Understanding the impact funding cuts on Environmental and regulatory services and gastrointestinal infections: a longitudinal ecological study [version 2; peer review: 2 approved]

Background Gastrointestinal (GI) infections result in 17 million cases annually, with foodborne illness costing the National Health Service (NHS) £60m per year. The burden of GI infection is unequally distributed, with greater impact in more socioeconomically disadvantaged groups and areas. Local authorities (LA) provide vital services that protect public health and wellbeing. The impact of funding cuts to local services and their effect on public health is an area of concern. Environmental and regulatory (ER) services are responsible for roles such as food safety and infectious disease control. This study aims to understand the impact of local funding cuts on ER and GI infection outcomes. Methods We will conduct an ecological longitudinal study in England from 2010-2019 at the LA level to examine how changes in ER expenditure overtime have impacted ER and GI infection outcomes. Data will be gathered on food hygiene enforcement, food hygiene compliance levels, GI infection hospitalisation, NHS 111 calls relating to GI infection symptoms, GI infection pathogen data, deprivation, and population density. Measures will be aggregated to LA level and statistical analysis will be carried out. Ethics and dissemination University of Liverpool Ethics committee have confirmed ethical approval will not be required. All data will be aggregated and anonymised, therefore only data sharing agreements will be required. Findings will be disseminated to the stakeholder group in addition to outputs through conferences and publications. These findings will help understand impact of key services on public health and should inform government and public health policy and strategy

Developing Porous Ortho- and Pyrophosphate-Containing Glass Microspheres; Structural and Cytocompatibility Characterisation

Phosphate-based glasses (PBGs) are promising materials for bone repair and regeneration as they can be formulated to be compositionally similar to the inorganic components of bone. Alterations to the PBG formulation can be used to tailor their degradation rates and subsequent release of biotherapeutic ions to induce cellular responses, such as osteogenesis. In this work, novel invert-PBGs in the series xP2O5·(56 − x)CaO·24MgO·20Na2O (mol%), where x is 40, 35, 32.5 and 30 were formulated to contain pyro (Q1) and orthophosphate (Q0) species. These PBGs were processed into highly porous microspheres (PMS) via flame spheroidisation, with ~68% to 75% porosity levels. Compositional and structural analysis using EDX and 31P-MAS NMR revealed that significant depolymerisation occurred with reducing phosphate content which increased further when PBGs were processed into PMS. A decrease from 50% to 0% in Q2 species and an increase from 6% to 35% in Q0 species was observed for the PMS when the phosphate content decreased from 40 to 30 mol%. Ion release studies also revealed up to a four-fold decrease in cations and an eight-fold decrease in phosphate anions released with decreasing phosphate content. In vitro bioactivity studies revealed that the orthophosphate-rich PMS had favourable bioactivity responses after 28 days of immersion in simulated body fluid (SBF). Indirect and direct cell culture studies confirmed that the PMS were cytocompatible and supported cell growth and proliferation over 7 days of culture. The P30 PMS with ~65% pyro and ~35% ortho phosphate content revealed the most favourable properties and is suggested to be highly suitable for bone repair and regeneration, especially for orthobiologic applications owing to their highly porous morphology

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Designing Business Case Writing As An Experiential Learning Project

The use of experiential learning approaches such as capstone seminars, simulations, case competitions, internships, service learning, and collaborative projects are all practices that are desirable and well documented in the teaching of business courses. Despite research that shows that business case writing can provide students with experiential learning that fosters the understanding of business challenges, ethical situations, and real-world decision-making processes, this pedagogical tool has gained little attention in the experiential learning curriculum (Vega, 2010). To demonstrate the effectiveness of business case writing as an experiential learning tool, we discuss the case writing experience and the learning outcomes for two undergraduate business students who participated in a summer case project at the David Berg Center of Ethics. This paper provides a model for integrating business case writing assignments into business experiential learning courses

Understanding the impact funding cuts on Environmental and regulatory services and gastrointestinal infections: a longitudinal ecological study

Background: Gastrointestinal (GI) infections result in 17 million cases annually, with foodborne illness costing the National Health Service (NHS) £60m per year. The burden of GI infection is unequally distributed, with greater impact in more socioeconomically disadvantaged groups and areas. Local authorities (LA) provide vital services that protect public health and wellbeing. The impact of funding cuts to local services and their effect on public health is an area of concern. Environmental and regulatory (ER) services are responsible for roles such as food safety and infectious disease control. This study aims to understand the impact of local funding cuts on ER and GI infection outcomes. Methods We will conduct an ecological longitudinal study in England from 2010-2019 at the LA level to examine how changes in ER expenditure overtime have impacted ER and GI infection outcomes. Data will be gathered on food hygiene enforcement, food hygiene compliance levels, GI infection hospitalisation, NHS 111 calls relating to GI infection symptoms, GI infection pathogen data, deprivation, and population density. Measures will be aggregated to LA level and statistical analysis will be carried out. Ethics and dissemination University of Liverpool Ethics committee have confirmed ethical approval will not be required. All data will be aggregated and anonymised, therefore only data sharing agreements will be required. Findings will be disseminated to the stakeholder group in addition to outputs through conferences and publications. These findings will help understand impact of key services on public health and should inform government and public health policy and strategy

Understanding the impact of local funding cuts on environmental health and regulatory services and gastrointestinal infection outcomes: a longitudinal ecological study protocol

Background: Gastrointestinal (GI) infections result in 17 million cases annually, with foodborne illness costing the National Health Service (NHS) £60m per year. The burden of GI infection is unequally distributed, with greater impact in more socioeconomically disadvantaged groups and areas. Local authorities (LA) provide vital services that protect public health and wellbeing. The impact of funding cuts to local services and their effect on public health is an area of concern. Environmental health and regulatory (EH) services are responsible for roles such as food safety and infectious disease control. This study aims to understand the impact of local funding cuts on EH and GI infection outcomes. Methods: We will conduct an ecological longitudinal study in England from 2010-2019 at the LA level to examine how changes in EH expenditure overtime have impacted EH and GI infection outcomes. Data will be gathered on food hygiene enforcement, food hygiene compliance levels, GI infection hospitalisation, NHS 111 calls relating to GI infection symptoms, GI infection pathogen data, deprivation, and population density. Measures will be aggregated to LA level and statistical analysis will be carried out. Ethics and dissemination: University of Liverpool Ethics committee have confirmed ethical approval will not be required. All data will be aggregated and anonymised, therefore only data sharing agreements will be required. Findings will be disseminated to the stakeholder group in addition to outputs through conferences and publications. These findings will help understand impact of key services on public health and should inform government and public health policy and strategy.</ns4:p