Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of ...50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-β and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.
OBJECTIVE:To compare epidural analgesia (EDA) to patient-controlled opioid-based analgesia (PCA) in patients undergoing laparoscopic colorectal surgery.
BACKGROUND:EDA is mainstay of multimodal pain ...management within enhanced recovery pathways enhanced recovery after surgery (ERAS). For laparoscopic colorectal resections, the benefit of epidurals remains debated. Some consider EDA as useful, whereas others perceive epidurals as unnecessary or even deleterious.
METHODS:A total of 128 patients undergoing elective laparoscopic colorectal resections were enrolled in a randomized clinical trial comparing EDA versus PCA. Primary end point was medical recovery. Overall complications, hospital stay, perioperative vasopressor requirements, and postoperative pain scores were secondary outcome measures. Analysis was performed according to the intention-to-treat principle.
RESULTS:Final analysis included 65 EDA patients and 57 PCA patients. Both groups were similar regarding baseline characteristics. Medical recovery required a median of 5 days (interquartile range IQR, 3–7.5 days) in EDA patients and 4 days (IQR, 3–6 days) in the PCA group (P = 0.082). PCA patients had significantly less overall complications 19 (33%) vs 35 (54%); P = 0.029 but a similar hospital stay 5 days (IQR, 4–8 days) vs 7 days (IQR, 4.5–12 days); P = 0.434. Significantly more EDA patients needed vasopressor treatment perioperatively (90% vs 74%, P = 0.018), the day of surgery (27% vs 4%, P < 0.001), and on postoperative day 1 (29% vs 4%, P < 0.001), whereas no difference in postoperative pain scores was noted.
CONCLUSIONS:Epidurals seem to slow down recovery after laparoscopic colorectal resections without adding obvious benefits. EDA can therefore not be recommended as part of ERAS pathways in laparoscopic colorectal surgery.
Abstract Background Enhanced recovery after surgery (ERAS) guidelines for colorectal surgery suggest routine transurethral bladder drainage with early removal to prevent urinary tract infection ...(UTI). The aim of this study was to identify risk factors for urinary retention (UR). Methods This retrospective analysis included all colorectal patients since ERAS implementation in May 2011-November 2014. From the prospective ERAS database, over 100 items related to demographics, surgery, compliance, and outcome were analyzed. Risk factors for UR were identified by multiple logistic regressions; then, UR was correlated to functional outcomes and UTI and acute kidney injury rates. Results The study cohort consisted of 513 consecutive patients. Of these, 73 patients (14%) presented with UR. Multivariate analysis identified male gender (odds ratio 1.4; 95% CI, 1-1.8; P = 0.045) and postoperative thoracic epidural anesthesia (EDA; odds ratio 2.6; 95% CI, 1.6-4.3; P ≤ 0.001) as independent risk factors for postoperative UR. Functional recovery was impeded in patients with UR, who were less mobile (mobilization day 1 >4 h: 57% versus 70%, P = 0.024) and gained more weight (2.8 ± 2.5 kg versus 1.6 ±3 kg on day 1, P = 0.001) due to fluid overload. Furthermore, patients with urinary catheters reported more pain (visual analog scales day 3: 3.1 ± 2.5 versus 2.2 ± 2.4, P = 0.002) and depended longer on intravenous fluid administration (termination of intravenous fluids later than day 1: 53% versus 39%, P = 0.021). Ten of 73 patients (14%) developed UTI in patients with UR and 42 of 440 (10%) in patients without UR ( P = 0.276). Six of 73 patients (8%) developed acute kidney injury in patients with UR and 36 of 440 (8%) in patients without UR ( P = 0.991). Conclusions Male gender and EDA were independent risk factors for postoperative UR which appeared to be a significant impediment for functional recovery.
Whether gender bias contributes to women's under-representation in scientific fields is still controversial. Past research is limited by relying on explicit questionnaire ratings in mock-hiring ...scenarios, thereby ignoring the potential role of implicit gender bias in the real world. We examine the interactive effect of explicit and implicit gender biases on promotion decisions made by scientific evaluation committees representing the whole scientific spectrum in the course of an annual nationwide competition for elite research positions. Findings reveal that committees with strong implicit gender biases promoted fewer women at year 2 (when committees were not reminded of the study) relative to year 1 (when the study was announced) if those committees did not explicitly believe that external barriers hold women back. When committees believed that women face external barriers, implicit biases did not predict selecting more men over women. This finding highlights the importance of educating evaluative committees about gender biases.
Mass cytometry is a powerful tool that allows simultaneous analysis of more than 37 markers at the single cell level. Mass cytometry is of particular interest in the identification of a wide variety ...of cell phenotypes in autoimmune diseases. Moreover, cells can be labelled with palladium isotopes and pooled before staining (barcoding). Nevertheless, immunologists often face an important problem concerning the choice of markers to be included in a panel. This problem arises due to the incompatibility of different buffers used for the fixation and permeabilization of cells with various cell surface epitopes. In this study, we used a panel of 27 markers (19 surface markers and 8 intranuclear markers) to demonstrate disparities in the detection of cell surface antigens when comparing different buffers to stain unstimulated peripheral blood mononuclear cells. These disparities range from mild differences to very important differences in population frequencies depending on the buffers. Finally, we demonstrate the harmful effects of permeabilization prior to barcoding on the detection of some cell surface antigens. Here, we optimize a protocol that is suitable to use when targeting a large panel including both cell surface and intranuclear markers on unstimulated human peripheral blood mononuclear cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dengue virus (DENV) is responsible for approximately 100 million cases of dengue fever annually, including severe forms such as hemorrhagic dengue and dengue shock syndrome. Despite intensive vaccine ...research and development spanning several decades, a universally accepted and approved vaccine against dengue fever has not yet been developed. The major challenge associated with the development of such a vaccine is that it should induce simultaneous and equal protection against the four DENV serotypes, because past infection with one serotype may greatly increase the severity of secondary infection with a distinct serotype, a phenomenon known as antibody-dependent enhancement (ADE). Using a lentiviral vector platform that is particularly suitable for the induction of cellular immune responses, we designed a tetravalent T-cell vaccine candidate against DENV (“LV-DEN”). This vaccine candidate has a strong CD8
+
T-cell immunogenicity against the targeted non-structural DENV proteins, without inducing antibody response against surface antigens. Evaluation of its protective potential in the preclinical flavivirus infection model, i.e., mice knockout for the receptor to the type I IFN, demonstrated its significant protective effect against four distinct DENV serotypes, based on reduced weight loss, viremia, and viral loads in peripheral organs of the challenged mice. These results provide proof of concept for the use of lentiviral vectors for the development of efficient polyvalent T-cell vaccine candidates against all DENV serotypes.
Background
Enhanced recovery after surgery (ERAS) programs have been shown to ease the postoperative recovery and improve clinical outcomes for various surgery types. ERAS cost-effectiveness was ...demonstrated for colorectal surgery but not for liver surgery. The present study aim was to analyze the implementation costs and benefits of a specific ERAS program in liver surgery.
Methods
A dedicated ERAS protocol for liver surgery was implemented in our department in July 2013. The subsequent year all consecutive patients undergoing liver surgery were treated according to this protocol (ERAS group). They were compared in terms of real in-hospital costs with a patient series before ERAS implementation (pre-ERAS group). Mean costs per patient were compared with a bootstrap
T
test. A cost-minimization analysis was performed.
Results
Seventy-four ERAS patients were compared with 100 pre-ERAS patients. There were no significant pre- and intraoperative differences between the two groups, except for the laparoscopy number (
n
= 18 ERAS,
n
= 9 pre-ERAS,
p
= 0.010). Overall postoperative complications were observed in 36 (49 %) and 64 patients (64 %) in the ERAS and pre-ERAS groups, respectively (
p
= 0.046). The median length of stay was significantly shorter for the ERAS group (8 vs. 10 days,
p
= 0.006). The total mean costs per patient were €38,726 and €42,356 for ERAS and pre-ERAS (
p
= 0.467). The cost-minimization analysis showed a total mean cost reduction of €3080 per patient after ERAS implementation.
Conclusions
ERAS implementation for liver surgery induced a non-significant decrease in cost compared to standard care. Significant decreased complication rate and hospital stay were observed in the ERAS group.
COVID‐19 vaccines already in use or in clinical development may have reduced efficacy against emerging SARS‐CoV‐2 variants. In addition, although the neurotropism of SARS‐CoV‐2 is well established, ...the vaccine strategies currently developed have not taken into account protection of the central nervous system. Here, we generated a transgenic mouse strain expressing the human angiotensin‐converting enzyme 2, and displaying unprecedented brain permissiveness to SARS‐CoV‐2 replication, in addition to high permissiveness levels in the lung. Using this stringent transgenic model, we demonstrated that a non‐integrative lentiviral vector, encoding for the spike glycoprotein of the ancestral SARS‐CoV‐2, used in intramuscular prime and intranasal boost elicits sterilizing protection of lung and brain against both the ancestral virus, and the Gamma (P.1) variant of concern, which carries multiple vaccine escape mutations. Beyond induction of strong neutralizing antibodies, the mechanism underlying this broad protection spectrum involves a robust protective T‐cell immunity, unaffected by the recent mutations accumulated in the emerging SARS‐CoV‐2 variants.
SYNOPSIS
A lentiviral vector‐based vaccine, used in prime and intranasal boost, induces strong B‐ and T‐cell immunity. This vaccine candidate protects against both pulmonary and neurological COVID‐19 caused by either ancestral or emerging SARS‐CoV‐2.
A new human ACE2 transgenic mouse strain provides a model to assess the efficiency of vaccine candidates against the neurological COVID‐19.
A non‐integrative lentiviral vector, encoding for the ancestral SARS‐CoV‐2 Spike (LV::S), used in prime and intranasal boost, elicits strong protection of brain.
LV::S induces full cross‐protection of lung and brain against Gamma (P.1) variant of concern, which carries multiple vaccine escape mutations.
LV::S induces strong protective T‐cell immunity, unaffected by the recent mutations accumulated in the emerging SARS‐CoV‐2 variants.
A lentiviral vector‐based vaccine, used in prime and intranasal boost, induces strong B‐ and T‐cell immunity. This vaccine candidate protects against both pulmonary and neurological COVID‐19 caused by either ancestral or emerging SARS‐CoV‐2.
Lentiviral vectors (LVs) are highly efficient at inducing CD8+ T cell responses. However, LV-encoded antigens are processed inside the cytosol of antigen-presenting cells, which does not directly ...communicate with the endosomal major histocompatibility complex class II (MHC-II) presentation pathway. LVs are thus poor at inducing CD4+ T cell response. To overcome this limitation, we devised a strategy whereby LV-encoded antigens are extended at their N-terminal end with the MHC-II-associated light invariant chain (li), which contains an endosome-targeting signal sequence. When evaluated with an LV-encoded polyantigen composed of CD4+ T cell targets from Mycobacterium tuberculosis, intranasal vaccination in mice triggers pulmonary polyfunctional CD4+ and CD8+ T cell responses. Adjuvantation of these LVs extends the mucosal immunity to Th17 and Tc17 responses. A systemic prime and an intranasal boost with one of these LV induces protection against M. tuberculosis. This strategy improves the protective power of LVs against infections and cancers, where CD4+ T cell immunity plays an important role.
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•Conventional lentiviral vectors induce mainly MHC-I-restricted antigen presentation•Fusion of the invariant li chain to antigen optimizes lentiviral vector immunogenicity•Such optimized lentiviral vectors are suitable for mucosal CD4+ T cell induction•These lentiviral vectors induce anti-tuberculosis protection in mice
Lopez et al. show that lentiviral vaccination vectors encoding mycobacterial antigens attached to a component of a cellular antigen-presentation machinery display improved immunogenicity. Using antigens from Mycobacterium tuberculosis bacilli in this strategy, combined with intranasal vaccination, they observe protection potential against tuberculosis in mice.
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