The clinical use of many adenovirus vaccine vectors (AdVs) is limited by the presence of pre-existing antibodies in human populations, which prevent common AdVs from transducing cells and expressing ...immunogenic gene products. Rare serotype AdVs, such as HAdV-28D can bypass pre-existing immunity. However, rare AdVs stimulate high-levels of type I interferon (IFN), which suppresses antigenic gene expression and therefore limits immunogenicity. Recent studies identified Gas6 as a factor that connects enveloped viruses to host-cell receptor tyrosine kinases, in turn generating signaling cascades that antagonize type I IFN responses. We discovered that Gas6 bound to the fiber proteins of common AdV serotypes, such as HAdV-5C, with a higher affinity than rare HAd-28D fibers. AdV-associated Gas6 suppressed IFN production by common AdVs and enhanced long-term expression of AdV encoded genes. We hypothesize that rare AdV serotypes might be engineered to include Gas6 binding motifs, thereby generating novel vectors that are more effective.
•Gas6 binds to a non-enveloped virus.•Gas6 binds the adenovirus serotype 5 fiber protein.•Gas6 suppresses type I IFN responses against adenovirus serotype-5 based vectors and enhances virus-encoded gene expression.
Hepatopancreatoduodenectomy (HPD) is an aggressive operation for treatment of advanced bile duct and gallbladder cancer associated with high perioperative morbidity and mortality, and uncertain ...oncological benefit in terms of survival. Few reports on HPD from Western centers exist. The purpose of this study was to evaluate safety and efficacy for HPD in European centers.
Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients operated with HPD for bile duct or gallbladder cancer between January 2003 and January 2018. The patient and tumor characteristics, perioperative and survival outcomes were analyzed.
In total, 66 patients from 19 European centers were included in the analysis. 90-day mortality rate was 17% and 13% for bile duct and gallbladder cancer respectively. All factors predictive of perioperative mortality were patient and disease-specific. The three-year overall survival excluding 90-day mortality was 80% for bile duct and 30% for gallbladder cancer (P = 0.013). In multivariable analysis R0-resection had a significant impact on overall survival.
HPD, although being associated with substantial perioperative mortality, can offer a survival benefit in patient subgroups with bile duct cancer and gallbladder cancer. To achieve negative resection margins is paramount for an improved survival outcome.
Objective
To evaluate treatment with MEDI‐551, a humanized anti‐human CD19 monoclonal antibody, in a model of autoimmunity involving mice transgenic (Tg) for Sle1 and human CD19 (hCD19).
Methods
...Sle1.hCD19‐Tg mice were given either a single intravenous dose of MEDI‐551 or repeated doses of MEDI‐551 biweekly for up to 12 weeks. The numbers of B cells in the blood, spleen, and bone marrow were determined by flow cytometry assay. In the spleen and bone marrow, the number of IgM‐ and IgG‐specific antibody‐secreting cells (ASCs) and the number of ASCs specific for anti–double‐stranded DNA (anti‐dsDNA) were determined by enzyme‐linked immunospot assay. Serum autoantibody and total immunoglobulin levels were determined by enzyme‐linked immunosorbent assay, and levels of inflammatory proteins were tested using a multianalyte profiling platform.
Results
MEDI‐551 treatment of Sle1.hCD19‐Tg mice resulted in effective and sustained B cell depletion throughout the duration of the experiment. The frequency of IgM and IgG ASCs in the spleen was reduced by ≥90%, whereas in the bone marrow, the total ASC frequency was not changed. Levels of autoantibodies specific for dsDNA as well as antihistone and antinuclear antibodies were each reduced by 40–80%, but total serum immunoglobulin levels were largely unchanged at the end of 12 weeks of treatment.
Conclusion
These findings highlight the ability of MEDI‐551 to deplete B cells and ASCs in autoimmune Sle1.hCD19‐Tg mice. MEDI‐551 treatment resulted in a robust reduction of autoantibodies but had minimal effect on total serum immunoglobulins. Thus, the novel ability of MEDI‐551 to remove a broad range of B cells as well as to lower most disease‐driving autoantibodies in an autoimmune disease mouse model warrants continued research. Several clinical studies to explore the safety and activity of MEDI‐551 in autoantibody‐associated autoimmune diseases are ongoing.
Continuous support from follicular CD4(+) T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In ...autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization.
Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model.
These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.
Objective: To determine whether participants with severe head injury (SHI) allocated to a brief compassion focused imagery (CFI) intervention show greater change in compassion than those exposed to ...relaxation imagery (RI).
Method: Participants were exposed to a preparatory video to promote engagement and then randomly allocated to intervention. Pre- and post-preparatory measures were Motivation for Intervention and Fears of Compassion Scales, State-Trait Anxiety Inventory (STAI) and PANAS. Pre- and post-intervention self-report measures were the Empathy Quotient, Self-Compassion Scale, STAI and Relaxation Scale. Heart rate variability (HRV) was monitored throughout.
Results: Motivation for therapy increased after the preparatory video (z = 3.44, p = 0.001). Across the intervention, group differences were not found on self-report measures or HRV changes. When CFI and RI groups were pooled, improvement in relaxation (r = .41, p < 0.01) and state anxiety (r = .29, p < 0.05) were found across the intervention; these outcomes were not associated with changes in self-compassion or HRV.
Conclusion: Brief CFI, a central aspect of compassion focused therapy, did not produce a reliable change in people with SHI. Enhanced motivation for psychological therapy after a brief preparatory video is relevant and underlines the need to understand mechanisms of action rather than the pursuing whole protocol approaches to therapy.
Itaconic acid is an important metabolite produced by macrophages after stimulation with LPS. The role of itaconate in the inflammatory cascade is unclear. Here we used 13Citaconate and dimethyl ...13Citaconate (DMI) to probe itaconate metabolism, and find that 13CDMI is not metabolized to itaconate. 13CItaconate in the cell culture medium leads to elevated intracellular levels of unlabeled succinate, with no evidence of intracellular uptake. The goal of this study is to encourage the development of effective pro-drug strategies to increase the intracellular levels of itaconate, which will enable more conclusive analysis of its action on macrophages and other cell and tissue types.
Objective The purpose of this study was to examine the relationship among methadone maintenance treatment, perinatal outcomes, and neonatal abstinence syndrome. Study Design This was a retrospective ...cohort study of 61,030 singleton births at a large maternity hospital from 2000-2007. Results There were 618 (1%) women on methadone at delivery. Methadone-exposed women were more likely to be younger, to book late for antenatal care, and to be smokers. Methadone exposure was associated with an increased risk of very preterm birth <32 weeks of gestation (adjusted odds ratio aOR, 2.47; 95% confidence interval CI, 1.40–4.34), being small for gestational age <10th percentile (aOR, 3.27; 95% CI, 2.49–4.28), admission to the neonatal unit (aOR, 9.14; 95% CI, 7.21–11.57), and diagnosis of a major congenital anomaly (aOR, 1.94; 95% CI, 1.10–3.43). There was a dose-response relationship between methadone and neonatal abstinence syndrome. Conclusion Methadone exposure is associated with an increased risk of adverse perinatal outcomes, even when known adverse sociodemographic factors have been accounted for. Methadone dose at delivery is 1 of the determinants of neonatal abstinence syndrome.
Continuous support from follicular CD4.sup.+ T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In ...autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.
Many patients with major depressive disorder have treatment-resistant depression, defined as no adequate response to two consecutive courses of antidepressants. Some evidence suggests that ...antiglucocorticoid augmentation of antidepressants might be efficacious in patients with major depressive disorder. We aimed to test the proof of concept of metyrapone for the augmentation of serotonergic antidepressants in the clinically relevant population of patients with treatment-resistant depression.
This double-blind, randomised, placebo-controlled trial recruited patients from seven UK National Health Service (NHS) Mental Health Trusts from three areas (northeast England, northwest England, and the Leeds and Bradford area). Eligible patients were aged 18-65 years with treatment-resistant depression (Hamilton Depression Rating Scale 17-item score of ≥18 and a Massachusetts General Hospital Treatment-Resistant Depression staging score of 2-10) and taking a single-agent or combination antidepressant treatment that included a serotonergic drug. Patients were randomly assigned (1:1) through a centralised web-based system to metyrapone (500 mg twice daily) or placebo, in addition to their existing antidepressant regimen, for 21 days. Permuted block randomisation was done with a block size of two or four, stratified by centre and primary or secondary care setting. The primary outcome was improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation, analysed in the modified intention-to-treat population of all randomly assigned patients that completed the MADRS assessment at week 5. The study has an International Standard Randomised Controlled Trial Number (ISRCTN45338259) and is registered with the EU Clinical Trial register, number 2009-015165-31.
Between Feb 8, 2011, and Dec 10, 2012, 165 patients were recruited and randomly assigned (83 to metyrapone and 82 to placebo), with 143 (87%) completing the primary outcome assessment (69 83% in the metyrapone and 74 90% in the placebo group). At 5 weeks, MADRS score did not significantly differ between groups (21·7 points 95% CI 19·2-24·4 in the metyrapone group vs 22·6 points 20·1-24·8 in the placebo group; adjusted mean difference of -0·51 points 95% CI -3·48 to 2·46; p=0·74). 12 serious adverse events were reported in four (5%) of 83 patients in the metyrapone group and six (7%) of 82 patients in the placebo group, none of which were related to study treatment. 134 adverse events occurred in 58 (70%) patients in the metyrapone group compared with 95 events in 45 (55%) patients in the placebo group, of which 11 (8%) events in the metyrapone group and four (4%) in the placebo group were judged by principle investigators at the time of occurrence to be probably related to the study drug.
Metyrapone augmentation of antidepressants is not efficacious in a broadly representative population of patients with treatment-resistant depression within the NHS and therefore is not an option for patients with treatment-resistant depression in routine clinical practice at this time. Further research is needed to clarify if such augmentation might benefit subpopulations with demonstrable hypothalamic-pituitary-adrenal axis abnormalities.
Efficacy and Mechanism Evaluation (EME) programme, a UK Medical Research Council and National Institute for Health Research partnership.
Abstract Background Women who have an abnormal cervical cytology test may be referred for a colposcopy. Accumulating evidence suggests some women may experience distress after colposcopy. This ...exploratory study examined women's differing experiences of post-colposcopy distress with the aim of identifying factors that are predictive of, or protective against, distress. Methods We carried out semistructured, qualitative interviews with 23 women who had undergone colposcopies. Interviews were transcribed verbatim, coded, and analyzed thematically. The Framework Approach was used to summarize and organize the data and identify emerging higher order themes. Results Two forms of post-colposcopy distress emerged: 1) short term and 2) long term. Short-term distress was experienced immediately after the colposcopy and in the days afterward, and was usually related to the physical experience of the colposcopy. Long-term distress typically persisted over time and was related to concerns about fertility, cervical cancer, and sexual intercourse. The drivers of short-term and long-term distress differed. Factors related to short-term distress were feeling unprepared for the procedure, having a negative experience of the procedure, and attending the clinic alone. Factors related to long-term distress were future intentions to have (more) children, having physical after-effects of the procedure that impacted on the woman's life, and being under on-going clinic surveillance. Absence of these factors (e.g., being accompanied to the clinic) was protective against short- and long-term distress. Conclusions Colposcopy can lead to short- and long-term post-procedural distress for some women. We identified a range of factors, some potentially modifiable, that seem to influence the chances of experiencing distress. These results may inform the development of strategies or interventions aimed at preventing or minimizing distress after colposcopy and related procedures.
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