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The typical evolution of rheumatoid arthritis (RA) is that a person, with genetic risk factors, develops autoantibodies and subclinical inflammation under relevant environmental influences. There are indications that the primary site of the pathology is at mucosal surfaces (e.g. in the gums, lungs, and/or the gut), after which the disease translocates to the joints. Preclinical RA can be defined at the phase during which no clinically apparent features are present (i.e. no symptoms of inflammatory arthritis or clinically apparent joint swelling) but during which RA related biologic derangements such as the presence of autoantibodies are present. This chapter presents an overview of the risk factors, stages, and events occurring during the pre-RA phase. A better understanding of the factors involved will enable more accurate prediction of RA at the individual level and selection of high-risk individuals for inclusion in preventive studies. Several pharmacologic and non-pharmacologic studies aiming to prevent or delay the onset of RA in at-risk individuals are currently underway. It is hoped that such interventions in the pre-RA and indeed in the preclinical-RA phases will allow us to reduce the risk of RA and prevent RA developing in at least a proportion of at-risk patients.

Intra-articular drug delivery can be effective in targeting a diseased joint but is hampered by rapid clearance times from the diarthrodial joint. The synovium is a multi-layered tissue that surrounds the diarthrodial joint and governs molecular transport into and out of the joint. No models of drug clearance through synovium exist to quantify diffusivity across solutes, tissue type and disease pathology. We previously have developed a finite element model of synovium as a porous, permeable, fluid-filled tissue and used an inverse method to determine urea’s effective diffusivity (D(eff)) in de-vitalized synovium explants.(22) Here we apply this method to determine D(eff) from unsteady diffusive transport of model solutes and confirm the role of molecular weight in solute transport. As molecular weight increased, D(eff) decreased in both human and porcine tissues, with similar behavior across the two species. Unsteady transport was well-described by a single exponential transient decay in concentration, yielding solute half-lives (t(1/2)) that compared favorably with the D(eff) determined from the finite element model fit. Determined values for D(eff) parallel prior observations of size-dependent in vivo drug clearance and provide an intrinsic parameter with greater ability to resolve size-dependence in vitro. Thus, this work forms the basis for understanding the influence of size on drug transport in synovium and can guide future studies to elucidate the role of charge and tissue pathology on the transport of therapeutics in healthy and pathological human synovium.

The quantification of metabolites in blood and urine allows nurses to explore new hypotheses about the microbiome. This review summarizes findings from recent studies with a focus on how the state of the science can influence future nursing research initiatives. Metabolomics can advance nursing research by identifying physiologic/pathophysiologic processes underlying patients’ symptoms and can be useful for testing the effects of nursing interventions. To date, metabolomics has been used to study cardiovascular, respiratory, endocrine, autoimmune, and infectious conditions, with research focused on understanding the microbial metabolism of substrates resulting in circulating/excreted biomarkers such as trimethylamine N-oxide. This review provides specific recommendations for the collection of specimens and goals for future studies.

This paper presents a comprehensive review of publicly available online dyslexia learning modules with a particular focus on the extent to which modules address the prevalent myth that dyslexia is caused by “backwards reading.” The authors conducted a systematic internet search to identify publicly available online dyslexia learning modules and coded the content across education, neurocognition, and policy disciplinary domains. We identified 18 topics across a small number (N = 14) of publicly available modules that focused on dyslexia, with only two modules directly addressing this dyslexia myth. While both identified this myth as false, neither provided information about the neurocognitive underpinnings of dyslexia to explain why this myth is false. This review will be useful for guiding further development of online dyslexia learning modules which are urgently needed due to persisting misinformation about this disorder. The coded content reviews of each module will also be beneficial for directing attention to existing resources for professional development on dyslexia.

Plain English summary Patient and public involvement (PPI) improves the quality of health research and ensures that research is relevant to patients’ needs. Though PPI is increasingly evident in clinical and health services research, there are few examples in the research literature of effective PPI in translational and laboratory-based research. In this paper, we describe the development and evaluation of PPI in a multi-centre European project (EuroTEAM – Towards Early biomarkers in Arthritis Management) that included both translational and laboratory-based and psychosocial research. We found that although most PPI in EuroTEAM was centred around the psychosocial research, there were examples of PPI in the laboratory studies. As the project evolved, researchers became better at accommodating PPI and identifying PPI opportunities. It was generally agreed that PPI had a positive impact on the project overall, particularly on public engagement with the research. We concluded that the inclusion of both psychosocial and laboratory-based research in the same project facilitated PPI across all aspects of the research. In future projects, we would try to specify individual PPI activities in more detail at the project-planning stage, and better accommodate patient partners who are not native speakers of English. Abstract Background Patient and public involvement (PPI) enhances research quality and relevance and is central to contemporary health policy. The value of PPI has been recognised in rheumatology research, though there are limited examples of PPI in basic and translational science. The EU FP7 funded ‘EuroTEAM’ (Towards Early biomarkers in Arthritis Management) project was established to develop biomarker-based approaches to predict the future development of rheumatoid arthritis and incorporated psychosocial research to investigate the perceptions of ‘at risk’ individuals about predictive testing, and to develop informational resources about rheumatoid arthritis (RA) risk. Patient involvement was central to EuroTEAM from the inception of the project. The objective of this paper is to describe the development of PPI in EuroTEAM, formatively assess the impact of PPI from the perspectives of researchers and patient research partners (PRPs), reflect on successes and lessons learned, and formulate recommendations to guide future projects. Methods Two mixed-methods surveys (for PRPs and researchers) and a teleconference were undertaken to assess the impact of PPI on individual work packages and on EuroTEAM overall. Results There was consensus about the positive impact of PPI on the research and on the experiences of those involved. In particular, the positive impact of PPI on the personal development of researchers, and on effective public engagement with EuroTEAM research were highlighted. Researchers described adapting their practice in future projects to facilitate PPI. Spin-off projects and ongoing collaborations between PRPs and researchers reflected the value of PPI to participants. PPI was more frequently integrated in psychosocial research, though examples of PPI in laboratory/translational science were also described. PRPs asked for more opportunities to contribute meaningfully to basic scientific research and for more extensive feedback on their contributions. Conclusions The findings were used to formulate recommendations to guide effective involvement of patients in future similar projects, including identifying specific training requirements for PRPs and researchers, the identification of PRP focused tasks/deliverables at the project planning stage, and supporting access to involvement for all PRPs. Importantly, the distinctive multidisciplinary approach of EuroTEAM, incorporating both basic science and psychosocial research, facilitated patient involvement in the project overall.

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN.

Severe weather events including tornadoes, damaging winds, hail, and their combination produce changes in land surface vegetation and urban settings that are frequently observed through remote sensing. Capabilities continue to improve through a growing constellation of governmental and commercial assets, increasing the spatial resolution of visible, near to shortwave infrared, and thermal infrared remote sensing. Here, we highlight cases where visual interpretation of imagery benefitted severe weather damage assessments made within the NOAA/NWS Damage Assessment Toolkit. Examples demonstrate utility of imagery in assessing tracks and changes in remote areas where staffing limitations or access prevent a ground-based assessment.

The multiple deficit model (MDM) was proposed because the prevailing single-deficit model provided an inadequate account of atypical neuropsychological development. Across methods and levels of analysis, there has been support for the two fundamental tenets of the MDM, that multiple predictors contribute probabilistically to neurodevelopmental disorders and shared risk factors contribute to comorbidity. Diagnostically, the multiplicity of factors means that no single cognitive deficit or combination of deficits can be used to rule in or out most neurodevelopmental disorders. Challenges for the MDM are that the theory is difficult to falsify and that current cross-sectional studies cannot establish causality. Prospects for further development of the MDM include incorporating an explicit focus on promotive and protective factors and pursuing mechanistic connections between multiple factors across levels of analysis.

We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC).Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA).All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3.AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

Summary Objective This study aimed to examine the temporal activation of NF-κB and its relationship to the development of pain-related sensitivity and behavioral changes in a non-invasive murine knee loading model of PTOA. Method Following knee injury NF-κB activity was assessed longitudinally via in vivo imaging in FVB. Cg-Tg (HIV-EGFP,luc)8Tsb/J mice. Measures of pain-related sensitivity and behavior were also assessed longitudinally for 16 weeks. Additionally, we antagonized NF-κB signaling via intra-articular delivery of an IκB kinase two antagonist to understand how local NF-κB inhibition might alter disease progression. Results Following joint injury NF-κB signaling within the knee joint was transiently increased and peaked on day 3 with an estimated 1.35 p/s/cm2/sr (95% CI 0.913.1.792 p/s/cm2/sr) fold increase in signaling when compared to control joints. Furthermore, injury resulted in the long-term development of hindpaw allodynia. Hyperalgesia withdrawal thresholds were reduced at injured knee joints, with the largest reduction occurring 2 days following injury (estimate of between group difference 129.1 g with 95% CI 60.9,197.4 g), static weight bearing on injured limbs was also reduced. Local delivery of an NF-κB inhibitor following joint injury reduced chondrocyte death and influenced the development of pain-related sensitivity but did not reduce long-term cartilage degeneration. Conclusion These findings underscore the development of behavioral changes in this non-invasive loading model of PTOA and their relationships to NF-κB activation and pathology. They also highlight the potential chondroprotective effects of NF-κB inhibition shortly following joint injury despite limitations in preventing the long-term development of joint degeneration in this model of PTOA.

The American Academy of Pediatrics recommends donor human milk (DHM) as the preferred feeding strategy for preterm infants when the milk of the mother is unavailable, based on conclusive evidence of lower rates of necrotizing enterocolitis with DHM feedings compared with preterm infant formula. The nutritional composition of DHM may differ from maternal milk for many reasons including differences in maternal characteristics, milk collection methods, and the impact of donor milk banking practices. The purpose of this systematic review is to examine the literature regarding research on the fat, protein, carbohydrate, vitamin, and mineral composition of DHM obtained through nonprofit milk banks or commercial entities. PubMed, CINAHL, and Scopus databases were searched for articles published between 1985 and 30 April, 2019. In total, 164 abstracts were screened independently by 2 investigators, and 14 studies met all inclusion criteria. Studies were predominantly small (

In the original publication of the article, the initial of Professor Stefan Priebe has been incorrectly published as ‘P’ instead of’S’. The correct author name is given in this erratum.

Background The benefits of human milk for the preterm infant are well established. Preterm infants have lower breastfeeding rates and often face breastfeeding challenges. It is important that feeding practices for preterm infants optimize their chances of breastfeeding. Objective The purpose of this integrated review is to synthesize and critically analyze research related to the safety and efficacy of cup feeding as an alternative, supplemental feeding method for breastfed infants. Data Sources The electronic data bases of PubMed, CINAHL and were used to identify studies published in English from 1998- 2017. Design Using inclusion and exclusion criteria, 27 articles were initially assessed. After further screening 19 articles were included in the full review and of these 5 more were excluded. Lastly, an in-depth review of these 14 studies resulted in 2 more exclusions, for a total of 12 studies that met full inclusion and exclusion criteria. Review Methods Studies were examined for information on safety and efficacy of cup feeding as an alternative, supplemental feeding method for preterm breastfed infants. Studies were grouped into categories of outcomes that included (a) safety and physiologic properties; (b) breastfeeding outcomes. Results Use of cup feeding resulted in more stable heart rate and oxygen saturation than bottle feeding with similar weight gain. Additionally, breastfeeding rates were higher at discharge with continued higher rates at 3 and 6 months post-discharge for cup fed infants. Conclusions Premature infants face more breastfeeding obstacles than term infants. The potential for cup feeding as an alternative to bottle-feeding for breast fed preterm infants is positively supported by these results It is fundamentally important for NICU professionals to establish a protocol, education and training for the potential use of this feeding method for this vulnerable population.

Key Clinical Message Spontaneous coronary artery dissection (SCAD) is a common cause of acute coronary syndrome particularly in younger women. Good outcomes with conservative management are generally expected. However, there is uncertainty of how to manage symptomatic or unstable patients. Percutaneous angioplasty may propagate the subintimal hematoma compromising coronary blood flow. Cutting balloon angioplasty can relieve the compressive effects of a propagated subintimal hematoma in SCAD.

Ischemia reperfusion injuries (IRI) are unavoidable in solid organ transplantation. IRI augments alloimmunity but the mechanisms involved are poorly understood. Herein, we examined the effect of IRI on antigen specific alloimmunity. We demonstrate that ischemia promotes alloimmune activation, leading to more severe histological features of rejection, and increased CD4+ and CD8+ T cell graft infiltration, with a predominantly CD8+ IFNγ+ infiltrate. This process is dependent on the presence of alloreactive CD4+ T cells, where depletion prevented infiltration of ischemic grafts by CD8+ IFNγ+ T cells. IL-6 is a known driver of ischemia-induced rejection. Herein, depletion of donor antigen-presenting cells reduced ischemia-induced CD8+ IFNγ+ allograft infiltration, and improved allograft outcomes. Following prolonged ischemia, accelerated rejection was observed despite treatment with CTLA4Ig, indicating that T cell costimulatory blockade failed to overcome the immune activating effect of IRI. However, despite severe ischemic injury, treatment with anti-IL-6 and CTLA4Ig blocked IRI-induced alloimmune injury and markedly improved allograft survival. We describe a novel pathway where IRI activates innate immunity, leading to upregulation of antigen specific alloimmunity, resulting in chronic allograft injury. Based on these findings, we describe a clinically relevant treatment strategy to overcome the deleterious effect of IRI, and provide superior long-term allograft outcomes.

T-cell immunoglobulin and mucin domain-containing molecule (TIM)4 is a costimulatory molecule and phosphatidylserine receptor. Its dominant function varies according to the expressing cell and site of activation. In recent years, studies have identified its role in diverse disease processes and increasingly in alloimmunity. Herein, we will comprehensively review the literature on TIM4 and outline its function in shaping the alloimmune response.TIM4 expression on dendritic cells increases following transplantation. Blockade of TIM4 in vivo leads to increased differentiation of regulatory T cells and improved allograft survival. TIM4 binds phosphatidylserine-expressing apoptotic cells. Previously thought of as a tethering molecule, recent studies have demonstrated that TIM4 interacts with integrins to mediate uptake of apoptotic cells. TIM4 B cells have recently been identified, which produce high levels of IFNγ and promote allograft rejection. Targeting these B cells improved allograft survival and promoted the development of TIM1 regulatory B cells.TIM4 is expressed in niche compartments and has many immunological effects. However, inhibition of TIM4 has been demonstrated to prolong allograft survival, through varied mechanisms. A unifying explanation for the role of TIM4 in alloimmunity remains to be found, but this pathway appears to hold considerable promise in transplantation.

According to the Healthy People 2020 goals, the sustainability of breastfeeding duration rates within the United States has not been achieved. To increase these rates, it is important that women with breastfeeding difficulties receive the support needed to continue breastfeeding. When supplementation occurs, it is essential that the breastfeeding relationship be preserved. Various methods of supplementation are often recommended including use of the supplemental feeding tube device (SFTD).The question guiding this brief is "What evidence exists to support the use of an SFTD as a method of supplementation for breastfed infants?"The PubMed and CINAHL databases were queried for original research published in English from 1990 through July 2016. Search terms included "supplemental feeding tube," "breastfeeding," "term infants," "premature infants," "Supplemental Nursing System," "Lact-aid," and "supply line."Very limited research exists on the use of SFTDs as a method of supplementation for breastfed infants; however, existing research suggests that an SFTD may be useful as a supplementation method for breastfed infants. High-quality research is needed to evaluate the efficacy of using an SFTD for supporting exclusive and all breastfeeding rates.Nurses and providers need to be educated and trained in the use of SFTDs as well as all supplemental feeding methods. Information on efficacy and SFTD use should also be included in policies related to breastfeeding and human milk use.Further research should determine best methods of supplementation for breastfed infants and should examine differences in breastfeeding rates when using the SFTD for supplementation.

Objective. Magnetic resonance elastography (MRE) is widely adopted as a biomarker of liver fibrosis. However, in vivo MRE accuracy is difficult to assess. Approach. Finite element model (FEM) simulation was employed to evaluate liver MRE accuracy and inform methodological optimisation. MRE data was simulated in a 3D FEM of the human torso including the liver, and compared with spin-echo echo-planar imaging MRE acquisitions. The simulated MRE results were compared with the ground truth magnitude of the complex shear modulus (∣G*∣) for varying: (1) ground truth liver ∣G*∣; (2) simulated imaging resolution; (3) added noise; (4) data smoothing. Motion and strain-based signal-to-noise (SNR) metrics were evaluated on the simulated data as a means to select higher-quality voxels for preparation of acquired MRE summary statistics of ∣G*∣. Main results. The simulated MRE accuracy for a given ground truth ∣G*∣ was found to be a function of imaging resolution, motion-SNR and smoothing. At typical imaging resolutions, it was found that due to under-sampling of the MRE wave-field, combined with motion-related noise, the reconstructed simulated ∣G*∣ could contain errors on the scale of the difference between liver fibrosis stages, e.g. 54% error for ground truth ∣G*∣ = 1 kPa. Optimum imaging resolutions were identified for given ground truth ∣G*∣ and motion-SNR levels. Significance. This study provides important knowledge on the accuracy and optimisation of liver MRE. For example, for motion-SNR ≤ 5, to distinguish between liver ∣G*∣ of 2 and 3 kPa (i.e. early-stage liver fibrosis) it was predicted that the optimum isotropic voxel size is 4–6 mm.

High-water content biopolymer gels are widely used in diverse areas of research and in many commercial processes, including a significant proportion of importance to the food and pharmaceutical industries. The internal structures of these hydrogels are complex and span many length scales, the specifics of which are important in determining functionality. Elucidating these structures is critically important in extending and tailoring their use. Cryo-scanning electron microscopy (cryo-SEM) is a popular method for structural elucidation. A critical step in this imaging technique is cryo-fixation. However, consideration of the literature reveals that images of inefficiently cryo-fixed networks remain widely reported as being representative of the native structure of gels despite being significantly damaged by ice formation. Here, we show that the application of slow freezing methods, like the very commonly used slushy nitrogen method, indeed yield erroneous structures and produce singularly common structures for both protein and polysaccharide hydrogels. On the contrary, we demonstrate, by rapidly freezing thin samples of low concentration protein amyloid fibril hydrogels using a propane jet freezer, that cryo-SEM imaging of biopolymer hydrogels in their native state is feasible. In contrast, while the use of cryo-protectants is successful in reducing ice crystallisation, it can affect the bonding within hydrogels and hence, modify the structure under examination.

Phosphorus (P) Index evaluations are critical to advancing nutrient management planning in the United States. However, most assessments until now have focused on the risks of P losses in surface runoff. In artificially drained agroecosystems of the Atlantic Coastal Plain, subsurface flow is the predominant mode of P transport, but its representation in most P Indices is often inadequate. We explored methods to evaluate the subsurface P risk routines of five P Indices from Delaware, Maryland (two), Virginia, and North Carolina using available water quality and soils datasets. Relationships between subsurface P risk scores and published dissolved P loads in leachate (Delaware, Maryland, and North Carolina) and ditch drainage (Maryland) were directionally correct and often statistically significant, yet the brevity of the observation periods (weeks to several years) and the limited number of sampling locations precluded a more robust assessment of each P Index. Given the paucity of measured P loss data, we then showed that soil water extractable P concentrations at depths corresponding with the seasonal high water table (WEP) could serve as a realistic proxy for subsurface P losses in ditch drainage. The associations between WEP and subsurface P risk ratings reasonably mirrored those obtained with sparser water quality data. As such, WEP is seen as a valuable metric that offers interim insight into the directionality of subsurface P risk scores when water quality data are inaccessible. In the long term, improved monitoring and modeling of subsurface P losses clearly should enhance the rigor of future P Index appraisals.

Phosphatidylinositol-3-kinases (PI3K) γ and δ are preferentially enriched in leukocytes, and defects in these signaling pathways have been shown to impair T cell activation. The effects of PI3Kγ and PI3Kδ on alloimmunity remain underexplored. Here, we show that both PI3Kγ −/− and PI3Kδ D910A/D910A mice receiving heart allografts have suppression of alloreactive T effector cells and delayed acute rejection. However, PI3Kδ mutation also dampens regulatory T cells (Treg). After treatment with low dose CTLA4-Ig, PI3Kγ −/−, but not PI3Κδ D910A/D910A, recipients exhibit indefinite prolongation of heart allograft survival. PI3Kδ D910A/D910A Tregs have increased apoptosis and impaired survival. Selective inhibition of PI3Kγ and PI3Kδ (using PI3Kδ and dual PI3Kγδ chemical inhibitors) shows that PI3Kγ inhibition compensates for the negative effect of PI3Kδ inhibition on long-term allograft survival. These data serve as a basis for future PI3K-based immune therapies for transplantation., Phosphatidylinositol-3-kinases (PI3K) γ and δ are key regulators of T cell signaling. Here the author show, using mouse heart allograft transplantation models, that PI3Kγ or PI3Kδ deficiency prolongs graft survival, but selective inhibition of PI3Kγ or PI3Kδ reveals alternative transplant survival outcomes post CTLA4-Ig treatment.

Objectives:Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity.Methods:Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders.Results:For EFs (working memory, inhibition, and shifting/ flexibility), we observed weaknesses in all diagnostic groups when participants’ own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders.Conclusions:Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. (JINS, 2018,24, 91–103)

Vulnerable preterm infants experience repeated and prolonged pain/stress stimulation during a critical period in their development while in the neonatal intensive care unit (NICU). The contribution of cumulative pain/stressors to altered neurodevelopment remains unclear. The study purpose was to investigate the impact of early life painful/stressful experiences on neurobehavioral outcomes of preterm infants in the NICU.A prospective exploratory study was conducted with fifty preterm infants (28 0/7-32 6/7weeks gestational age) recruited at birth and followed for four weeks. Cumulative pain/stressors (NICU Infant Stressor Scale) were measured daily and neurodevelopmental outcomes (NICU Network Neurobehavioral Scale) were examined at 36-37weeks post-menstrual age. Data analyses were conducted on the distribution of pain/stressors experienced over time and the linkages among pain/stressors and neurobehavioral outcomes.Preterm infants experienced a high degree of pain/stressors in the NICU, both in numbers of daily acute events (22.97±2.30 procedures) and cumulative times of chronic/stressful exposure (42.59±15.02h). Both acute and chronic pain/stress experienced during early life significantly contributed to the neurobehavioral outcomes, particularly in stress/abstinence (p0.05) and habituation responses (p0.01), meanwhile, direct breastfeeding and skin-to-skin holding were also significantly associated with habituation (p0.01-0.05).Understanding mechanisms by which early life experience alters neurodevelopment will assist clinicians in developing targeted neuroprotective strategies and individualized interventions to improve infant developmental outcomes.

Breast milk stem cells are hypothesized to be involved in infant health and development. Our research team is the first known team to enroll mothers of hospitalized preterm infants during the first few weeks of lactation and compare stem cell phenotypes and gene expression to mothers of healthy full-term infants.Participants were recruited from a Level IV Neonatal Intensive Care Unit (preterm dyads) and the community (full-term dyads) in the northeastern United States.Mothers of hospitalized preterm infants (37 weeks gestational age at birth) and mothers of healthy full-term infants (39 weeks gestational age at birth).Breast milk stem-like cell populations were identified in both preterm and full-term breast milk samples. The data suggest variability in the proportion of stem cell phenotypes present, as well as statistically significant differential expression (both over- and underexpression) of stem cell-specific genetic markers when comparing mothers' milk for preterm and full-term births.Our findings indicate that (1) stem cells are present in preterm breast milk; (2) differential expression of stem cell-specific markers can be detected in preterm and full-term breast milk samples; and (3) the percentage of cells expressing the various stem cell-specific markers differs when preterm and full-term breast milk samples are compared.

Infants who begin early life in the medicalized environment of the neonatal intensive care unit (NICU) experience disruption to numerous fundamental expectancies. In the NICU, infants are exposed to chronic, extreme stressors that include painful medical procedures and parental separation. Due to their preverbal stage of development, infants are unable to fully express these experiences, and linking these experiences to long-term outcomes has been difficult. This clinical article proposes the terminology Infant Medical Trauma in the NICU (IMTN) to describe the infant experience. Following a discussion of the NICU as an adverse childhood event, the article has three sections: (a) the unique and critical factors that define the newborn period, (b) a review of the IMTN conceptual model, and (c) recommendations for supportive neuroprotective strategies to moderate the intensity of adverse NICU infant experiences.

The transforming growth factor-β-activated kinase 1 (TAK1) encoded by mitogen-activated protein kinase kinase kinase 7 (MAP3K7) is widely expressed and participates in multiple molecular and cellular processes, including growth, differentiation, inflammation, and apoptosis. Pathogenic variants in MAP3K7 have recently been associated with two disorders: cardiospondylocarpofacial syndrome (CSCFS) and frontometaphyseal dysplasia 2 (FMD2). To date, all small in-frame deletions and splice variants in MAP3K7 have been associated with CSCFS, whereas missense variants have been reported in both CSCFS and FMD2. Here, we present a patient with a novel heterozygous likely pathogenic variant, c.125_127del, p.(Val42del), in MAP3K7, only the sixth variant associated with CSCFS to be described in the literature. Although this patient has a phenotype that is most consistent with that of CSCFS, including valvular heart disease, short stature, fusions of the spine and bones of the hands and feet, and certain facial dysmorphisms, he interestingly has some features reported previously in FMD2 but not CSCFS. These include flexion contractures of the elbow and widely spaced first and second toes, highlighting new points of overlap between these two syndromes. We additionally point out features in the patient presented here that are rare but recurrent among CSCFS patients previously reported in the literature, as well as a new distinctive cutaneous finding not previously reported.

Better understanding of feeding behaviour will be vital in reducing obesity and metabolic syndrome, but we lack a standard model that captures the complexity of feeding behaviour. We construct an accurate stochastic model of rodent feeding at the bout level in order to perform quantitative behavioural analysis. Analysing the different effects on feeding behaviour of peptide YY3-36 (PYY3-36), lithium chloride, glucagon-like peptide 1 (GLP-1), and leptin shows the precise behavioural changes caused by each anorectic agent. Our analysis demonstrates that the changes in feeding behaviour evoked by the anorectic agents investigated do not mimic the behaviour of well-fed animals and that the intermeal interval is influenced by fullness. We show how robust homeostatic control of feeding thwarts attempts to reduce food intake and how this might be overcome. In silico experiments suggest that introducing a minimum intermeal interval or modulating upper gut emptying can be as effective as anorectic drug administration., A quantitative study of rodent feeding behaviour reveals that anorectic agents may have substantially different behavioural effects from one another and from the satiated state they are intended to evoke. In silico studies suggest alternative strategies for reducing food intake.

This research was conducted to identify species causing powdery mildew on cucurbits and to determine genetic variations among isolates of the pathogen. We collected 109 isolates from six cucurbit species hosts (

Soil testing is an important practice for nutrient management in agricultural production systems. In the United States, soil‐test methods and interpretations vary across state lines, making institutional collaborations challenging and crop fertilization guidelines inconsistent. Uniformity and transparency in P and K soil fertility testing and fertilizer recommendations are needed to enhance end‐user adoption. The Fertilizer Recommendation Support Tool (FRST) project is developing a comprehensive database of P and K correlation–calibration results that can be accessed through an online tool for use in research and fertilizer recommendation development. This collaborative project, which includes over 30 land‐grant universities, the USDA‐ARS, the USDA‐NRCS, and several not‐for‐profit organizations, contains a national survey describing the current status of soil testing, minimum requirements for correlation–calibration data inclusion, and database population and creating FRST as a user‐friendly online decision support tool. The FRST project will provide more consistent, transparent, and science‐based information for crop nutrient recommendations across the United States.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes.A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation.At levels of condFDR0.01 and conjFDR0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1), whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (rWe identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.

Trans-synovial solute transport plays a critical role in the clearance of intra-articularly (IA) delivered drugs. In this study, we present a computational finite element model (FEM) of solute transport through the synovium validated by experiments on synovial explants. Unsteady diffusion of urea, a small uncharged molecule, was measured through devitalized porcine and human synovium using custom-built diffusion chambers. A multiphasic computational model was constructed and optimized with the experimental data to extract effective diffusivity for urea within the synovium. A monotonic decrease in urea concentration was observed in the donor bath over time, with an effective diffusivity found to be an order of magnitude lower in synovium versus that measured in free solution. Parametric studies incorporating an intimal cell layer with varying thickness and varying effective diffusivities were performed, revealing a dependence of drug clearance kinetics on both parameters. The findings of this study indicate that the synovial matrix impedes urea solute transport out of the joint with little retention of the solute in the matrix.

Background Mother's own milk (MOM) is the preferred nutrition for premature infants, particularly for the very low birth-weight (VLBW) cohort. Benefits are well documented; yet, numerous barriers exist for provision of MOM in the neonatal intensive care unit (NICU). Lactation consultants (LCs) can optimize breastfeeding support for NICU mothers; however, understanding of the impact of NICU-dedicated LCs is limited. Purpose Evaluate the effectiveness of NICU-dedicated LCs in improving breastfeeding outcomes and MOM provision in VLBW infants. Methods A retrospective chart review of 167 VLBW infants comparing breastfeeding outcomes between 2 NICUs, one with NICU-dedicated LCs (hospital A; n = 48) and one without (hospital B; n = 119). Primary outcome measures included feeding percentages of MOM received by infants at 3 intervals, throughout hospitalization, and number of direct breastfeeding events. Secondary outcome measures included number of days to first enteral feed, days to reach full feeds, days of nil per os, days on total parenteral nutrition, and length of stay. Findings Neonatal intensive care unit-specific lactation support increased the number of direct breastfeeding events on day of discharge (P = .048). No statistical significance was found at each of the 3 time intervals, or throughout hospitalization (week 1: P = .18; midpoint: P = .40; discharge: P = .16; total hospitalization: P = .19). No statistical significance was demonstrated in secondary outcome measures (days to first enteral feed: P = .22; days to full feeds: P = .25; nil per os days: P = .27; total parenteral nutrition days: P = .34; length of stay: P = .01). Length of stay not found to be significant after correcting for confounding variables. Implication for practice Increased direct breastfeeding events on day of discharge with exposure to NICU-dedicated LCs in the VLBW population. Implication for research Prospective studies regarding NICU-specific lactation support with larger samples are warranted.

Introduction Turkey hosts the highest number of Syrian refugees in Europe. Refugees are often vulnerable to situational forms of psychosocial distress as a consequence of exposure to war and violence which may result in more profound mental health problems if no treatment is sought. The aim of this study is to report evidence on mental health and psychosocial support (MHPSS) needs, access and barriers to MHPSS care among Syrians refugees living in Istanbul, Turkey. Methods A cross-sectional survey was conducted among Syrian refugees aged 18 years or over in Istanbul (Sultanbeyli) between February and May 2018. Data among 1’678 Syrian refugees were collected on mental health outcomes using the Posttraumatic Stress Disorder (PTSD) Checklist (PCL-5) and the Hopkins Symptoms Checklist (HSCL-25) for depression and anxiety. We also collected data on health care utilization, barriers to seeking and continuing care as well as knowledge and attitudes towards mental health. Descriptive analyses were used. Results The prevalence of PTSD, depression and anxiety was 19.6%, 34.7% and 36.1% respectively. The treatment gap was 89% for PTSD, 90% for anxiety and 88% for depression. 249 respondents (15%) screened positive for either PTSD, depression or anxiety in our survey and self-reported emotional/behavioural problems since arriving in Sultanbeyli. Several structural and attitudinal barriers for not seeking care were reported. Conclusions To overcome the treatment gap, mental health care programmes need to be more responsive to the needs of Syrian refugees. Barriers to seeking and continuing care can be overcome by providing MHPSS services in the community which facilitate access to care. Community-based programmes of care should be supported by activities which increase awareness about mental health issues and tackle negative attitudes towards mental illness. Key messages This study provides the first nationally representative data on the mental health of Syrian refugees in Turkey, and shows that refugees have high mental health needs. Syrian refugees do not seek mental health care despite availability of mental health services in the community.

Introduction Melanoma differentiation-associated gene 5 (MDA5) is a myositis-associated autoantibody. It is increasingly being recognised that this antibody presents with typical skin lesions and the potential for a rapidly progressive interstitial lung disease but without muscle involvement. We present two cases of patients with MDA5 positive dermatomyositis who both developed rapidly progressive lung disease and despite intensive treatment passed away. Case description A previously well 48-year-old Caucasian man presented with a few months history of inflammatory arthritis, Raynaud’s and Gottron’s papules. He also described exertional breathlessness and was found to have fine inspiratory crackles bibasally. An HRCT scan showed cryptogenic organising pneumonia (COP). Inflammatory markers and creatine kinase were normal but an extended myositis panel showed positive anti-MDA5 antibodies consistent with a diagnosis of amyopathic dermatomyositis. He was started on cyclophosphamide as part of a research trial, given iloprost and sildenafil for worsening digital ischaemia and commenced on home oxygen. He was admitted with worsening shortness of breath after the second cycle of cyclophosphamide and found to have pneumocystis jirovecii (PCP) positive sputum. He developed pyrexia with a positive influenza A swab and increasing oxygen requirements requiring transfer to ITU. Despite further antibiotics, antivirals, steroids, IV immunoglobulin and rituximab infusion he deteriorated further and died 13 days later. The second patient was a 45-year-old Asian man. He was initially seen by dermatology with alopecia and a scaly rash on his face, elbow and hands. He was then diagnosed with early inflammatory arthritis and commenced steroids and methotrexate. He developed skin ulceration and respiratory symptoms with a CT chest showing features of COP. He was ANA negative but anti-Ro and anti-Scl-70 positive. He was given antibiotics, methylprednisolone and switched to mycophenolate mofetil. Whilst abroad he was admitted to hospital, diagnosed with anti-MDA5 positive amyopathic dermatomyositis and given methylprednisolone and cyclophosphamide. Cyclophosphamide was continued on his return to the UK, with PCP prophylaxis but he also required home oxygen. He was admitted to hospital with increasing breathlessness and given further methylprednisolone and treatment dose co-trimoxazole. Two weeks later he deteriorated further and repeat CT scan showed a pneumomediastinum. He received antibiotics, antifungals and rituximab but died after three days on ITU. Discussion Although in both cases it was recognised the patients had some form of inflammatory condition the diagnosis of anti-MDA5 positive dermatomyositis took some time. The lack of muscle involvement is typical and means clinicians need to give more thought to the possible diagnosis particularly when patients present with skin lesions and look specifically for MDA5 antibodies. These cases also show how rapidly the lung disease can progress. Being aware that a patient is MDA5 positive gives important information to the clinical team regarding the potential prognosis and in these cases it has been questioned whether these concerns were entirely relayed to the patients and their families. High serum ferritin, ground-glass opacities in all six lung fields and worsening of pulmonary infiltrates during therapy have been suggested as further poor prognostic factors. Both patients presented particular challenges in trying to decide whether their deterioration was due to infection in the context of immunosuppression, disease progression or both and consequently full infection screens were performed including bronchoscopies at various points. Given how unwell both patients were all available treatments were considered. Once it was recognised how rapidly the lung disease was progressing they both received cyclophosphamide and rituximab. IV immunoglobulin was requested for both patients but only agreed for the first patient as he had proven PCP pneumonia. Key learning points Anti-MDA5 positive dermatomyositis commonly presents with typical mucocutaneous lesions (such as cutaneous ulceration, alopecia and oral ulcers) which can differ from those seen in classical dermatomyositis. It is important to consider the possibility of anti-MDA5 positive dermatomyositis in a patient with skin abnormalities and a normal CK, and in such circumstances request an extended myositis screen ensuring MDA5 is included. Patients who are MDA5 positive and have lung involvement often have rapidly progressive interstitial lung disease. Prognosis is especially poor when patients are admitted to ITU and worse than patients with anti-synthetase syndrome. Spontaneous pneumomediastinum can be a feature when the outcome is almost always poor in a ventilated patient. Treatment options are limited, generally aggressive immunosuppression is recommended when there is lung involvement and induction therapy with cyclophosphamide or rituximab has been tried. There are emerging reports of JAK inhibitors being used in dermatomyositis and so this may be something to consider in this subset of difficult to treat patients. Consideration should be given to vaccinating against influenza and pneumococcal infections as soon as possible, together with PCP prophylaxis and aggressive treatment of superadded infections. When appropriate patients and relatives should be made aware of the potentially poor prognosis. It is important to work closely with other specialities such as dermatology, respiratory and when necessary ITU. Due to the complexity and severity of this condition an MDT approach is recommended. Conflict of interest The authors declare no conflicts of interest.

First responders, including Emergency Medical Services personnel and firefighters, support community members in times of crisis. When responding to emergencies, first responders often experience both direct and vicarious trauma. Over time, the pace and intensity of a career as a first responder leads to poor health habits and high risk for mental health issues including posttraumatic stress disorder. Due to concern about peer perception and mental health stigma, these professionals are less likely to seek mental health supports to manage and process trauma. This chapter explores Narrative Therapy as an ideal option for mental health treatment of first responder trauma, providing a collaborative approach to therapy using the natural coping strategy of storytelling.

Premature infants often experience extended stays in the neonatal intensive care unit (NICU) as opposed to home with parents. This prolonged separation creates a strain for both parents and infants, decreasing attachment and parental caregiving. One strategy to combat this shared stress is increasing parental participation, particularly through the use of their voices whether parents are present or not.This Evidence-Based Practice Brief column explores the connection between mother and child, specifically the effects of maternal voice on infant autonomic stability, weight gain, and behavioral states.A systematic search of CINAHL, PubMed, and PsycInfo was used to identify studies involving the use of maternal voice intervention with preterm infants in the NICU.Fifteen studies were identified. Three intervention categories emerged: (1) live maternal speech, (2) recorded maternal speech (subcategories included whether intervention content was prescribed or not), and (3) recorded maternal speech that was combined with biological maternal sounds (heart rate). Within each category, studies were organized chronologically to reflect how knowledge has changed overtime.Maternal voice has physiological as well as behavioral and emotional effect on preterm infants. Several studies found that maternal voice increased autonomic stability improving (heart rate and respirations) as well as weight gain. No negative effects were identified. Given these findings, incorporating different types of maternal voice into routine care by the bedside nurse can assist the mother in feeling more involved in her infant's care without seemingly being a distraction or obstacle to providers.A major limitation for generalizability was sample size; more research is needed with larger sample sizes replicating interventions types to discern best outcomes.Video Abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?videoId=31autoPlay=true.

Objectives To evaluate the effect of early breastfeeding cessation on incidence of diarrhea in a cohort of U.S. infants. Design, sample, and measurements A secondary data analysis was conducted using data from 2,340 mother-infant dyads participating in the Infant Feeding Practices Study II. We examined associations between duration of feeding type (e.g., exclusive breastfeeding [EBF], any breastfeeding [BF], formula feeding) and incidence of diarrhea before one year. Results The sample included mother-infant dyads that were 86.2% White, 3% Black, and 5% Hispanic. Interruption of EBF before 3 months was significantly associated with higher odds of having diarrhea at 6 months (OR = 1.80, p value ≤ 0.01) and between 6 and 12 months (OR = 1.45, p ≤ .01). Breastfeeding interruption before 6 months was associated with higher odds of having diarrhea at 6 months (OR = 3.19, p ≤ .01). Formula feeding for ≥3 months was associated with higher odds of diarrhea between 6 and 12 months. Conclusions Exclusive breastfeeding for 3 months accompanied by any breastfeeding for 6 months provided the most protective effect against diarrhea. Public health interventions should address disparities in breastfeeding practices and provide support across clinical, workplace and community settings. Research should include more diverse population groups.

Objectives Investigate the determinants of hamstring fascicle length in professional rugby league players. Design Retrospective cohort study Methods Thirty-three elite male athletes underwent testing in the pre-season and in-season periods. Fascicle length measurements of the biceps femoris long head, 3D kinematics and elapsed time-periods at thigh angular velocities between 20 °/s to peak velocity during a single-leg Nordic hamstring strength test, GPS-derived running loads, age and previous injury history were all recorded. Fixed effect determinants for fascicle length were analyzed using multiple linear regression. Results Significant determinants of hamstring fascicle length were observed. Multivariate regression analysis showed modifiable factors including chronic (56 days) running volumes >80% of measured peak velocity and maximum velocity itself collectively explained 43% of the variability in the fascicle length data, whilst peak eccentric strength and elapsed time under load from 20 °/s to peak thigh angular velocity collectively contributed an additional 44%. Chronic running volumes >90% of individually measured peak velocity and the ‘break angle’ during a Nordic eccentric contraction were not significant contributors to the final model. Non-modifiable risk factors (age and previous injury) contributed the remaining 13%. Conclusions Managing high velocity running exposure as well as eccentric strength allows for ˜90% of the controllable determinants in fascicle length within elite athlete populations. An important contributor to the explained variability within fascicle length (superseded only by chronic velocity exposure and peak eccentric strength) was an athletes ability to achieve a prolonged contraction at long lengths during eccentric strength training rather than the angle of failure during the contraction in itself.

Background: According to the Baby Friendly Hospital Initiative, when supplementary feeding occurs, mothers should be counseled on the use and risks of feeding bottles and teats. To help support this initiative it is important to understand the supplementation practices of Internationally Board Certified Lactation Consultants (IBCLC)®. Research aims: To determine (1) if the location of an IBCLC’s practice has any impact on supplemental feeding methods; (2) the preferred methods of and the main reasons for supplementation; (3) the level of an IBCLC’s confidence with supplemental feeding methods; (4) who is making supplemental feeding decisions; and (5) if there are geographical differences among supplementation choices and reasons for supplementation. Methods: An exploratory, descriptive, cross sectional survey of IBCLCs was conducted to generate data about their use of supplemental feeding methods. The survey was sent via email invitation through the International Board of Lactation Consultant’s Board of Examiners, with a response rate of 11.5% ( N = 2,308). Results: There was no standard method of supplementation among participants. Participants indicated that they were confident advising mothers on alternative feeding methods. Only 17.6% ( n = 406) of participants reported that the IBCLC was the caregiver who recommended the method of supplementation used. The majority of participants believed the Supplemental Feeding Tube Device SFTD) best preserves the breastfeeding relationship, and this was their preferred method of supplementation. However, the bottle was ranked as the number one method used in the United States, Australia, and Canada. The use of alternative feeding methods may be overwhelming to the mother. Conclusion: Supplementation by alternative feeding methods might help preserve the breastfeeding relationship and help reach the World Health Organization’s goal of increasing exclusive breastfeeding rates.

Background Clinical ladder programs (CLPs) are often utilized by healthcare organizations to monitor and incentivize staff nurse development. Few studies exist related to this topic, yet implementation of CLPs can be an important factor in staff nurse retention and satisfaction, and therefore requires better understanding. Aim To identify and examine the factors that contribute to a successful CLP. Methods A systematic search of the literature was conducted in PubMed and CINAHL. Studies were not limited by year and were included if the focus was CLP attributes. PRISMA and PICOT were used to guide the process. A matrix of the existing studies was used, and interrater reliability was established at 90% with consensus building for inclusion of studies by the research team. Results Twenty-nine studies were identified for inclusion. Most were program evaluation. Institution's organizational culture was identified as the overarching attribute contributing to a successful CLP. Common themes identified as important to a supportive organizational culture were (a) education and experience; (b) competence and critical thinking; (c) job satisfaction and retention; and (d) compensation and institutional cost. Each of these components can play a significant role in the overall success of a CLP. Linking evidence to action While further research of a higher caliber is needed, some recommendations for practice can be made: (a) CLP description and terminology needs to be consistent with intent, (b) mandatory CLP engagement has positive implications, and (c) implementation needs to be driven by bedside nurses and includes both continuous education and refinement of program requirements and incentives.

Late blight of potato (Solanum tuberosum), caused by Phytophthora infestans, recently reappeared in Wisconsin and was a significant production problem in 1994. P. infestans isolates collected in Wisconsin from 1993 to 1995 were characterized for the following traits: mating type, sensitivity to metalaxyl, and allozyme genotype for Glucose-6-phosphate isomerase (Gpi). Characterization of these isolates revealed that a new, more aggressive population (A2 mating type, metalaxyl resistant, and Gpi genotype 100/111/122) is displacing the old population (A1 mating type, metalaxyl sensitive, and Gpi genotype 86/100) in Wisconsin.