Mucosal Infections and Invasive Potential of Nonencapsulated <i>Streptococcus pneumoniae</i> Are Enhanced by Oligopeptide Binding Proteins AliC and AliD.

Nonencapsulated &lt;i&gt;Streptococcus pneumoniae&lt;/i&gt; (NESp) is an emerging human pathogen that colonizes the nasopharynx and is associated with noninvasive diseases such as otitis media (OM), conjunctivitis, and nonbacteremic pneumonia. Since capsule expression was previously thought to be necessary for establishment of invasive pneumococcal disease (IPD), serotype-specific polysaccharide capsules are targeted by currently licensed pneumococcal vaccines. Yet, NESp expressing oligopeptide binding proteins AliC and AliD have been isolated during IPD. Thus, we hypothesize AliC and AliD are major NESp virulence determinants that facilitate persistence and development of IPD. Our study reveals that NESp expressing AliC and AliD have intensified virulence compared to isogenic mutants. Specifically, we demonstrate AliC and AliD enhance murine nasopharyngeal colonization and pulmonary infection and are required for OM in a chinchilla model. Furthermore, AliC and AliD increase pneumococcal survival in chinchilla whole blood and aid in resistance to killing by human leukocytes. Comparative proteome analysis revealed significant alterations in protein levels when AliC and AliD were absent. Virulence-associated proteins, including a pneumococcal surface protein C variant (CbpAC), were significantly downregulated, while starvation response indicators were upregulated in the double mutant relative to wild-type levels. We also reveal that differentially expressed CbpAC was essential for NESp adherence to epithelial cells, virulence during OM, reduction of C3b deposition on the NESp surface, and binding to nonspecific IgA. Altogether, the rise in NESp prevalence urges the need to understand how NESp establishes disease and persists in a host. This study highlights the roles of AliC, AliD, and CbpAC in the pathogenesis of NESp. &lt;b&gt;IMPORTANCE&lt;/b&gt; Despite the effective, widespread use of licensed pneumococcal vaccines over many decades, pneumococcal infections remain a worldwide burden resulting in high morbidity and mortality. NESp subpopulations are rapidly rising in the wake of capsule-targeted vaccine strategies, yet there is very little knowledge on NESp pathogenic potential and virulence mechanisms. Although NESp lacks a protective capsule, NESp lineages expressing AliC and AliD have been associated with systemic infections. Furthermore, higher antibiotic resistance rates and transformation efficiencies associated with emerging NESp threaten treatment strategies needed to control pneumococcal infections and transmission. Elucidating how NESp survives within a host and establishes disease is necessary for development of broadened pneumococcal prevention methods. Our study identifies virulence determinants and host survival mechanisms employed by NESp with a high pathogenic potential. Moreover, our study also identifies virulence determinants shared by NESp and encapsulated strains that may serve as broad prevention and therapeutic targets

Improving Patient Outcomes With High Nurse To Patient Ratios: A Quality Improvement Study

According to the United States Registered Nurse Workforce Report Card and Shortage Forecast: A Revisit published in the May/June 2018 issue of the American Journal of Medical Quality, a shortage of registered nurses is projected to spread across the country between 2016 and 2030. Surveyed nurses see the shortage in the future as a catalyst for increasing stress on nurses (98%), lowering patient care quality (93%) and causing nurses to leave the profession (93%) (American Association of Colleges of Nursing, 2021). A thorough literature review was conducted, and 40 studies were reviewed. Common themes that emerged include: high nurse to patient ratios increased the risk for hospital acquired infections, higher levels of understaffing are associated with higher mistreatment rates, and there is a decrease in patient outcomes associated with nurse understaffing. A set of guidelines have been developed to assist the nursing staff during a shortage of nurses or nursing technicians.https://scholarworks.moreheadstate.edu/celebration_posters_2021/1026/thumbnail.jp

Surface proteins and pneumolysin of encapsulated and nonencapsulated Streptococcus pneumoniae mediate virulence in a chinchilla model of otitis media

Streptococcus pneumoniae infections result in a range of human diseases and are responsible for almost one million deaths annually. Pneumococcal disease is mediated in part through surface structures and an anti-phagocytic capsule. Recent studies have shown that nonencapsulated Streptococcus pneumoniae (NESp) make up a significant portion of the pneumococcal population and are able to cause disease. NESp lack some common surface proteins expressed by encapsulated pneumococci, but express surface proteins unique to NESp. A chinchilla model of otitis media (OM) was used to determine the effect various pneumococcal mutations have on pathogenesis in both NESp and encapsulated pneumococci. Epithelial cell adhesion and invasion assays were used to examine the effects in relation to deletion of intrinsic genes or expression of novel genes. A mouse model of colonization was also utilized for comparison of various pneumococcal mutants. It was determined that pneumococcal surface protein K (PspK) and pneumolysin (Ply) affect NESp middle ear pathogenesis, but only PspK affected epithelial cell adhesion. Experiments in an OM model were done with encapsulated strains testing the importance of native virulence factors and treatment of OM. First, a triple deletion of the common virulence factors PspA, PspC, and Ply, (ΔPAC), from an encapsulated background abolished virulence in an OM model while a PspC mutant had detectable, but reduced amounts of recoverable bacteria compared to wildtype. Next, treatment of OM was effective when starting antibiotic treatment within 24 hrs with resolution by 48 hrs post treatment. Expression of NESp-specific virulence factor PspK in an encapsulated strain has not been previously studied, and we showed significantly increased adhesion and invasion of human epithelial cells by pneumococci. Murine colonization was not significantly increased when an encapsulated strain expressed PspK, but colonization was increased when a capsule mutant expressed PspK. The ability of PspK expression to increase colonization in a capsule mutant despite no increase in adhesion can be attributed to other functions of PspK, such as sIgA binding or immune modulation. OM is a substantial economic burden, thus a better understanding of both encapsulated pneumococcal pathogenesis and the emerging pathogen NESp is necessary for effective prevention and treatment

Quantitative trait loci for bone traits segregating independently of those for growth in an F-2 broiler X layer cross

An F broiler-layer cross was phenotyped for 18 skeletal traits at 6, 7 and 9 weeks of age and genotyped with 120 microsatellite markers. Interval mapping identified 61 suggestive and significant QTL on 16 of the 25 linkage groups for 16 traits. Thirty-six additional QTL were identified when the assumption that QTL were fixed in the grandparent lines was relaxed. QTL with large effects on the lengths of the tarsometatarsus, tibia and femur, and the weights of the tibia and femur were identified on GGA4 between 217 and 249 cM. Six QTL for skeletal traits were identified that did not co-locate with genome wide significant QTL for body weight and two body weight QTL did not coincide with skeletal trait QTL. Significant evidence of imprinting was found in ten of the QTL and QTL x sex interactions were identified for 22 traits. Six alleles from the broiler line for weight- and size-related skeletal QTL were positive. Negative alleles for bone quality traits such as tibial dyschondroplasia, leg bowing and tibia twisting generally originated from the layer line suggesting that the allele inherited from the broiler is more protective than the allele originating from the layer

Brass Happenings

Presenting a student recital for brass students in USU\u27s Music Department.https://digitalcommons.usu.edu/music_programs/1107/thumbnail.jp

A Review of Swine Transportation Research on Priority Welfare Issues:A Canadian Perspective

The purpose of this review is to present the best available scientific knowledge on key animal welfare issues during swine transport, such as transport duration and distance, time off feed and water, rest intervals, environmental conditions, loading density, and transport of young animals, based on their impact on stress, injury, fatigue, dehydration, body temperature, mortality, and carcass and meat quality. The review was limited to this set of priority welfare issues which were identified by the National Farm Animal Care Council (NFACC) Scientific Committee to help with the development of the livestock transportation Codes of Practice. This review focuses primarily on research related to the transport of market pigs (100–135 kg) which is a reflection of the current literature available on pig transportation. This information presented here can be used to support other animal welfare codes, guidelines, standards or legislations regulating the welfare of pigs during transport. Based on the available literature, clear conclusions can be drawn on the impact of vehicle design, pre-transport fasting, control of environmental conditions and loading density on the welfare of pigs during transport and on pork quality. However, the effects of journey duration are still unclear and a recommendation on the maximum transport time cannot be provided. Further studies investigating the impact of factors, such as ambient conditions within the transport vehicle, loading density at extreme ambient conditions, travel distances, maximum travel duration, rest/stop duration, and management of pigs during rest stops are required. More specifically, further research in relation to the welfare of market weight, newly weaned and breeding pigs, and cull sows and boars during transport is needed

Minimising impairment: Protocol for a multicentre randomised controlled trial of upper limb orthoses for children with cerebral palsy.

BACKGROUND: Upper limb orthoses are frequently prescribed for children with cerebral palsy (CP) who have muscle overactivity predominantly due to spasticity, with little evidence of long-term effectiveness. Clinical consensus is that orthoses help to preserve range of movement: nevertheless, they can be complex to construct, expensive, uncomfortable and require commitment from parents and children to wear. This protocol paper describes a randomised controlled trial to evaluate whether long-term use of rigid wrist/hand orthoses (WHO) in children with CP, combined with usual multidisciplinary care, can prevent or reduce musculoskeletal impairments, including muscle stiffness/tone and loss of movement range, compared to usual multidisciplinary care alone. METHODS/DESIGN: This pragmatic, multicentre, assessor-blinded randomised controlled trial with economic analysis will recruit 194 children with CP, aged 5-15 years, who present with flexor muscle stiffness of the wrist and/or fingers/thumb (Modified Ashworth Scale score =1). Children, recruited from treatment centres in Victoria, New South Wales and Western Australia, will be randomised to groups (1:1 allocation) using concealed procedures. All children will receive care typically provided by their treating organisation. The treatment group will receive a custom-made serially adjustable rigid WHO, prescribed for 6 h nightly (or daily) to wear for 3 years. An application developed for mobile devices will monitor WHO wearing time and adverse events. The control group will not receive a WHO, and will cease wearing one if previously prescribed. Outcomes will be measured 6 monthly over a period of 3 years. The primary outcome is passive range of wrist extension, measured with fingers extended using a goniometer at 3 years. Secondary outcomes include muscle stiffness, spasticity, pain, grip strength and hand deformity. Activity, participation, quality of life, cost and cost-effectiveness will also be assessed. DISCUSSION: This study will provide evidence to inform clinicians, services, funding agencies and parents/carers of children with CP whether the provision of a rigid WHO to reduce upper limb impairment, in combination with usual multidisciplinary care, is worth the effort and costs. TRIAL REGISTRATION: ANZ Clinical Trials Registry: U1111-1164-0572

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice