Calsequestrin as a risk factor in Graves’ hyperthyroidism and Graves’ ophthalmopathy patients

Background: The pathogenesis of Graves’ ophthalmopathy (GO), Graves’ hyperthyroidism (GH) and the mechanisms for its link to thyroid autoimmunity are poorly understood. Our research focuses on the role of the skeletal muscle calcium binding protein calsequestrin (CASQ1) in thyroid. We measured the concentration of the CASQ1 protein correlating levels with parameters of the eye signs, CASQ1 antibody levels and CASQ1 gene polymorphism rs3838284. Methods: CASQ1 protein was measured by quantitative Western Blotting. The protein concentrations were expressed as pmol/mg total protein by reference to CASQ1 standards. Results: Western blot analysis showed the presence of two forms of CASQ1 in the thyroid. The mean concentration of CASQ1 protein was significantly reduced in patients with Graves’ disease, compared to thyroid from control subjects with multi-nodular goitre or thyroid cancer. Although in patients with GO it was lower than that, compared with patients with GH this difference was not significant. Reduced CASQ1 in Graves’ thyroid correlated with the homozygous genotype of the rs3838284 CASQ1 polymorphism. Conclusions: Decreased CASQ1 in the thyroid of patients with Graves’ disease compared to thyroid from control subjects is not explained but may reflect consumption of the protein during an autoimmune reaction against CASQ1 in the thyroid

Molecular characteristics of carbapenemase-producing Enterobacterales in the Netherlands; results of the 2014–2018 national laboratory surveillance

Objectives: Carbapenem resistance mediated by mobile genetic elements has emerged worldwide and has become a major public health threat. To gain insight into the molecular epidemiology of carbapenem resistance in The Netherlands, Dutch medical microbiology laboratories are requested to submit suspected carbapenemase-producing Enterobacterales (CPE) to the National Institute for Public Health and the Environment as part of a national surveillance system. Methods: Meropenem MICs and species identification were confirmed by E-test and MALDI-TOF and carbapenemase production was assessed by the Carbapenem Inactivation Method. Of all submitted CPE, one species/carbapenemase gene combination per person per year was subjected to next-generation sequencing (NGS). Results: In total, 1838 unique isolates were received between 2014 and 2018, of which 892 were unique CPE isolates with NGS data available. The predominant CPE species were Klebsiella pneumoniae (n = 388, 43%), Escherichia coli (n = 264, 30%) and Enterobacter cloacae complex (n = 116, 13%). Various carbapenemase alleles of the same carbapenemase gene resulted in different susceptibilities to meropenem and this effect varied between species. Analyses of NGS data showed variation of prevalence of carbapenemase alleles over time with blaOXA-48 being predominant (38%, 336/892), followed by blaNDM-1 (16%, 145/892). For the first time in the Netherlands, blaOXA-181, blaOXA-232 and blaVIM-4 were detected. The genetic background of K. pneumoniae and E. coli isolates was highly diverse. Conclusions: The CPE population in the Netherlands is diverse, suggesting multiple introductions. The predominant carbapenemase alleles are blaOXA-48 and blaNDM-1. There was a clear association between species, carbapenemase allele and susceptibility to meropenem

Decontamination of the digestive tract and oropharynx in ICU patients.

Contains fulltext : 79996.pdf (publisher's version ) (Open Access)BACKGROUND: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) are infection-prevention measures used in the treatment of some patients in intensive care, but reported effects on patient outcome are conflicting. METHODS: We evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 intensive care units (ICUs), all in The Netherlands. Patients with an expected duration of intubation of more than 48 hours or an expected ICU stay of more than 72 hours were eligible. In each ICU, three regimens (SDD, SOD, and standard care) were applied in random order over the course of 6 months. Mortality at day 28 was the primary end point. SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach. SOD consisted of oropharyngeal application only of the same antibiotics. Monthly point-prevalence studies were performed to analyze antibiotic resistance. RESULTS: A total of 5939 patients were enrolled in the study, with 1990 assigned to standard care, 1904 to SOD, and 2045 to SDD; crude mortality in the groups at day 28 was 27.5%, 26.6%, and 26.9%, respectively. In a random-effects logistic-regression model with age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, intubation status, and medical specialty used as covariates, odds ratios for death at day 28 in the SOD and SDD groups, as compared with the standard-care group, were 0.86 (95% confidence interval [CI], 0.74 to 0.99) and 0.83 (95% CI, 0.72 to 0.97), respectively. CONCLUSIONS: In an ICU population in which the mortality rate associated with standard care was 27.5% at day 28, the rate was reduced by an estimated 3.5 percentage points with SDD and by 2.9 percentage points with SOD. (Controlled Clinical Trials number, ISRCTN35176830.

Selective digestive tract decontamination and selective oropharyngeal decontamination and antibiotic resistance in patients in intensive-care units: an open-label, clustered group-randomised, crossover study

Item does not contain fulltextBACKGROUND: Previously, we assessed selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) on survival and prevention of bacteraemia in patients in intensive-care units. In this analysis, we aimed to assess effectiveness of these interventions for prevention of respiratory tract colonisation and bacteraemia with highly resistant microorganisms acquired in intensive-care units. METHODS: We did an open-label, clustered group-randomised, crossover study in 13 intensive-care units in the Netherlands between May, 2004, and July, 2006. Participants admitted to intensive-care units with an expected duration of mechanical ventilation of more than 48 h or an expected stay of more than 72 h received SOD (topical tobramycin, colistin, and amphotericin B in the oropharynx), SDD (SOD antibiotics in the oropharynx and stomach plus 4 days' intravenous cefotaxime), or standard care. The computer-randomised order of study regimens was applied by an independent clinical pharmacist who was masked to intensive-care-unit identity. We calculated crude odds ratios (95% CI) for rates of bacteraemia or respiratory tract colonisation with highly resistant microorganisms in patients who stayed in intensive-care units for more than 3 days (ie, acquired infection). This trial is registered at http://isrctn.org, number ISRCTN35176830. FINDINGS: Data were available for 5927 (>99%) of 5939 patients, of whom 5463 (92%) were in intensive-care units for more than 3 days. 239 (13%) of 1837 patients in standard care acquired bacteraemia after 3 days, compared with 158 (9%) of 1758 in SOD (odds ratio 0.66, 95% CI 0.53-0.82), and 124 (7%) of 1868 in SDD (0.48, 0.38-0.60). Eight patients acquired bacteraemia with highly resistant microorganisms during SDD, compared with 18 patients (with 19 episodes) during standard care (0.41, 0.18-0.94; rate reduction [RR] 59%, absolute risk reduction [ARR] 0.6%) and 20 during SOD (0.37, 0.16-0.85; RR 63%, ARR 0.7%). Of the patients staying in intensive-care units for more than 3 days, we obtained endotracheal aspirate cultures for 881 (49%) patients receiving standard care, 886 (50%) receiving SOD, and 828 (44%) receiving SDD. 128 (15%) patients acquired respiratory tract colonisation with highly resistant microorganisms during standard care, compared with 74 (8%) during SDD (0.58, 0.43-0.78; RR 38%, ARR 5.5%) and 88 (10%) during SOD (0.65, 0.49-0.87; RR 32%, ARR 4.6%). Acquired respiratory tract colonisation with Gram-negative bacteria or cefotaxime-resistant and colistin-resistant pathogens was lowest during SDD. INTERPRETATION: Widespread use of SDD and SOD in intensive-care units with low levels of antibiotic resistance is justified. FUNDING: None

Ecological effects of selective decontamination on resistant gram-negative bacterial colonization.

Contains fulltext : 88783.pdf (publisher's version ) (Closed access)RATIONALE: Selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD) eradicate gram-negative bacteria (GNB) from the intestinal and respiratory tract in intensive care unit (ICU) patients, but their effect on antibiotic resistance remains controversial. OBJECTIVES: We quantified the effects of SDD and SOD on bacterial ecology in 13 ICUs that participated in a study, in which SDD, SOD, or standard care was used during consecutive periods of 6 months (de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, et al. N Engl J Med 2009;360:20-31). METHODS: Point prevalence surveys of rectal and respiratory samples were performed once monthly in all ICU patients (receiving or not receiving SOD/SDD). Effects of SDD on rectal, and of SDD/SOD on respiratory tract, carriage of GNB were determined by comparing results from consecutive point prevalence surveys during intervention (6 mo for SDD and 12 mo for SDD/SOD) with consecutive point prevalence data in the pre- and postintervention periods. MEASUREMENTS AND MAIN RESULTS: During SDD, average proportions of patients with intestinal colonization with GNB resistant to either ceftazidime, tobramycin, or ciprofloxacin were 5, 7, and 7%, and increased to 15, 13, and 13% postintervention (P < 0.05). During SDD/SOD resistance levels in the respiratory tract were not more than 6% for all three antibiotics but increased gradually (for ceftazidime; P < 0.05 for trend) during intervention and to levels of 10% or more for all three antibiotics postintervention (P < 0.05). CONCLUSIONS: SOD and SDD have marked effects on the bacterial ecology in an ICU, with rising ceftazidime resistance prevalence rates in the respiratory tract during intervention and a considerable rebound effect of ceftazidime resistance in the intestinal tract after discontinuation of SDD