Follow-up in newborn hearing screening – a systematic review

Introduction The quality and efficiency of newborn hearing screening programs (NHS) rely heavily on appropriate follow-up. The Joint Committee on Infant Hearing recommends a follow-up rate of more than 95% of infants who fail the initial hearing screening. However, a 70% benchmark is considered to be more feasible. This high loss to follow-up (LTF) rate acts as a threat to the overall success of NHS programs. The objective of the study was to identify and examine the reported rates of LTF, attributed reasons for LTF and strategies undertaken to reduce LTF. Methods Using a systematic search, articles published between 2005 to December 2015 were identified from PubMed/Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Educational Resources Information Center (ERIC), Scopus, Ovid, ProQuest, and Cochrane Library. To be included in the review, the study should be exploring the loss to follow-up or drop-out rate in newborn hearing screening programs and be published in an indexed peer-reviewed journal in the English language. The main outcome measures were overall rate of LTF, factors leading to LTF and measures adopted to overcome LTF. Results 53 articles were short-listed for data extraction. Out of these, 27 were single-centre studies, 19 were multi-centre, 3 compared multiple databases, and 4 used survey-based methods. Overall LTF rates of 20% in single-centre and 21% in multiple-centre studies were observed. Educational disparity and lack of adequate knowledge among parents were associated with LTF. The most commonly used strategy to overcome LTF suggested by studies was the use of an adequate data management system. Conclusion This review is a novel attempt to explore the LTF among NHS studies, reasons for LTF and strategies to reduce LTF. This review can act as a basis for planning and execution of effective NHS programs

The safety and efficacy of systemic delivery of a new liver-de-targeted TGFβ signaling inhibiting adenovirus in an immunocompetent triple negative mouse mammary tumor model

Aberrant TGFβ signaling is linked to metastasis and tumor immune escape of many cancers including metastatic triple negative breast cancer (mTNBC). Previously, we have found that oncolytic adenoviruses expressing a TGFβ signaling inhibitory protein (sTGFβRIIFc) induced immune activation in a mouse TNBC (4T1) immunocompetent subcutaneous model with intratumoral injection. Systemic administration of adenoviruses can be a superior route to treat mTNBC but faces the challenges of increased toxicity and viral clearance. Thus, we created a liver-de-targeted sTGFβRIIFc- and LyP-1 peptide-expressing adenovirus (mHAdLyp.sT) with enhanced breast cancer cell tropism. Its safety and immune response features were profiled in the 4T1 model. Our data showed that the systemic administration of mHAdLyp.sT resulted in reduced hepatic and systemic toxicity. mHAdLyp.sT was also effective in increasing Th1 cytokines and anti-tumor cell populations by cytokine analysis, spleen/tumor qRT-PCR, and flow cytometry. We further tested the therapeutic effects of mHAdLyp.sT alone and in combination with immune checkpoint inhibitors (ICIs). mHAdLyp.sT alone and with all ICI combinations elicited significant inhibition of lung metastasis by histological analysis. When mHAdLyp.sT was combined with both anti-PD-1 and anti-CTLA-4 antibodies, primary 4T1 tumor growth was also significantly inhibited. We are confident in advancing this new treatment option for mTNBC

IL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells

Earlier, we have shown that GM-CSF-exposed CD8α− DCs that express low levels of pro-inflammatory cytokines IL-12 and IL-1β can induce Foxp3+ Tregs leading to suppression of autoimmunity. Here, we examined the differential effects of IL-12 and IL-1β on Foxp3 expression in T cells when activated in the presence and absence of DCs. Exogenous IL-12 abolished, but IL-1β enhanced, the ability of GM-CSF-exposed tolerogenic DCs to promote Foxp3 expression. Pre-exposure of DCs to IL-1β and IL-12 had only a modest effect on Foxp3− expressing T cells; however, T cells activated in the absence of DCs but in the presence of IL-1β or IL-12 showed highly significant increase and decrease in Foxp3+ T cell frequencies respectively suggesting direct effects of these cytokines on T cells and a role for IL-1β in promoting Foxp3 expression. Importantly, purified CD4+CD25+ cells showed a significantly higher ability to maintain Foxp3 expression when activated in the presence of IL-1β. Further analyses showed that the ability of IL-1β to maintain Foxp3 expression in CD25+ T cells was dependent on TGF-β1 and IL-2 expression in Foxp3+Tregs and CD25− effectors T cells respectively. Exposure of CD4+CD25+ T cells to IL-1β enhanced their ability to suppress effector T cell response in vitro and ongoing experimental autoimmune thyroidits in vivo. These results show that IL-1β can help enhance/maintain Tregs, which may play an important role in maintaining peripheral tolerance during inflammation to prevent and/or suppress autoimmunity

Extraction and characterisation of pectin methylesterase from black carrot (Daucus carota L.)

This study was carried out to determine some of the biochemical properties of pectin methylesterase (PME) from black carrot. The enzyme showed very high activity in a broad pH range of 6.5-8.5, with the optimum pH occurring at 7.5. The optimum temperature for maximal PME activity was found to be 55 °C. NaCl enhanced PME activity, particularly at 0.2 M. Km and Vmax values for black carrot PME using apple pectin as substrate were found to be 2.14 mg/ml (r2 = 0.988) and 3.75 units/ml, respectively. The enzyme was stable between the temperatures of 30-50 °C/5 min whereas it lost nearly all of its activity at 70 °C/5 min. Ea and Z values were found to be 196.8 kJmol-1 (r2 = 0.996) and 2.16 °C (r2 = 0.995), respectively. © 2009 Elsevier Ltd. All rights reserved.This study (ZF2006.YL.84) was funded by the Research Fund of the University of Cukurova, Turkey

Rapidly responsive smart adhesive-coated micropillars utilizing catechol–boronate complexation chemistry

Smart adhesive hydrogels containing 10 mol% each of dopamine methacrylamide (DMA) and 3-acrylamido phenylboronic acid (APBA) were polymerized in situ onto polydimethylsiloxane (PMDS) micropillars with different aspect ratios (AR = 0.4, 1 and 2). Using Johnson–Kendall–Roberts (JKR) contact mechanics tests, the adhesive-coated pillars demonstrated strong wet adhesion at pH 3 (Wadh = 420 mJ m−2) and can be repeatedly deactivated and reactivated by changing the pH value (pH 9 and 3, respectively). When compared to the bulk adhesive hydrogel of the same composition, the adhesive-coated pillars exhibited a significantly faster rate of transition (1 min) between strong and weak adhesion. This was attributed to an increased surface area to volume ratio of the adhesive hydrogel-coated pillars, which permitted rapid diffusion of ions into the adhesive matrix to form or break the catechol–boronate complex

Target-Driven Design of a Coumarinyl Chalcone Scaffold Based Novel EF2 Kinase Inhibitor Suppresses Breast Cancer Growth in Vivo

Eukaryotic elongation factor 2 kinase (eEF-2K) is an unusual alpha kinase involved in protein synthesis through phosphorylation of elongation factor 2 (EF2). eEF-2K is highly overexpressed in breast cancer, and its activity is associated with significantly shortened patient survival and proven to be a potential molecular target in breast cancer. The crystal structure of eEF-2K remains unknown, and there is no potent, safe, and effective inhibitor available for clinical applications. We designed and synthesized several generations of potential inhibitors. The effect of the inhibitors at the binding pocket of eEF-2K was analyzed after developing a 3D target model by using a domain of another ?-kinase called myosin heavy-chain kinase A (MHCKA) that closely resembles eEF-2K. In silico studies showed that compounds with a coumarin-chalcone core have high predicted binding affinities for eEF-2K. Using in vitro studies in highly aggressive and invasive (MDA-MB-436, MDA-MB-231, and BT20) and noninvazive (MCF-7) breast cancer cells, we identified a lead compound that was highly effective in inhibiting eEF-2K activity at submicromolar concentrations and at inhibiting cell proliferation by induction of apoptosis with no toxicity in normal breast epithelial cells. In vivo systemic administration of the lead compound encapsulated in single lipid-based liposomal nanoparticles twice a week significantly suppressed growth of MDA-MB-231 tumors in orthotopic breast cancer models in nude mice with no observed toxicity. In conclusion, our study provides a highly potent and in vivo effective novel small-molecule eEF-2K inhibitor that may be used as a molecularly targeted therapy breast cancer or other eEF-2K-dependent tumors. © 2021 American Chemical Society.1R01CA244344; University of Texas MD Anderson Cancer Center; Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK: 215S008, TUBITAK-BIDEB 2214AThis study was funded by The Scientific and Technological Research Council of Turkey (TUBITAK) (grant number 215S008 and TUBITAK-BIDEB 2214A program, F.C.O.) and The University of Texas-MD Anderson Cancer Center Bridge fund (B.O. and N.K.) and NIH-NCI 1R01CA244344 grants (B.O. and N.K.)

Recombinant Desmoglein 3 Has the Necessary Epitopes to Adsorb and Induce Blister-Causing Antibodies

The development of an animal model for studying the pathogenesis of pemphigus vulgaris (PV) has been hampered by the unavailability of the purified full length autoantigen desmoglein 3 (Dsg 3). Therefore, we expressed Dsg 3 using a baculovirus expression system. The expressed protein was identified as Dsg 3 by its reactivity with a pan-cadherln anti-serum, an anti-serum to a Dsg 3 synthetic peptide, or patient serum, and by amino-terminal sequencing. Carbohydrate analysis showed that recombinant Dsg 3 was glycosylated. While a majority of the recombinant protein was cell associated, by immunoprecipitation, some Dsg 3 was demonstrated in the medium. The Dsg 3 could adsorb out blister-causing antibodies from patient sera. Rabbit anti-Dsg 3 antibodies induced by the recombinant Dsg 3 showed specific binding to intercellular spaces of monkey esophagus by indirect immunofluorescence. Moreover, these antibodies induced PV-like blisters in neonatal mice and weakly bound perilesional epidermis. Availability of large quantities of relatively pure Dsg 3 should now facilitate studies aimed at understanding Dsg 3 structure and pathogenesis of PV, with implications for developing specific immunotherapies