CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection

Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses

The RAC1 target NCKAP1 plays a crucial role in progression of BRAF/PTEN -driven melanoma in mice

BRAF V600E is the most common driver mutation in human cutaneous melanoma and is frequently accompanied by loss of the tumor suppressing phosphatase PTEN. Recent evidence suggests a co-operative role for RAC1 activity in BRAF V600E -driven melanoma progression and drug resistance. However, the underlying molecular mechanisms and the role of RAC1 downstream targets are not well explored. Here, we examine the role of the NCKAP1 subunit of the pentameric cytoskeletal SCAR/WAVE complex, a major downstream target of RAC1, in a mouse model of melanoma driven by BRAF V600E; PTEN loss. The SCAR/WAVE complex is the major driver of lamellipodia formation and cell migration downstream of RAC1 and depends on NCKAP1 for its integrity. Targeted deletion of Nckap1 in the melanocyte lineage delayed tumor onset and progression of a mutant Braf ; Pten loss driven melanoma mouse model. Nckap1 depleted tumors displayed fibrotic stroma with increased collagen deposition concomitant with enhanced immune infiltration. Nckap1 loss slowed proliferation and tumor growth, highlighting a role in cell cycle progression. Altogether, we propose that NCKAP1-orchestrated actin polymerization is essential for tumor progression and maintenance of tumor tissue integrity in a mutant Braf ; Pten loss driven mouse model for melanoma

Services for disabled children and their families Report of an inspection in Walsall Social Services Department

SIGLEAvailable from British Library Document Supply Centre- DSC:GPC/04921 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Which volume matters more? A systematic review and meta-analysis of hospital vs surgeon volume in intra-abdominal emergency surgery

Background: Understanding the impact of hospital and surgeon volume on emergency intra-abdominal surgery procedures and determining which measure is more influential in improving outcomes can guide regionalization of care. This systematic review, meta-analysis, and meta-regression synthesizes evidence regarding the impact of hospital and surgeon volume on mortality.Methods: A literature search without language restriction was performed in the PubMed, Web of Science, and Cochrane databases. Cohort studies assessing the impact of hospital/surgeon volume on mortality after intra-abdominal emergency procedures with data collected after the year 2000 were included and analyzed using a random effects model. A sub-group analysis assessing impact of hospital volume on high and low complexity procedures and ruptured aortic artery aneurysm (RAAA) repair was performed. Another sub-group analysis comparing high-volume surgeons in a low-volume hospital and low-volume surgeons in a high-volume hospital was also performed. PROSPERO: CRD42022358879.Results: The search yielded 2153 articles, of which 33 cohort studies were included and determined to be good quality using the Newcastle Ottawa Scale. In 22 studies with available data for the meta-analysis, mortality was significantly higher in the low hospital volume and low surgeon volume cohort. The sub-group analysis found significantly higher mortality only in high complexity procedures and RAAA repair. Mortality was significantly lower in the cohort with high-volume surgeons at low-volume hospitals.Conclusion: High hospital volume was associated with lower mortality in all except low-complexity intra-abdominal emergency procedures. High surgeon volume was associated with lower mortality and there is limited evidence of it being the most protective

Does practice make perfect? The impact of hospital and surgeon volume on complications after intra-abdominal procedures

Background: There is increasing interest in the regionalization of surgical procedures. However, evidence on the volume-outcome relationship for emergency intra-abdominal surgery is not well-synthesized. This systematic review and meta-analysis summarize evidence regarding the impact of hospital and surgeon volume on complications.Methods: We identified cohort studies assessing the impact of hospital/surgeon volume on postoperative complications after emergency intra-abdominal procedures, with data collected after the year 2000 through a literature search without language restriction in the PubMed, Web of Science, and Cochrane databases. A weighted overall complication rate was calculated, and a random effect regression model was used for a summary odds ratio. A sensitivity analysis with the removal of studies contributing to heterogeneity was performed (PROSPERO: CRD42022358879).Results: The search yielded 2,153 articles, of which 9 cohort studies were included and determined to be good quality according to the Newcastle Ottawa Scale. These studies reported outcomes for the following procedures: cholecystectomy, colectomy, appendectomy, small bowel resection, peptic ulcer repair, adhesiolysis, laparotomy, and hernia repair. Eight studies (2,358,093 patients) with available data were included in the meta-analysis. Low hospital volume was not significantly associated with higher complications. In the sensitivity analysis, low hospital volume was significantly associated with higher complications when appropriate heterogeneity was achieved. Low surgeon volume was associated with higher complications, and these findings remained consistent in the sensitivity analysis.Conclusion: We found that hospital and surgeon volume was significantly associated with higher complications in patients undergoing emergency intra-abdominal surgery when appropriate heterogeneity was achieved