Major sporting events may influence attendance levels at hospital emergency departments (ED). Previous research has focussed on the impact of single games, or wins/losses for specific ...teams/countries, limiting wider generalisations. Here we explore the impact of the Euro 2016 football championships on ED attendances across four participating nations (England, France, Northern Ireland, Wales), using a single methodology. Match days were found to have no significant impact upon daily ED attendances levels. Focussing upon hourly attendances, ED attendances across all countries in the four hour pre-match period were statistically significantly lower than would be expected (OR 0.97, 95% CI 0.94-0.99) and further reduced during matches (OR 0.94, 95% CI 0.91-0.97). In the 4 hour post-match period there was no significant increase in attendances (OR 1.01, 95% CI 0.99-1.04). However, these impacts were highly variable between individual matches: for example in the 4 hour period following the final, involving France, the number of ED attendances in France increased significantly (OR 1.27, 95% CI 1.13-1.42). Overall our results indicate relatively small impacts of major sporting events upon ED attendances. The heterogeneity observed makes it difficult for health providers to predict how major sporting events may affect ED attendances but supports the future development of compatible systems in different countries to support cross-border public health surveillance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 2012 national recommendations for cervical cancer screening will produce a lower level of cervical cancer protection than previously afforded by annual cytology or 3-year cotesting. After a ...single negative cotest result, the risk of cervical cancer is twice as large at 5 years as it is at 3 years. Modeling published since the 2012 guidelines were drafted indicates that extending the cotesting screening interval from 3 to 5 years at ages 30–64 years will result in an additional 1 woman in 369 compliant with screening receiving a cervical cancer diagnosis during her lifetime, and an additional 1 in 1,639 dying of cervical cancer. The authors believe that a significant number of patients and providers would not choose to accept these additional risks if they understood them, despite the recognition of potential harms associated with more intensive screening.
Chronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell ...destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabetes in mice and humans with pre-existing autoimmunity against beta cells. However, it is not known if other immune checkpoint molecules, such as TIGIT, can also negatively regulate self-reactive T cells. TIGIT negatively regulates the CD226 costimulatory pathway, T-cell receptor (TCR) signaling, and hence T-cell function.
The phenotype and function of TIGIT expressing islet infiltrating T cells was studied in non-obese diabetic (NOD) mice using flow cytometry and single cell RNA sequencing. To determine if TIGIT restrains self-reactive T cells, we used a TIGIT blocking antibody alone or in combination with anti-PDL1 antibody.
We show that TIGIT is highly expressed on activated islet infiltrating T cells in NOD mice. We identified a subset of stem-like memory CD8+ T cells expressing multiple immune checkpoints including TIGIT, PD1 and the transcription factor EOMES, which is linked to dysfunctional CD8+ T cells. A known ligand for TIGIT, CD155 was expressed on beta cells and islet infiltrating dendritic cells. However, despite TIGIT and its ligand being expressed, islet infiltrating PD1+TIGIT+CD8+ T cells were functional. Inhibiting TIGIT in NOD mice did not result in exacerbated autoimmune diabetes while inhibiting PD1-PDL1 resulted in rapid autoimmune diabetes, indicating that TIGIT does not restrain islet infiltrating T cells in autoimmune diabetes to the same degree as PD1. Partial inhibition of PD1-PDL1 in combination with TIGIT inhibition resulted in rapid diabetes in NOD mice.
These results suggest that TIGIT and PD1 act in synergy as immune checkpoints when PD1 signaling is partially impaired. Beta cell specific stem-like memory T cells retain their functionality despite expressing multiple immune checkpoints and TIGIT is below PD1 in the hierarchy of immune checkpoints in autoimmune diabetes.
Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, contribute to the destruction of insulin-secreting β cells by CD8
T cells in type 1 ...diabetes (T1D). We previously showed that JAK1/JAK2 inhibitors reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own does not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain cytokines, including IL-2, IL-7 IL-15, and IL-21, may also affect the progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We used a JAK1-selective inhibitor, ABT 317, to better understand the specific role of JAK1 signaling in autoimmune diabetes. ABT 317 reduced IL-21, IL-2, IL-15 and IL-7 signaling in T cells and IFN-γ signaling in β cells, but ABT 317 did not affect GM-CSF signaling in granulocytes. When given
to NOD mice, ABT 317 reduced CD8
T cell proliferation as well as the number of KLRG
effector and CD44
CD62L
effector memory CD8
T cells in spleen. ABT 317 also prevented MHC class I upregulation on β cells. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with ABT 317 while still on treatment at 40 days and 44% remained normoglycemic after a further 60 days from discontinuing the drug. Our results indicate that ABT 317 blocks common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFN-γ receptor deficiency alone. Our studies suggest use of this class of drug for the treatment of type 1 diabetes.
We present a case of an obese 22-year-old man with activating
variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia ...with a family history of hypoglycemia. Genetic testing yielded a novel
missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in
cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated
and
genes and downregulated
and
genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient's pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of
mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion.
Data on the effectiveness of the diphtheria-tetanus-acellular pertussis (DTaP) vaccine in the first 4 years of life are sparse. We evaluated the vaccine effectiveness (VE) of 1 and 2 doses of DTaP ...before 6 months of age and of 3 doses from 6 months of age in Australia, where, since 2003, a fourth dose is not given until 4 years.
We matched reported pertussis cases aged 2 to 47 months between January 2005 and December 2009 to controls from a population-based immunization register by date of birth and region of residence. VE by number of doses and age group was calculated as (1 - odds ratio) × 100%.
VE against hospitalization increased from 55.3% (95% confidence interval CI, 42.7%-65.1%) for 1 dose before 4 months of age to 83.0% (95% CI, 70.2%-90.3%) for 2 doses before 6 months. The VE of 3 doses of DTaP against all reported pertussis was 83.5% (95% CI, 79.1%-87.8%) between 6 and 11 months, declining to 70.7% (95% CI, 64.5%-75.8%) between 2 and 3 years of age and 59.2% (95% CI, 51.0%-66.0%) between 3 and 4 years of age.
DTaP provided good protection against pertussis in the first year of life from the first dose. Without a booster dose, the effectiveness of 3 doses waned more rapidly from 2 to 4 years of age than previously documented for children >6 years of age who had received 5 doses.
Proapoptotic BH3-Only Protein Bid Is Essential For Death Receptor–Induced Apoptosis of Pancreatic β-Cells
Mark D. McKenzie 1 ,
Emma M. Carrington 1 ,
Thomas Kaufmann 2 ,
Andreas Strasser 2 ,
David ...C.S. Huang 2 ,
Thomas W.H. Kay 1 ,
Janette Allison 1 and
Helen E. Thomas 1
1 St. Vincent's Institute, Fitzroy, Australia
2 Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
Corresponding author: Dr. Helen Thomas, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria,
3065, Australia. E-mail: hthomas{at}svi.edu.au
Abstract
OBJECTIVE— Apoptosis of pancreatic β-cells is critical in both diabetes development and failure of islet transplantation. The role in
these processes of pro- and antiapoptotic Bcl-2 family proteins, which regulate apoptosis by controlling mitochondrial integrity,
remains poorly understood. We investigated the role of the BH3-only protein Bid and the multi-BH domain proapoptotic Bax and
Bak, as well as prosurvival Bcl-2, in β-cell apoptosis.
RESEARCH DESIGN AND METHODS— We isolated islets from mice lacking Bid, Bax, or Bak and those overexpressing Bcl-2 and exposed them to Fas ligand, tumor
necrosis factor (TNF)-α, and proinflammatory cytokines or cytotoxic stimuli that activate the mitochondrial apoptotic pathway
(staurosporine, etoposide, γ-radiation, tunicamycin, and thapsigargin). Nuclear fragmentation was measured by flow cytometry.
RESULTS— Development and function of islets were not affected by loss of Bid, and Bid-deficient islets were as susceptible as wild-type
islets to cytotoxic stimuli that cause apoptosis via the mitochondrial pathway. In contrast, Bid-deficient islets and those
overexpressing antiapoptotic Bcl-2 were protected from Fas ligand–induced apoptosis. Bid-deficient islets were also resistant
to apoptosis induced by TNF-α plus cycloheximide and were partially resistant to proinflammatory cytokine-induced death. Loss
of the multi-BH domain proapoptotic Bax or Bak protected islets partially from death receptor–induced apoptosis.
CONCLUSIONS— These results demonstrate that Bid is essential for death receptor–induced apoptosis of islets, similar to its demonstrated
role in hepatocytes. This indicates that blocking Bid activity may be useful for protection of islets from immune-mediated
attack and possibly also in other pathological states in which β-cells are destroyed.
CHX, cycloheximide
CTL, cytotoxic T-lymphocyte
dnFADD, dominant-negative Fas-associated death domain
ER, endoplasmic reticulum
FADD, Fas-associated death domain
FasL, Fas ligand
FLIP, FADD-like IL-1β–converting enzyme inhibitory protein
IFN-γ, γ-interferon
IL, interleukin
NMMA, NG-monomethyl-l-arginine
TNF, tumor necrosis factor
zVAD.fmk, z-Val-Ala-Asp-fluoromethylketone
Footnotes
Published ahead of print at http://dx.doi.org/10.2337/db07-1692 on 5 February 2008. DOI: 10.2337/db07-1692.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1692 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 30, 2008.
Received November 30, 2007.
DIABETES
Granzyme A is a protease implicated in the degradation of intracellular DNA. Nucleotide complexes are known triggers of systemic autoimmunity, but a role in organ-specific autoimmune disease has not ...been demonstrated. To investigate whether such a mechanism could be an endogenous trigger for autoimmunity, we examined the impact of granzyme A deficiency in the NOD mouse model of autoimmune diabetes. Granzyme A deficiency resulted in an increased incidence in diabetes associated with accumulation of ssDNA in immune cells and induction of an interferon response in pancreatic islets. Central tolerance to proinsulin in transgenic NOD mice was broken on a granzyme A-deficient background. We have identified a novel endogenous trigger for autoimmune diabetes and an in vivo role for granzyme A in maintaining immune tolerance.
Cytokines that signal through the JAK-STAT pathway, such as interferon-γ (IFN-γ) and common γ chain cytokines, play an important role in facilitating the destruction of insulin-secreting β cells by ...CD8+ T cells in type 1 diabetes. We previously showed that inhibiting JAK1/JAK2 reversed autoimmune insulitis in non-obese diabetic (NOD) mice and also blocked IFN-γ mediated MHC class I upregulation on β cells. Blocking interferons on their own did not prevent diabetes in knockout NOD mice, so we tested whether JAK inhibitor action on signaling downstream of common γ chain family cytokines, including IL-2, IL-21, IL-7 and IL-15, may also affect progression of diabetes in NOD mice. Common γ chain cytokines activate JAK1 and JAK3 to regulate T cell proliferation. We compared JAK1-selective inhibitors with our previous data with JAK1/JAK2 inhibition. JAK1-selective inhibitors reduced IL-21, IL-2 and IL-7 signaling in T cells (p<0.05) and IFN-γ signaling in β cells, but did not affect GM-CSF signaling in granulocytes. When given in vivo to NOD mice, JAK1-selective inhibitors reduced CD8+ T cell proliferation (Ki-67) in islets, reduced immune cell infiltration into islets and prevented MHC class I upregulation on β cells as measured by flow cytometry. Newly diagnosed diabetes was reversed in 94% NOD mice treated twice daily with JAK1-selective inhibitors.
Our results indicate that JAK inhibitors block common γ chain cytokines in lymphocytes and interferons in lymphocytes and β cells and are thus more effective against diabetes pathogenesis than IFNγ receptor deficiency alone. Our studies pave the way for use of this class of drug in clinical trials for type 1 diabetes.
Disclosure
G. Jhala: None. T. Ge: None. B. Krishnamurthy: None. T. Kay: None. H.E. Thomas: None.
Funding
National Health and Medical Research Council of Australia (GNT1145507); JDRF (1-SRA-2018-599-S-B)
Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort ...with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.
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•Breakthrough infection elicits a rapid recall of CD4+ and CD8+ spike-specific T cells•CD4+ T cell recall is robust and coordinated, peaking by day 5 post symptoms•CD8+ T cells become activated but variably expand following infection•Spike-specific CD8+ T cell activation inversely correlates with the rate of viral decay
Our understanding of T cell responses to SARS-CoV-2 vaccination and breakthrough infection has lagged behind B cells and antibodies. Here, Koutsakos et al. utilize longitudinal sampling to demonstrate a rapid activation of SARS-CoV-2-specific CD4+ and CD8+ T cells during breakthrough infection. Furthermore, spike-specific CD8+ T cell activation correlates with viral clearance.
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