218 research outputs found
Epicutaneous immunization with ovalbumin and CpG induces TH1/TH17 cytokines, which regulate IgE and IgG2a production
Background: Subcutaneous allergen-specific immunotherapy is
a standard route for the immunotherapy of allergic diseases. It
modulates the course of allergy and can generate long-term
remission. However, subcutaneous allergen-specific
immunotherapy can also induce anaphylaxis in some patients,
and therefore additional routes of administration should be
investigated to improve the safety and tolerability of
immunotherapy.
Objective: We sought to determine whether epicutaneous
treatment with antigen in the presence of a Toll-like receptor 9
agonist can suppress TH2-mediated responses in an antigenspecific manner.
Methods: Epicutaneous immunization was performed by
applying a skin patch soaked with ovalbumin (OVA) plus CpG,
and its suppressor activity was determined by using the mouse
model of atopic dermatitis. Finally, adoptive cell transfers were
implemented to characterize the regulatory cells that are
induced by epicutaneous immunization.
Results: Epicutaneous immunization with OVA and CpG
reduces the production of OVA-specific IgE and increases the
synthesis of OVA-specific IgG2a antibodies in an antigen-specific
manner. Moreover, eosinophil peroxidase activity in the skin
and production of IL-4, IL-5, IL-10, and IL-13 are suppressed.
The observed reduction of IgE synthesis is transferable with
T-cell receptor (TCR) ab1CD41CD252 cells, whereas IgG2a
production is dependent on both TCRab1 and TCRgd1 T cells.
Further experiments show that the described phenomenon is
myeloid differentiation primary response 88, IFN-g, and
IL-17A dependent. Finally, the results suggest that epicutaneous
immunization with OVA and CpG decreases the synthesis of
OVA-specific IgE and skin eosinophil peroxidase activity in mice
with ongoing skin allergy.
Conclusion: Epicutaneous application of protein antigen in
the presence of adjuvant could be an attractive needle-free and
self-administered immunotherapy for allergic diseases
2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.
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2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.
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withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation
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Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021
BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed
Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model
Background: Medical advances in the field of infection therapy
have led to an increasing use of antibiotics, which, apart from
eliminating pathogens, also partially eliminate naturally
existing commensal bacteria. It has become increasingly clear
that less exposure to microbiota early in life may contribute to
the observed rise in ‘‘immune-mediated’’ diseases, including
autoimmunity and allergy.
Objective: We sought to test whether the change of gut
microbiota with the broad spectrum antibiotic enrofloxacin will
modulate contact sensitivity (CS) in mice.
Methods: Natural gut microbiota were modified by oral
treatment with enrofloxacin prior to sensitization with
trinitrophenyl chloride followed by CS testing. Finally, adoptive
cell transfers were performed to characterize the regulatory
cells that are induced by microbiota modification.
Results: Oral treatment with enrofloxacin suppresses CS and
production of anti–trinitrophenyl chloride IgG1 antibodies.
Adoptive transfer experiments show that antibiotic
administration favors induction of regulatory cells that suppress
CS. Flow cytometry and adoptive transfer of purified cells show
that antibiotic-induced suppression of CS is mediated by TCR
ab1CD41CD251FoxP31 Treg, CD191B2201CD51 IL-101, IL101 Tr1, and IL-101 TCR gd1 cells. Treatment with the
antibiotic induces dysbiosis characterized by increased
proportion of Clostridium coccoides (cluster XIVa), C coccoides–
Eubacterium rectale (cluster XIVab), Bacteroidetes, and
Bifidobacterium spp, but decreased segmented filamentous
bacteria. Transfer of antibiotic-modified gut microbiota inhibits
CS, but this response can be restored through oral transfer of
control gut bacteria to antibiotic-treated animals.
Conclusions: Oral treatment with a broad spectrum antibiotic
modifies gut microbiota composition and promotes antiinflammatory response, suggesting that manipulation of gut
microbiota can be a powerful tool to modulate the course of CS
Do management reports on internal control over financial reporting improve financial reporting?
The effect of external audits of internal control over financial reporting on financial reporting for clients of Big 4, Second-tier, and small audit firms
Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study
OBJECTIVES: Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. DESIGN: A multicentre, international, collaborative cohort study. SETTING: 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. PARTICIPANTS: Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, Wilms' tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. MAIN OUTCOME MEASURE: All-cause mortality at 30 days and 90 days. RESULTS: 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). CONCLUSIONS: The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally
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