration (r = -0.48; p < 0.01) in subjects with asthma. We conclude that induced sputum contains high concentrations of eicosanoids and that sputum LTC(4)/D(4)/E(4) concentrations are significantly greater in subjects with asthma than in normal subjects. The inverse relationship between eosinophilic airway inflammation and sputum PGE(2) concentration would be consistent, with the latter having an anti-inflammatory role.

<A<em>b</em>stractText>Until recently, the World Hea<em>lt</em>h Organization (WHO) estimated the annual mortality <em>b</em>urden of influenza to <em>b</em>e 250 000 to 500 000 all-cause deaths glo<em>b</em>ally; however, a 2017 study indicated a su<em>b</em>stantially higher mortality <em>b</em>urden, at 290 000-650 000 influenza-associated deaths from respiratory causes alone, and a 2019 study estimated 99 000-200 000 deaths from lower respiratory tract infections directly caused <em>b</em>y influenza. Here we revisit glo<em>b</em>al and regional estimates of influenza mortality <em>b</em>urden and explore mortality trends over time and geography.</A<em>b</em>stractText><A<em>b</em>stractText>We compiled influenza-associated excess respiratory mortality estimates for 31 countries representing 5 WHO regions during 2002-2011. From these we extrapolated the influenza <em>b</em>urden for all 193 countries of the world using a mu<em>lt</em>iple imputation approach. We then used mixed linear regression models to identify factors associated with high seasonal influenza mortality <em>b</em>urden, including influenza types and su<em>b</em>types, hea<em>lt</em>h care and socio-demographic development indicators, and <em>b</em>aseline mortality levels.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>We estimated an average of 389 000 (uncertainty range 294 000-518(<em>b</em>)</<em>b</em>)000) respiratory deaths were associated with influenza glo<em>b</em>ally each year during the study period, corresponding to ~ 2% of all annual respiratory deaths. Of these, 67% were among people 65 years and older. Glo<em>b</em>al <em>b</em>urden estimates were ro<em>b</em>ust to the choice of countries included in the extrapolation model. For people &<em>lt</em>;65 years, higher <em>b</em>aseline respiratory mortality, lower level of access to hea<em>lt</em>h care and seasons dominated <em>b</em>y the A(H1N1)pdm09 su<em>b</em>type were associated with higher influenza-associated mortality, while lower level of socio-demographic development and A(H3N2) dominance was associated with higher influenza mortality in adu<em>lt</em>s ≥65 years.</p><A<em>b</em>stractText>Our glo<em>b</em>al estimate of influenza-associated excess respiratory mortality is consistent with the 2017 estimate, despite a different modelling strategy, and the lower 2019 estimate which only captured deaths directly caused <em>b</em>y influenza. Our finding that <em>b</em>aseline respiratory mortality and access to hea<em>lt</em>h care are associated with influenza-related mortality in persons &<em>lt</em>;65 years suggests that hea<em>lt</em>h care improvements in low and middle-income countries might su<em>b</em>stantially reduce seasonal influenza mortality. Our estimates add to the <em>b</em>ody of evidence on the variation in influenza <em>b</em>urden over time and geography, and <em>b</em>egin to address the relationship <em>b</em>etween influenza-associated mortality, hea<em>lt</em>h and development.</A<em>b</em>stractText>

(<em>b</em>)Background:</<em>b</em>) The aim of the study was to document cardiovascular clinical findings, cardiac imaging and la<em>b</em>oratory markers in children presenting with the novel mu<em>lt</em>isystem inflammatory syndrome (MIS-C) associated with COVID-19 infection. (<em>b</em>)Methods:</<em>b</em>) A real-time internet-<em>b</em>ased survey endorsed <em>b</em>y the Association for European Paediatric and Congenital Cardiologists (AEPC) Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Inclusion criteria was children 0-18 years admitted to hospital <em>b</em>etween Fe<em>b</em>ruary 1 and June 6, 2020 with diagnosis of an inflammatory syndrome and acute cardiovascular complications. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (IQR 3.8-12.4 years) and 67% were males. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients and a vast majority of children had raised cardiac troponin (cTnT) when checked. The <em>b</em>iochemical markers of inflammation were raised in majority of patients on admission: elevated CRP, serum ferritin, procalcitonin, NT-proBNP, IL-6 level and D-dimers. There was a statistically significant correlation <em>b</em>etween degree of elevation in cardiac and <em>b</em>iochemical parameters and need for intensive care support (p &<em>lt</em>;0.05). Polymerase chain reaction (PCR) for SARS-CoV-2 was positive in 33.6% while IgM and IgG anti<em>b</em>odies were positive in 15.7% and IgG 43.6 % cases, respectively when checked. One child died in the study cohort. (<em>b</em>)Conclusions:</<em>b</em>) Cardiac involvement is common in children with mu<em>lt</em>isystem inflammatory syndrome associated with Covid-19 pandemic. A majority of children have significantly raised levels of NT pro-BNP, ferritin, D-dimers and cardiac troponin in addition to high CRP and procalcitonin levels. Compared to adu<em>lt</em>s with Covid-19, mortality in children with MIS-C is uncommon despite mu<em>lt</em>i-system involvement, very elevated inflammatory markers and need for intensive care support.

Keywords: MIS-C; PIMS-TS; SARS-COV-2.

Lymphotoxin (LT) is a cytokine related to TNF, found in human systems in both secreted and membrane bound forms. The well characterized secreted form is a trimer of a single protein, LT-alpha, whereas the surface form is composed of a complex between two related molecules, LT-alpha and LT-beta. Because there is a distinct receptor for the complex, the membrane form is believed to signal via events different from those elicited by TNF and secreted LT-alpha. By using a battery of anti-LT-alpha and LT-beta mAbs, it is clear that two LT surface forms exist on the surface of PMA-activated II-23 cells, a human T cell hybridoma. Assuming that these surface forms are trimers, a minor form appears early after induction having an apparent stoichiometry of LT-alpha 2/beta 1 and is recognized by one group of anti-LT-alpha mAbs and the p55-TNF receptor. The second and predominant form has an apparent LT-alpha 1/beta 2 composition and is recognized by a second group of pantrophic anti-LT-alpha mAbs and the LT-beta receptor. Neither of the heteromeric forms nor a putative LT-beta homotrimeric form were found to be secreted. The properties of surface LT on the II-23 cell system were similar to those of the surface LT forms on Chinese hamster ovary cells transfected with both LT-alpha and LT-beta genes and a number of lymphoid tumor lines. These experiments point toward the LT-alpha 1/beta 2 complex as the predominant membrane form of LT on the lymphocyte surface, and this complex is the primary ligand for the LT-beta receptor.

Within the Burkholderia cepacia complex (Bcc), B. cenocepacia portends increased mortality compared with other species. We investigated the impact of Bcc infection on mortality and re-infection following lung transplant (LT). Species designation for isolates from Bcc-infected patients was determined using 16S rDNA and recA gene analyses. Of 75 cystic fibrosis patients undergoing LT from September 1992 to August 2002, 59 had no Bcc and 16 had Bcc (including 7 B. cenocepacia) isolated in the year before LT. Of the latter, 87.5% had Bcc recovered after transplantation, and all retained their pretransplant strains. Survival was 97%, 92%, 76% and 63% for noninfected patients; 89%, 89%, 67% and 56% for patients infected with Bcc species other than B. cenocepacia; and 71%, 29%, 29% and 29% for patients with B. cenocepacia (p = 0.014) at 1 month, 1 year, 3 years and 5 years, respectively. Patients infected with B. cenocepacia before transplant were six times more likely to die within 1 year of transplant than those infected with other Bcc species (p = 0.04) and eight times than noninfected patients (p < 0.00005). Following LT, infection with Bcc species other than B. cenocepacia does not significantly impact 5-year survival whereas infection with B. cenocepacia pretransplant is associated with decreased survival.

The NOD/Lt mouse, a widely used model of human autoimmune IDDM, was used to establish the mode of beta-cell death responsible for the development of IDDM. Apoptotic cells were present within the islets of Langerhans in hematoxylin and eosin-stained sections of pancreases harvested from 3- to 18-week-old female NOD/Lt mice (a range of 11-50 apoptotic cells per 100 islets). Immunohistochemical localization of insulin to the dying cells confirmed the beta-cell origin of the apoptosis. Although some islets from age-matched control female NOD/scid mice contained apoptotic cells, virtually all of these cells were insulin negative as determined by immunohistochemistry. The small number of apoptotic insulin-positive cells identified in islets from NOD/scid mice (a range of 0-1 apoptotic cells per 100 islets) was not statistically significant, compared with the numbers recorded in NOD/Lt mice. All dying cells showed the morphological changes characteristic of cell death by apoptosis and stained positively with the TUNEL method for end-labeling DNA strand breaks. The maximum mean amount of beta-cell apoptosis occurring in NOD/Lt mice was at week 15 (50 apoptotic cells per 100 islets), which coincided with the earliest onset of diabetes as determined by blood glucose, urine glucose, and pancreatic immunoreactive insulin measurements. While there was no peak incidence of beta-cell apoptosis throughout the time period studied (weeks 3-18), the incidence of apoptosis decreased at week 18, by which time 50% of the animals had overt diabetes. The low levels of beta-cell apoptosis observed is indicative of a gradual deletion of the beta-cell population throughout the extensive preclinical period seen in this model and would be sufficient to account for the beta-cell loss resulting in IDDM. Apoptosis of beta-cells preceded the appearance of T-cells (CD3-positive by immunohistochemistry) in islets. Lymphocytic infiltration of islets (insulitis) was not detected until week 6. The results show that beta-cell apoptosis is responsible for the development of IDDM in the NOD/Lt mouse and that its onset precedes lymphocytic infiltration of the islets.

Protective host immune responses to anthrax infection in humans and animal models are characterized by the development of neutralizing Abs against the receptor-binding anthrax protective Ag (PA), which, together with the lethal factor (LF) protease, composes anthrax lethal toxin (LT). We now report that B cells, in turn, are targets for LT. Anthrax PA directly binds primary B cells, resulting in the LF-dependent cleavage of the MAPK kinases (MAPKKs) and disrupted signaling to downstream MAPK targets. Although not directly lethal to B cells, anthrax LT treatment causes severe B cell dysfunction, greatly reducing proliferative responses to IL-4-, anti-IgM-, and/or anti-CD40 stimulation. Moreover, B cells treated with anthrax LT in vitro or isolated from mice treated with anthrax LT in vivo have a markedly diminished capacity to proliferate and produce IgM in response to TLR-2 and TLR-4 ligands. The suppressive effects of anthrax LT on B cell function occur at picomolar concentrations in vitro and at sublethal doses in vivo. These results indicate that anthrax LT directly inhibits the function of B cells in vitro and in vivo, revealing a potential mechanism through which the pathogen could bypass protective immune responses.