A genome-informed higher rank classification of the biotechnologically important fungal subphylum Saccharomycotina.

The subphylum Saccharomycotina is a lineage in the fungal phylum Ascomycota that exhibits levels of genomic diversity similar to those of plants and animals. The Saccharomycotina consist of more than 1 200 known species currently divided into 16 families, one order, and one class. Species in this subphylum are ecologically and metabolically diverse and include important opportunistic human pathogens, as well as species important in biotechnological applications. Many traits of biotechnological interest are found in closely related species and often restricted to single phylogenetic clades. However, the biotechnological potential of most yeast species remains unexplored. Although the subphylum Saccharomycotina has much higher rates of genome sequence evolution than its sister subphylum, Pezizomycotina, it contains only one class compared to the 16 classes in Pezizomycotina. The third subphylum of Ascomycota, the Taphrinomycotina, consists of six classes and has approximately 10 times fewer species than the Saccharomycotina. These data indicate that the current classification of all these yeasts into a single class and a single order is an underappreciation of their diversity. Our previous genome-scale phylogenetic analyses showed that the Saccharomycotina contains 12 major and robustly supported phylogenetic clades; seven of these are current families (Lipomycetaceae, Trigonopsidaceae, Alloascoideaceae, Pichiaceae, Phaffomycetaceae, Saccharomycodaceae, and Saccharomycetaceae), one comprises two current families (Dipodascaceae and Trichomonascaceae), one represents the genus Sporopachydermia, and three represent lineages that differ in their translation of the CUG codon (CUG-Ala, CUG-Ser1, and CUG-Ser2). Using these analyses in combination with relative evolutionary divergence and genome content analyses, we propose an updated classification for the Saccharomycotina, including seven classes and 12 orders that can be diagnosed by genome content. This updated classification is consistent with the high levels of genomic diversity within this subphylum and is necessary to make the higher rank classification of the Saccharomycotina more comparable to that of other fungi, as well as to communicate efficiently on lineages that are not yet formally named. Taxonomic novelties: New classes: Alloascoideomycetes M. Groenew., Hittinger, Opulente & A. Rokas, Dipodascomycetes M. Groenew., Hittinger, Opulente & A. Rokas, Lipomycetes M. Groenew., Hittinger, Opulente, A. Rokas, Pichiomycetes M. Groenew., Hittinger, Opulente & A. Rokas, Sporopachydermiomycetes M. Groenew., Hittinger, Opulente & A. Rokas, Trigonopsidomycetes M. Groenew., Hittinger, Opulente & A. Rokas. New orders: Alloascoideomycetes: Alloascoideales M. Groenew., Hittinger, Opulente & A. Rokas; Dipodascomycetes: Dipodascales M. Groenew., Hittinger, Opulente & A. Rokas; Lipomycetes: Lipomycetales M. Groenew., Hittinger, Opulente & A. Rokas; Pichiomycetes: Alaninales M. Groenew., Hittinger, Opulente & A. Rokas, Pichiales M. Groenew., Hittinger, Opulente & A. Rokas, Serinales M. Groenew., Hittinger, Opulente & A. Rokas; Saccharomycetes: Phaffomycetales M. Groenew., Hittinger, Opulente & A. Rokas, Saccharomycodales M. Groenew., Hittinger, Opulente & A. Rokas; Sporopachydermiomycetes: Sporopachydermiales M. Groenew., Hittinger, Opulente & A. Rokas; Trigonopsidomycetes: Trigonopsidales M. Groenew., Hittinger, Opulente & A. Rokas. New families: Alaninales: Pachysolenaceae M. Groenew., Hittinger, Opulente & A. Rokas; Pichiales: Pichiaceae M. Groenew., Hittinger, Opulente & A. Rokas; Sporopachydermiales: Sporopachydermiaceae M. Groenew., Hittinger, Opulente & A. Rokas. Citation: Groenewald M, Hittinger CT, Bensch K, Opulente DA, Shen X-X, Li Y, Liu C, LaBella AL, Zhou X, Limtong S, Jindamorakot S, Gonçalves P, Robert V, Wolfe KH, Rosa CA, Boekhout T, Cadez N, Péter G, Sampaio JP, Lachance M-A, Yurkov AM, Daniel H-M, Takashima M, Boundy-Mills K, Libkind D, Aoki K, Sugita T, Rokas A (2023). A genome-informed higher rank classification of the biotechnologically important fungal subphylum Saccharomycotina. Studies in Mycology 105: 1-22. doi: 10.3114/sim.2023.105.01 This study is dedicated to the memory of Cletus P. Kurtzman (1938-2017), a pioneer of yeast taxonomy.

Is the Patient Activation Measure a valid measure of osteoarthritis self-management attitudes and capabilities? Results of a Rasch analysis.

BACKGROUND: The Patient Activation Measure (PAM-13) was developed using Rasch analysis to assess knowledge, skills and confidence in the management of one's health. Previous studies report positive relationships between PAM-13 scores, self-management behaviours and longitudinal health outcomes in adults with chronic disease. There is little extant measurement property evidence for the use of PAM-13 in specific osteoarthritis (OA) populations. This study tested measurement properties of the PAM-13 in people living with hip and knee OA. METHODS: Item response frequency analysis was conducted. Rasch analysis evaluated the fit of the PAM-13 data to the Rasch model. Model-data fit was evaluated using infit and outfit statistics; person/item reliability and person separation indices were computed. Unidimensionality was evaluated using Principal Components Analysis of Rasch residuals and the data were assessed for item redundancy. Differential Item Functioning (DIF) examined bias in respondent subgroups and correlations tested relationships between PAM-13 and other patient-reported outcomes. RESULTS: Two-hundred-and-seventeen PAM-13 surveys were completed; there were no missing responses, floor or ceiling effects. Person and item reliability were acceptable (0.98 and 0.87 respectively) with good separation (person separation index 2.58). Unidimensionality was evaluated, with 49.4% of the variance explained by the first eigenvector. There was evidence of potential local response-dependence. The Rasch fit statistics were acceptable (except for item-2). There were some issues identified with targeting of the PAM-13 items to people with higher ability and the item difficulty order was different to that proposed in original cohorts. Significant DIF was identified for sex and educational level for a small number of items. PAM-13 scores were moderately correlated with depressive symptoms on the Depression Anxiety Stress Scale and Assessment of Quality of Life-6D. There were small correlations between PAM-13 and Knee injury and Osteoarthritis Outcome Score pain and activities of daily living scores. CONCLUSIONS: This study provides some evidence of adequate person and item reliability, unidimensionality, and construct validity to support the use of PAM-13 to measure patient activation in people living with hip and knee OA. Possible limitations regarding targeting, different item difficulty order, DIF and local response dependence should be investigated in future research.

Preserving US microbe collections sparks future discoveries.

Collections of micro-organisms are a crucial element of life science research infrastructure but are vulnerable to loss and damage caused by natural or man-made disasters, the untimely death or retirement of personnel, or the loss of research funding. Preservation of biological collections has risen in priority due to a new appreciation for discoveries linked to preserved specimens, emerging hurdles to international collecting and decreased funding for new collecting. While many historic collections have been lost, several have been preserved, some with dramatic rescue stories. Rescued microbes have been used for discoveries in areas of health, biotechnology and basic life science. Suggestions for long-term planning for microbial stocks are listed, as well as inducements for long-term preservation.

Osteoarthritis year in review 2018: rehabilitation and outcomes.

OBJECTIVE: Conduct a systematic review of systematic reviews and randomised controlled trials (RCTs) from the past year evaluating rehabilitation for people with osteoarthritis, and provide narrative synthesis of findings focused on core recommended treatments for osteoarthritis (exercise, education, biomechanical interventions, weight loss). DESIGN: A comprehensive search strategy was used to search PubMed, EMBASE and Cochrane databases (16th May 2017 to 22nd March 2018). Search terms included 'osteoarthritis', 'rehabilitation', 'systematic review', and 'randomised controlled trial'. Inclusion criteria were: (1) RCT, or systematic review of randomised clinical trials (RCTs); (2) human participants with osteoarthritis (any joint); (3) evaluation of rehabilitation intervention; and (4) at least one patient-reported measure. Methodological quality was evaluated using the Assessment of Multiple Systematic Reviews (AMSTAR) tool (systematic reviews) and PEDro rating scale (RCTs). Narrative synthesis mapped findings to core recommendations from existing osteoarthritis clinical guidelines. RESULTS: From 1994 records, 13 systematic reviews and 36 RCTs were included. 73% of these evaluated knee osteoarthritis (36 studies). The remaining studies evaluated hand osteoarthritis (6 studies), hip, hip/knee and general osteoarthritis (each 2 studies), and neck osteoarthritis (1 study). Exercise was the most common intervention evaluated (31%). Updated recommendations for exercise prescription and preliminary guidance for psychological interventions are provided. CONCLUSION: Level 1 and 2 osteoarthritis rehabilitation literature continues to be dominated by knee osteoarthritis studies. Consistent with current clinical guidelines, exercise should be a core treatment for osteoarthritis, but future studies should ensure that exercise programs follow published dose guidelines. There is a clear need for research on rehabilitation for hip, hand, foot/ankle, shoulder and spine osteoarthritis.

Current concepts in joint pain in knee osteoarthritis.

Joint pain attributable to osteoarthritis (OA) is complex and influenced by a myriad of factors beyond local joint pathology. Current practice continues to predominantly adopt a biomedical approach to OA despite emerging evidence of the importance of a more holistic approach. This paper will summarise evidence for the presence of multidimensional pain profiles in knee joint pain and the presence of subgroups characterized by systemic features such as psychological distress, high comorbidity load or sensitisation of the nervous system. These factors have the potential to influence patient outcomes making them relevant for clinicians and highlighting the necessity of a broader multifactorial approach to assessment and treatment. This review describes the current state of the evidence for treatments of people with knee OA-related pain, including those receiving strong recommendations from current clinical guidelines, namely exercise, weight loss, self-management advice and pharmacological approaches. Other pain-modulating treatment options are emerging such as sleep and psychological interventions, pain education and multisensory retraining. The evidence and rationale for these newer therapeutic approaches is discussed. Finally, this review will highlight some of the limitations of current international guidelines for the management of OA and make recommendations for future research.

Effects of metritis on stall use and social behavior at the lying stall.

Metritis in dairy cows has been associated with changes in behavior at the feed bunk, but little is known about the effects on behavior at the lying stall. The aim of this study was to investigate stall use by primiparous dairy cows diagnosed with metritis, specifically time spent in the stall, social interactions at the stall, and lying-related behaviors. After parturition, primiparous cows were housed in a mixed-parity pen with a constant group size of 20. Cows had access to 12 electronic feed bins, 2 electronic water bins, and 24 lying stalls. Four cameras installed above the experimental pen allowed for observation of cows in the feeding and lying area. Every 3 d after parturition, cows were examined for metritis by evaluation of the visual appearance and olfactory character of vaginal discharge. Cows diagnosed with metritis (n = 16) were compared with healthy individuals (i.e., cows without metritis or other clinical disease, n = 16). Healthy individuals were selected based on data availability, body weight, and calving date and, based on these criteria, paired with metritic cows. Video of the 3 d before diagnosis (d -3 to d -1) in the metritic animals (and video from the corresponding days in milk for paired healthy cows) were used to measure behavior. Behaviors assessed included those in the stall (lying, perching, and standing fully in the stall), social behaviors (when a cow either displaced or was displaced by another cow; i.e., actor and reactor replacements), and lying-related behaviors (including visits when the cow entered and left the stall without lying down, aborted lying events when behaviors indicative of the onset of a lying bout were not followed by the cow lying down, and latency to lie down, defined as the time between an aborted lying event and the first lying bout). Cows with metritis spent more time standing fully in the stall on all 3 d, resulting in more time spent standing on d -2 and -1. Cows with metritis tended to have more aborted lying events on d -2, and significantly more on d -1. Cows with metritis tended to be replaced more often at the lying stall on d -3 and tended to have a longer latency to lie down on d -2. We observed no differences between health groups in the number of actor replacements or the number of visits to the stall. In summary, cows with metritis spent more time standing fully in the lying stall and had more aborted lying events. These results suggest that primiparous cows with metritis may be identified by altered behavior at the lying stall.

Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence.

Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.

Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review.

OBJECTIVE: To systematically review the literature for studies investigating knee osteoarthritis (OA) phenotypes to examine what OA characteristics are relevant for phenotyping. METHODS: A comprehensive search was performed in Medline, EMBASE, Web of Sciences, CINAHL, and Scopus databases from inception to September 2016. Inclusion was limited to observational studies of individuals with symptomatic knee OA that identified phenotypes based on any OA characteristics and assessed their association with clinically important outcomes. A descriptive synthesis of the data was performed. RESULTS: Of the 2777 citations retrieved, 34 studies were included. Clinical phenotypes were investigated most frequently, followed by laboratory, imaging and aetiologic phenotypes. Eight studies defined subgroups based on outcome trajectories (pain, function and radiographic progression trajectories). Most studies used a single patient or disease characteristic to identify patients subgroups while five included characteristics from multiple domains. We found evidence from multiple studies suggesting that pain sensitization, psychological distress, radiographic severity, body mass index (BMI), muscle strength, inflammation and comorbidities are associated with clinically distinct phenotypes. Gender, obesity and other metabolic abnormalities, the pattern of cartilage damage, and inflammation may be implicated in delineating distinct structural phenotypes. Only a few studies investigated the external validity of the phenotypes or their prospective validity using longitudinal outcomes. CONCLUSIONS: There is marked heterogeneity in the data selected by the studies investigating knee OA phenotypes. We identified the phenotypic characteristics that can be considered for a comprehensive phenotype classification in future studies. A framework for the investigation of phenotypes could be useful for future studies. PROTOCOL REGISTRATION: PROSPERO CRD42016036220.

Instruments assessing attitudes toward or capability regarding self-management of osteoarthritis: a systematic review of measurement properties.

OBJECTIVE: To make a recommendation on the "best" instrument to assess attitudes toward and/or capabilities regarding self-management of osteoarthritis (OA) based on available measurement property evidence. METHODS: Electronic searches were performed in MEDLINE, EMBASE, CINAHL and PsychINFO (inception to 27 December 2016). Two reviewers independently rated measurement properties using the Consensus-based Standards for the selection of Health Measurement Instruments (COSMIN) 4-point scale. Best evidence synthesis was determined by considering COSMIN ratings for measurement property results and the level of evidence available for each measurement property of each instrument. RESULTS: Eight studies out of 5653 publications met the inclusion criteria, with eight instruments identified for evaluation: Multidimensional Health Locus of Control (MHLC), Perceived Behavioural Control (PBC), Patient Activation Measure (PAM), Educational Needs Assessment (ENAT), Stages of Change Questionnaire in Osteoarthritis (SCQOA), Effective Consumer Scale (EC-17) and Perceived Efficacy in Patient-Physician Interactions five item (PEPPI-5) and ten item scales. Measurement properties assessed for these instruments included internal consistency (k = 8), structural validity (k = 8), test-retest reliability (k = 2), measurement error (k = 1), hypothesis testing (k = 3) and cross-cultural validity (k = 3). No information was available for content validity, responsiveness or minimal important change (MIC)/minimal important difference (MID). The Dutch PEPPI-5 demonstrated the best measurement property evidence; strong evidence for internal consistency and structural validity but limited evidence for reliability and construct validity. CONCLUSION: Although PEPPI-5 was identified as having the best measurement properties, overall there is a poor level of evidence currently available concerning measurement properties of instruments to assess attitudes toward and/or capabilities regarding osteoarthritis self-management. Further well-designed studies investigating measurement properties of existing instruments are required.

Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy.

There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)-induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen-challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum-induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica.

Minimal important improvement thresholds for the six-minute walk test in a knee arthroplasty cohort: triangulation of anchor- and distribution-based methods.

BACKGROUND: The 6-minute walk test (6MWT) is a commonly used metric for measuring change in mobility after knee arthroplasty, however, what is considered an improvement after surgery has not been defined. The determination of important change in an outcome assessment tool is controversial and may require more than one approach. This study, nested within a combined randomised and observational trial, aimed to define a minimal important improvement threshold for the 6MWT in a knee arthroplasty cohort through a triangulation of methods including patient-perceived anchor-based thresholds and distribution-based thresholds. METHODS: Individuals with osteoarthritis performed a 6MWT pre-arthroplasty then at 10 and 26 weeks post-surgery. Each rated their perceived improvement in mobility post-surgery on a 7-point transition scale anchored from "much better" to "much worse". Based on these responses the cohort was dichotomised into 'improved' and 'not improved'. The thresholds for patient-perceived improvements were then identified using two receiver operating curve methods producing sensitivity and specificity indices. Distribution-based change thresholds were determined using two methods utilising effect size (ES). Agreement between the anchor- and distribution-based methods was assessed using kappa. RESULTS: One hundred fifty-eight from 166 participants in the randomised cohort and 222 from 243 in the combined randomised and observational cohort were included at 10 and 26 weeks, respectively. The slightly or more patient-perceived improvement threshold at 26 weeks (an absolute improvement of 26 m) was the only one to demonstrate sensitivity and specificity results both better than chance. At 10- and 26-weeks, the ES based on the mean change score divided by the baseline standard deviation (SD), was an absolute change of 24.5 and 37.9 m, respectively. The threshold based on a moderate ES (a 0.5 SD of the baseline score) was a change of 55.0 and 55.4 m at 10- and 26-weeks, respectively. The level of agreement between the 26-week anchor-based and distribution-based minimal absolute changes was very good (k = 0.88 (95 % CI 0.81 0.95)). CONCLUSION: A valid threshold of improvement for the 6MWT can only be proposed for changes identified from baseline to 26 weeks post-surgery. The level of agreement between anchor- and distribution-based methods indicates that a true minimal or more threshold of meaningful improvement following surgery is likely within the ranges proposed by the triangulation of all four methods, that is, 26 to 55 m.

Body mass index and colorectal cancer prognosis: a systematic review and meta-analysis.

Colorectal cancer is one of the most common cancers worldwide. However, it is unclear what influence body mass index (BMI) has on colorectal cancer prognosis. We conducted a systematic review and meta-analysis of observational studies to examine the association of BMI with colorectal cancer outcomes. We searched MEDLINE and EMBASE databases from inception to February 2015 and references of identified articles. We selected observational studies that reported all-cause mortality, colorectal cancer-specific mortality, recurrence and disease-free survival according to BMI category. Random-effects meta-analyses were conducted to combine estimates. We included 18 observational studies. Obese patients had an increased risk of all-cause mortality [relative risk (RR) 1.14; 95 % confidence interval (CI) 1.07-1.21], cancer-specific mortality (RR 1.14; 95 % CI 1.05-1.24), recurrence (RR 1.07; 95 % CI 1.02-1.13) and worse disease-free survival (RR 1.07; 95 % CI 1.01-1.13). Underweight patients also had an increased risk of all-cause mortality (RR 1.43; 95 % CI 1.26-1.62), cancer-specific mortality (RR 1.50; 95 % CI 1.20-1.87), recurrence (RR 1.13; 95 % CI 1.05-1.21) and worse disease-free survival (RR 1.27; 95 % CI 1.13-1.43). Overweight patients had no increased risk for any of the outcomes studied. Both obese and underweight patients with colorectal cancer have an increased risk of all-cause mortality, cancer-specific mortality, disease recurrence and worse disease-free survival compared to normal weight patients.

Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a prospective cohort study.

BACKGROUND: This prospective cohort study aimed to identify symptom and patient factors that influence time to lung cancer diagnosis and stage at diagnosis. METHODS: Data relating to symptoms were collected from patients upon referral with symptoms suspicious of lung cancer in two English regions; we also examined primary care and hospital records for diagnostic routes and diagnoses. Descriptive and regression analyses were used to investigate associations between symptoms and patient factors with diagnostic intervals and stage. RESULTS: Among 963 participants, 15.9% were diagnosed with primary lung cancer, 5.9% with other thoracic malignancies and 78.2% with non-malignant conditions. Only half the cohort had an isolated first symptom (475, 49.3%); synchronous first symptoms were common. Haemoptysis, reported by 21.6% of cases, was the only initial symptom associated with cancer. Diagnostic intervals were shorter for cancer than non-cancer diagnoses (91 vs 124 days, P=0.037) and for late-stage than early-stage cancer (106 vs 168 days, P=0.02). Chest/shoulder pain was the only first symptom with a shorter diagnostic interval for cancer compared with non-cancer diagnoses (P=0.003). CONCLUSIONS: Haemoptysis is the strongest symptom predictor of lung cancer but occurs in only a fifth of patients. Programmes for expediting earlier diagnosis need to focus on multiple symptoms and their evolution.

Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer: Diagnostic and therapeutic potential.

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC.

Determining Relative Importance and Effective Settings for Genetic Algorithm Control Parameters.

Setting the control parameters of a genetic algorithm to obtain good results is a long-standing problem. We define an experiment design and analysis method to determine relative importance and effective settings for control parameters of any evolutionary algorithm, and we apply this method to a classic binary-encoded genetic algorithm (GA). Subsequently, as reported elsewhere, we applied the GA, with the control parameter settings determined here, to steer a population of cloud-computing simulators toward behaviors that reveal degraded performance and system collapse. GA-steered simulators could serve as a design tool, empowering system engineers to identify and mitigate low-probability, costly failure scenarios. In the existing GA literature, we uncovered conflicting opinions and evidence regarding key GA control parameters and effective settings to adopt. Consequently, we designed and executed an experiment to determine relative importance and effective settings for seven GA control parameters, when applied across a set of numerical optimization problems drawn from the literature. This paper describes our experiment design, analysis, and results. We found that crossover most significantly influenced GA success, followed by mutation rate and population size and then by rerandomization point and elite selection. Selection method and the precision used within the chromosome to represent numerical values had least influence. Our findings are robust over 60 numerical optimization problems.

Vitamin E, γ-tocopherol, diminishes ex vivo basophil response to dust mite allergen.

Epidemiologic studies suggest that dietary vitamin E is a candidate intervention for atopic disease. We used in vitro and ex vivo exposures to test the hypothesis that the most common dietary isoform of vitamin E, γ-tocopherol (γT), could suppress FcεRI-mediated basophil activation. Rat basophilic leukemia (RBL)-SX38 cells that express human FcεRI were treated with or without γT, followed by stimulation with α-IgE. In the ex vivo study, 20 Der f 1-allergic volunteers consumed a γT-enriched supplement for 7 days. Their basophils were challenged ex vivo with α-IgE and graded doses of Der f 1 before and after the supplementation period. γt treatment of RBL-SX38 cells significantly reduced basophil degranulation and de novo TH2 cytokine production. Daily consumption of a γT-rich supplement by dust mite-allergic volunteers reduced basophil activation after ex vivo dust mite challenge. Vitamin E supplements rich in γT may be useful adjuncts in decreasing atopic disease.

Recognition of advanced level practice against multiprofessional capabilities: Experiences of the first radiography applicants.

INTRODUCTION: Advanced practice is well established in the health professions with multiprofessional capabilities in place in England. To recognise achievement of these capabilities an ePortfolio (supported) route was initiated in 2022. This study aimed to review the demographics and experiences of radiographers applying for recognition in the first year of operation. METHODS: The multi method evaluation consisted of quantitative data analysis of information regarding the first three cohorts of radiographers (n = 40) participating in the NHS England (NHSE) scheme. Interviews with 12 participants was undertaken with thematic analysis of the transcripts. RESULTS: Self-rated scores of expertise were significantly higher by therapeutic radiographers (n = 8) compared to their 32 diagnostic colleagues (t = 5.556; p < 0.01). Radiographers saw the ePortfolio as an opportunity to validate their experience and to evidence parity with other professions. Participants felt the process also enabled critical reflection and gave unseen insight into themselves and their roles. The support of experienced educational supervisors was felt to be vital in this process and for successful completion of portfolio. CONCLUSIONS: Several radiographers have now achieved the necessary standards to achieve NHSE recognition. The evaluation exposed that most radiographers did not have the relevant evidence to hand and the ongoing collection of evidence around capabilities and impact is critical to evidencing advanced practice capabilities. IMPLICATIONS FOR PRACTICE: Radiographers are able to achieve the capabilities expected for multiprofessional practice. Cultural change is required to normalise recording of evidence within practice including case-based discussions, clinical supervision and feedback from colleagues and patients. The support of an experienced educational supervisor aided the critical reflection on practice level.

International recruitment of radiographers and the development of a workplace integration support package: Project evaluation.

INTRODUCTION: In October 2020, a regional workforce action group was established jointly by Health Education England (HEE) and NHS England and Improvement (NHSEI) in the South West to work collaboratively to address the workforce challenges within diagnostic imaging. Fifty-eight internationally recruited radiographers were offered employment in departments across the region, the majority of them taking up their posts in the UK in early 2021. The aim of the study presented here was to evaluate the efficacy of a training resource developed by Plymouth Marjon University, with input from HEE and NHSEI, to support workplace and cultural integration for the new recruits. METHODS: The training package to help newly recruited radiographers from outside the UK integrate into their host departments was developed using flexible learning opportunities centred on reusable digital learning assets. Self-paced e-learning sessions were augmented by group 'connected' sessions online. Two surveys were undertaken, exploring the impact of this workforce integration programme for International radiographers joining the NHS. RESULTS: Survey results indicate that the integration programme's three-phase strategy has seen an impact on 6 out of 12 self-efficacy measures, raised awareness of challenges, and increased personal awareness of implications for practice. By the end of the programme, delegates were in the top two quintiles for their average well-being score. CONCLUSION: Principal recommendations include ensuring digital accessibility for new recruits as part of the on-boarding process, considering the timing of delivery of any online connected support sessions, the provision of long-term pastoral support; and mandating the training requirement for managers and team leaders. IMPLICATIONS FOR PRACTICE: Success of international recruitment campaigns can be enhanced through the implementation of an online integration package.

The neutralising and stimulatory effects of antimicrobial peptide LL-37 in human gingival fibroblasts.

OBJECTIVES: To investigate the effects of LL-37, a broad spectrum antimicrobial peptide expressed in periodontal tissues, on human gingival fibroblast responsiveness to microbial challenge and to explore the direct effects of LL-37 on human gingival fibroblasts. DESIGN: The effect of LL-37 on bacterial lipopolysaccharide-induced expression of Interleukin (IL-6) and chemokine C-X-C motif ligand (CXCL) 8 was determined by enzyme linked immunosorbent assay (ELISA). LL-37's influence on bacterial lipopolysaccharide-induced IκBα degradation was investigated by western blot. DNA microarray analysis initially determined the direct effects of LL-37 on gene expression, these findings were subsequently confirmed by quantitative polymerase chain reaction and ELISA analysis of selected genes. RESULTS: Bacterial lipopolysaccharide-induced IL-6 and CXCL8 production by human gingival fibroblasts was significantly reduced in the presence of LL-37 at concentrations in the range of 1-10 µg/ml. LL-37 led to a reduction in lipopolysaccharide-induced IκBα degradation by Escherichia coli lipopolysaccharide and Porphyromonas gingivalis lipopolysaccharide (10 µg/ml). LL-37 (50 µg/ml) significantly altered the gene expression of 367 genes in human gingival fibroblasts by at least 2-fold. CXCL1, CXCL2, CXCL3, Interleukin-24 (IL-24), CXCL8, Chemokine (C-C motif) Ligand 2, and Suppressor of Cytokine Signalling 3 mRNA were significantly upregulated by LL-37. LL-37 also significantly stimulated expression of CXCL8, hepatocyte growth factor and CXCL1 at the protein level. CONCLUSION: LL-37 plays an important regulatory role in the immunomodulatory activity of gingival fibroblasts by inhibiting lipopolysaccharide -induced expression of inflammatory cytokines and directly stimulating the expression of an array of bioactive molecules involved in inflammation and repair.

Remission from post-traumatic stress disorder in the general population.

BACKGROUND: Few studies have focused on post-traumatic stress disorder (PTSD) remission in the population, none have modelled remission beyond age 54 years and none have explored in detail the correlates of remission from PTSD. This study examined trauma experience, symptom severity, co-morbidity, service use and time to PTSD remission in a large population sample. METHOD: Data came from respondents (n=8841) of the 2007 Australian National Survey of Mental Health and Wellbeing (NSMHWB). A modified version of the World Health Organization's World Mental Health Composite International Diagnostic Interview (WMH-CIDI) was used to determine the presence and age of onset of DSM-IV PTSD and other mental and substance use disorders, type, age, and number of lifetime traumas, severity of re-experiencing, avoidance and hypervigilance symptoms and presence and timing of service use. RESULTS: Projected lifetime remission rate was 92% and median time to remission was 14 years. Those who experienced childhood trauma, interpersonal violence, severe symptoms or a secondary anxiety or affective disorder were less likely to remit from PTSD and reported longer median times to remission compared to those with other trauma experiences, less severe symptoms or no co-morbidity. CONCLUSIONS: Although most people in the population with PTSD eventually remit, a significant minority report symptoms decades after onset. Those who experience childhood trauma or interpersonal violence should be a high priority for intervention.