Characterising the allergic fungal rhinosinusitis microenvironment using full-length 16S rRNA gene amplicon sequencing and fungal ITS sequencing.

INTRODUCTION: Allergic fungal rhinosinusitis (AFRS) is a severe phenotype of chronic rhinosinusitis with nasal polyposis (CRSwNP), characterised by localised and exaggerated type 2 inflammation. While fungal antigenic stimulation of unregulated Th2-mediated inflammation is the core pathophysiological mechanism, the direct and synergistic role of bacteria in disease modification is a pervasive hypothesis. We set out to define the microenvironment of AFRS to elucidate virulent organisms that may be implicated in the pathophysiology of AFRS. METHODOLOGY: We undertook a cross-sectional study of AFRS patients and non-fungal CRSwNP patients. Demographics, disease severity, culture and microbiome sequences were analysed. Multimodality microbiome sequencing included short-read next-generation sequencing (NGS) on the Illumina Miseq (16S rRNA and ITS) and full-length 16S rRNA sequencing on the Oxford Nanopore Technologies GridION (ONT). RESULTS: Thirty-two AFRS and 29 non-fungal CRSwNP patients (NF) were included in this study. Staphylococcus aureus was the dominant organism cultured and sequenced in both AFRS and NF groups (AFRS 27.54%; NF 18.04%; p = .07). Streptococcus pneumoniae (AFRS 12.31%; NF 0.98%; p = .03) and Haemophilus influenzae (AFRS 15.03%; NF 0.24%; p = .005) were significantly more abundant in AFRS. Bacterial diversity (Shannon's index) was considerably lower in AFRS relative to NF (AFRS 0.6; NF 1.0, p = .008). Aspergillus was the most cultured fungus in AFRS (10/32, 31.3%). The AFRS sequenced mycobiome was predominantly represented by Malassezia (43.6%), Curvularia (18.5%) and Aspergillus (16.8%), while the NF mycobiome was nearly exclusively Malassezia (84.2%) with an absence of Aspergillus or dematiaceous fungi. CONCLUSION: A low diversity, dysbiotic microenvironment dominated by Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae characterised the bacterial microbiome of AFRS, with a mycobiome abundant in Malassezia, Aspergillus and Curvularia. While Staphylococcus aureus has been previously implicated in AFRS through enterotoxin superantigen potential, Streptococcus pneumoniae and Haemophilus influenzae are novel findings that may represent alternate cross-kingdom pathophysiological mechanisms.

Comparing self-report medication data from a longitudinal study on intellectual disability and national dispensing records.

BACKGROUND: Medication data are a valuable resource in epidemiological studies. As the most common data collection method of medication data is self-report, it is important to understand the accuracy of this in comparison with other methods such as dispensing records. The aim of this study was to compare the agreement between two different sources of medication data of older adults with intellectual disability (ID). METHODS: Self-report medication data were gathered from the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing and linked to national pharmacy dispensing records. The kappa statistic was used to measure agreement between the two data sources for psychotropic medication. RESULTS: The lowest agreement level was 'moderate' for the number of anxiolytics reported (kappa 0.56). The highest level of agreement was 'almost perfect' for the binary variable of antipsychotics (kappa 0.91). Other agreement results were 'substantial' or 'almost perfect'. CONCLUSIONS: Good agreement was found between the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing medication dataset and national dispensing records. Self-report medication data appear to be a valid method of data collection in psychotropic medication use in adults with ID.

Enhanced phylogenetic insights into the microbiome of chronic rhinosinusitis through the novel application of long read 16S rRNA gene amplicon sequencing.

INTRODUCTION: 16S rRNA next generation sequencing (NGS) has been the de facto standard of microbiome profiling. A limitation of this technology is the inability to accurately assign taxonomy to a species order. Long read 16S sequencing platforms, including Oxford Nanopore Technologies (ONT), have the potential to overcome this limitation. The paranasal sinuses are an ideal niche to apply this technology, being a low biomass environment where bacteria are implicated in disease propagation. Characterising the microbiome to a species order may offer new pathophysiological insights. METHODOLOGY: Cohort series comparing ONT and NGS biological conclusions. Swabs obtained endoscopically from the middle meatus of 61 CRSwNP patients underwent DNA extraction, amplification and dual sequencing (Illumina Miseq (NGS) and ONT GridION). Agreement, relative abundance, prevalence, and culture correlations were compared. RESULTS: Mean microbiome agreement between sequencers was 61.4%. Mean abundance correlations were strongest at a familial/genus order and declined at a species order where NGS lacked resolution. The most significant discrepancies applied to Corynebacterium and Cutibacterium, which were estimated in lower abundance by ONT. ONT accurately identified 84.2% of cultured species, which was significantly higher than NGS. CONCLUSIONS: ONT demonstrated superior resolution and culture correlations to NGS, but underestimated core sinonasal taxa. Future application and optimisation of this technology can advance our understanding of the sinonasal microenvironment.

Ulcerative stomatitis associated with yellow bristle grass in New Zealand dairy cows.

CASE HISTORY: A line of 25 cull cows were all found to have ulcerative lesions of the tongue at post-mortem inspection in a New Zealand slaughter plant. A further 9 of 10 cows inspected at the farm of origin had similar oral lesions. There were no other clinical signs or indicators of ill-health observed at ante-mortem inspection in the abattoir or on the farm. The cows had been fed baleage for 3 weeks prior to slaughter, made from pasture in paddocks heavily contaminated with yellow bristle grass (Setaria pumila). CLINICAL FINDINGS: There was extensive and deep transverse linear ulceration in the lingual fossa immediately rostral to the torus linguae. At histological examination, full-thickness ulceration of the stratified squamous epithelium was observed with a bed of disorganised collagenous tissue and extensive mixed inflammatory infiltrate extending into the sub-epithelial connective tissue and skeletal muscle. Barbed plant fragments were embedded in both the superficial and deeper areas of inflammation. Detailed examination of the baleage also found that yellow bristle grass seedheads were present. DIAGNOSIS: Based on the presence of barbed plant material in the tongue and yellow bristle grass seeds in the baleage, a diagnosis of ulcerative stomatitis associated with yellow bristle grass was made. CLINICAL RELEVANCE: Clinicians should be aware of the potential for hay or baleage contaminated with yellow bristle grass to cause oral lesions in cattle.

An outbreak of ischaemic teat necrosis in a dairy herd in Taranaki, New Zealand.

CASE HISTORY: In spring 2021, on a seasonally calving, pastorally based, Taranaki dairy farm, 12 first-calving heifers (≤ 30 days post-calving) developed similar dry, red to black, crusting lesions on the medial aspect of the teat udder junction extending down the medial teat. Some cows had multiple teats affected. Treatment was initially unrewarding and did not slow the progression of the disease. Overall, 8/12 cows recovered, and 4/12 cows were culled, with three of the cows culled after a teat sloughed and the fourth after surgical amputation of a teat. Outbreaks of the same condition, on the same farm but affecting fewer animals, occurred in spring 2022 (n = 6) and spring 2023 (n = 3). CLINICAL FINDINGS: An initial scab-like or crusting lesion progressed to resemble a thick eschar consisting of very dry and hard dead tissue. The unaffected areas of the teat felt normal but immediately under the dead tissue, there was a warm, firmer area consistent with an inflammatory reaction. Removing the scab led to profuse bleeding, with no visible bed of granulation underneath the scab. There was no leaking of milk in those cows that lost a teat, and no smell to the lesions themselves. Serology and virology ruled out the involvement of bovine alphaherpesvirus (BoHV-2) bovine gammaherpesvirus (BoHV-4), orthopoxviruses (cowpox) and parapoxviruses (pseudocowpox). Histopathology of an affected and surgically amputated teat showed multifocal erosion and ulceration of the epidermis, covered by a thick serocellular crust. In areas of ulceration, there were numerous neutrophils, and the dermis was expanded by granulation tissue with variable numbers of neutrophils, eosinophils, and lymphocytes around small blood vessels. DIAGNOSIS: Based on the similarity of the history, presentation, and histopathological changes to those described for a novel disease reported in the UK, a diagnosis of ischaemic teat necrosis (ITN) was made. CLINICAL RELEVANCE: If ITN is an emerging condition in New Zealand and becomes as prevalent as it has in the UK, clinicians will be confronted with a significant new welfare problem in dairy cows. Anecdotally, there have been reports of other ITN outbreaks in New Zealand, and the Ministry for Primary Industries would be interested in collating reports from other New Zealand veterinarians.

Short-Term Concerns Primarily Determine Patient Preference for Abdominal Aortic Aneurysm Repair.

INTRODUCTION: Abdominal aortic aneurysm (AAA) repair may be performed through open or endovascular approaches, but the factors influencing a patient's repair-type preference are not well characterized. Here we performed a qualitative analysis to better understand factors influencing patient preference within the Preference for Open Versus Endovascular Repair of AAA Trial. METHODS: Open-ended responses regarding primary (n = 21) and secondary (n = 47) factors influencing patient preference underwent qualitative analysis using the constant comparative method with iterative reviews. Codes were used to generate themes and themes grouped into categories, with each step conducted via consensus agreement between three researchers. Relative prevalence of themes were compared to ascertain trends in patient preference. RESULTS: Patient responses regarding both primary and secondary factors fell into four categories: Short-term concerns, long-term concerns, advice & experience, and other. Patients most frequently described short-term concerns (23) as their primary influence, with themes including post-op complications, hospitalization & recovery, and intraoperative concerns. Long-term concerns were more prevalent (20) as secondary factors, which included themes such as survival, and chronic management. The average age of patients voicing only long-term concerns as a primary factor was 11 years younger than those listing only short-term concerns. CONCLUSION: Short-term concerns relating to the procedure and recovery are more often the primary factor influencing patient preference, while long term concerns play a more secondary role. Long-term concerns are more often a primary factor in younger patients. Vascular surgeons should consider this information in shared decision making to reach an optimal outcome.

Vancomycin-Resistant Enterococci in Patients Attending for Colonoscopy: An Estimate of Community Prevalence.

Aims Ireland has the highest vancomycin-resistant Enterococcus faecium (VRE) bloodstream infection prevalence in Europe. Two patterns of VRE carriage are recognised. European, with widespread community prevalence and North American, where carriage is predominantly nosocomial. It is unclear which pattern is dominant in Ireland. This uncertainty limits infection control measures. This study sought to explore this issue via a cross sectional point prevalence study. Methods Asymptomatic community volunteers, represented by patients undergoing elective outpatient colonoscopy testing, were opportunistically screened for VRE. Demographic and risk factor data were collected via a patient survey. Rectal swabs were collected before colonoscopy and VRE was identified using the VITEK MS system. Results 102 patients were cultured. A single patient tested positive, representing a prevalence rate of 0.98% (95% CI <0.01-5.8%). This patient demonstrated traditional risk factors, suggesting nosocomial rather than community acquisition. 94% (N=94) of patients had no knowledge of VRE, while 83% (N=83) had low levels of concern regarding hospital acquired infections. Conclusion There is a low incidence of VRE in the Irish community setting, in contrast to other European Countries, suggesting asymptomatic community colonization is not responsible for the high rates of VRE seen in Ireland. Wider screening or atypical infection control measures would not be supported by this data.

Major quantitative trait loci influencing milk production and conformation traits in Guernsey dairy cattle detected on Bos taurus autosome 19.

The goal of this study was to identify potential quantitative trait loci (QTL) for 27 production, fitness, and conformation traits of Guernsey cattle through genome-wide association (GWA) analyses, with extra emphasis on BTA19, where major QTL were observed for several traits. Animals' de-regressed predicted transmitting abilities (PTA) from the December 2018 traditional US evaluation were used as phenotypes. All of the Guernsey cattle included in the QTL analyses were predictor animals in the reference population, ranging from 1,077 to 1,685 animals for different traits. Single-trait GWA analyses were carried out by a mixed-model approach for all 27 traits using imputed high-density genotypes. A major QTL was detected on BTA19, influencing several milk production traits, conformation traits, and livability of Guernsey cattle, and the most significant SNP lie in the region of 26.2 to 28.3 Mb. The myosin heavy chain 10 (MYH10) gene residing within this region was found to be highly associated with milk production and body conformation traits of dairy cattle. After the initial GWA analyses, which suggested that many significant SNP are in linkage with one another, conditional analyses were used for fine mapping. The top significant SNP on BTA19 were fixed as covariables in the model, one at a time, until no more significant SNP were detected on BTA19. After this fine-mapping approach was applied, only 1 significant SNP was detected on BTA19 for most traits, but multiple, independent significant SNP were found for protein yield, dairy form, and stature. In addition, the haplotype that hosts the major QTL on BTA19 was traced to a US Guernsey born in 1954. The haplotype is common in the breed, indicating a long-term influence of this QTL on the US Guernsey population.

A Survey of Latent Tuberculosis Screening and Treatment Practices in a Tertiary Centre.

Aim Knowledge of latent tuberculosis infection (LTBI) screening and treatment practices are lacking in Ireland, where LTBI is not programmatically surveyed or managed. The aim of this research was to describe current clinical practice when screening and treating patients for LTBI in a tertiary referral centre in Ireland. Methods A 17-question survey relating to LTBI screening and management practices with both open-ended questions and close ended multiple-choice questions was created using SurveyMonkey. The survey target sample was healthcare workers in the tertiary centre who direct LTBI screening and treatment for patients at risk of TB disease in their respective departments. Results The response rate to the survey was 45% (21/47). Seventy-one percent (15/21) of those surveyed responded to the question "What barriers exist to screening patients for latent TB in your clinical practice?". Fifty-three percent (8/15) said that they found it difficult to access LTBI testing and 27% (4/15) cited accessing the interferon-gamma release assay (IGRA) result as a barrier. Forty-three percent (9/21) responded that there was not a clear referral pathway for patients that they would like specialist input on when diagnosing and managing patients with LTBI. Conclusion Access to LTBI testing, LTBI test results, TB specialist services and the use of rifamycin-based regimens should be improved in this tertiary centre. Consideration should be given to developing a national LTBI education programme for healthcare professionals and updating national LTBI treatment guidelines.

Efficacy and safety of the first-in-class imidazoline-2 receptor ligand CR4056 in pain from knee osteoarthritis and disease phenotypes: a randomized, double-blind, placebo-controlled phase 2 trial.

OBJECTIVE: CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. DESIGN: This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0-100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. RESULTS: 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12-18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. CONCLUSIONS: Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2015-001136-37.

Genomic prediction of residual feed intake in US Holstein dairy cattle.

Genomic selection is an important tool to introduce feed efficiency into dairy cattle breeding. The goals of the current research are to estimate genomic breeding values of residual feed intake (RFI) and to assess the prediction reliability for RFI in the US Holstein population. The RFI data were collected from 4,823 lactations of 3,947 Holstein cows in 9 research herds in the United States, and were pre-adjusted to remove phenotypic correlations with milk energy, metabolic body weight, body weight change, and for several environmental effects. In the current analyses, genomic predicted transmitting abilities of milk energy and of body weight composite were included into the RFI model to further remove the genetic correlations that remained between RFI and these energy sinks. In the first part of the analyses, a national genomic evaluation for RFI was conducted for all the Holsteins in the national database using a standard multi-step genomic evaluation method and 60,671 SNP list. In the second part of the study, a single-step genomic prediction method was applied to estimate genomic breeding values of RFI for all cows with phenotypes, 5,252 elite young bulls, 4,029 young heifers, as well as their ancestors in the pedigree, using a high-density genotype chip. Theoretical prediction reliabilities were calculated for all the studied animals in the single-step genomic prediction by direct inversion of the mixed model equations. In the results, breeding values were estimated for 1.6 million genotyped Holsteins and 60 million ungenotyped Holsteins, The genomic predicted transmitting ability correlations between RFI and other traits in the index (e.g., fertility) are generally low, indicating minor correlated responses on other index traits when selecting for RFI. Genomic prediction reliabilities for RFI averaged 34% for all phenotyped animals and 13% for all 1.6 million genotyped animals. Including genomic information increased the prediction reliabilities for RFI compared with using only pedigree information. All bulls had low reliabilities, and averaged to only 16% for the top 100 net merit progeny-tested bulls. Analyses using single-step genomic prediction and high-density genotypes gave similar results to those obtained from the national evaluation. The average theoretical reliability for RFI was 18% among the elite young bulls under 5 yr old, being lower in the younger generations of elite bulls compared with older bulls. To conclude, the size of the reference population and its relationship to the predicted population remain as the limiting factors in the genomic prediction for RFI. Continued collection of feed intake data is necessary so that reliabilities can be maintained due to close relationships of phenotyped animals with breeding stock. Considering the currently low prediction reliability and high cost of data collection, focusing RFI data collection on relatives of elite bulls that will have the greatest genetic contribution to the next generation will give more gains and profit.

Biopsychosocial factors associated with depression and anxiety in older adults with intellectual disability: results of the wave 3 Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing.

BACKGROUND: Depression and anxiety are amongst the most prevalent mental health disorders in the older population with intellectual disability (ID). There is a paucity of research that pertains to associative biopsychosocial factors for depression and anxiety in this population. The aim of this study is to determine the biopsychosocial factors associated with depression and anxiety in a population of older adults with ID in Ireland. METHODS: The study was part of 'The Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing'. Depressive symptoms were assessed using the Glasgow Depression Scale for people with a Learning Disability. Anxiety symptoms were measured using the Glasgow Anxiety Scale for people with a Learning Disability. The cross-sectional associations of depression and anxiety with biopsychosocial parameters were measured using a variety of self-report and proxy-completed questionnaires. RESULTS: For the study population, 9.97% met the criteria for depression, and 15.12% met the criteria for an anxiety disorder. Participants meeting criteria for depression were more likely to be taking regular mood stabiliser medications and to exhibit aggressive challenging behaviour. Participants meeting criteria for anxiety were more likely to have sleep difficulties and report loneliness. Participants meeting criteria for either/both depression and anxiety were more likely to report loneliness. CONCLUSIONS: This study identified both treatable and modifiable, as well as unmodifiable, biopsychosocial factors associated with depression and/or anxiety in older adults with ID. A longitudinal study follow-up will further develop our knowledge on the causality and direction of associated biopsychosocial factors with depression and anxiety in older adults with ID and better inform management strategies, prevention policies and funding of services.

Integration of a recent infection testing algorithm into HIV surveillance in Ireland: improving HIV knowledge to target prevention.

Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04-6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.

Calling known variants and identifying new variants while rapidly aligning sequence data.

Whole-genome sequencing studies can identify causative mutations for subsequent use in genomic evaluations. Speed and accuracy of sequence alignment can be improved by accounting for known variant locations during alignment instead of calling the variants after alignment as in previous programs. The new programs Findmap and Findvar were compared with alignment using Burrows-Wheeler alignment (BWA) or SNAP and variant identification using Genome Analysis ToolKit (GATK) or SAMtools. Findmap stores the reference map and any known variant locations while aligning reads and counting reference and alternate alleles for each DNA source. Findmap also outputs potential new single nucleotide variant, insertion, and deletion alleles. Findvar separates likely true variants from read errors and outputs genotype probabilities. Strategies were tested using cattle, human, and a completely random reference map and simulated or actual data. Most tests simulated 10 bulls, each with 10× simulated sequence reads containing 39 million variants from the 1000 Bull Genomes Project. With 10 processors, clock times for processing 100× data were 105 h for BWA, 25 h for GATK, and 11 h for SAMtools but only about 4 h for SNAP, 3 h for Findmap, and 1 h for Findvar. Alignment programs required about the same total memory; BWA used 46 GB (4.6 GB/processor), whereas >10 processors can share the same memory in SNAP and Findmap, which used 40 and 46 GB, respectively. Findmap correctly mapped 92.9% of reads (compared with 92.6% from SNAP and 90.5% from BWA) and had high accuracy of calling alleles for known variants. For new variants, Findvar found 99.8% of single nucleotide variants, 79% of insertions, and 67% of deletions; GATK found 99.4, 95, and 90%, respectively; and SAMtools found 99.8, 12, and 16%, respectively. False positives (as percentages of true variants) were 11% of single nucleotide variants, 0.4% of insertions, and 0.3% of deletions from Findvar; 12, 8.4, and 2.9%, respectively, from GATK; and 37, 1.3, and 0.4%, respectively, from SAMtools. Advantages of Findmap and Findvar are fast processing, precise alignment, more useful data summaries, more compact output, and fewer steps. Calling known variants during alignment allows more efficient and accurate sequence-based genotyping.

The association of life events and mental ill health in older adults with intellectual disability: results of the wave 3 Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing.

BACKGROUND: Exposures to life events are associated with emotional, psychological and behavioural problems in those with intellectual disability (ID). Older adults with ID may experience different life events given differences in living circumstances, cognitive decline, greater dependency on others and less autonomy. This study examines the relationship of life events and mental ill health in an older ID population in Ireland. METHODS: The study was part of 'The Intellectual Disability Supplement to The Irish Longitudinal Study on Ageing'. The frequency of life events was assessed using a 20-item checklist, and the level of stress experienced was assessed using a three-point Likert scale measuring the burden of the life event. The associations of life events with factors associated with mental ill health were measured using a variety of self-report and proxy completed questionnaires. RESULTS: For the study population, 88.1% had been exposed to at least one life event in the preceding 12 months and 64.5% to two or more life events. Frequency and burden of life events were significantly higher in individuals living in institutional settings and in individuals with any current psychiatric condition, increased depressive and anxiety symptoms, challenging behaviour and reported poorer self-rated mental and physical health. More life events were significantly associated with new psychiatric diagnoses as well as initiation and increased dosage of mood stabilising, hypnotic and sedative medications. CONCLUSIONS: Life events are significantly associated with mental ill health in the older ID population. Service providers must focus on limiting the exposure to these events and, in situations where they cannot be avoided, should support and manage individuals compassionately and effectively, prioritising their mental and physical well-being.

Determination of quantitative trait nucleotides by concordance analysis between quantitative trait loci and marker genotypes of US Holsteins.

Experimental designs that exploit family information can provide substantial predictive power in quantitative trait nucleotide discovery projects. Concordance between quantitative trait locus genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 30 trait-by-chromosomal segment effects segregating in the US Holstein population with probabilities of <10-20 to accept the null hypotheses of no segregating gene affecting the trait within the chromosomal segment. Genotypes for 83 grandsires and 17,217 sons were determined by either complete sequence or imputation for 3,148,506 polymorphisms across the entire genome; 471 Holstein bulls had a complete genome sequence, including 64 of the grandsires. Complete concordance was obtained only for stature on chromosome 14 and daughter pregnancy rate on chromosome 18. For each quantitative trait locus, effects of the 30 polymorphisms with highest concordance scores for the analyzed trait were computed by stepwise regression for predicted transmitting abilities of 26,750 bulls with progeny test and imputed genotypes. Effects for stature on chromosome 11, daughter pregnancy rate on chromosome 18, and protein percentage on chromosome 20 met 3 criteria: complete or almost complete concordance, nominal significance of the polymorphism effect after correction for all other polymorphisms, and marker coefficient of determination >40% of total multiple-regression coefficient of determination for the 30 polymorphisms with highest concordance. An intronic variant marker on chromosome 5 at 93,945,738 bp explained 7% of variance for fat percentage and 74% of total multiple-marker regression variance but was concordant for only 24 of 30 families. The missense polymorphism Phe279Tyr in GHR at 31,909,478 bp on chromosome 20 was confirmed as the causative mutation for fat and protein concentration. For effect on fat percentage on chromosome 14, 12 additional missense polymorphisms were found that had almost complete concordance with the suggested causative polymorphism (missense mutation Ala232Glu in DGAT1). The only polymorphism found likely to improve predictive power for genomic evaluation of dairy cattle was on chromosome 15; that polymorphism had a frequency of 0.45 for the allele with economically positive effects on all production traits.

Blood lactate accumulation decreases during the slow component of oxygen uptake without a decrease in muscular efficiency.

Pulmonary oxygen uptake ([Formula: see text]) slowly increases during exercise above the anaerobic threshold, and this increase is called the slow component of [Formula: see text]. The mechanism of the increase in [Formula: see text] is assumed to be due to increasing energy cost associated with increasingly inefficient muscle contraction. We hypothesized that the increase in [Formula: see text] would be accompanied by a constant or increasing rate of accumulation of blood lactate, indicating sustained anaerobic metabolism while [Formula: see text] increased. Ten male subjects performed cycle ergometry for 3, 6, and 9 min at a power output representing 60% of the difference between lactate threshold and maximal [Formula: see text] while [Formula: see text] and blood lactate accumulation were measured. Blood lactate accumulation decreased over time, providing the energy equivalent of (mean ± SD) 1586 ± 265, 855 ± 287, and 431 ± 392 ml of [Formula: see text] during 0-3, 3-6, and 6-9 min of exercise, respectively. As duration progressed, [Formula: see text] supplied 86.3 ± 2.0, 93.6 ± 1.9, and 96.8 ± 2.9% of total energy from 0 to 3, 3 to 6, and 6 to 9 min, respectively, while anaerobic contribution decreased. There was no change in total energy cost after 3 min, except that required by ventilatory muscles for the progressive increase in ventilation. The slow component of [Formula: see text] is accompanied by decreasing anaerobic energy contribution beyond 3 min during heavy exercise.

A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer.

BACKGROUND: ARCHER 1042, a randomized phase II trial, explored the impact of prophylactic treatment on select dermatologic adverse events of interest (SDAEI), diarrhea, and mucositis associated with dacomitinib, an oral irreversible pan-human epidermal growth factor receptor (HER) inhibitor, in development for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC treated with dacomitinib were enrolled in two cohorts. Cohort I patients were randomized 1:1 to receive oral doxycycline or placebo (4 weeks). Cohort II patients received oral VSL#3 probiotic plus topical alclometasone. Primary end points for Cohorts I and II were incidence of all grade and grade ≥2 SDAEI in the first 8 weeks of treatment and quality of life (QoL) assessed by the Skindex-16 survey. Additional primary end points for Cohort II were incidence of all grade and grade ≥2 diarrhea and mucositis in the first 8 weeks of treatment; QoL regarding diarrhea and mucositis incidence was assessed by the modified-Oral Mucositis Daily Questionnaire. RESULTS: Cohort I randomized 114 evaluable patients: 56 in the doxycycline arm, 58 in the placebo arm. Cohort II enrolled 59 evaluable patients. Doxycycline significantly reduced the incidence of grade ≥2 SDAEI by 50% (P = 0.016) compared with placebo. The incidence of all grade SDAEI was lower with doxycycline than with placebo but did not reach statistical significance. Doxycycline was associated with less deterioration in QoL compared with placebo. Alclometasone was associated with less deterioration in QoL compared with placebo but did not statistically significantly reduce the incidence of all grade or grade ≥2 SDAEI. VSL#3 did not reduce the incidence of all grade or grade ≥2 diarrhea and did not impact mucositis scores. CONCLUSIONS: Doxycycline was effective as a prophylactic treatment for dacomitinib-induced grade ≥2 SDAEI. Both doxycycline and alclometasone reduced the negative impact in patient-reported dermatologic AEs. The probiotic was not effective for preventing diarrhea or mucositis.

Domain wall conductivity in semiconducting hexagonal ferroelectric TbMnO3 thin films.

Although enhanced conductivity of ferroelectric domain boundaries has been found in BiFeO3 and Pb(Zr,Ti)O3 films as well as hexagonal rare-earth manganite single crystals, the mechanism of the domain wall conductivity is still under debate. Using conductive atomic force microscopy, we observe enhanced conductance at the electrically-neutral domain walls in semiconducting hexagonal ferroelectric TbMnO3 thin films where the structure and polarization direction are strongly constrained along the c-axis. This result indicates that domain wall conductivity in ferroelectric rare-earth manganites is not limited to charged domain walls. We show that the observed conductivity in the TbMnO3 films is governed by a single conduction mechanism, namely, the back-to-back Schottky diodes tuned by the segregation of defects.

Reporting of Acute Flaccid Paralysis in Children under 15 years of age: Improving Surveillance, January 2009 - December 2014.

Acute Flaccid Paralysis (AFP) surveillance, including case investigation and specimen collection is a gold standard method for poliomyelitis surveillance. The expected annual non-polio AFP rate <15 years of age in Ireland is = 1/100 000 population. This study reviewed all cases of AFP reported to the Irish Paediatric Surveillance Unit and the Health Protection Surveillance Centre between January 2009 and December 2014 and compared reporting rates with the expected incidence rate annually. We assessed quality of surveillance data in terms of completeness of investigation for each case reported. Forty-three AFP cases in children <15 years were notified; 35 of which were confirmed. Guillain-Barre Syndrome (GBS) accounted for 48.6% (n=17) of AFP notifications. In 2014, the expected annual AFP target rate was reached. This study identified possible under-reporting of AFP paediatric cases in Ireland between 2009-2013. Completeness of investigations has improved over time, but requires further work.