Maternal awareness, acceptability and willingness towards respiratory syncytial virus (RSV) vaccination during pregnancy in Ireland.

BACKGROUND: Respiratory syncytial virus (RSV) is the world's leading cause of viral acute lower respiratory infections (ALRI) in infants. WHO has identified maternal RSV vaccination a priority and candidate vaccines are in development; however, vaccine hesitancy remains an impediment to successful implementation of maternal immunization. This study, the largest antenatal survey conducted to-date, aimed to examine maternal RSV awareness, likely acceptance of RSV vaccination in pregnancy, and attitudes to maternal vaccination. METHODS: Pregnant women of all gestations attending antenatal clinic of a university maternity hospital in Ireland were invited to participate. An information leaflet provided, consent obtained, and survey administered examining RSV awareness, willingness to avail of antenatal RSV vaccination, factors influencing acceptability and preferred sources of assistance. Research Ethics Committee (REC) approval obtained, and general data protection regulation (GDPR) guidelines followed. RESULTS: 528 women completed the survey. A large proportion (75.6%) had never heard of RSV, yet 48.5% would still avail of a vaccine, 45.8% were undecided and only 5.3% would not. The main factor making vaccination acceptable to women (76.4%) was that it protects their infant from illness (p < .001, CV 0.336 for association with acceptance) and general practitioner (GP) was the preferred guidance source in decision-making (57.7%). CONCLUSIONS: Despite low levels of maternal awareness of RSV, pregnant women in Ireland are open to availing of antenatal vaccination. Maternal immunization strategies need to focus on infant's protection from RSV-associated ALRI along with vaccine safety, and build on an interdisciplinary collaboration of maternal, neonatal, primary care and public health services.

The evolution of nutrition management in children with severe neurological impairment with a focus on cerebral palsy.

Nutritional management of children with severe neurological impairment (SNI) is highly complex, and the profile of this population is changing. The aim of this narrative review was to give the reader a broad description of evolution of the nutritional management of children with SNI in a high resource setting. In the last decade, there has been an emphasis on using multiple anthropometric measures to monitor nutritional status in children with SNI, and several attempts at standardising the approach have been made. Tools such as the Feeding and Nutrition Screening Tool, the Subjective Global Nutrition Assessment, the Eating and Drinking Ability Classification System and the Focus on Early Eating and Drinking Swallowing (FEEDS) toolkit have become available. There has been an increased understanding of how the gut microbiome influences gastrointestinal symptoms common in children with SNI, and the use of fibre in the management of these has received attention. A new diagnosis, 'gastrointestinal dystonia', has been defined. The increased use and acceptance of blended food tube feeds has been a major development in the nutritional management of children with SNI, with reported benefits in managing gastrointestinal symptoms. New interventions to support eating and drinking skill development in children with SNI show promise. In conclusion, as the life expectancy of people with SNI increases due to advances in medical and nutrition care, our approach necessitates a view to long-term health and quality of life. This involves balancing adequate nutrition to support growth, development and well-being while avoiding overnutrition and its associated detrimental long-term effects.

Experiences and perceptions of multidisciplinary paediatric teams of blended tube feeding in children.

Background: Blended tube feeding (BTF) is the administration of pureed whole foods via gastric feeding tubes. There is some evidence to suggest that BTF may have clinical and psychosocial benefits when compared to commercial formula, but further investigation of how BTF is understood and recommended by health professionals is needed. This study aims to investigate awareness and knowledge of BTF among multi-disciplinary paediatric staff in Ireland. Methods: A cross-sectional observational study was conducted among paediatric staff in Children's Health Ireland (CHI). The 16-item anonymous online survey gathered information on awareness of BTF, willingness to recommend BTF, confidence in BTF knowledge, and self-assessed competence in managing BTF. Results: Of the 207 responses, doctors (n68), nurses (n66), and dietitians (n32) provided 80.3% of responses. Two-thirds (n136, 66%) of the total group were aware of BTF. Of these, 68.1% had cared for a child on BTF and 70% (n = 63/90) were willing to recommend BTF. Three in five (n = 39/63, 61.9%) stated they were somewhat confident in their BTF knowledge and one in five (n = 12/56, 21.4%) were not yet competent in managing children on BTF. The most common reasons for recommending BTF were parental desire (n17, 39.5%) and commercial formula intolerance (n15, 34.9%). The most common barrier to recommending BTF was family logistics (n18, 41.9%). The most valuable sources of information on BTF for two-thirds (68.3%) of participants were other healthcare professionals (HCPs) and patients/caregivers. Conclusion: Healthcare settings should provide evidence-based training to HCPs on BTF to optimise the treatment and safety of children under their care.

Blended diet for enteral tube feeding in young people: A systematic review of the benefits and complications.

BACKGROUND: Interest and use of blended diets (BD) for young people who are tube fed has significantly increased in the last decade, driven primarily by the desires of motivated caregivers. This review identified, appraised and synthesised the available evidence on the benefits and complications of BD versus commercial feeds. METHODS: A systematic review following PRISMA guidance and registered with PROSPERO was conducted across PubMed, Embase, CINAHL, Scopus and Cochrane up to August 2022. INCLUSION CRITERIA: English language studies including (1) children, (2) original research (interventional and observational) and (3) examination of BD outcomes. Exclusion criteria were (1) unoriginal research or case reports, (2) focus on feeding management, preparations or attitudes and (3) comparing commercial blends only. Data were synthesised using an established narrative synthesis approach using the Mixed Methods Appraisal Tool. RESULTS: Eight hundred and six database results were identified and 61 were sought for retrieval. A full-text article review revealed seven eligible studies, involving 267 participants (age range 9 months to 26 years). Studies reported differences in gastrointestinal symptoms (n = 222), medication use (n = 119), growth (n = 189) and complications or adverse events (n = 91). The results indicate positive outcomes, particularly in gastrointestinal symptom control, with few reports of mild adverse events in the included studies. CONCLUSIONS: There is a paucity of data in this area and much heterogeneity in the included studies, but the available literature points towards positive outcomes. This is an important and highly relevant topic, and more primary research, ideally using standardised reporting, is required to answer the key questions.

Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, Senicapoc, in non-alcoholic liver disease.

AIM: To evaluate a calcium activated potassium channel (KCa3.1) inhibitor attenuates liver disease in models of non-alcoholic fatty liver disease (NAFLD). METHODS: We have performed a series of in vitro and in vivo studies using the KCa3.1 channel inhibitor, Senicapoc. Efficacy studies of Senicapoc were conducted in toxin-, thioacetamide (TAA) and high fat diet (HFD)-induced models of liver fibrosis in rats. Efficacy and pharmacodynamic effects of Senicapoc was determined through biomarkers of apoptosis, inflammation, steatosis and fibrosis. RESULTS: Upregulation of KCa3.1 expression was recorded in TAA-induced and high fat diet-induced liver disease. Treatment with Senicapoc decreased palmitic acid-driven HepG2 cell death. (P < 0.05 vs control) supporting the finding that Senicapoc reduces lipid-driven apoptosis in HepG2 cell cultures. In animals fed a HFD for 6 wk, co-treatment with Senicapoc, (1) reduced non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8 scale), (2) decreased steatosis and (3) decreased hepatic lipid content (Oil Red O, P < 0.05 vs vehicle). Randomization of TAA animals and HFD fed animals to Senicapoc was associated with a decrease in liver fibrosis as evidenced by hydroxyproline and Masson's trichrome staining (P < 0.05 vs vehicle). These results demonstrated that Senicapoc mitigates both steatosis and fibrosis in liver fibrosis models. CONCLUSION: These data suggest that Senicapoc interrupts more than one node in progressive fatty liver disease by its anti-steatotic and anti-fibrotic activities, serving as a double-edged therapeutic sword.

Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors.

The receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated by EGFR is the phosphatidylinositol 3'-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin (mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the sensitivity of non-small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is dependent on inhibition of the phosphatidylinositol 3'-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention. Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived from a variety of tissue types (non-small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance response to erlotinib.

Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a novel thiophene kinase inhibitor OSI-930.

OSI-930, a potent thiophene inhibitor of the Kit, KDR, and platelet-derived growth factor receptor tyrosine kinases, was used to selectively inhibit tyrosine phosphorylation downstream of juxtamembrane mutant Kit in the mast cell leukemia line HMC-1. Inhibition of Kit kinase activity resulted in a rapid dephosphorylation of Kit and inhibition of the downstream signaling pathways. Attenuation of Ras-Raf-Erk (phospho-Erk, phospho-p38), phosphatidyl inositol-3' kinase (phospho-p85, phospho-Akt, phospho-S6), and signal transducers and activators of transcription signaling pathways (phospho-STAT3/5/6) were measured by affinity liquid chromatography tandem mass spectrometry, by immunoblot, and by tissue microarrays of fixed cell pellets. To more globally define additional components of Kit signaling temporally altered by kinase inhibition, a novel multiplex quantitative isobaric peptide labeling approach was used. This approach allowed clustering of proteins by temporal expression patterns. Kit kinase, which dephosphorylates rapidly upon kinase inhibition, was shown to regulate both Shp-1 and BDP-1 tyrosine phosphatases and the phosphatase-interacting protein PSTPIP2. Interactions with SH2 domain adapters [growth factor receptor binding protein 2 (Grb2), Cbl, Slp-76] and SH3 domain adapters (HS1, cortactin, CD2BP3) were attenuated by inhibition of Kit kinase activity. Functional crosstalk between Kit and the non-receptor tyrosine kinases Fes/Fps, Fer, Btk, and Syk was observed. Inhibition of Kit modulated phosphorylation-dependent interactions with pathways controlling focal adhesion (paxillin, leupaxin, p130CAS, FAK1, the Src family kinase Lyn, Wasp, Fhl-3, G25K, Ack-1, Nap1, SH3P12/ponsin) and septin-actin complexes (NEDD5, cdc11, actin). The combined use of isobaric protein quantitation and expression clustering, immunoblot, and tissue microarray strategies allowed temporal measurement signaling pathways modulated by mutant Kit inhibition in a model of mast cell leukemia.