A Nanoparticle/enzyme System For The Simultaneous Detection And Decontamination Of Organophosphates

The need for a direct visual response system for the detection of organophosphorus compounds stems from the continued threat and use of these toxic agents in military and terrorist conflicts. The development of an enzyme-inhibitor triggered release system allows for direct visual detection with high specificity. Mesoporous silica nanoparticles (MSNs) have physical features that make them attractive as scaffolds for the construction of these systems, such as pore diameters (20-500 Á) that can be synthetically controlled, large surface areas (300-1500 m2g-1), large pore volumes, chemical inertness, stability at elevated temperatures, and surfaces that can be easily functionalized. In our studies, the dye Congo Red was loaded into the pores of MSNs, which were then capped by tethering an enzyme (organophosphorus hydrolase (OPH) or acetylcholinesterase (AChE)) to the external surfaces of MSNs through a competitive inhibitor (diethyl 4-aminobenzyl phosphonate (DEABP) or tacrine, respectively). OPH has been extensively studied for its ability to hydrolyze a wide range of organophosphorus compounds, rendering them non-toxic. AChE has been commonly used for organophosphate detection resulting from its sensitivity to phosphorylation. Upon addition of organophosphorus compounds to suspensions of the modified MSNs, the enzymes detached from the MSN surface, releasing the dye and providing a visual confirmation of organophosphate presence. Enzyme kinetics were studied using 31P NMR or UV-Visible spectroscopy; Congo Red release was also monitored by UV-Visible spectroscopy. The system was sensitive and specific for organophosphorus compounds both in phosphate-buffered saline and in human serum. The rate of dye release directly correlated with the rate of organophosphorus conversion for OPH and the rate of phosphorylation for AChE

Broad spectrum SARS‐CoV ‐2‐specific immunity in hospitalized First Nations peoples recovering from COVID ‐19

Indigenous peoples globally are at increased risk of COVID‐19‐associated morbidity and mortality. However, data that describe immune responses to SARS‐CoV‐2 infection in Indigenous populations are lacking. We evaluated immune responses in Australian First Nations peoples hospitalized with COVID‐19. Our work comprehensively mapped out inflammatory, humoral and adaptive immune responses following SARS‐CoV‐2 infection. Patients were recruited early following the lifting of strict public health measures in the Northern Territory, Australia, between November 2021 and May 2022. Australian First Nations peoples recovering from COVID‐19 showed increased levels of MCP‐1 and IL‐8 cytokines, IgG‐antibodies against Delta‐RBD and memory SARS‐CoV‐2‐specific T cell responses prior to hospital discharge in comparison with hospital admission, with resolution of hyperactivated HLA‐DR+CD38+ T cells. SARS‐CoV‐2 infection elicited coordinated ASC, Tfh and CD8+ T cell responses in concert with CD4+ T cell responses. Delta and Omicron RBD‐IgG, as well as Ancestral N‐IgG antibodies, strongly correlated with Ancestral RBD‐IgG antibodies and Spike‐specific memory B cells. We provide evidence of broad and robust immune responses following SARS‐CoV‐2 infection in Indigenous peoples, resembling those of non‐Indigenous COVID‐19 hospitalized patients

Robust and prototypical immune responses toward COVID-19 vaccine in First Nations peoples are impacted by comorbidities

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people

Validation of a host response assay, SeptiCyte LAB, for discriminating sepsis from systemic inflammatory response syndrome in the ICU

Rationale: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. Objectives: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. Methods: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the largeMARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands (www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. Measurements and Main Results: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. Conclusions: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London