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Background A challenge to the design of improved therapeutic agents and prevention strategies for neuroinvasive infection and associated disease is the lack of known natural immune correlates of protection. A relevant model to study such correlates is offered by the Collaborative Cross (CC), a panel of recombinant inbred mouse strains that exhibit a range of disease manifestations upon infection. Methods We performed an extensive screen of CC-F1 lines infected with West Nile virus (WNV), including comprehensive immunophenotyping, to identify groups of lines that exhibited viral neuroinvasion or neuroinvasion with disease and lines that remained free of WNV neuroinvasion and disease. Results Our data reveal that protection from neuroinvasion and disease is multifactorial and that several immune outcomes can contribute. Immune correlates identified include decreased suppressive activity of regulatory T cells at steady state, which correlates with peripheral restriction of the virus. Further, a rapid contraction of WNV-specific CD8+ T cells in the brain correlated with protection from disease. Conclusions These immune correlates of protection illustrate additional networks and pathways of the WNV immune response that cannot be observed in the C57BL/6 mouse model. Additionally, correlates of protection exhibited before infection, at baseline, provide insight into phenotypic differences in the human population that may predict clinical outcomes upon infection.

Aim Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening. Methods An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East. Results It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available. Conclusion Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre‐symptomatic treatment, but existing hurdles need to be overcome.

Context Primary carnitine deficiency (PCD) is an inborn error of fatty acid metabolism. Patients with PCD are risk for sudden heart failure upon fasting or illness if they are not treated with daily l-carnitine. Objective To investigate energy metabolism during exercise in patients with PCD with and without l-carnitine treatment. Design Interventional study. Setting Hospital exercise laboratories and department of cardiology. Participants Eight adults with PCD who were homozygous for the c.95A>G (p.N32S) mutation and 10 healthy age- and sex-matched controls. Intervention Four-day pause in l-carnitine treatment. Main outcome measures Total fatty acid and palmitate oxidation rates during 1-hour submaximal cycle ergometer exercise assessed with stable isotope method (U13C-palmitate and 2H2-d-glucose) and indirect calorimetry with and without l-carnitine. Results Total fatty acid oxidation rate was higher in patients with l-carnitine treatment during exercise than without treatment [12.3 (SD, 3.7) vs 8.5 (SD, 4.6) µmol × kg-1 × min-1; P = 0.008]. However, the fatty acid oxidation rate was still lower in patients treated with l-carnitine than in the healthy controls [29.5 (SD, 10.1) µmol × kg-1 × min-1; P < 0.001] and in the l-carnitine group without treatment it was less than one third of that in the healthy controls (P < 0.001). In line with this, the palmitate oxidation rates during exercise were lower in the no-treatment period [144 (SD, 66) µmol × kg-1 × min-1] than during treatment [204 (SD, 84) µmol × kg-1 × min-1; P = 0.004) . Conclusions The results indicate that patients with PCD have limited fat oxidation during exercise. l-Carnitine treatment in asymptomatic patients with PCD may not only prevent cardiac complications but also boost skeletal muscle fat metabolism during exercise.

This study examined experiences with and knowledge of non-suicidal self-injury (NSSI) among a multistate sample of 253 vocational rehabilitation (VR) counselors. Over 90% of counselors reported working with clients who had expressed thoughts or behaviors related to NSSI, and over 20% reported doing so once a month or more. Only 44.7% reported having received training on NSSI. Scores on a brief NSSI knowledge questionnaire demonstrated generally accurate responses but also some gaps in knowledge. These findings indicate that rehabilitation counselors in public VR settings frequently work with clients who display thoughts and behaviors related to NSSI and may benefit from training and support in this area.

Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose-rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to ≥2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT.

Many malignant cancers, including breast cancer, have a propensity to invade bones, leading to excruciating bone pain. Opioids are the primary analgesics used to alleviate this cancer-induced bone pain (CIBP) but are associated with numerous severe side effects, including enhanced bone degradation, which significantly impairs patients’ quality of life. In contrast, agonists activating only peripheral CB1 receptors (CB1Rs) have been shown to effectively alleviate multiple chronic pain conditions with limited side effects, yet no studies have evaluated their role(s) in CIBP. Here, we demonstrate for the first time that a peripherally selective CB1R agonist can effectively suppress CIBP. Our studies using a syngeneic murine model of CIBP show that both acute and sustained administration of a peripherally restricted CB1R agonist, 4-{2-[−(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl} morpholine (PrNMI), significantly alleviated spontaneous pain behaviors in the animals. This analgesic effect by PrNMI can be reversed by a systemic administration but not spinal injection of SR141716, a selective CB1R antagonist. Additionally, the cancer-induced bone loss in the animals was not exacerbated by a repeated administration of PrNMI. Furthermore, catalepsy and hypothermia, the common side effects induced by cannabinoids, were measured at the supra-therapeutic doses of PrNMI tested. PrNMI induced mild sedation, yet no anxiety nor a decrease in limb movements were detected. Overall, our studies demonstrate that CIBP can be effectively managed by using a peripherally restricted CB1R agonist, PrNMI, without inducing dose-limiting central side effects. Thus, targeting peripheral CB1Rs could be an alternative therapeutic strategy for the treatment of CIBP.

Introduction This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. Methods Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT). Results Mean relative change in S-oligo in the VA arm was −77.6% [95% confidence interval (CI) −81.6 to −72.8] at week 52 and −62.9% (95% CI −85.8 to −40.0) at LO; mean relative change in the placebo arm was −24.1% (95% CI −40.3 to −3.6) at week 52 and −55.7% (95% CI −76.4 to −34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was −1.1% (95% CI −9.0 to 7.6) and − % (95% CI −13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI −5.5 to 13.2) in the VA arm and 9.0% (95% CI −10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. Conclusions These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age. Electronic supplementary material The online version of this article (10.1007/s10545-018-0185-0) contains supplementary material, which is available to authorized users.

State and national educational leaders encourage the use of an integrated multitiered system of supports (MTSS) to improve services to students with academic and social behavior problems. Implementing and sustaining MTSS is facilitated by support from leaders in state education agencies (SEAs). The purpose of this study was to identify the specific events, resources, and supports that help or hinder the work of scaling up an integrated MTSS approach from the perspective of MTSS leaders in SEAs. Researchers interviewed leaders in 27 U.S. states using the critical incident technique, a qualitative methodology to identify critical incidents associated with changes in practice. Eight helping incident, seven hindering incident, and nine “wish list” categories were identified. Helping categories included multidisciplinary leadership, access to professional development, consistent language and/or practices, consultation with external partners, and a focus on student outcomes in evaluation and planning. Seven hindering categories included competing philosophies, high personnel turnover, varying levels of readiness, and inadequate data systems. Participants also identified two unique categories associated with the items they wished had happened or could happen in the future including access to personnel with high-level MTSS training and access to more effective interventions.

We examined the contribution of disability status to suicidality when accounting for depression and sociodemographic risk factors in 438 American adults, 82 (18.7%) of whom identified as having disabilities. Participants with disabilities had significantly higher depression scores and were more likely to be unemployed and unpartnered, all of which were also associated with increased suicidality. However, disability remained a significant predictor of suicidality even when depression and sociodemographic risk factors were accounted for in a linear regression. Other significant predictors of suicidality in this regression were female gender, depression symptoms, and family and friend suicide history; identifying as a member of a religion was a significant protective factor against suicidality. Our findings suggest that the contribution of disability to suicidality goes beyond that which can be explained by increased depression symptoms and sociodemographic vulnerability.

Grain boundary networks (GBNs) have a profound influence on the properties of both structural and functional materials. However, existing methods to characterize their complex structure have almost universally relied upon a binary classification of GBs as either “special” or “general”, which ignores the rich and continuous spectrum of GB types and properties. Furthermore, characterizing the aggregate network structure of GBs has proven complicated, with traditional methods focusing on local structure and also relying on a binary GB taxonomy, e.g. by evaluating how many “special” or “general” boundaries meet at triple junctions or quadruple nodes. Here we develop new structural metrics for GBNs, based on spectral graph theory, that encode both global network topology and the full spectrum of constituent GB properties, enabling high-fidelity characterization of arbitrary GBNs. Using these metrics, we derive an new structure-property relation for GBN diffusivity. The dominant term in this expression provides an efficient and accurate approximation, whose corresponding spectral metrics reveal the dominant microstructural features influencing the property of interest. The spectral index of this term serves as a type of global order parameter that reveals a fundamental structural transition in GBNs. This work provides a new framework to characterize the structure of GBNs in greater generality than previously possible and facilitates the development of new defect-sensitive structure-property models.

This study examined experiences with and knowledge of non-suicidal self-injury (NSSI) among a multistate sample of 111 vocational rehabilitation (VR) support staff. Over 80% of support staff reported working with clients who had expressed thoughts or behaviors related to NSSI, with over 15% doing so at least once a month. However, only about a quarter (27.0%) reported having received training on NSSI. Participants generally scored well on three true/false NSSI knowledge items but also demonstrated some gaps in knowledge. Support staff commonly work with individuals with NSSI in VR settings but may benefit from additional training and support in this area.

The pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, involves imbalanced T helper (TH) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated copeptin (an inert biomarker of arginine vasopressin (AVP)), secretion precedes the development of symptoms in preeclampsia in humans, and infusion of AVP proximal to and throughout gestation is sufficient to initiate cardiovascular and renal phenotypes of preeclampsia in wild-type C57BL/6J mice. We hypothesize that AVP infusion in wild-type mice is sufficient to induce the immune changes observed in human preeclampsia. AVP infusion throughout gestation in mice resulted in increased pro-inflammatory interferon gamma (IFNg) (TH1) in the maternal plasma. The TH17-associated cytokine IL-17 was elevated in the maternal plasma, amniotic fluid, and placenta following AVP infusion. Conversely, the TH2-associated anti-inflammatory cytokine interleukin (IL)-4 was decreased in the maternal and fetal kidneys from AVP-infused dams while IL-10 was decreased in the maternal kidney and all fetal tissues. Collectively, these results demonstrate the sufficiency of AVP to induce the immune changes typical of preeclampsia. We investigated if T cells can respond directly to AVP by evaluating the expression of AVP receptors (AVPRs) on mouse and human CD4+ T cells. Mouse and human T cells expressed AVPR1a, AVPR1b, and AVPR2. The expression of AVPR1a was decreased in CD4+ T cells obtained from preeclampsia-affected women. In total, our data are consistent with a potential initiating role for AVP in the immune dysfunction typical of preeclampsia and identifies putative signaling mechanism(s) for future investigation.

Purpose/objective The rejection-identification model (RIM) argues that the negative impacts of stigma, such as decreased self-esteem, may be mitigated when members of the stigmatized group choose to identify with each other rather than with the majority culture. A previously unstudied potential RIM stigma-reduction mechanism is disability pride, which views disability as a source of valuable, enriching, and positive experience. Impairment, personal, and environmental factors based on the International Classification of Functioning, Disability and Health (ICF) predict whether people will categorize themselves as disabled, but predictors of pride have received little examination. The purpose of this study was to (a) explore whether ICF factors predict disability pride, and (b) assess whether disability pride mediates a relationship between stigma and self-esteem, supporting RIM. Research Method/Design: Participants completed an Internet-based survey assessing pride, self-esteem, and ICF factors. Disability was not mentioned in recruitment materials to prevent selection biases. People who reported at least 1 impairment (n = 710) were included in analyses. Results ICF personal and environmental factors (stigma, social support, and being a person of color), but not impairment factors, predicted disability pride. Supporting RIM, disability pride partially mediated the relationship between stigma and self-esteem. Conclusions/implications Disability pride is a promising way to protect self-esteem against stigma. Disability pride is still a rare phenomenon. Given that pride is associated with social support, stigma, and, to a lesser extent, ethnicity, but not impairment characteristics, interventions might focus on personal and environmental factors like these to promote pride. (PsycINFO Database Record

Aims Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40-49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population. Methods and results Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46-0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ. Conclusion These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).

We present a straightforward and robust method for simultaneous quantification of succinylacetone and nitisinone in plasma using LC-ESI-MS/MS. The method has been developed for routine therapeutic drug monitoring in hepatorenal tyrosinemia type 1 (HT1) patients undergoing nitisinone treatment. Previous methods are based on separate analyses of succinylacetone and nitisinone, often using the potentially harmful compound hydrazine for derivatization of the former. In the present procedure, succinylacetone is derivatized in a single-step using butanolic HCl. Analyte extraction and sample clean-up is carried out by simple protein precipitation. The linear range for both analytes is 0.1 up to 125μM, covering the vast majority of encountered levels in real-life samples. The sensitivity and limit of quantification allows measurement of succinylacetone in the therapeutical range for HT1 patients. Stability studies show that succinylacetone is highly sensitive to storage conditions, whereas nitisinone shows little to no degradation. Correct sample handling is therefore important for reliable results when monitoring succinylacetone concentrations.

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon’s action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (HbA1c), and cholesterol levels (β = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a “liver-α-cell axis” in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.

Aim The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I). Methods An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real‐world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested. Results An algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler–Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) – 16 Hurler, nine Hurler–Scheie and seven Scheie patients – would have been referred earlier if the algorithm had been used. Conclusion The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.

Purpose Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome. Methods Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment. Results There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. Conclusion In our small patient cohort, there seems to be no phenotype–genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype.Purpose Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder caused by pathogenic variants in GAMT. Brain creatine depletion and guanidinoacetate accumulation cause developmental delay, seizures and movement disorder. Treatment consists of creatine, ornithine and arginine-restricted diet. We initiated an international treatment registry using Research Electronic Data Capture (REDCap) software to evaluate treatment outcome. Methods Physicians completed an online REDCap questionnaire. Clinical severity score applied pre-treatment and on treatment. Results There were 22 patients. All had developmental delay, 18 had seizures and 8 had movement disorder. Based on the clinical severity score, 5 patients had a severe, 14 patients had a moderate and 3 patients had a mild phenotype. All patients had pathogenic variants in GAMT. The phenotype ranged from mild to moderate in patients with the most common c.327G > A variant. The phenotype ranged from mild to severe in patients with truncating variants. All patients were on creatine, 18 patients were on ornithine and 15 patients were on arginine- or protein-restricted diet. Clinical severity score improved in 13 patients on treatment. Developmental delay improved in five patients. One patient achieved normal development. Eleven patients became seizure free. Movement disorder resolved in four patients. Conclusion In our small patient cohort, there seems to be no phenotype–genotype correlation. Creatine and ornithine and/or arginine- or protein-restricted diet were the most useful treatment to improve phenotype.

The use of a mouse model to study the breadth of symptoms and disease severity seen in human West Nile virus (WNV) infection can provide insight into the kinetics of the immune response and the specific pathways responsible for control of WNV infection and viral clearance. Here, we provide protocols for performing WNV infection of mice, as well as complete immunophenotyping analysis of the cellular immune response to infection in both the periphery and the central nervous system in a mouse model of WNV infection. © 2017 by John Wiley & Sons, Inc.

Summary We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets., Graphical abstract, Highlights Circulating immune cell frequencies are modified in individuals with CD101 variants CD101 variants are associated with increased proinflammatory T cell function Individuals with a particular CD101 variant have reduced Treg cell suppression capacity CD101 contributes to regulation of inflammation at steady state, Genetic variation in CD101 is associated with increased risk of HIV acquisition, but the mechanism linking the genotype and observed phenotype has not been established. Richert-Spuhler et al. demonstrate an immunologic link by uncovering an association between these CD101 variants and homeostatic regulation of inflammation.

Despite the high prevalence of suicide both overall and among people with disabilities in particular, little research has explored suicide in the context of the vocational rehabilitation (VR) system or in counseling support staff in general. We analyzed the responses of 14 VR support staff who responded to an open-ended qualitative prompt regarding their experiences with suicide training and competency. Key themes included a perceived lack of and desire for more training regarding suicide, seeking and receiving suicide training outside of VR, and a perceived lack of resources for working with suicidal clients. Responses also underscored the heavy emotional impact of working with these clients, especially when one feels unprepared to do so. These results suggest that it is important to provide VR support staff with resources and training for addressing suicide in their client populations.

PURPOSE/OBJECTIVE According to Social Identity Theory, minority group members, like people with disabilities, manage stigma by either "passing" as majority group members or identifying with their minority group. Approximately 15% of the world's population has a disability, but only a fraction of those individuals identify themselves as people with disabilities. Disability identification has been associated with positive outcomes including psychosocial well-being, self-advocacy, and political engagement. The International Classification of Functioning (ICF) recognizes that "disability" is constructed through the intersection of impairment and context (i.e., personal and environmental factors). This is the first study to examine ICF impairment factors (duration, noticeability, presence congenital impairment, pain, severity, and total number of impairments), personal factors (age, ethnicity, gender, income, and psychological distress), and environmental factors (social support and stigma) that predict disability self-identification. Research Method/Design: Participants living in the United States completed an online survey measuring the factors listed above. To avoid selection bias, disability was not mentioned in recruitment materials. Those who reported at least 1 impairment (n = 710) were retained for analysis. RESULTS Supporting the ICF proposition that disability results from a combination of impairment and contextual factors, disability identification was predicted by severity, age, income, and stigma. Stigma partially mediated the relationship between severity and identification. CONCLUSIONS/IMPLICATIONS Stigma and severity were the strongest predictors of disability identification. Future work should examine ways to foster positive disability identity such as cross-impairment connections through support groups, mentoring, and collective action against stigma. (PsycINFO Database Record

Fabry disease is an X- linked inherited lysosomal storage disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A). The possible pathological significance of the D313Y variant in the GLA gene has not been verified and it may be a Fabry variant. Our aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males, and the presence in Fabry females did not significantly enhance the phenotype of a known causative mutation in the GLA gene (G271S). Our findings indicate that the D313Y variant is not causative to nor enhancing Fabry disease phenotype. The D313Y variant in the GLA gene was not disease causative in 2 Danish families. Investigating male family members were crucial in excluding the Fabry phenotype, and thus very important for proper genetic counceling of all family members, as well as overdiagnosing a devastating genetic disease.

This study examined the internal consistency, overall mean scores, and response patterns of 485 American adults, including 92 who identified as people with disabilities, on the Suicidal Behavior Questionnaire–Revised (SBQ-R). The measure demonstrated acceptable internal consistency in both groups. Participants with disabilities had higher mean total scores as well as more concerning response patterns on SBQ-R items assessing suicide attempts, plans, recent suicidal ideation, and perceived likelihood of future suicide attempts.

Despite the well-documented elevated rates of suicidality among people with disabilities, no published research has examined rehabilitation counselors’ experiences or perceived competency in suicide assessment or intervention. In the present study, we surveyed 223 vocational rehabilitation (VR) counselors from state VR offices in eight states regarding their experiences with, knowledge of, and perceived comfort with and competency in suicide assessment and intervention. Almost a quarter of participants worked with suicidal clients once a month or more, with more than half reporting working with suicidal clients at least once a year. Two thirds of participants reported having received some training related to suicide, and participants demonstrated both a good knowledge of suicide myths and facts, and a willingness to work with suicidal clients. However, most participants did not perceive themselves as being competent in core skills related to suicide assessment and intervention. These results suggest that more clinical training in suicide assessment and intervention is needed for VR counselors.

The prevalence of both bilingual children and children with autism spectrum disorder (ASD) is growing rapidly, and early childhood educators may be increasingly likely to encounter bilingual children with ASD in their classrooms. Because ASD significantly affects communication, many parents and professionals may have questions or concerns about the impact of bilingualism on language development in children with ASD. The present article presents a systematic review of the literature comparing monolingual to bilingual development in children with ASD. Seven articles were included, covering a wide variety of languages and involving predominantly young, simultaneously bilingual children with ASD. Results generally showed small, varied differences in both receptive and expressive language outcomes for bilingual and monolingual children with ASD, thus providing tentative support for the idea that bilingualism does not have a consistent or large negative effect on language development in children with ASD. Implications for research and practice are discussed.

BACKGROUND Patients with reduced left ventricular ejection fraction (EF

Lipases are interfacially activated enzymes that catalyze the hydrolysis of ester bonds and constitute prime candidates for industrial and biotechnological applications ranging from detergent industry, to chiral organic synthesis. As a result, there is an incentive to understand the mechanisms underlying lipase activity at the molecular level, so as to be able to design new lipase variants with tailor-made functionalities. Our understanding of lipase function primarily relies on bulk assay averaging the behavior of a high number of enzymes masking structural dynamics and functional heterogeneities. Recent advances in single molecule techniques based on fluorogenic substrate analogues revealed the existence of lipase functional states, and furthermore so how they are remodeled by regulatory cues. Single particle studies of lipases on the other hand directly observed diffusional heterogeneities and suggested lipases to operate in two different modes. Here to decipher how mutations in the lid region controls Thermomyces lanuginosus lipase (TLL) diffusion and function we employed a Single Particle Tracking (SPT) assay to directly observe the spatiotemporal localization of TLL and rationally designed mutants on native substrate surfaces. Parallel imaging of thousands of individual TLL enzymes and HMM analysis allowed us to observe and quantify the diffusion, abundance and microscopic transition rates between three linearly interconverting diffusional states for each lipase. We proposed a model that correlate diffusion with function that allowed us to predict that lipase regulation, via mutations in lid region or product inhibition, primarily operates via biasing transitions to the active states.

Although the phenomenon of disability-related abuse has been well-documented in adults with disabilities, the occurrence of disability-related abuse in childhood has not been studied. Therefore, the purpose of this study was to establish proof of concept for childhood disability-related abuse. American adults ( n = 485) retrospectively report on physical, sexual, and disability-related abuse that they experienced before the age of 18. The sample consisted of 382 participants with no disability, 55 participants with an adult-onset disability, and 48 participants with a childhood-onset disability. Disability-related abuse was conceptualized as involving either (a) the denial of assistive technology or (b) the denial of care, permission, or assistance with an activity of self-care. Childhood denial of assistive technology was rare in all groups (1.3%-2.1%), but denial of care, assistance, or permission was significantly higher in the childhood-onset disability group (20.8%) than either the adult-onset (7.3%) or no-disability (6.5%) groups. The three groups did not significantly differ in the rates of reported childhood physical or sexual abuse. This study provides preliminary proof-of-concept evidence for childhood disability-related abuse, particularly denial of care.

Background Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines, as well as the early identification of individuals with the highest risk that may require supportive treatment. Methods We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, SARS-coronavirus, and West Nile virus. Results CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality following infection and strains exhibiting no mortality. We then used comprehensive pre-infection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. Conclusions These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.

Primary carnitine deficiency (PCD) not treated with L-Carnitine can lead to sudden cardiac death. To our knowledge, it is unknown if asymptomatic patients treated with L-Carnitine suffer from myocardial scarring and thus be at greater risk of potentially serious arrhythmia. Cardiac evaluation of function and myocardial scarring is non-invasively best supported by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). The study included 36 PCD patients, 17 carriers and 17 healthy subjects. A CMR cine stack in the short-axis plane were acquired to evaluate left ventricle (LV) systolic and diastolic function and a similar LGE stack to evaluate myocardial scarring and replacement fibrosis. LV volumes and ejection fraction were not different between PCD patients, carriers and healthy subjects. However, LV mass was higher in PCD patients with the severe homozygous mutation, c.95 A > G (p = 0.037; n = 17). Among homozygous PCD patients there were two cases of unexplained myocardial scarring and this is in contrast to no myocardial scarring in any of the other study participants (p = 0.10). LV mass was increased in PCD patients. L-carnitine supplementation is essential in order to prevent potentially lethal cardiac arrhythmia and serious adverse cardiac remodeling.

Tissue-resident memory CD8 T cells (CD8 TRM) are critical for maintaining barrier immunity. CD8 TRM have been mainly studied in the skin and gut with recent studies suggesting that the signals that control tissue-residence and phenotype are highly tissue-dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B+ and TCF-1-. To address if this phenotype is driven by CVT tissue-residence, we used a mouse model to control for environmental factors. Using localized and systemic infection models, we found that CD8 TRM in the mouse CVT gradually acquired a granzyme B+, TCF-1- phenotype as seen in human CVT. In contrast to CD8 TRM in the gut, these CD8 TRM were not stably maintained regardless of the initial infection route, which led to reductions in local immunity. Our data show that residence in the CVT is sufficient to progressively shape the size and function of its CD8 TRM compartment.SummaryThe tissue-resident memory (TRM) CD8 T cell compartment in human and mouse cervicovaginal tissue (CVT) is remarkably similar. The CVT TRM compartment is maintained autonomously and does not reach phenoypical or numerical equilibrium. The numerical decline leads to impaired viral control in a secondary challenge.

Arginine vasopressin (AVP) has been shown to play a role in preeclampsia, a hypertensive and immune-mediated disorder in pregnancy. Chronic infusion of AVP during gestation into wild-type mice results in the pregnancy-specific physiological changes (hypertension, kidney damage, fetal growth restriction) as well as increased CD4+ T H 1 and T H 17 associated cytokine responses observed in human pregnancies affected by preeclampsia. Further, human CD4+ T cells isolated from preeclamptic women were found to differentially express AVP receptors (AVPRs) 1a and 2 compared to control pregnancies. Abnormalities in other immune cells are seen during preeclampsia, including auto-antibody production (B cells), poor placental development (natural killer (NK) cells), and increased pro-inflammatory T cells responses (via dendritic cells (DC)). We, therefore, hypothesize that B cells, NK cells, and DC express AVPRs. To begin to understand 1) the expression pattern of AVPRs on CD4- lymphocytes and 2) if there are differences in expression between males and females, we evaluated the expression of AVPR 1a, 2, and 1b specifically on B cells, NK cells, and DC. Each subset was purified via negative selection from de-identified human peripheral blood mononuclear cells obtained through Leukocyte Reduction System (LRS) cone donors at the DeGowin Blood Center followed by qPCR for AVPR 1a, 2, and 1b expression (N=6 per cell type). B cells, NK cells, and DC expressed all three AVPRs 1a, 2, and 1b. All three lymphocyte populations showed a lower expression of AVPR1b compared to expression of 1a and 2, with B cells having the lowest expression of AVPR1b (p

West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease., Author summary In recent years, outbreaks of emerging and re-emerging neuroinvasive West Nile virus (WNV) infection have brought about a critical need to understand host factors that restrict neuropathology and disease. WNV infection in humans typically is either asymptomatic or results in a mild febrile illness, but in some cases virus spreads to the central nervous (CNS) causing a more severe form of neuropathological disease. Previous studies established that both innate and adaptive immune responses are essential for controlling WNV disease and restricting the virus from the CNS. In this study, we examined the role of Stimulator of Interferon Genes (STING) in conferring host defense during WNV infection in a murine model. Our studies revealed that STING is essential for restricting pathology in the CNS during WNV infection. Further, STING is required for effective programming of the innate and adaptive immune response to WNV. In the absence of STING, aberrant immune development leads to ineffective viral clearance and immunopathology in the CNS. These studies uncover a critical and previously unidentified role for STING in the restriction of WNV that may have broader implications for a role in conferring host defense against RNA viruses.

Allison-type emittance scanners are widely used to measure projected 2D phase space distributions of low energy beams. This paper extends the conventional data analysis model to introduce three significant corrections that commonly arise in the pursuit of high resolution measurements. First, effective longitudinal asymmetry in the E-dipole placement (typically resulting from directional choice of relief cuts in thick slit-plates) causes deviation from the ideal voltage-to-angle conversion relation. Second, finite slit thickness generates variation in weights of data points that should be compensated. Third, when the interval between data points is smaller than the device resolution (ordinary in the angular data accumulation), a detailed account of the phase space region contributing to each data point can be used to resolve the beam distribution more accurately. These findings are illustrated by simulations with numerically generated phase space distributions. The improved model is applied to experimental measurements of an Ar ion beam with an Allison scanner operating at the front-end of the Facility for Rare Isotope Beams (FRIB) at Michigan State University. Results show that the improved model obtains better agreement among a set of measurements and modifies beam moments significantly (can be $\ensuremath{\sim}10%$ relative to conventional methods, with larger deviations at increasing angular divergence), thus rendering the corrections important for accurate high resolution phase-space characterizations. Python code tools that implement the improved analysis described are made available. These tools are readily applicable to any Allison scanner given a specification of the device geometry and scan ranges associated with each measurement.

Methods used to isolate Listeria spp. from raw milk were compared during a 13-month period (April 1989-April 1990). Raw milk was obtained bimonthly from 12 dairy farms during this time period. Three enrichments were compared: Listeria enrichment broth (LEB); University of Vermont medium (UVM), followed by a secondary enrichment with Fraser broth; and LPALCAMY. Four selective plating media, including Listeria selective agar-Oxford formulation; Modified McBride Listeria agar (MMLA); Lithium chloride-phenylethanol-moxalactam (LPM) agar; and L-PALCAM agar, were compared. L-PALCAMY enrichment broth enhanced isolation of L. monocytogenes and other Listeria spp. The greatest numbers of positive Listeria samples were obtained on Oxford and PALCAM agars, while the poorest isolation was obtained using the combination of LEB with MMLA. L. monocytogenes was found to be present in 3.0% (9/300) of the samples analyzed. The incidence of Listeria spp. was 28.0%; Listeria innocua , 26.7%; and Listeria welshimeri , 1.7%. Listeria ivanovii was not isolated. The incidence of Listeria was highest during the warmer months of April-July, while the lowest incidences occurred in December and February. Somatic cell counts (SCC) and standard plate counts (SPC) were determined by the cooperative that supplied the raw milk. In general, a producer's milk with high SPC corresponded to a high incidence of Listeria spp., while low SPC corresponded to a low incidence. A particular producer's milk with the highest incidence of Listeria spp. also had the highest SCC.

Preeclampsia is characterized by new onset hypertension and fetal growth restriction and is associated with aberrant activation of the innate immune complement system and stressed or ischemic placenta. Previous studies have suggested a role for both endothelin and complement system activation products in new onset hypertension in pregnancy, but inter-relationships of the pathways are unclear. We hypothesized that complement activation following placental ischemia stimulates the endothelin pathway to cause hypertension and impair fetal growth. The Reduced Uterine Perfusion Pressure (RUPP) model results in hypertension and fetal growth restriction in a pregnant rat due to placental ischemia caused by mechanical obstruction of blood flow to uterus and placenta. The effect of inhibitor of complement activation soluble Complement Receptor 1 (sCR1) and endothelin A receptor (ET(A)) antagonist atrasentan on hypertension, fetal weight, complement activation (systemic circulating C3a and local C3 placental deposition) and endothelin [circulating endothelin and message for preproendothelin (PPE), ET(A) and endothelin B receptor (ET(B) in placenta] in the RUPP rat model were determined. Following placental ischemia, sCR1 attenuated hypertension but increased message for PPE and ET(A) in placenta, suggesting complement activation causes hypertension via an endothelin independent pathway. With ET(A) antagonism the placental ischemia-induced increase in circulating C3a was unaffected despite inhibition of hypertension, indicating systemic C3a alone is not sufficient. In normal pregnancy, inhibiting complement activation increased plasma endothelin but not placental PPE message. Atrasentan treatment increased fetal weight, circulating endothelin and placental ET(A) message, and unexpectedly increased local complement activation in placenta (C3 deposition) but not C3a in circulation, suggesting endothelin controls local placental complement activation in normal pregnancy. Atrasentan also significantly decreased message for endogenous complement regulators Crry and CD55 in placenta and kidney in normal pregnancy. Results of our study indicate that complement/endothelin interactions differ in pregnancies complicated with placental ischemia vs normal pregnancy, as well as locally vs systemically. These data clearly illustrate the complex interplay between complement and endothelin indicating that perturbations of either pathway may affect pregnancy outcomes.

Control of the botulism risk in refrigerated, processed foods with extended durability (REPFED) which do not contain intrinsic safety factor(s) has been analyzed. There are insufficient data on the heat resistance of spores of nonproteolytic Clostridium botulinum types B, E, and F, to ensure that the heating process used in preparation of REPFEDs provides adequate lethality. During portioning of foods and filling of trays, products may be exposed to recontamination if this process is not carried out under aseptic conditions. Pasteurization of sealed trays at a temperature of about 75°C for several minutes is a process which spores of C. botulinum can easily survive. For these reasons, REPFEDs must be stored at a temperature < 3.3°C, since such low storage temperatures prevent growth and formation of toxin by C. botulinum . At 8°C, a temperature to which chilled foods are often exposed during and after retail sale, nonproteolytic strains of C. botulinum can produce toxin within 3 weeks. In addition prestorage at 3°C for up to 2-4 weeks stimulates the toxinogenesis of nonproteolytic C. botulinum type B at a subsequent storage at 8°C. Heating of REPFEDs before consumption was not always sufficient to inactivate botulinum toxin completely. In order to ensure that the risk of botulism from these foods is controlled adequately, REPFEDs must be stored at a temperature < 3.3°C. If, however, this temperature cannot be guaranteed, the storage time has to be limited.

The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low tissue-resident CD8+ T-cell density (TRM) are unknown. We analyzed shedding episodes during chronic HSV-2 infection: viral clearance always occurred within 24 hours of detection even if viral load exceeded 107HSV DNA copies; surges in granzyme B and interferon-γoccurred within the early hours after reactivation. We next developed a mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of TRMin situproliferation, trafficking, cytolytic effects and cytokine alarm signaling from murine studies with viral kinetics, histopathology and lesion size data from humans. A sufficiently high density of HSV-2 specific TRMpredicted rapid contact-mediated elimination of infected cells. At lower TRMdensities, TRMmust initiate a rapidly diffusing, polyfunctional cytokine response in order to eliminate of a majority of infected cells and eradicate briskly spreading HSV-2 infection.One Sentence SummaryControl of herpes simplex virus-2 is primarily mediated by rapidly diffusing cytokines secreted by tissue-resident T cells.

Introduction Homozygous familial hypercholesterolaemia (HoFH) is a rare, autosomal disease affecting the clearance of low-density lipoprotein cholesterol (LDL-C) from circulation, and leading to early-onset atherosclerotic cardiovascular disease (ASCVD). Treatment consists mainly of statins, lipoprotein apheresis (LA) and, more recently, the microsomal triglyceride transfer protein inhibitor lomitapide. Lomitapide is not licensed for use in children, but has been made available through an expanded access programme or on a named patient basis. Methods This case series includes 11 HoFH patients in 10 different centres in eight countries, less than 18 years of age (mean 11.6 ± 1.1 years, 64% male), with signs of ASCVD, and who have received treatment with lomitapide (mean dose 24.5 ± 4.3 mg/day; mean exposure 20.0 ± 2.9 months). Background lipid-lowering therapy was given according to local protocols. Lomitapide was commenced with a stepwise dose escalation from 2.5 mg or 5 mg/day; dietary advice and vitamin supplements were provided as per the product label for adults. Laboratory analysis was conducted as part of regular clinical care. Results In the 11 cases, mean baseline LDL-C was 419 ± 74.6 mg/dL and was markedly reduced by lomitapide to a nadir of 176.7 ± 46.3 mg/dL (58.4 ± 6.8% decrease). Six patients achieved recommended target levels for children below 135 mg/dL, five of whom had LA frequency reduced. In one case, LDL-C levels were close to target when lomitapide was started but remained stable despite 75% reduction in LA frequency (from twice weekly to biweekly). Adverse events were mainly gastrointestinal in nature, occurred early in the treatment course and were well managed. Three patients with excursions in liver function tests were managed chiefly without intervention; two patients had decreases in lomitapide dose. Conclusions Lomitapide demonstrated promising effectiveness in paediatric HoFH patients. Adverse events were manageable, and the clinical profile of the drug is apparently similar to that in adult patients. Funding Amryt Pharma.