A Cerberus‐Inspired Anti‐Infective Multicomponent Gatekeeper Hydrogel against Infections with the Emerging “Superbug” Yeast Candida auris

The pathogenic yeast Candida auris has received increasing attention due to its ability to cause fatal infections, its resistance toward important fungicides, and its ability to persist on surfaces including medical devices in hospitals. To brace health care systems for this considerable risk, alternative therapeutic approaches such as antifungal peptides are urgently needed. In clinical wound care, a significant focus has been directed toward novel surgical (wound) dressings as first defense lines against C. auris. Inspired by Cerberus the Greek mythological “hound of Hades” that prevents the living from entering and the dead from leaving hell, the preparation of a gatekeeper hybrid hydrogel is reported featuring lectin-mediated high-affinity immobilization of C. auris cells from a collagen gel as a model substratum in combination with a release of an antifungal peptide drug to kill the trapped cells. The vision is an efficient and safe two-layer medical composite hydrogel for the treatment of severe wound infections that typically occur in hospitals. Providing this new armament to the repertoire of possibilities for wound care in critical (intensive care) units may open new routes to shield and defend patients from infections and clinical facilities from spreading and invasion of C. auris and probably other fungal pathogens

Modeling the cognitive effects of diet discontinuation in adults with phenylketonuria (PKU) using pegvaliase therapy in PAH-deficient mice

Existing phenylalanine hydroxylase (PAH)-deficient mice strains are useful models of untreated or late-treated human phenylketonuria (PKU), as most contemporary therapies can only be initiated after weaning and the pups have already suffered irreversible consequences of chronic hyperphenylalaninemia (HPA) during early brain development. Therefore, we sought to evaluate whether enzyme substitution therapy with pegvaliase initiated near birth and administered repetitively to C57Bl/6-Pahenu2/enu2 mice would prevent HPA-related behavioral and cognitive deficits and form a model for early-treated PKU. The main results of three reported experiments are: 1) lifelong weekly pegvaliase treatment prevented the cognitive deficits associated with HPA in contrast to persisting deficits in mice treated with pegvaliase only as adults. 2) Cognitive deficits reappear in mice treated with weekly pegvaliase from birth but in which pegvaliase is discontinued at 3 months age. 3) Twice weekly pegvaliase injection also prevented cognitive deficits but again cognitive deficits emerged in early-treated animals following discontinuation of pegvaliase treatment during adulthood, particularly in females. In all studies, pegvaliase treatment was associated with complete correction of brain monoamine neurotransmitter content and with improved overall growth of the mice as measured by body weight. Mean total brain weight however remained low in all PAH deficient mice regardless of treatment. Application of enzyme substitution therapy with pegvaliase, initiated near birth and continued into adulthood, to PAH-deficient Pahenu2/enu2 mice models contemporary early-treated human PKU. This model will be useful for exploring the differential pathophysiologic effects of HPA at different developmental stages of the murine brain. Keywords: Behavior; Cognition; Dopamine; Hyperphenylalaninemia; Pegvaliase; Phenylalanine hydroxylase; Phenylketonuria; Serotonin; Tryptophan; Tryptophan hydroxylase; Tyrosine; Tyrosine hydroxylase

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis. METHODS: A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, in each treatment setting, was assigned a level of evidence, based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy

Defining optimal DEM resolutions and point densities for modelling hydrologically sensitive areas in agricultural catchments dominated by microtopography

AbstractDefining critical source areas (CSAs) of diffuse pollution in agricultural catchments depends upon the accurate delineation of hydrologically sensitive areas (HSAs) at highest risk of generating surface runoff pathways. In topographically complex landscapes, this delineation is constrained by digital elevation model (DEM) resolution and the influence of microtopographic features. To address this, optimal DEM resolutions and point densities for spatially modelling HSAs were investigated, for onward use in delineating CSAs. The surface runoff framework was modelled using the Topographic Wetness Index (TWI) and maps were derived from 0.25m LiDAR DEMs (40 bare-earth points m−2), resampled 1m and 2m LiDAR DEMs, and a radar generated 5m DEM. Furthermore, the resampled 1m and 2m LiDAR DEMs were regenerated with reduced bare-earth point densities (5, 2, 1, 0.5, 0.25 and 0.125 points m−2) to analyse effects on elevation accuracy and important microtopographic features. Results were compared to surface runoff field observations in two 10km2 agricultural catchments for evaluation. Analysis showed that the accuracy of modelled HSAs using different thresholds (5%, 10% and 15% of the catchment area with the highest TWI values) was much higher using LiDAR data compared to the 5m DEM (70–100% and 10–84%, respectively). This was attributed to the DEM capturing microtopographic features such as hedgerow banks, roads, tramlines and open agricultural drains, which acted as topographic barriers or channels that diverted runoff away from the hillslope scale flow direction. Furthermore, the identification of ‘breakthrough’ and ‘delivery’ points along runoff pathways where runoff and mobilised pollutants could be potentially transported between fields or delivered to the drainage channel network was much higher using LiDAR data compared to the 5m DEM (75–100% and 0–100%, respectively). Optimal DEM resolutions of 1–2m were identified for modelling HSAs, which balanced the need for microtopographic detail as well as surface generalisations required to model the natural hillslope scale movement of flow. Little loss of vertical accuracy was observed in 1–2m LiDAR DEMs with reduced bare-earth point densities of 2–5 points m−2, even at hedgerows. Further improvements in HSA models could be achieved if soil hydrological properties and the effects of flow sinks (filtered out in TWI models) on hydrological connectivity are also considered

Mutually Positive Regulatory Feedback Loop between Interferons and Estrogen Receptor-α in Mice: Implications for Sex Bias in Autoimmunity

gene) and stimulates expression of target genes. female mice had relatively higher steady-state levels of mRNAs encoded by the IFN and ERα-responsive genes as compared to the age-matched males.Our observations identify a novel mutually positive regulatory feedback loop between IFNs and ERα in immune cells in mice and support the idea that activation of this regulatory loop contributes to sex bias in SLE

APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The <it>APOE </it>ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (<it>APOE</it>) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the <it>APOE </it>ε4 allele on the risk and the age at onset of AD in this population.</p> <p>Methods</p> <p>376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the <it>APOE </it>alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.</p> <p>Results</p> <p>Odds Ratio (OR) for developing AD was significantly increased in carriers of the <it>APOE </it>ε4 allele compared to individuals with the <it>APOE </it>ε3/ε3 genotype. Individuals carrying <it>APOE </it>ε4/ε4 had OR of 12.9 for developing AD, while carriers of <it>APOE </it>ε2/ε4 and <it>APOE </it>ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the <it>APOE </it>ε4 allele was weaker with increasing age. Carrying the <it>APOE </it>ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the <it>APOE </it>ε4 allele, to 75.3 in carriers of one <it>APOE </it>ε4 allele and 72.9 in carriers of two <it>APOE </it>ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by <it>APOE </it>ε4 alleles.</p> <p>Conclusion</p> <p><it>APOE </it>ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.</p

The MASCC/ISOO Mucositis Guidelines: dissemination and clinical impact

This editorial introduces the second set of articles related to the update of the clinical practice guidelines for mucositis, developed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO)

Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis

The aim of this study was to systematically review and meta-analyze published data on the diagnostic performance of combined 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the detection of primary tumors in patients with cancer of unknown primary (CUP). A systematic search for relevant studies was performed of the PubMed/MEDLINE and Embase databases. Methodological quality of the included studies was assessed. Reported detection rates, sensitivities and specificities were meta-analyzed. Subgroup analyses were performed if results of individual studies were heterogeneous. The 11 included studies, comprising a total sample size of 433 patients with CUP, had moderate methodological quality. Overall primary tumor detection rate, pooled sensitivity and specificity of FDG-PET/CT were 37%, 84% (95% CI 78–88%) and 84% (95% CI 78–89%), respectively. Sensitivity was heterogeneous across studies (P = 0.0001), whereas specificity was homogeneous across studies (P = 0.2114). Completeness of diagnostic workup before FDG-PET/CT, location of metastases of unknown primary, administration of CT contrast agents, type of FDG-PET/CT images evaluated and way of FDG-PET/CT review did not significantly influence diagnostic performance. In conclusion, FDG-PET/CT can be a useful method for unknown primary tumor detection. Future studies are required to prove the assumed advantage of FDG-PET/CT over FDG-PET alone and to further explore causes of heterogeneity