Upregulated selenoprotein I during lipopolysaccharide-induced B cell activation promotes lipidomic changes and is required for effective differentiation into IgM-secreting plasma B cells.

The mechanisms driving metabolic reprogramming during B cell activation are unclear, particularly roles for enzymatic pathways involved in lipid remodeling. We found that murine B cell activation with lipopolysaccharide (LPS) led to a 1.6-fold increase in total lipids that included higher levels of phosphatidylethanolamine (PE) and plasmenyl PE. Selenoprotein I (SELENOI) is an ethanolamine phospholipid transferase involved in the synthesis of both PE and plasmenyl PE, and SELENOI expression was also upregulated during activation. Selenoi knockout (KO) B cells exhibited decreased levels of plasmenyl PE, which plays an important antioxidant role. Lipid peroxidation was measured and found to increase ∼2-fold in KO vs. wild-type (WT) B cells. Cell death was not impacted by KO in LPS-treated B cells and proliferation was only slightly reduced, but differentiation into CD138 + Blimp-1+ plasma B cells was decreased ∼2-fold. This led to examination of B cell receptors important for differentiation that recognize the ligand B cell activating factor, and levels of TACI (transmembrane activator, calcium-modulator, and cytophilin ligand interactor) (CD267) were significantly decreased on KO B cells compared with WT control cells. Vaccination with ovalbumin/adjuvant led to decreased ovalbumin-specific immunoglobulin M (IgM) levels in sera of KO mice compared with WT mice. Real-time polymerase chain reaction analyses revealed a decreased switch from surface to secreted IgM in spleens of KO mice induced by vaccination or LP-BM5 retrovirus infection. Overall, these findings detail the lipidomic response of B cells to LPS activation and reveal the importance of upregulated SELENOI for promoting differentiation into IgM-secreting plasma B cells.

Inhibition of myeloid-derived suppressor cell (MDSC) activity by redox-modulating agents restores T and B cell proliferative responses in murine AIDS.

The mechanisms by which myeloid-derived suppressor cells (MDSCs) mediate inhibition prominently include the production of reactive nitrogen species, in particular those generated by inducible nitric oxide synthase (iNOS), and reactive oxygen species. LP-BM5 murine retroviral infection results in a profound immunodeficiency, known as murine AIDS, as well as in increased numbers and activity of monocytic-type MDSCs (M-MDSCs) that suppress both T and B cell responses. While M-MDSCs suppress T cells ex vivo in a fully iNOS/NO-dependent manner, M-MDSC suppression of B cell responses is only partially due to iNOS/NO. This study preliminarily explored the role of two redox-modulating compounds in inhibiting the M-MDSC suppressive activity in LP-BM5 infection. The tested molecules were: I-152 consisting in a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-cysteamine (SMEA) and C4-GSH that is the n-butanoyl glutathione (GSH) derivative. The results show that both molecules, tested in a concentration range between 3 and 20 mM, blocked the M-MDSC suppression of activated B and T cells ex vivo and restored their proliferative capacity in vivo. Ex vivo I-152 blockade of M-MDSC suppressiveness was more significant for T cell (about 70%) while M-MDSC blockade by C4-GSH was preferential for B cell responsiveness (about 60%), which was also confirmed by in vivo investigation. Beyond insights into redox-dependent suppressive effector mechanism(s) of M-MDSCs in LP-BM5 infection, these findings may ultimately be important to identify new immunotherapeutics against infectious diseases.

The Royal Berkshire NHS Foundation Trust outpatient services transformation programme to improve quality and effectiveness of patient care.

Background: The Royal Berkshire NHS Foundation Trust outpatient services transformation programme is a strategic change programme delivered as a collaborative approach through the Berkshire West Integrated Care Partnership. The main aim of redesign is to improve capacity in clinics and improve patient experience. Methods: This was done through a best practice menu and 'how to' guides. This simplified and standardised the process for moving activity from face-to-face to virtual, maximising remote monitoring and moving clinics off the main acute site. Results: We have successfully implemented six different work streams to transform outpatient services. Referrals are now triaged and streamed. The number of patients reviewed virtually, on patient-initiated follow-up and seen closer to home has increased. Conclusion: The outpatient services transformation programme has resulted in improvements within the trust and the integrated care partnership. This programme supports the vision by the Royal College of Physicians and NHS England to modernise and transform outpatient services.

Exposure sources, amounts and time course of gluten ingestion and excretion in patients with coeliac disease on a gluten-free diet.

BACKGROUND: A major deficit in understanding and improving treatment in coeliac disease (CD) is the lack of empiric data on real world gluten exposure. AIMS: To estimate gluten exposure on a gluten-free diet (GFD) using immunoassays for gluten immunogenic peptides (GIP) and to examine relationships among GIP detection, symptoms and suspected gluten exposures METHODS: Adults with biopsy-confirmed CD on a GFD for 24 months were recruited from a population-based inception cohort. Participants kept a diary and collected urine samples for 10 days and stools on days 4-10. 'Doggie bags' containing » portions of foods consumed were saved during the first 7 days. Gluten in food, stool and urine was quantified using A1/G12 ELISA. RESULTS: Eighteen participants with CD (12 female; age 21-70 years) and three participants on a gluten-containing diet enrolled and completed the study. Twelve out of 18 CD participants had a median 2.1 mg gluten per exposure (range 0.2 to >80 mg). Most exposures were asymptomatic and unsuspected. There was high intra-individual variability in the interval between gluten ingestion and excretion. Participants were generally unable to identify the food. CONCLUSIONS: Gluten exposure on a GFD is common, intermittent, and usually silent. Excretion kinetics are highly variable among individuals. The amount of gluten varied widely, but was typically in the milligram range, which was 10-100 times less than consumed by those on an unrestricted diet. These findings suggest that a strict GFD is difficult to attain, and specific exposures are difficult to detect due to variable time course of excretion.

A multidimensional Rasch analysis of the screener and opioid assessment for patients with pain-revised.

OBJECTIVE: Pilot study to assess psychometric indices of the screener and opioid assessment for patients with pain-revised (SOAPP-R©) with item response theory. DESIGN: Correlational. SETTING: Patients. OUTCOME MEASURES: The SOAPP-R©, the pain self-efficacy questionnaire (PSE-Q), and the patient health questionnaire-9 (PHQ-9) and a demographic -questionnaire. RESULTS: A three-dimensional model provided the best fit for the SOAPP-R© item responses, with scales entitled drug-alcohol concerns, pain medication, and emotional stress; reliabilities were 0.77, 0.71, and 0.80 for those three scales. Significant correlations were found with the PSE-Q, the PHQ-9, and the SPQ for the drug-alcohol scale but not for the two remaining scales. CONCLUSIONS: The SOAPP-R© showed invariance and support for validity, but with a three-dimensional scale structure.

I-152, a supplier of N-acetyl-cysteine and cysteamine, inhibits immunoglobulin secretion and plasma cell maturation in LP-BM5 murine leukemia retrovirus-infected mice by affecting the unfolded protein response.

Excessive production of immunoglobulins (Ig) causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR). Hypergammaglobulinemia and lymphadenopathy are hallmarks of murine AIDS that develops in mice infected with the LP-BM5 murine leukemia retrovirus complex. In these mice, Th2 polarization and aberrant humoral response have been previously correlated to altered intracellular redox homeostasis. Our goal was to understand the role of the cell's redox state in Ig secretion and plasma cell (PC) maturation. To this aim, LP-BM5-infected mice were treated with I-152, an N-acetyl-cysteine and cysteamine supplier. Intraperitoneal I-152 administration (30 µmol/mouse three times a week for 9 weeks) decreased plasma IgG and increased IgG/Syndecan 1 ratio in the lymph nodes where IgG were in part accumulated within the ER. PC containing cytoplasmic inclusions filled with IgG were present in all animals, with fewer mature PC in those treated with I-152. Infection induced up-regulation of signaling molecules involved in the UPR, i.e. CHAC1, BiP, sXBP-1 and PDI, that were generally unaffected by I-152 treatment except for PDI and sXBP-1, which have a key role in protein folding and PC maturation, respectively. Our data suggest that one of the mechanisms through which I-152 can limit hypergammaglobulinemia in LP-BM5-infected mice is by influencing IgG folding/assembly as well as secretion and affecting PC maturation.

Development of the Dietitian Integrated Evaluation Tool for Gluten-free Diets (DIET-GFD).

OBJECTIVES: Celiac disease (CD) treatment involves a gluten-free diet (GFD). There is no standardized tool for dietitians to objectively grade GFD adherence. This study aimed to develop a standardized tool for dietitians to evaluate and communicate GFD adherence. METHODS: Participants were recruited from the Manitoba Celiac Disease Cohort. Using a consensus process, an expert panel of gastroenterologists, dietitians, clinical health psychologists, and persons with CD developed the Dietitian Integrated Evaluation Tool for Gluten-free Diets (DIET-GFD). Two dietitians performed duplicate assessments of 27 newly diagnosed participants who had been advised to follow a GFD. The global adherence scale was further revised after panel discussions of the cases where there was uncertainty or discordance on dietitian ratings. Subsequently, the scoring system was evaluated using duplicate assessments of an additional 37 participants with CD. Interrater agreement was assessed using square-weight Cohen's kappa. RESULTS: The DIET-GFD includes features related to frequency and quantity of gluten ingestion based on self-reporting and food frequency evaluation, shopping and dining habits, how and where food is prepared and consumed, eating behaviors, and label reading skills. The DIET-GFD global assessment is reported using a 10-point ordinal descriptive scale, ranging from 1 (takes few precautions and regularly eats gluten) to 10 (no gluten in kitchen and rarely eats food prepared outside the home). The kappa of DIET-GFD global assessment was 0.845, which indicates excellent agreement. CONCLUSIONS: DIET-GFD is a useful tool for dietitians to evaluate GFD adherence. Further studies are needed to confirm that the score from the DIET-GFD is reliable across various settings.

A cohort investigation of patient-reported function and satisfaction after the implementation of advanced practice occupational therapy-led care for patients with chronic hand conditions at eight Australian public hospitals.

STUDY DESIGN: Prospective cohort. INTRODUCTION: Patients referred to medical specialist outpatient clinics in Australian public hospitals often wait longer than the recommended timeframe for their first appointment. This study examines the use of advanced hand therapy practitioners to facilitate access to care for long-waitlisted patients with chronic hand conditions. PURPOSE OF STUDY: To examine patient-reported function and satisfaction outcomes with advanced practice hand therapy. METHODS: Data was collected from eight public hospital outpatient departments in Queensland, Australia. Patients with chronic hand conditions were screened from waitlists at each site and invited to participate in the hand therapy program while waiting to see a medical practitioner. RESULTS: A total of 1947 patients were screened from the waitlists, and 1116 patients completed advanced practice therapy. Patients completing hand therapy were older (P ≤ .001) and more likely to have more than one diagnosis (P ≤ .001). They reported a significant improvement in function using the Michigan Hand Questionnaire (P ≤ .001) and demonstrated increased grip strength (left injuries P = .016, right injuries P = .001). Ninety-three percent were satisfied or highly satisfied with hand therapy care. Some variation in Michigan Hand Questionnaire scores was observed across different diagnoses, with those with carpal tunnel syndrome and trigger finger reporting the best outcomes. CONCLUSIONS: Advanced practice hand therapy for long-waitlisted patients with chronic hand conditions was associated with improvements in patient function and satisfaction. Further research is warranted to study the specific response of different diagnostic groups to intervention using this model of care.

Can individuals with celiac disease identify gluten-free foods correctly?

BACKGROUND & AIMS: Patients with celiac disease (CD) often report inadvertent gluten exposures and challenges reading labels. The most common cause of non-responsive CD is gluten exposure. We aimed to assess whether recently diagnosed CD patients can determine whether a food is gluten-free based on labeling, and to assess skills over time. A secondary aim was to identify factors associated with label reading proficiency. METHODS: Inception cohort with follow-up at 6, 12, and 24 months after diagnosis. Participants were asked to determine whether 25 food items were gluten-free based on labeling information. Diet adherence was assessed using the Celiac Diet Assessment Tool (CDAT) and the Gluten-Free Eating Assessment Tool (GF-EAT). 144 adults with newly diagnosed celiac disease were enrolled. The initial quiz at 6 months was completed by 83%. Quizzes were completed by 72% at 12 months and 70% at 24 months. RESULTS: Median overall accuracy scores were: 23/25, 24/25 and 21/25 at 6, 12 and 24 months respectively. Gluten-free products with explicit "gluten-free" claims had the fewest errors. Quiz scores were not correlated with tTG IgA levels, or CDAT or GF-EAT scores. Diet adherence was generally good (>85% with CDAT <13 suggesting adequate GFD adherence); however, at 24 months, only 11% reported no gluten exposure. CONCLUSIONS: CD patients may be unable to consistently choose gluten-free foods based on product labeling. Explicit identification of gluten-free products may be helpful. Label reading ability appears stable over time. Further studies are needed to evaluate whether erroneous label reading or misleading labels are associated with persistent villous atrophy.

Evaluation of occupational therapy-led advanced practice hand therapy clinics for patients on surgical outpatient waiting lists at eight Australian public hospitals.

STUDY DESIGN: This is a prospective cohort study. INTRODUCTION: Evidence is emerging that advanced practice hand therapy clinics improve patient outcomes. PURPOSE OF THE STUDY: The aim of this study was to evaluate an advanced practice hand therapy model of care for patients with chronic hand conditions on surgical outpatient waiting lists at eight Australian public hospitals. METHODS: Nonurgent and semiurgent patients were screened and treated, as required, by an advanced practice hand therapist and then discharged from the surgical outpatient waiting list as appropriate. Outcomes included patient safety, impact on the waiting list, patient satisfaction, and patients' perception of change as measured by Global Rating of Change (GROC). The GROC score was also compared across diagnoses. The relationship between the waiting time and need for surgical review during hand therapy treatment was also assessed. As appropriate, T-tests and analysis of variance were used for statistical analyses. RESULTS: A total of 37.2% of patients who commenced hand therapy were removed or discharged from the surgical outpatient waiting lists. Of the subset of patients who completed hand therapy (n = 1116), 28.4% were discharged without requiring surgical follow-up. A further 7.53% requested return to the waiting list despite discharge being recommended. The model of care was safe, and patient satisfaction was above 90%. The mean GROC score was +2.09 (±3.58) but varied across diagnoses with trigger finger or trigger thumb showing the greatest improvement (+4.21 ± 2.92, P < .01). Patients who did not require surgical consultation during hand therapy had a shorter wait time for their initial hand therapy appointment (P < .001). CONCLUSIONS: The advanced practice hand therapy model of care was safe and effective in reducing hospital surgical outpatient waiting lists. Patients reported high satisfaction.

Assessing the Reliability of the Framework for Equitable and Effective Teaching With the Many-Facet Rasch Model.

This manuscript reports results of an empirical assessment of a newly developed measure designed to assess apprentice teaching proficiency. In this study, Many Facets Rasch model software was used to evaluate the psychometric quality of the Framework for Equitable and Effective Teaching (FEET), a rater-mediated assessment. The analysis focused on examining variability in (1) supervisor severity in ratings, (2) level of item difficulty, (3) time of assessment, and (4) teacher apprentice proficiency. Added validity evidence showed moderate correlation with self-reports of apprentice teaching. The findings showed support for the FEET as yielding reliable ratings with a need for added rater training.

Rasch analysis of the Brief Symptom Inventory-18 with African American and White students.

Although the United States offers some of the most advanced psychological services in the world, not everyone in the country shares these services equally, resulting in health disparities. Health disparities persist when assessments do not appropriately measure different populations' mental health problems. To address this assessment issue, we conducted principal axis factoring, confirmatory factor analysis, and Rasch analyses to assess the psychometric characteristics of the Brief Symptom Inventory-18 (BSI-18) to evaluate whether the BSI is culturally appropriate for assessing African American students' psychological distress. The dimensional structure of the BSI was first identified and held up under cross-validation with a second sample and a white sample. The measure was unidimensional among African American and white students. Our results suggested BSI in our samples presented characteristics such as low person separation, stability across samples, and little differential item functioning. Most African American and white students identified themselves on the low end of the categories in a 0-4 rating scale, indicating their low endorsement of the items on the BSI. Rasch analyses were completed with the original scale but also collapsing the scale to three points, with some increase in separation and reliability for the collapsed scale. As anticipated, differences in mean BSI scores were found for mental health-related variables. Implications for theory and research on multicultural health scales are discussed as are effects of item skewness on analyses. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Rasch Analysis of the Brief Symptom Inventory-18 with African Americans.

Although the United States offers some of the most advanced psychological services in the world, not everyone in U.S. shares equally in these services, and health disparities persist when assessments do not appropriately measure different populations' mental health problems. To address this assessment issue, we conducted factor and Rasch analyses to assess the psychometric characteristics of the Brief Symptom Inventory-18 (BSI-18) to evaluate whether the BSI is culturally appropriate for assessing African Americans' psychological distress. The dimensional structure of the BSI was first identified and held up under cross-validation with a second subsample. The measure was unidimensional among African Americans. Our results also suggested minimal person separation, stability across subsamples, and little differential item functioning. Most African Americans identified themselves on the low end of the categories in a 0-4 rating scale, indicating their low endorsement of the items on the BSI. Rasch analyses were completed with the original scale but also collapsing the scale to three points, with some increase in separation and reliability for the collapsed scale. Differences in mean person position were found for mental health-related variables, consistent with hypotheses. Implications for theory and research on multicultural health scales are discussed as are effects of severe item skewness on analyses.

A Rasch analysis of the Current Opioid Misuse Measure for patients with chronic pain.

OBJECTIVE: Pilot study to assess psychometric indices of the Current Opioid Misuse Measure (COMM). DESIGN: Correlational. SETTING: Patients with varied chronic pain from a family healthcare center. PATIENTS: Inclusion criteria were over 21 years of age and prescribed opioids for any-origin noncancer pain; 46 patients were enrolled. OUTCOME MEASURE(S): The COMM, the Pain Self-Efficacy Questionnaire (PSE-Q), and the Patient Health Questionnaire-9 (PHQ-9) and a demographic -questionnaire. RESULTS: Preliminary analysis indicated issues with dimensionality and scale use. Analysis after remedial procedures yielded unidimensionality and appropriate scale use, with the measure showing invariance across sex and low significant correlation with the PHQ-9 but not the PSE-Q. CONCLUSIONS: The COMM had adequate reliability, measured a distinct construct, and no significant differential item function was found. However, scale use for this sample was questionable, and three items misfit the Rasch model. Replication with a larger sample is needed to ensure the measure's psychometric quality for diagnostic use.

Evaluation of the Parent-Report Inventory of Callous-Unemotional Traits in a Sample of Children Recruited from Intimate Partner Violence Services: A Multidimensional Rasch Analysis.

OBJECTIVE: Our study applied multidimensional item response theory (MIRT) to compare structural models of the parent-report version of the Inventory of Callous and Unemotional Traits (ICU; English and North American Spanish translations). METHOD: A total of 291 maternal caregivers were recruited from community-based domestic violence services and reported on their children (77.9% ethnic minority; 47% female), who ranged in age from 7 to 12 years (mean = 9.07, standard deviation = 1.64). We compared 9 models that were based on prior psychometric evaluations of the ICU. RESULTS: MIRT analyses indicated that a revised 18-item version comprising 2 factors (callous-unemotional and empathic-prosocial) was more suitable for our sample. Differential item functioning was found for several items across ethnic and language groups, but not for child gender or age. Evidence of construct validity was found. CONCLUSION: We recommend continued research and revisions to the ICU to better assess the presence of callous-unemotional traits in community samples of school-age children.

Rasch analysis of the Rosenberg Self-Esteem Scale with African Americans.

Effectively diagnosing African Americans' self-esteem has posed an unresolved challenge. To address this assessment issue, we conducted exploratory factor analysis and Rasch analysis to assess the psychometric characteristics of the Rosenberg Self-Esteem Scale (RSES, Rosenberg, 1965) for African American college students. The dimensional structure of the RSES was first identified with the first subsample (i.e., calibration subsample) and then held up under cross-validation with a second subsample (i.e., validation subsample). Exploratory factor analysis and Rasch analysis both supported unidimensionality of the measure, with that finding replicated for a random split of the sample. Response scale use was generally appropriate, items were endorsed at a high level reflecting high levels of self-esteem, and person separation and reliability of person separation were adequate, and reflected results similar to those found in prior research. However, as some categories were infrequently used, we also collapsed scale points and found a slight improvement in scale and item indices. No differential item functioning was found by sex or having received professional assistance versus not; there were no mean score differences by age group, marital status, or year in college. Two items were seen as problematic. Implications for theory and research on multicultural mental health are discussed. (PsycINFO Database Record

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics.

UNLABELLED: Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine (I-152), an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCE: The first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/Th2 imbalance to be more effectively combated.

Subpopulations of M-MDSCs from mice infected by an immunodeficiency-causing retrovirus and their differential suppression of T- vs B-cell responses.

Monocytic (CD11b(+)Ly6G(±/Lo)Ly6C(+)) myeloid derived suppressor cells (M-MDSCs) expand following murine retroviral LP-BM5 infection and suppress ex vivo polyclonal T-cell and B-cell responses. M-MDSCs 3 weeks post LP-BM5 infection have decreased suppression of T-cell, but not B-cell, responses and alterations in the degree of iNOS/NO dependence of suppression. M-MDSCs from LP-BM5 infected mice were sorted into four quadrant populations (Ly6C/CD11b density): all quadrants suppressed B-cell responses, but only M-MDSCs expressing the highest levels of Ly6C and CD11b (Q2) significantly suppressed T-cell responses. Further subdivision of this Q2 population revealed the Ly6C(+/Hi) M-MDSC subpopulation as the most suppressive, inhibiting T- and B-cell responses in a full, or partially, iNOS/NO-dependent manner, respectively. In contrast, the lower/moderate levels of suppression by the Ly6C(+/Lo) and Ly6C(+/Mid) M-MDSC Q2 subpopulations, whether versus T- and/or B-cells, displayed little/no iNOS dependency for suppression. These results highlight differential phenotypic and functional immunosuppressive M-MDSC subsets in a retroviral immunodeficiency model.

Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus.

Inhibition of T-cell responses in tumor microenvironments by myeloid-derived suppressor cells (MDSCs) is widely accepted. We demonstrated augmentation of monocytic MDSCs whose suppression of not only T-cell, but also B-cell, responsiveness paralleled the immunodeficiency during LP-BM5 retrovirus infection. MDSCs inhibited T cells by inducible nitric oxide synthase (iNOS)/nitric oxide (NO), but uniquely, inhibition of B cells was ~50% dependent each on iNOS/NO and the MDSC-expressed negative-checkpoint regulator VISTA. Blockade with a combination of iNOS/NO and VISTA caused additive or synergistic abrogation of MDSC-mediated suppression of B-cell responsiveness.

Assessing exertional dyspnea in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Dyspnea is a hallmark symptom of idiopathic pulmonary fibrosis (IPF), and dyspnea induced physical activity limitation is a prominent driver of quality of life impairment among IPF patients. METHODS: We examined response data for the 21 physical activity items (the first 21 of 24) from the University of California San Diego Shortness of Breath Questionnaire (UCSD) collected at baseline in a recently conducted IPF trial. We used Rasch analysis and hypothesis testing with conventional statistical methodology to achieve three objectives: 1) to examine the items to identify the one characteristic that distinguishes one from another; 2) to asses these items for their ability to measure dyspnea severity in IPF; 3) to use the items to develop a dyspnea ruler. RESULTS: The sample comprised 178 subjects. The 21 items fit the Rasch model. There was very strong correlation between Rasch item severity and their metabolic equivalents (METS) values (r = -0.86, p < 0.0001). With the sample stratified on scores from the 21 items, there were significant between group differences in FVC%, DLCO% and distance walked during the six-minute walk test. The dyspnea ruler can be used to put dyspnea levels in a more easily understood clinical context. CONCLUSIONS: The first 21 items from the UCSD compose a unidimensional dyspnea-with-activity scale and are both sensibly ordered and distinguished from each other by their METS values. These 21 items can be used confidently to formulate clinically-relevant inferences about IPF patients and should be considered for use as a meaningful endpoint in IPF research.