Comparisons of In Vitro and In Vivo Digestibility Assays for Phosphorus in Feline Diets and Associations with Dietary Nutrient Content.

Phosphorus (P) is an essential nutrient; however, potential health impacts of high dietary levels of added soluble, highly bioavailable P salts especially are a concern. P sources with lower bioavailability are considered safer. Yet, speciation of different P sources to assess diets' risk to health is challenging. This investigation tested the value of in vitro water extraction and digestion assays to predict in vivo P apparent bioavailability/digestibility in feline diets. Thirty wet (n = 18) and dry (n = 12) format experimental and commercial cat foods were analyzed for nutrient content. Triplicate samples were subjected to in vitro water extraction, single-phase acidic (gastric; G) digestion, and dual-phase gastric and small intestinal (G-SI) digestion assays. Soluble and insoluble P were determined in the supernatant and pellet, respectively. A subset of the diets (seven wet, nine dry diets) was fed to healthy, adult cats (n = 7-24) to determine in vivo apparent P digestibility. Information on the soluble P salt sources and their contribution to total dietary P was available for some diets. Associations between data from the different in vitro assays and in vivo digestibility trials and the influence of different diet parameters were obtained using Pearson correlation and linear regression modeling. The % soluble P obtained from G-SI digestion assay correlated well with in vivo apparent P digestibility for wet (Pearson coefficient 0.926, p = 0.003), but not for dry diets (Pearson coefficient -0.074, p = 0.849). In contrast, the % soluble P determined by water extraction correlated well with the % soluble P salt contribution to total P for dry (Pearson coefficient 0.901, p < 0.001), but not for wet diets (Pearson coefficient -0.407, p = 0.365). Thus, 20 min water extraction can be used to predict soluble P salt content in dry diets; however, differing Ca:P ratios and water solubility of the P sources may affect the outcome and false-positive results can occur. The G-SI digestion assay employed can also be used to predict in vivo P digestibility. However, again, diet format, Ca:P ratios in diets, and possibly other factors can impact the results. Thus, data from in vitro assays to assess P sources and bioavailability need to be interpreted with care.

Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins.

BACKGROUND: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins. OBJECTIVES: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these. DATA SOURCES: Medline, Embase and Cochrane Library databases were searched on 2 January 2020. STUDY ELIGIBILITY CRITERIA: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded. PARTICIPANTS: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included. METHODS: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model. RESULTS: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043). CONCLUSIONS: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens.

Correction to: A Systematic Review of the Clinical Utility of Cycle Threshold Values in the Context of COVID-19.

The original article can be found online.

A Systematic Review of the Clinical Utility of Cycle Threshold Values in the Context of COVID-19.

BACKGROUND: The ability to predict likely prognosis and infectiousness for patients with COVID-19 would aid patient management decisions. Diagnosis is usually via real-time PCR, and it is unclear whether the semi-quantitative capability of this method, determining viral load through cycle threshold (Ct) values, can be leveraged. OBJECTIVES: We aim to review available knowledge on correlations between SARS-COV-2 Ct values and patient- or healthcare-related outcomes to determine whether Ct values provide useful clinical information. SOURCES: A PubMed search was conducted on 1 June 2020 based on a search strategy of (Ct value OR viral load) AND SARS-CoV-2. Data were extracted from studies reporting on the presence or absence of an association between Ct values, or viral loads determined via Ct value, and clinical outcomes. CONTENT: Data from 18 studies were relevant for inclusion. One study reported on the correlation between Ct values and mortality and one study reported on the correlation between Ct values and progression to severe disease; both reported a significant association (p < 0.001 and p = 0.008, respectively). Fourteen studies reported on the correlation between Ct value or viral loads determined via Ct value and disease severity, and an association was observed in eight (57%) studies. Studies reporting on the correlation of viral load with biochemical and haematological markers showed an association with at least one marker, including increased lactate dehydrogenase (n = 4), decreased lymphocytes (n = 3) and increased high-sensitivity troponin I (n = 2). Two studies reporting on the correlation with infectivity showed that lower Ct values were associated with higher viral culture positivity. IMPLICATIONS: Data suggest that lower Ct values may be associated with worse outcomes and that Ct values may be useful in predicting the clinical course and prognosis of patients with COVID-19; however, further studies are warranted to confirm clinical value.

Targeting Staphylococcus aureus quorum sensing with nonpeptidic small molecule inhibitors.

A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

Multiple essential roles for EzrA in cell division of Staphylococcus aureus.

In Bacillus subtilis, EzrA is involved in preventing aberrant formation of FtsZ rings and has also been implicated in the localization cycle of Pbp1. We have identified the orthologue of EzrA in Staphylococcus aureus to be essential for growth and cell division in this organism. Phenotypic analyses following titration of EzrA levels in S. aureus have shown that the protein is required for peptidoglycan synthesis as well as for assembly of the divisome at the midcell and cytokinesis. Protein interaction studies revealed that EzrA forms a complex with both the cytoplasmic components of the division machinery and those with periplasmic domains, suggesting that EzrA may be a scaffold molecule permitting the assembly of the division complex and forming an interface between the cytoplasmic cytoskeletal element FtsZ and the peptidoglycan biosynthetic apparatus active in the periplasm.