British Society of Gastroenterology guidelines on sedation in gastrointestinal endoscopy.

Over 2.5 million gastrointestinal endoscopic procedures are carried out in the United Kingdom (UK) every year. Procedures are carried out with local anaesthetic r with sedation. Sedation is commonly used for gastrointestinal endoscopy, but the type and amount of sedation administered is influenced by the complexity and nature of the procedure and patient factors. The elective and emergency nature of endoscopy procedures and local resources also have a significant impact on the delivery of sedation. In the UK, the vast majority of sedated procedures are carried out using benzodiazepines, with or without opiates, whereas deeper sedation using propofol or general anaesthetic requires the involvement of an anaesthetic team. Patients undergoing gastrointestinal endoscopy need to have good understanding of the options for sedation, including the option for no sedation and alternatives, balancing the intended aims of the procedure and reducing the risk of complications. These guidelines were commissioned by the British Society of Gastroenterology (BSG) Endoscopy Committee with input from major stakeholders, to provide a detailed update, incorporating recent advances in sedation for gastrointestinal endoscopy.This guideline covers aspects from pre-assessment of the elective 'well' patient to patients with significant comorbidity requiring emergency procedures. Types of sedation are discussed, procedure and room requirements and the recovery period, providing guidance to enhance safety and minimise complications. These guidelines are intended to inform practising clinicians and all staff involved in the delivery of gastrointestinal endoscopy with an expectation that this guideline will be revised in 5-years' time.

Device-assisted enteroscopy performance measures in the United Kingdom: DEEP-UK quality improvement project.

BACKGROUND: Device-assisted enteroscopy (DAE) has become a well-established diagnostic and therapeutic tool for the management of small-bowel pathology. We aimed to evaluate the performance measures for DAE across the UK against the quality benchmarks proposed by the European Society of Gastrointestinal Endoscopy (ESGE). METHODS: We retrospectively collected data on patient demographics and DAE performance measures from electronic endoscopy records of consecutive patients who underwent DAE for diagnostic and therapeutic purposes across 12 enteroscopy centers in the UK between January 2017 and December 2022. RESULTS: A total of 2005 DAE procedures were performed in 1663 patients (median age 60 years; 53% men). Almost all procedures (98.1%) were performed for appropriate indications. Double-balloon enteroscopy was used for most procedures (82.0%), followed by single-balloon enteroscopy (17.2%) and spiral enteroscopy (0.7%). The estimated depth of insertion was documented in 73.4% of procedures. The overall diagnostic yield was 70.0%. Therapeutic interventions were performed in 42.6% of procedures, with a success rate of 96.6%. Overall, 78.0% of detected lesions were marked with a tattoo. Patient comfort was significantly better with the use of deep sedation compared with conscious sedation (99.7% vs. 68.5%; P<0.001). Major adverse events occurred in only 0.6% of procedures. CONCLUSIONS: Performance measures for DAE in the UK meet the ESGE quality benchmarks, with high diagnostic and therapeutic yields, and a low incidence of major adverse events. However, there is room for improvement in optimizing sedation practices, standardizing the depth of insertion documentation, and adopting marking techniques to aid in the follow-up of detected lesions.

The Role of Soil Abundance of TxtAB in Potato Common Scab Disease Severity.

Common scab is an economically costly soilborne disease of potato endemic in many potato-growing regions. The disease is caused by species of Streptomyces bacteria that produce the phytotoxin thaxtomin A. The primary disease management tool available to growers is planting resistant cultivars, but no cultivar is fully resistant to common scab, and partially resistant cultivars are often not the preferred choice of growers because of agronomic or market considerations. Therefore, growers would benefit from knowledge of the presence and severity of common scab infestations in field soils to make informed planting decisions. We implemented a quantitative PCR diagnostic assay to enable field detection and quantification of all strains of Streptomyces that cause common scab in the United States through amplification of thaxtomin A biosynthetic genes. Greenhouse trials confirmed that pathogen abundance was highly correlated with disease severity for five distinct phytopathogenic Streptomyces species, although the degree of disease severity was dependent on the pathogen species. Correlations between the abundance of the thaxtomin biosynthetic genes from field soil with disease on tubers at field sites across four U.S. states and across 2 years were not as strong as correlations observed in greenhouse assays. We also developed an effective droplet digital PCR diagnostic assay that also has potential for field quantification of thaxtomin biosynthetic genes. Further improvement of the PCR assays and added modeling of other environmental factors that impact disease outcome, such as soil composition, can aid growers in making informed planting decisions.

Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells.

Chronic active Epstein-Barr virus (CAEBV) typically presents as persistent infectious mononucleosis-like disease and/or hemophagocytic lymphohistocytosis (HLH), reflecting ectopic Epstein-Barr virus (EBV) infection and lymphoproliferation of T and/or NK cells. Clinical behavior ranges from indolent, stable disease through to rapidly progressive, life-threatening disease. Although it is thought the chronicity and/or progression reflect an escape from immune control, very little is known about the phenotype and function of the infected cells vs coresident noninfected population, nor about the mechanisms that could underpin their evasion of host immune surveillance. To investigate these questions, we developed a multicolor flow cytometry technique combining phenotypic and functional marker staining with in situ hybridization for the EBV-encoded RNAs (EBERs) expressed in every infected cell. This allows the identification, phenotyping, and functional comparison of infected (EBERPOS) and noninfected (EBERNEG) lymphocyte subset(s) in patients' blood samples ex vivo. We have characterized CAEBV and HLH cases with monoclonal populations of discrete EBV-activated T-cell subsets, in some cases accompanied by EBV-activated NK-cell subsets, with longitudinal data on the infected cells' progression despite standard steroid-based therapy. Given that cytotoxic CD8+ T cells with relevant EBV antigen specificity were detectable in the blood of the best studied patient, we searched for means whereby host surveillance might be impaired. This revealed a unique feature in almost every patient with CAEBV studied: the presence of large numbers of myeloid-derived suppressor cells that exhibited robust inhibition of T-cell growth. We suggest that their influence is likely to explain the host's failure to contain EBV-positive T/NK-cell proliferation.

Developmental trajectories of delay discounting from childhood to young adulthood: longitudinal associations and test-retest reliability.

Delay discounting (DD) indexes an individual's preference for smaller immediate rewards over larger delayed rewards, and is considered a form of cognitive impulsivity. Cross-sectional studies have demonstrated that DD peaks in adolescence; longitudinal studies are needed to validate this putative developmental trend, and to determine whether DD assesses a temporary state, or reflects a more stable behavioral trait. In this study, 140 individuals aged 9-23 completed a delay discounting (DD) task and cognitive battery at baseline and every-two years thereafter, yielding five assessments over approximately 10 years. Models fit with the inverse effect of age best approximated the longitudinal trajectory of two DD measures, hyperbolic discounting (log[k]) and area under the indifference-point curve (AUC). Discounting of future rewards increased rapidly from childhood to adolescence and appeared to plateau in late adolescence for both models of DD. Participants with greater verbal intelligence and working memory displayed reduced DD across the duration of the study, suggesting a functional interrelationship between these domains and DD from early adolescence to adulthood. Furthermore, AUC demonstrated good to excellent reliability across assessment points that was superior to log(k), with both measures demonstrating acceptable stability once participants reached late adolescence. The developmental trajectories of DD we observed from childhood through young adulthood suggest that DD may index cognitive control more than reward sensitivity, and that despite modest developmental changes with maturation, AUC may be conceptualized as a trait variable related to cognitive control vs impulsivity.

Neuroplasticity, the Prefrontal Cortex, and Psychopathology-Related Deviations in Cognitive Control.

A basic survival need is the ability to respond to, and persevere in the midst of, experiential challenges. Mechanisms of neuroplasticity permit this responsivity via functional adaptations (flexibility), as well as more substantial structural modifications following chronic stress or injury. This review focuses on prefrontally based flexibility, expressed throughout large-scale neuronal networks through the actions of excitatory and inhibitory neurotransmitters and neuromodulators. With substance use disorders and stress-related internalizing disorders as exemplars, we review human behavioral and neuroimaging data, considering whether executive control, particularly cognitive flexibility, is impaired premorbidly, enduringly compromised with illness progression, or both. We conclude that deviations in control processes are consistently expressed in the context of active illness but operate through different mechanisms and with distinct longitudinal patterns in externalizing versus internalizing conditions.

An open-label prospective study to assess short incubation time white LED light photodynamic therapy in the treatment of superficial basal cell carcinoma.

Artificial white LED light photodynamic therapy (awl-PDT) is an effective, pain-free treatment for actinic keratosis. The efficacy of awl-PDT in the treatment of superficial basal cell carcinoma (sBCC) has not been assessed. Patients with histologically confirmed sBCC underwent two treatments of awl-PDT 1 week apart. Lesions were incubated with methyl 5-aminolaevulinic acid for 30 min and then illuminated using the Maquet Power LED 500 theatre light (405-800nm, 140 000 lux) to deliver an equivalent red light dose of 75 J/cm2 at a rate of 55 mW/cm2 . Pain was measured using a visual analogue scale during treatment. Clinical response was assessed at day 28. Follow-up continued 3 months for 1 year. Cosmetic outcome was assessed at 3 months and 1 year. Twenty-eight patients with 36 lesions and a mean age of 63.64 (SD 2.62) were recruited. The median lesion size was 15 mm (IQR 8.75). The response rate at day 28 was 100%. Recurrence rates were 3/36 (8.3%) at 3 months, 6/36 (16.7%) at 6 months, 10/36 (27.8%) at 9 months and 11/36 (30.6%) at 1 year. Median pain scores were 0/100 (IQR 0) and 0/100 (IQR 5) during treatments one and two, respectively. Cosmetic outcome was excellent or good in the majority of cases. Although initially effective for sBCC at 28 days, 30.6% of lesions recurred 1 year after awl-PDT. Pain scores were negligible, and the cosmetic outcome was favourable. Further head-to-head studies with optimised protocols are required to determine if awl-PDT has a role in the treatment of sBCC.

Molecular mapping of quantitative disease resistance loci for soybean partial resistance to Phytophthora sansomeana.

KEY MESSAGE: Two soybean QDRL were identified with additive interaction to P. sansomeana isolate MPS17-22. Further analyses uncovered four interaction patterns between the two QDRL and seven additional P. sansomeana isolates. Phytophthora sansomeana is a recently recognized species that contributes to root rot in soybean. Previous studies indicated that P. sansomeana is widely distributed among soybean growing regions and has a much wider host range than P. sojae, a well-known pathogen of soybean. Unlike P. sojae, no known disease resistance genes have been documented that can effectively control P. sansomeana. Therefore, it is important to identify resistance that can be quickly integrated into future soybean varieties. E13901 is an improved soybean line that confers partial resistance to P. sansomeana. A mapping population of 228 F4:5 families was developed from a cross between E13901 and a susceptible improved soybean variety E13390. Using a composite interval mapping method, two quantitative disease resistance loci (QDRL) were identified on Chromosomes 5 (designated qPsan5.1) and 16 (designated qPsan16.1), respectively. qPsan5.1 was mapped at 54.71 cM between Gm05_32565157_T_C and Gm05_32327497_T_C. qPsan5.1 was contributed by E13390 and explained about 6% of the disease resistance variation. qPsan16.1 was located at 39.01 cM between Gm16_35700223_G_T and Gm16_35933600/ Gm16_35816475. qPsan16.1 was from E13901 and could explain 5.5% of partial disease resistance. Further analysis indicated an additive interaction of qPsan5.1 and qPsan16.1 against P. sansomeana isolate MPS17-22. Marker assisted resistance spectrum analysis and progeny tests verified the two QDRL and their interaction patterns with other P. sansomeana isolates. Both QDRL can be quickly integrated into soybean varieties using marker assisted selection.

The longitudinal association between externalizing behavior and frontoamygdalar resting-state functional connectivity in late adolescence and young adulthood.

BACKGROUND: Externalizing behavior has been attributed, in part, to decreased frontolimbic control over amygdala activation. However, little is known about developmental trajectories of frontoamygdalar functional connectivity and its relation to externalizing behavior. The present study addresses this gap by examining longitudinal associations between adolescent and adult externalizing behavior and amygdala-anterior cingulate cortex (ACC) and amygdala-orbitofrontal cortex (OFC) resting-state functional connectivity in a sample of 111 typically developing participants aged 11-23 at baseline. METHODS: Participants completed two-to-four data waves spaced approximately two years apart, resulting in a total of 309 data points. At each data wave, externalizing behavior was measured using the Externalizing Behavior Broadband Scale from the Achenbach Youth/Adult Self-Report questionnaire. Resting-state fMRI preprocessing was performed using FSL. Amygdala functional connectivity was examined using AFNI. The longitudinal association between externalizing behavior and amygdala-ACC/OFC functional connectivity was examined using linear mixed effect models in R. RESULTS: Externalizing behavior was associated with increased amygdala-ACC and amygdala-OFC resting-state functional connectivity across adolescence and young adulthood. For amygdala-ACC connectivity, externalizing behavior at baseline primarily drove this association, whereas for amygdala-OFC functional connectivity, change in externalizing behavior relative to baseline drove the main effect of externalizing behavior on amygdala-OFC functional connectivity. No evidence was found for differential developmental trajectories of frontoamygdalar connectivity for different levels of externalizing behavior (i.e., age-by-externalizing behavior interaction effect). CONCLUSIONS: Higher externalizing behavior is associated with increased resting-state attunement between the amygdala and ACC/OFC, perhaps indicating a generally more vigilant state for neural networks important for emotional processing and control.

Initiation of Moderately Frequent Cannabis use in Adolescence and Young Adulthood is Associated with Declines in Verbal Learning and Memory: A Longitudinal Comparison of Pre- versus Post-Initiation Cognitive Performance.

OBJECTIVE: Cannabis use is associated with relative cognitive weaknesses as observed by cross-sectional as well as longitudinal research. Longitudinal studies, controlling for relevant confounds, are necessary to differentiate premorbid from post-initiation contributions to these effects. METHODS: We followed a sample of adolescents and young adults across ten years. Participants provided neurocognitive data and substance use information at two-year intervals. Participants who initiated cannabis and/or alcohol use were identified (n = 86) and split into alcohol-only initiators (n = 39) and infrequent (n = 29) and moderately frequent (n = 18) cannabis initiators. Participants completed the Rey Auditory Verbal Learning Task (RAVLT) and the Iowa Gambling Task (IGT). Group differences before and after substance use initiation and the extent to which alcohol, nicotine, and cannabis use frequencies contributed to cognitive functions over time were examined. RESULTS: After controlling for parental education, RAVLT new learning was worse in moderately frequent cannabis users prior to use initiation. RAVLT total learning and delayed recall showed significant declines from pre- to post-initiation in moderately frequent cannabis users. Regression analyses confirmed that frequencies of cannabis, but not alcohol, use contributed to post-initiation variations. Nicotine use showed an independent negative association with delayed memory. Findings for the IGT were not significant. CONCLUSIONS: Verbal learning and memory may be disrupted following the initiation of moderately frequent cannabis use while decreased new learning may represent a premorbid liability. Our use of a control group of alcohol-only users adds interpretive clarity to the findings and suggests that future studies should carefully control for comorbid substance use.

From Paris to Montreal: disease regression is common during long term follow-up of paediatric Crohn's disease.

Introduction: Paediatric Crohn's disease (PCD) often presents with extensive and a frequent pan-enteric phenotype at onset. However, its long term evolution into adulthood, especially since the widespread use of biological agents, is not well characterised. We conducted a single centre cohort study of all PCD patients transitioned to adult care to assess the long term disease evolution in the era of biologic therapy.Methods: We conducted a retrospective observational, study of all PCD patients who were subsequently transferred to the care of an adult gastroenterology unit and had a minimum follow up of 2 years. We examined the case notes for evolution of disease location and behaviour. Disease location and behaviour was characterised using Paris classification at diagnosis and Montreal classification at last follow-up. In addition, we examined variables associated with complicated disease behaviour and the need for CD related intestinal resection.Results: In total, 132 patients were included with a median age at diagnosis of 13 (IQR 11-14) and a median follow up of 11 years (range 4-14). At diagnosis, 23 (17.4%), 39 (29.6%) and 70 (53%) patients had ileal, colonic and ileocolonic disease respectively. In addition, 31 (23.5%) patients had L4a or L4b disease at diagnosis (proximal or distal to the ligament of treitz respectively) and 13 patients (9.8%) had both whilst 27 (20.4%) patients had perianal disease. At diagnosis, 27 (20.4%) patients had complicated disease behaviour but 83 (62.9)% of patients had an extensive 'pan-enteric' phenotype. Of these patients only 55 (66.3%) retained the pan-enteric phenotype at last follow-up (p = .0002). Disease extension was noted in 25 (18.9%) of patients and regression was noted in 47 (35.6%) of patients, whereas upper GI disease was noted in significantly fewer patients at last follow-up (21, 15.9%) (p = .0001). More patients had complicated disease behaviour (46 patients, 34.9%, p = .0018) at last follow-up. There was a high exposure to both thiopurines 121 (91.7%) and biologics 84 (63.6%). The cumulative probability (95% CI) of surgery was 0.05 (0.02, 0.11) at 1 year, 0.17 (0.11, 0.24) at 3 years and 0.22 (0.15, 0.30) at 5 years. Neither disease location nor behaviour were associated with the need for intestinal resectional surgery.Conclusions: Over the course of an extended follow-up period, there appeared to be changes in both disease location and behaviour in PCD. Interestingly, a significant proportion of patients had disease involution which may be related to a high rate of exposure to thiopurines and biologics. We were unable to identify any variables associated with complicated disease course or the need for intestinal surgery.

Pubertal development mediates the association between family environment and brain structure and function in childhood.

Psychosocial acceleration theory suggests that pubertal maturation is accelerated in response to adversity. In addition, suboptimal caregiving accelerates development of the amygdala-medial prefrontal cortex circuit. These findings may be related. Here, we assess whether associations between family environment and measures of the amygdala-medial prefrontal cortex circuit are mediated by pubertal development in more than 2000 9- and 10-year-old children from the Adolescent Brain Cognitive Development Study (http://dx.doi.org/10.15154/1412097). Using structural equation modeling, demographic, child-reported, and parent-reported data on family dynamics were compiled into a higher level family environment latent variable. Magnetic resonance imaging preprocessing and compilations were performed by the Adolescent Brain Cognitive Development Study's data analysis core. Anterior cingulate cortex (ACC) thickness, area, white matter fractional anisotropy, amygdala volume, and cingulo-opercular network-amygdala resting-state functional connectivity were assessed. For ACC cortical thickness and ACC fractional anisotropy, significant indirect effects indicated that a stressful family environment relates to more advanced pubertal stage and more mature brain structure. For cingulo-opercular network-amygdala functional connectivity, results indicated a trend in the expected direction. For ACC area, evidence for quadratic mediation by pubertal stage was found. Sex-stratified analyses suggest stronger results for girls. Despite small effect sizes, structural measures of circuits important for emotional behavior are associated with family environment and show initial evidence of accelerated pubertal development.

Different loci associated with root and foliar resistance to sudden death syndrome (Fusarium virguliforme) in soybean.

KEY MESSAGE: Different loci associated with root resistance to F. virguliforme colonization and foliar resistance to phytotoxin damage in soybean. Use of resistant cultivars is the most efficacious approach to manage soybean sudden death syndrome (SDS), caused by Fusarium virguliforme. The objectives of this study were to (1) map the loci associated with root and foliar resistance to F. virguliforme infection and (2) decipher the relationships between root infection, foliar damage, and plot yield. A mapping population consisting of 153 F4-derived recombinant inbred lines from the cross U01-390489 × E07080 was genotyped by SoySNP6 K BeadChip assay. Both foliar damage and F. virguliforme colonization in roots were investigated in the field, and a weak positive correlation was identified between them. Foliar damage had a stronger negative correlation with plot yield than F. virguliforme colonization. Twelve loci associated with foliar damage were identified, and four of them were associated with multiple traits across environments. In contrast, only one locus associated with root resistance to F. virguliforme colonization was identified and mapped on Chromosome 18. It colocalized with the locus associated with foliar damage in the same environment. The locus on Chromosome 6, qSDS6-2, and the locus on Chromosome 18, qSDS18-1, were associated with resistance to SDS phytotoxins and resistance to F. virguliforme colonization of roots, respectively. Both loci affected plot yield. Foliar damage-related traits, especially disease index, are valuable indicators for SDS resistance breeding because of consistency of the identified loci and their stronger correlation with plot yield. The information provided by this study will facilitate marker-assisted selection to improve SDS resistance in soybean.

Integrating GWAS and gene expression data for functional characterization of resistance to white mould in soya bean.

White mould of soya bean, caused by Sclerotinia sclerotiorum (Lib.) de Bary, is a necrotrophic fungus capable of infecting a wide range of plants. To dissect the genetic architecture of resistance to white mould, a high-density customized single nucleotide polymorphism (SNP) array (52 041 SNPs) was used to genotype two soya bean diversity panels. Combined with resistance variation data observed in the field and greenhouse environments, genome-wide association studies (GWASs) were conducted to identify quantitative trait loci (QTL) controlling resistance against white mould. Results showed that 16 and 11 loci were found significantly associated with resistance in field and greenhouse, respectively. Of these, eight loci localized to previously mapped QTL intervals and one locus had significant associations with resistance across both environments. The expression level changes in genes located in GWAS-identified loci were assessed between partially resistant and susceptible genotypes through a RNA-seq analysis of the stem tissue collected at various time points after inoculation. A set of genes with diverse biological functionalities were identified as strong candidates underlying white mould resistance. Moreover, we found that genomic prediction models outperformed predictions based on significant SNPs. Prediction accuracies ranged from 0.48 to 0.64 for disease index measured in field experiments. The integrative methods, including GWAS, RNA-seq and genomic selection (GS), applied in this study facilitated the identification of causal variants, enhanced our understanding of mechanisms of white mould resistance and provided valuable information regarding breeding for disease resistance through genomic selection in soya bean.

Guidelines for hospital privileges in vascular surgery and endovascular interventions: Recommendations of the Society for Vascular Surgery.

The Hospital Privileges Practice Guideline Writing Group of the Society for Vascular Surgery is making the following five recommendations concerning guidelines for hospital privileges for vascular surgery and endovascular therapy. Advanced endovascular procedures are currently entrenched in the everyday practice of specialized vascular interventionalists, including vascular surgeons, but open vascular surgery remains uniquely essential to the specialty. First, we endorse the Residency Review Committee for Surgery recommendations regarding open and endovascular cases during vascular residency and fellowship training. Second, applicants for new hospital privileges wishing to perform vascular surgery should have completed an Accreditation Council for Graduate Medical Education-accredited vascular surgery residency or fellowship or American Osteopathic Association-accredited training program before 2020 and should obtain American Board of Surgery certification in vascular surgery or American Osteopathic Association certification within 7 years of completion of their training. Third, we recommend that applicants for renewal of hospital privileges in vascular surgery include physicians who are board certified in vascular surgery, general surgery, or cardiothoracic surgery. These physicians with an established practice in vascular surgery should participate in Maintenance of Certification programs as established by the American Board of Surgery and maintain their respective board certification. Fourth, we provide recommendations concerning guidelines for endovascular procedures for vascular surgeons and other vascular interventionalists who are applying for new or renewed hospital privileges. All physicians performing open or endovascular procedures should track outcomes using nationally validated registries, ideally by the Vascular Quality Initiative. Fifth, we endorse the Intersocietal Accreditation Commission recommendations for noninvasive vascular laboratory interpretations and examinations to become a Registered Physician in Vascular Interpretation, which is included in the requirements for board eligibility in vascular surgery, but recommend that only physicians with demonstrated clinical experience in the diagnosis and management of vascular disease be allowed to interpret these studies.

QTL mapping and epistatic interaction analysis of field resistance to sudden death syndrome (Fusarium virguliforme) in soybean.

KEY MESSAGE: Two interactive quantitative trait loci (QTLs) controlled the field resistance to sudden death syndrome (SDS) in soybean. The interaction between them was confirmed. Sudden death syndrome (SDS), caused by Fusarium virguliforme, is a major disease of soybean [Glycine max (L.) Merr.] in the United States. Breeding for soybean resistance to SDS is the most cost-effective method to manage the disease. The objective of this study was to identify and characterize quantitative trait loci (QTLs) underlying field resistance to SDS in a recombinant inbred line population from the cross GD2422 × LD01-5907. This population was genotyped with 1786 polymorphic single nucleotide polymorphisms (SNPs) using SoySNP6 K iSelect BeadChip and evaluated for SDS resistance in a naturally infested field. Four SDS resistance QTLs were mapped on Chromosomes 4, 8, 12 and 18. The resistant parent, LD01-5907, contributed the resistance alleles for the QTLs on Chromosomes 8 and 18 (qSDS-8 and qSDS-18), while the other parent, GD2422, provided the resistance alleles for the QTLs on Chromosomes 4 and 12 (qSDS-4 and qSDS-12). The minor QTL on Chromosome 12 (qSDS-12) is novel. The QTL on Chromosomes 8 and 18 (qSDS-8 and qSDS-18) overlapped with two soybean cyst nematode resistance-related loci, Rhg4 and Rhg1, respectively. A significant interaction between qSDS-8 and qSDS-18 was detected by disease incidence. Individual effects together with the interaction effect explained around 70% of the phenotypic variance. The epistatic interaction of qSDS-8 and qSDS-18 was confirmed by the field performance across multiple years. Furthermore, the resistance alleles at qSDS-8 and qSDS-18 were demonstrated to be recessive. The SNP markers linked to these QTLs will be useful for marker-assisted breeding to enhance the SDS resistance.

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.

The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100-300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.-Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.

UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care.

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;1. Patient populations involved in AYP transition2. Risks of failing transition or poor transition3. Models of AYP transition4. Patient and carer/parent perspective in AYP transition5. Surgical perspective.

CXCL14 displays antimicrobial activity against respiratory tract bacteria and contributes to clearance of Streptococcus pneumoniae pulmonary infection.

CXCL14 is a chemokine with an atypical, yet highly conserved, primary structure characterized by a short N terminus and high sequence identity between human and mouse. Although it induces chemotaxis of monocytic cells at high concentrations, its physiological role in leukocyte trafficking remains elusive. In contrast, several studies have demonstrated that CXCL14 is a broad-spectrum antimicrobial peptide that is expressed abundantly and constitutively in epithelial tissues. In this study, we further explored the antimicrobial properties of CXCL14 against respiratory pathogens in vitro and in vivo. We found that CXCL14 potently killed Pseudomonas aeruginosa, Streptococcus mitis, and Streptococcus pneumoniae in a dose-dependent manner in part through membrane depolarization and rupture. By performing structure-activity studies, we found that the activity against Gram-negative bacteria was largely associated with the N-terminal peptide CXCL141-13. Interestingly, the central part of the molecule representing the ß-sheet also maintained ∼62% killing activity and was sufficient to induce chemotaxis of THP-1 cells. The C-terminal α-helix of CXCL14 had neither antimicrobial nor chemotactic effect. To investigate a physiological function for CXCL14 in innate immunity in vivo, we infected CXCL14-deficient mice with lung pathogens and we found that CXCL14 contributed to enhanced clearance of Streptococcus pneumoniae, but not Pseudomonas aeruginosa. Our comprehensive studies reflect the complex bactericidal mechanisms of CXCL14, and we propose that different structural features are relevant for the killing of Gram-negative and Gram-positive bacteria. Taken together, our studies show that evolutionary-conserved features of CXCL14 are important for constitutive antimicrobial defenses against pneumonia.

Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells.

The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. The expression of CCR8 during naive T cell activation is controlled by skin-specific factors derived from epidermal keratinocytes and not by resident dendritic cells. In this study, we show that the CCR8-inducing factors are heat stable and protease resistant and include the vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 and PGE2. The effect of either metabolite alone on CCR8 expression was weak, whereas their combination resulted in robust CCR8 expression. Elevation of intracellular cAMP was essential because PGE2 could be substituted with the adenylyl cyclase agonist forskolin, and CCR8 expression was sensitive to protein kinase A inhibition. For effective induction, exposure of naive T cells to these epidermal factors needed to occur either prior to or during T cell activation even though CCR8 was only detected 4-5 d later in proliferating T cells. The importance of tissue environments in maintaining cellular immune surveillance networks within distinct healthy tissues provides a paradigm shift in adaptive immunity. Epidermal-derived vitamin D3 metabolites and PGs provide an essential cue for the localization of CCR8(+) immune surveillance T cells within healthy human skin.