Abstract
Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we ...present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18–50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT
50
seroconversion after a single dose.
Radiotherapy is often used to treat pain in malignant pleural mesothelioma (MPM), although there is limited evidence to support this. The aim of this trial was to assess the role of radiotherapy for ...the treatment of pain in MPM.
A multicentre, single arm phase II trial was conducted. Eligible patients fulfilled the following criteria: pathological or radiological diagnosis of MPM; pain secondary to MPM; radiotherapy indicated for pain control; and more than 18 years of age. Patients had assessments of pain and other symptoms at baseline and then received 20 Gy in five daily fractions. Key follow-up points were 5 and 12 weeks posttreatment. The primary end point measure was assessment of pain at the site of radiotherapy at 5 weeks. Secondary end points included effects on quality of life, breathlessness, fatigue, mood, toxicity, and the radiological response.
Forty patients were recruited from three UK oncology centers. Fourteen patients had a clinically meaningful improvement in their pain 5 weeks post radiotherapy (intention to treat), with five patients having a complete improvement. On the basis of a complete case analysis of the 30 patients assessable at week 5, 47% (confidence intervals, 28.3–65.7) of patients alive at week 5 had an improvement in their pain. There was no improvement in other key symptoms or quality of life.
Radiotherapy for pain control in MPM is an effective treatment in a proportion of patients. Future studies examining differing radiotherapy regimens with a view to improving response rates are warranted.
Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill
-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential ...viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II
challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral 'TRM-like' cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM-like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.
Heterologous prime-boost strategies are known to substantially increase immune responses in viral vectored vaccines. Here we report on safety and immunogenicity of the poxvirus Modified Vaccinia ...Ankara (MVA) vectored vaccine expressing four Mycobacterium avium subspecies paratuberculosis antigens as a single dose or as a booster vaccine following a simian adenovirus (ChAdOx2) prime. We demonstrate that a heterologous prime-boost schedule is well tolerated and induced T-cell immune responses.
Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant ...risk to public health security because of an absence of currently available 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.
This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (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 objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by 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.
Between 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 available for follow-up at 6 months, but 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 by 12 months. One serious adverse event reported was deemed to be 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 be possibly, probably, 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<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed 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 antibodies capable of neutralisation in a pseudotyped virus neutralisation assay.
ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials.
UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.
Background
Type B aortic dissection (TBAD), is defined as a dissection involving the aorta distal to left subclavian artery with the ascending aorta and the aortic arch not affected. TBAD is ...classified due to the time frame and presence of complications. Complicated TBAD (co‐TBAD) patients have a greater mortality rate than uncomplicated TBAD (un‐TBAD) and thoracic endovascular aortic repair (TEVAR) is considered the gold‐standard intervention for these clinical challenges.
Methods
We undertook a systematic review of the literature regarding TEVAR intervention in co‐TBAD and un‐TBAD. A comprehensive search was undertaken across four major databases and was evaluated and assessed until June 2020.
Results
A total of 16,104 patients were included in the study (7772 patients co‐TBAD and 8352 un‐TBAD). A significantly higher proportion of comorbidities were seen in co‐TBAD patients compared with un‐TBAD. Acute dissection was more frequent in the co‐TBAD group (73.55% vs. 66.91%), while chronic dissection was more common in un‐TBAD patients (33.8% vs. 70.73%). Postprocedure stroke was higher in co‐TBAD (5.85% vs. 3.92%; p < .01), while postprocedural renal failure was higher in un‐TBAD patients (7.23 vs. 11.38%; p < .01). No difference was observed in in‐hospital mortality however the 30 days mortality was higher in the co‐TBAD group. One‐year survival was higher in the uncomplicated group but this difference was not observed in the 5‐year survival.
Conclusion
In our analysis we can appreciate that despite significantly higher comorbidities in the co‐TBAD cohort, there was no difference in in‐hospital mortality between the two groups and the 5‐year survival did not have any difference.
In the search for consensus on a definition of beauty, fitting the task of appreciating a ship’s design, this research revealed that other components of visual appraisal and 3d pattern analysis are ...required for a systemic approach. The model process presented is built around local adaptation and Gestalt psychology and uses retrospective case studies to categorise and calculate proportions, and recognisable patterns. The number of results from each type of vessel were found to be different, due to each ship or boats various geometries and anatomy, which illuminated the importance of standardising a procedure of categorisation in the appreciative approach. The categorisation of functions around the philosophy of functional beauty and the maths of summation series, it is suggested here, will allow a library of algebraic patterns and parameters to penetrate further into the impending or emulated integrated systems of ship design. The process to derive physical parameters via the culturally focussed narrative of functional beauty, is deemed as a manageable and novel addition to the naval architect's role. However, for the results to have a decisive impact on commercial design or education, variance and validation through further case studies is required.
Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated ...synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.
Microglia Priming with Aging and Stress Niraula, Anzela; Sheridan, John F; Godbout, Jonathan P
Neuropsychopharmacology (New York, N.Y.),
01/2017, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The population of aged individuals is increasing worldwide and this has significant health and socio-economic implications. Clinical and experimental studies on aging have discovered myriad changes ...in the brain, including reduced neurogenesis, increased synaptic aberrations, higher metabolic stress, and augmented inflammation. In rodent models of aging, these alterations are associated with cognitive decline, neurobehavioral deficits, and increased reactivity to immune challenges. In rodents, caloric restriction and young blood-induced revitalization reverses the behavioral effects of aging. The increased inflammation in the aged brain is attributed, in part, to the resident population of microglia. For example, microglia of the aged brain are marked by dystrophic morphology, elevated expression of inflammatory markers, and diminished expression of neuroprotective factors. Importantly, the heightened inflammatory profile of microglia in aging is associated with a 'sensitized' or 'primed' phenotype. Mounting evidence points to a causal link between the primed profile of the aged brain and vulnerability to secondary insults, including infections and psychological stress. Conversely, psychological stress may also induce aging-like sensitization of microglia and increase reactivity to secondary challenges. This review delves into the characteristics of neuroinflammatory signaling and microglial sensitization in aging, its implications in psychological stress, and interventions that reverse aging-associated deficits.
Repeated social defeat (RSD) stress promotes the release of bone marrow-derived monocytes into circulation that are recruited to the brain, where they augment neuroinflammation and cause prolonged ...anxiety-like behavior. Physiological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal gland (HPA) axis, and both of these systems play a role in the physiological, immunological, and behavioral responses to stress. The purpose of this study was to delineate the role of HPA activation and corticosterone production in the immunological responses to stress in male C57BL/6 mice. Here, surgical (adrenalectomy) and pharmacological (metyrapone) interventions were used to abrogate corticosterone signaling during stress. We report that both adrenalectomy and metyrapone attenuated the stress-induced release of monocytes into circulation. Neither intervention altered the production of monocytes during stress, but both interventions enhanced retention of these cells in the bone marrow. Consistent with this observation, adrenalectomy and metyrapone also prevented the stress-induced reduction of a key retention factor, CXCL12, in the bone marrow. Corticosterone depletion with metyrapone also abrogated the stress-induced glucocorticoid resistance of myeloid cells. In the brain, these corticosterone-associated interventions attenuated stress-induced microglial remodeling, neurovascular expression of the adhesion molecule intercellular cell adhesion molecule-1, prevented monocyte accumulation and neuroinflammatory signaling. Overall, these results indicate that HPA activation and corticosterone production during repeated social defeat stress are critical for monocyte release into circulation, glucocorticoid resistance of myeloid cells, and enhanced neurovascular cell adhesion molecule expression.
Recent studies of stress have identified the presence of monocytes that show an exaggerated inflammatory response to immune challenge and are resistant to the suppressive effects of glucocorticoids. Increased presence of these proinflammatory monocytes has been implicated in neuropsychiatric symptoms and the development of chronic cardiovascular, autoimmune, and metabolic disorders. In the current study, we show novel evidence that corticosterone produced during stress enhances the release of proinflammatory monocytes from the bone marrow into circulation, augments their recruitment to the brain and the induction of a neuroinflammatory profile. Overproduction of corticosterone during stress is also the direct cause of glucocorticoid resistance, a key phenotype in individuals exposed to chronic stress. Inhibiting excess corticosterone production attenuates these inflammatory responses to stress.
PDF
