A systemic macrophage response is required to contain a peripheral poxvirus infection.

The goal of the innate immune system is to reduce pathogen spread prior to the initiation of an effective adaptive immune response. Following an infection at a peripheral site, virus typically drains through the lymph to the lymph node prior to entering the blood stream and being systemically disseminated. Therefore, there are three distinct spatial checkpoints at which intervention to prevent systemic spread of virus can occur, namely: 1) the site of infection, 2) the draining lymph node via filtration of lymph or 3) the systemic level via organs that filter the blood. We have previously shown that systemic depletion of phagocytic cells allows viral spread after dermal infection with Vaccinia virus (VACV), which infects naturally through the skin. Here we use multiple depletion methodologies to define both the spatial checkpoint and the identity of the cells that prevent systemic spread of VACV. Subcapsular sinus macrophages of the draining lymph node have been implicated as critical effectors in clearance of lymph borne viruses following peripheral infection. We find that monocyte populations recruited to the site of VACV infection play a critical role in control of local pathogenesis and tissue damage, but do not prevent dissemination of virus. Following infection with virulent VACV, the subcapsular sinus macrophages within the draining lymph node become infected, but are not exclusively required to prevent systemic spread. Rather, small doses of VACV enter the bloodstream and the function of systemic macrophages, but not dendritic cells, is required to prevent further spread. The results illustrate that a systemic innate response to a peripheral virus infection may be required to prevent widespread infection and pathology following infection with virulent viruses, such as poxviruses.

GM-CSF overexpression after influenza a virus infection prevents mortality and moderates M1-like airway monocyte/macrophage polarization.

BACKGROUND: Influenza A viruses cause life-threatening pneumonia and lung injury in the lower respiratory tract. Application of high GM-CSF levels prior to infection has been shown to reduce morbidity and mortality from pathogenic influenza infection in mice, but the mechanisms of protection and treatment efficacy have not been established. METHODS: Mice were infected intranasally with influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced in the airways using the double transgenic GM-CSF (DTGM) or littermate control mice starting on 3 days post-infection (dpi). Assessment of respiratory mechanical parameters was performed using the flexiVent rodent ventilator. RNA sequence analysis was performed on FACS-sorted airway macrophage subsets at 8 dpi. RESULTS: Supra-physiologic levels of GM-CSF conferred a survival benefit, arrested the deterioration of lung mechanics, and reduced the abundance of protein exudates in bronchoalveolar (BAL) fluid to near baseline levels. Transcriptome analysis, and subsequent validation ELISA assays, revealed that excess GM-CSF re-directs macrophages from an "M1-like" to a more "M2-like" activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus during IAV infection elicits expression of anti-inflammatory mediators and moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-γ). CONCLUSIONS: Our data indicate that application of high levels of GM-CSF in the lung after influenza A virus infection alters pathogenic "M1-like" macrophage inflammation. These results indicate a possible therapeutic strategy for respiratory virus-associated pneumonia and acute lung injury.

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection.

UNLABELLED: Viruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8α(+) DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8α(+) DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection. IMPORTANCE: Prior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design.

Prolonged antigen presentation following an acute virus infection requires direct and then cross-presentation.

Antiviral CD8(+) T cell recognition of MHC class I-peptide complexes on the surface of professional APCs is a requisite step in an effective immune response following many potentially lethal infections. Although MHC class I-peptide production is thought to be closely linked to the continued presence of virus, several studies have shown that the persistence of Ag presentation occurs for an extended period of time following the clearance of RNA viruses. However, the mechanism responsible for Ag presentation persistence following viral clearance was unknown until now. In this study, we used a recombinant DNA virus expressing different forms of a model Ag to study the mechanism of prolonged Ag presentation in mice. We determined that the persistence of Ag presentation consists of three distinct mechanistic phases, as follows: ongoing viral replication, persistence of virally infected cells, and cross-presentation of Ag. These data will allow manipulation of the form of Ag contained within viral vectors to produce the most effective and protective CD8(+) T cell response to be generated following vaccination.

MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2.

UNLABELLED: Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations in vitro and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms. IMPORTANCE: Vaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection.

How do patients respond when confronted with telephone access barriers to care?

OBJECTIVE: To gain an in-depth understanding of patient barriers to accessing telephone care, subsequent responses to telephone access issues and recommendations for system improvement within a large integrated health-care system. STUDY DESIGN: Cross-sectional qualitative focus group study. METHODS: One focus group was conducted at each of 17 Veterans Affairs facilities with a total of 123 Veteran users of VA health care. All facilities followed a focus group discussion guide, and purposively sampled patients receiving care at their VA facility in primary and/or specialty care. Focus groups' recordings were sent to the authors' independent evaluation centre, transcribed verbatim and analysed using qualitative content analysis methodology. RESULTS: Participants described many issues with the phone system that resulted in delays to care needs being addressed, including difficulty getting someone to answer the phone, out-dated phone directories, frequent disconnections and incorrect transfers. Participants most frequently responded to access issues by doing nothing or waiting to contact at a later time, or seeking unscheduled in-person care in the emergency department or primary care clinic. Participants offered recommendations for improving telephone care, including access to direct extensions, and upgrades to the telephone system. CONCLUSIONS: Telephone access issues could result in increased patient harm and/or increased wait times for in-person primary care or emergency services. Periodic evaluation of telephone systems is necessary to ensure telephone systems adequately meet patient needs while using resources efficiently to optimize the delivery of high quality, safe health care.

VA experience in implementing Patient-Centered Medical Home using a breakthrough series collaborative.

BACKGROUND: Veterans Health Administration (VHA) seeks to improve the delivery of patient-centered care. A Patient-Centered Medical Home (PCMH) Model, named Patient Aligned Care Team (PACT), was implemented to transform the VHA primary care delivery process. VHA used a collaborative learning model as a key approach to disseminate PACT concepts and changes. OBJECTIVE: To describe and examine VHA's experience disseminating PACT transformation using a Breakthrough Series Collaborative method. DESIGN: Observational study. PARTICIPANTS: Approximately 250-350 individuals from 141 teams participated in six face-to-face learning sessions across 21 months. MAIN MEASURES: 1) PACT Collaborative participant surveys; 2) Coach Assessment Scores and Plan-Do-Study-Act (PDSA) data; and 3) PACT Compass (national measures to assess PACT implementation within VA healthcare system). KEY RESULTS: A majority of the participants indicated that the PACT Collaborative was necessary to implement PACT. The number of PDSAs increased steadily during the Collaborative period; 93 % (n = 1,547) of PDSAs were successfully implemented. Teams successfully achieved over 80 % of their aims, which were highly correlated with PDSAs implemented (R(2) = 0.88). The most successful aims achieved were offering same-day appointments, increasing non-face-to-face care, and improving team communication. PACT Compass indicated an improvement after the Collaborative (p-value < .000), and providers observed differences in their care practice (p-value < 0.002). This positive impact may be due to the spread of the PACT Model through the PACT Collaborative, among other learning initiatives. CONCLUSIONS: For complex collaborative models such as PACT, more than three learning sessions may be required. As VHA continues to disseminate the PACT Model through primary care, into specialty/surgical care and beyond, the Collaborative Learning Model may continue to be an effective way to leverage a small number of faculty, coaches, and industrial engineers across an extremely large population.

Sex differences in immune protection in mice conferred by heterologous vaccines for pneumonic plague.

Background: Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. Methods: In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. Results: The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. Conclusions: This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

CD11b⁺, Ly6G⁺ cells produce type I interferon and exhibit tissue protective properties following peripheral virus infection.

The goal of the innate immune system is containment of a pathogen at the site of infection prior to the initiation of an effective adaptive immune response. However, effector mechanisms must be kept in check to combat the pathogen while simultaneously limiting undesirable destruction of tissue resulting from these actions. Here we demonstrate that innate immune effector cells contain a peripheral poxvirus infection, preventing systemic spread of the virus. These innate immune effector cells are comprised primarily of CD11b⁺Ly6C⁺Ly6G⁻ monocytes that accumulate initially at the site of infection, and are then supplemented and eventually replaced by CD11b⁺Ly6C⁺Ly6G⁺ cells. The phenotype of the CD11b⁺Ly6C⁺Ly6G⁺ cells resembles neutrophils, but the infiltration of neutrophils typically occurs prior to, rather than following, accumulation of monocytes. Indeed, it appears that the CD11b⁺Ly6C⁺Ly6G⁺ cells that infiltrated the site of VACV infection in the ear are phenotypically distinct from the classical description of both neutrophils and monocyte/macrophages. We found that CD11b⁺Ly6C⁺Ly6G⁺ cells produce Type I interferons and large quantities of reactive oxygen species. We also observed that depletion of Ly6G⁺ cells results in a dramatic increase in tissue damage at the site of infection. Tissue damage is also increased in the absence of reactive oxygen species, although reactive oxygen species are typically thought to be damaging to tissue rather than protective. These data indicate the existence of a specialized population of CD11b⁺Ly6C⁺Ly6G⁺ cells that infiltrates a site of virus infection late and protects the infected tissue from immune-mediated damage via production of reactive oxygen species. Regulation of the action of this population of cells may provide an intervention to prevent innate immune-mediated tissue destruction.

Functional assays to screen and select monoclonal antibodies that target Yersinia pestis.

Yersinia pestis is a gram-negative bacterium that causes plague in animals and humans. Depending on the route of disease transmission, the bacterium can cause an acute, often fatal disease that has a narrow window for treatment with antibiotics. Additionally, antibiotic resistant strains have been identified, emphasizing the need for novel treatments. Antibody therapy is an appealing option that can direct the immune system to clear bacterial infections. Advances in biotechnology have made both engineering and producing antibodies easier and more affordable. In this study, two screening assays were optimized to evaluate the ability of antibodies to promote phagocytosis of Y. pestis by macrophages and to induce a cytokine signature in vitro that may be predictive of protection in vivo. We evaluated a panel of 21 mouse monoclonal antibodies targeting either the anti-phagocytic capsule F1 protein or the LcrV antigen, which is part of the type 3 secretion system that facilitates translocation of virulence factors into the host cell, using two functional assays. Anti-F1 and anti-LcrV monoclonal antibodies both increased bacterial uptake by macrophages, with greater uptake observed in the presence of antibodies that were protective in the mouse pneumonic plague model. In addition, the protective anti-F1 and anti-LcrV antibodies produced unique cytokine signatures that were also associated with in vivo protection. These antibody-dependent characteristics from in vitro functional assays will be useful in down-selecting efficacious novel antibodies that can be used for treatment of plague.

Polyclonal Antibodies Derived from Transchromosomic Bovines Vaccinated with the Recombinant F1-V Vaccine Increase Bacterial Opsonization In Vitro and Protect Mice from Pneumonic Plague.

Plague is an ancient disease that continues to be of concern to both the public health and biodefense research communities. Pneumonic plague is caused by hematogenous spread of Yersinia pestis bacteria from a ruptured bubo to the lungs or by directly inhaling aerosolized bacteria. The fatality rate associated with pneumonic plague is significant unless effective antibiotic therapy is initiated soon after an early and accurate diagnosis is made. As with all bacterial pathogens, drug resistance is a primary concern when developing strategies to combat these Yersinia pestis infections in the future. While there has been significant progress in vaccine development, no FDA-approved vaccine strategy exists; thus, other medical countermeasures are needed. Antibody treatment has been shown to be effective in animal models of plague. We produced fully human polyclonal antibodies in transchromosomic bovines vaccinated with the recombinant F1-V plague vaccine. The resulting human antibodies opsonized Y. pestis bacteria in the presence of RAW264.7 cells and afforded significant protection to BALB/c mice after exposure to aerosolized Y. pestis. These data demonstrate the utility of this technology to produce large quantities of non-immunogenic anti-plague human antibodies to prevent or possibly treat pneumonic plague in human.

Developing and sustaining quality improvement partnerships in the VA: the Colorectal Cancer Care Collaborative.

OBJECTIVE: The Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) seeks to develop partnerships between VA health services researchers and clinical managers, with the goal of designing and evaluating interventions to improve the quality of VA health care. METHODS: In the present report we describe one such initiative aimed at enhancing the continuum of colorectal cancer (CRC) care, including diagnosis, treatment and surveillance-the Colorectal Cancer Care Collaborative (C4). RESULTS: We describe the process and thinking that led to two parallel quality improvement "collaboratives" that addressed (1) CRC screening and diagnostic follow-up and (2) the guideline concordance and timeliness of CRC treatment. Additionally, we discuss ongoing effort to spread lessons learned during the first stages of the project, which initially occurred at only a subset of VA facilities, throughout the VA health care system. The description of this initiative is organized around key questions that must be answered when developing, sustaining and spreading multi-component quality improvement interventions. CONCLUSION: We conclude with a discussion of lessons learned that we believe would apply to similar initiatives elsewhere, even if they address different clinical issues in health care settings with different organizational structures.

Call center performance affects patient perceptions of access and satisfaction.

OBJECTIVES: There is little research on the relationship between call center performance and patient-centered outcomes. In this study, we quantified the relationships between 2 measures of telephone access, average speed of answer (ASA) and abandonment rate (AR), and patient satisfaction outcomes within the Veterans Health Administration (VHA). STUDY DESIGN: We analyzed 2015 and 2016 data from the Survey of Healthcare Experiences of Patients and linked them with administrative data to gather features of the patient visit and monthly measures of telephone access for each medical center. METHODS: We used mixed effects logistic regression models to estimate the effects of ASA and AR on a variety of access and satisfaction outcomes. Models were adjusted for patient-level demographics, time-varying facility-level characteristics, features of the patient visit, and facility-level random effects to control for care quality and case mix differences. RESULTS: The VHA made substantial strides in both access measures between 2015 and 2016. We found that a center's ASA was inversely associated with patients' perceptions of their ability both to access urgent care appointments and to do so in a timely manner. In contrast, telephone AR was not associated with any of the patient satisfaction outcomes. CONCLUSIONS: Our results associate decreased telephone waits with improved perceptions of urgent care access even without concomitant decreases in observed appointment waits. These findings may have important implications for regulators as well as for healthcare organizations that must decide resource levels for call centers, including hospitals, federal health insurance exchanges, and insurers.

Consult Coordination Affects Patient Experience.

OBJECTIVES: The Medicare accountable care organization (ACO) program financially rewards ACOs for providing high-quality healthcare, and also factors in the patient experience of care. This study examined whether administrative measures of wait times for specialist consults are associated with self-reported patient satisfaction. STUDY DESIGN: Analyses used administrative and survey data from a clinically integrated healthcare system similar to an ACO. METHODS: Veterans Health Administration (VHA) data from 2012 was obtained. Administrative access metrics included the number of days between the creation of the consult request and: 1) first action taken on the consult, 2) scheduling of the consult, and 3) completion of the consult. The Survey of Healthcare Experiences of Patients-which is modeled after the Consumer Assessment of Healthcare Providers and Systems family of survey instruments used by ACOs to measure patient experience-provided the outcome measures. Outcomes included general VHA satisfaction measures and satisfaction with timeliness of care, including wait times for specialists and treatments. Logistic regression models predicted the likelihood of patients reporting being satisfied on each outcome. Models were risk adjusted for demographics, self-reported health, and healthcare use. RESULTS: Longer waits for the scheduling of consults and completed consults were found to be significantly associated with decreased patient satisfaction. CONCLUSIONS: Because patients often report high levels of powerlessness and uncertainty while waiting for consultation, these wait times are an important patient-centered access metric for ACOs to consider. ACOs should have systems and tools in place to streamline the specialist consult referral process and increase care coordination.

Protein delivery and clinical outcomes in the critically ill: a systematic review and meta-analysis.

OBJECTIVES: Protein is a fundamental component of critical care nutrition, but there has been uncertainty about the optimal amount. We undertook this systematic review and meta-analysis to examine the relationship between delivered protein and mortality in randomised controlled trials (RCTs) of nutritional interventions involving critically ill adults. Secondary outcomes included the effect of protein dose on lengths of stay, mechanical ventilation and incidence of infections. METHODS: We reviewed the relevant English-language literature published between 1966 and 2015 and identified RCTs comparing different strategies of nutritional support lasting at least 48 hours in critically ill adults. Articles were included if mortality was reported and the difference in delivered protein between interventions was significant (P < 0.05). We calculated summary estimates for mortality as odds ratios (ORs) with 95% confidence intervals (CIs) using a random-effects estimator, and we used meta-regression to assess the effect of delivered protein on mortality. RESULTS: From 3016 assessed records, 357 full-text articles were reviewed and 14 studies, investigating various interventions and routes of nutrition and comprising 3238 patients, were included. The mean protein delivered was 42.95 g/day (SD, 20.45 g/day) or 0.67 g//kg/day (SD, 0.38 g/kg/day) in patients receiving less protein, and 67.15 g/day (SD, 28.47 g/day) or 1.02 g/kg/day (SD, 0.42 g/kg/day) in the higher protein group. Provision of less protein did not influence mortality risk (pooled OR, 0.935; 95% CI, 0.716 -1.219; P = 0.618; I2 = 48.2%). Meta-regression analysis did not show a relationship between mean daily protein delivered and mortality (P = 0.433; I2 = 50.18%). There were no differences between groups in any secondary outcomes. CONCLUSIONS: Delivery of varying amounts of nutritional protein was not associated with any effect on mortality.

Predicting NK cell subsets using gene expression levels in peripheral blood and endometrial biopsy specimens.

PROBLEM: In molecular analysis of tissue biopsy specimens, one crucial aspect is characterization of immune cell populations. This is especially important for evaluation of uterine receptivity by assessing levels of lymphocyte populations including CD56bright CD16- uterine NK cells and CD56dim CD16+ conventional NK cells. Our objective was to investigate whether measuring total RNA transcripts from a tissue specimen would accurately reflect immune cell levels and be a new technique to assess immune cell subsets. METHOD OF STUDY: Peripheral blood mononuclear cells (PBMCs) and endometrial tissues were used. Flow cytometry was utilized for the analysis of lymphocyte subsets in PBMCs, and RT-qPCR was applied to quantify RNA transcripts indicative of lymphocyte and granulocyte populations. RESULTS: In PBMC specimens, there were significant correlations between gene expression levels and cell subsets. NK cells correlated with CD16A, NKp46, and CD56 transcripts, B cells correlated with EBF1, and CD8+ T cells correlated with CD8ß. Finally, endometrial tissues displayed high CD56 expression and very low CD3ε, CD16A, and NKp30, reflecting the characteristic endometrial NK cell subsets. CONCLUSION: Strong correlations between RT-qPCR data and levels of lymphocyte subsets indicate that gene expression analysis will be a useful technique for characterizing levels of CD56+ cells in endometrial tissues.

Serum Vitamin D Level and Rheumatoid Arthritis Disease Activity: Review and Meta-Analysis.

BACKGROUND: The evidence from epidemiological studies concerning the relationship between serum vitamin D concentrations and rheumatoid arthritis (RA) is inconsistent. This meta-analysis is aimed at determining the magnitude of the correlation between this common autoimmune disease and vitamin D, an important nutrient known to dampen adaptive immune responses. METHODS: Through multiple search strategies, relevant literature was identified and evaluated for quality before May 16 2015. Data extracted from eligible studies was synthesized to calculate pooled correlation coefficient (r), mean difference (MD) and odds ratio (OR). The Venice criteria were applied to assess the credibility of the evidence for each statistically significant association. RESULTS: A total of 24 reports involving 3489 patients were selected for analysis. RA patients had lower vitamin D levels than healthy controls (MD:-16.52 nmol/L, 95% confidence intervals [CI]:-18.85 to -14.19 nmol/L). There existed a negative relationship between serum 25-hydroxyvitamin D (25OHD) level and disease activity index, e.g. 25OHD vs. Disease Activity Score in 28 joints (DAS28): r = -0.13, 95% CI -0.16 to -0.09; 25OHD vs. C-reactive protein: r = -0.12, 95% CI -0.23 to -0.00. Additionally, latitude-stratified subgroup analysis yielded a relatively stronger negative correlation between 25OHD and DAS28 in low-latitude areas. This inverse relationship also appeared more significant in developing countries than in developed countries. No publication bias was detected. CONCLUSION: RA patients had lower vitamin D values than healthy controls. There was a negative association between serum vitamin D and RA disease activity. However, more strictly controlled studies are needed to validate these findings.

Large-Scale No-Show Patterns and Distributions for Clinic Operational Research.

Patient no-shows for scheduled primary care appointments are common. Unused appointment slots reduce patient quality of care, access to services and provider productivity while increasing loss to follow-up and medical costs. This paper describes patterns of no-show variation by patient age, gender, appointment age, and type of appointment request for six individual service lines in the United States Veterans Health Administration (VHA). This retrospective observational descriptive project examined 25,050,479 VHA appointments contained in individual-level records for eight years (FY07-FY14) for 555,183 patients. Multifactor analysis of variance (ANOVA) was performed, with no-show rate as the dependent variable, and gender, age group, appointment age, new patient status, and service line as factors. The analyses revealed that males had higher no-show rates than females to age 65, at which point males and females exhibited similar rates. The average no-show rates decreased with age until 75-79, whereupon rates increased. As appointment age increased, males and new patients had increasing no-show rates. Younger patients are especially prone to no-show as appointment age increases. These findings provide novel information to healthcare practitioners and management scientists to more accurately characterize no-show and attendance rates and the impact of certain patient factors. Future general population data could determine whether findings from VHA data generalize to others.

SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation.

The surfactant protein (SP-A) receptor SP-R210 has been shown to increase phagocytosis of SP-A-bound pathogens and to modulate cytokine secretion by immune cells. SP-A plays an important role in pulmonary immunity by enhancing opsonization and clearance of pathogens and by modulating macrophage inflammatory responses. Alternative splicing of the Myo18A gene results in two isoforms: SP-R210S and SP-R210L, with the latter predominantly expressed in alveolar macrophages. In this study we show that SP-A is required for optimal expression of SP-R210L on alveolar macrophages. Interestingly, pre-treatment with SP-A prepared by different methods either enhances or suppresses responsiveness to LPS, possibly due to differential co-isolation of SP-B or other proteins. We also report that dominant negative disruption of SP-R210L augments expression of receptors including SR-A, CD14, and CD36, and enhances macrophages' inflammatory response to TLR stimulation. Finally, because SP-A is known to modulate CD14, we used a variety of techniques to investigate how SP-R210 mediates the effect of SP-A on CD14. These studies revealed a novel physical association between SP-R210S, CD14, and SR-A leading to an enhanced response to LPS, and found that SP-R210L and SP-R210S regulate internalization of CD14 via distinct macropinocytosis-like mechanisms. Together, our findings support a model in which SP-R210 isoforms differentially regulate trafficking, expression, and activation of innate immune receptors on macrophages.

Which outpatient wait-time measures are related to patient satisfaction?

Long waits for appointments decrease patient satisfaction. Administrative wait-time measures are used by managers, but relationships between these measures and satisfaction have not been studied. Data from the Veterans Health Administration are used to examine the relationship between wait times and satisfaction. Outcome measures include patient-reported satisfaction and timely appointment access. Capacity and retrospective and prospective time stamp measures are calculated separately for new and returning patients. The time stamp measures consist of the date when the appointment was created in the scheduling system (create date [CD]) or the date the appointment was desired as the start date for wait-time computation. Logistic regression models predict patient satisfaction using these measures. The new-patient capacity, new-patient time stamp measures using CD, and the returning-patient desired-date prospective measure were significantly associated with patient satisfaction. Standard practices can be improved by targeting wait-time measures to patient subpopulations.