Search

Sex, age, and the macrophage: Peritoneal macrophages are known to contribute to the pathology of peritonitis, endometriosis, and cancer, but the effects of age and sex on the biology of these cells are not well understood. Here, Bain et al. show that replenishment of peritoneal macrophages from the bone marrow is much higher in males compared with females. This results in marked sexual dimorphisms in the phenotypic identity of peritoneal macrophages between the sexes, including differential CD209b expression. Age- and sex-associated differences in macrophage turnover also affect resistance to pneumococcal peritonitis. These findings provide insight into the effects of sex and age on peritoneal inflammation and infection. Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the etiology of pathologies including peritonitis, endometriosis, and metastatic cancer; thus, understanding the factors that govern their behavior is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover, and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single-cell RNA sequencing revealed marked dimorphisms in gene expression between male and female peritoneal macrophages that was, in part, explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2−/− mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow, whereas others are reliant on local microenvironment signals. We demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious diseases. [ABSTRACT FROM AUTHOR]

Background: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection.Methods: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses.Results: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses.Conclusions: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.). [ABSTRACT FROM AUTHOR]

Abstract Background Little is known about drug cost communications of Medicare Part D beneficiaries with chronic conditions such as diabetes. The purpose of this study is to assess Medicare Part D beneficiaries with diabetes' levels of communication with physicians regarding prescription drug costs; the perceived importance of these communications; levels of prescription drug switching due to cost; and self-reported cost-related medication non-adherence. Methods Data were obtained from a cross-sectional survey (58% response rate) of 1,458 Medicare beneficiaries with diabetes who entered the coverage gap in 2006; adjusted percentages of patients with communication issues were obtained from multivariate regression analyses adjusting for patient demographics and clinical characteristics. Results Fewer than half of patients reported discussing the cost of medications with their physicians, while over 75% reported that such communications were important. Forty-eight percent reported their physician had switched to a less expensive medication due to costs. Minorities, females, and older adults had significantly lower levels of communication with their physicians regarding drug costs than white, male, and younger patients respectively. Patients with < $25 K annual household income were more likely than higher income patients to have talked about prescription drug costs with doctors, and to report cost-related non-adherence (27% vs. 17%, p < .001). Conclusions Medicare Part D beneficiaries with diabetes who entered the coverage gap have low levels of communication with physicians about drug costs, despite the high perceived importance of such communication. Understanding patient and plan-level characteristics differences in communication and use of cost-cutting strategies can inform interventions to help patients manage prescription drug costs.

An abstract of the research paper on immunogenic selection of HIV-1 MPER epitopes that helps in improving vaccine design by L. Wieczorek colleagues at AIDS Vaccine 2012 in Boston, Massachusetts is presented.

Background: Little is known about drug cost communications of Medicare Part D beneficiaries with chronic conditions such as diabetes. The purpose of this study is to assess Medicare Part D beneficiaries with diabetes' levels of communication with physicians regarding prescription drug costs; the perceived importance of these communications; levels of prescription drug switching due to cost; and self-reported cost-related medication non-adherence.Methods: Data were obtained from a cross-sectional survey (58% response rate) of 1,458 Medicare beneficiaries with diabetes who entered the coverage gap in 2006; adjusted percentages of patients with communication issues were obtained from multivariate regression analyses adjusting for patient demographics and clinical characteristics.Results: Fewer than half of patients reported discussing the cost of medications with their physicians, while over 75% reported that such communications were important. Forty-eight percent reported their physician had switched to a less expensive medication due to costs. Minorities, females, and older adults had significantly lower levels of communication with their physicians regarding drug costs than white, male, and younger patients respectively. Patients with < $25 K annual household income were more likely than higher income patients to have talked about prescription drug costs with doctors, and to report cost-related non-adherence (27% vs. 17%, p < .001).Conclusions: Medicare Part D beneficiaries with diabetes who entered the coverage gap have low levels of communication with physicians about drug costs, despite the high perceived importance of such communication. Understanding patient and plan-level characteristics differences in communication and use of cost-cutting strategies can inform interventions to help patients manage prescription drug costs. [ABSTRACT FROM AUTHOR]

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22qll.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22qll.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5xl014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22qll.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease., (© 2022. The Author(s).)

Even the best school physical education programs fall short of providing enough physical activity (PA) to meet students' PA guidelines thus increasing PA at other times throughout the school day could help students meet recommended PA levels. Unstructured leisure-time periods during the school day represent an opportunity to promote PA, particularly among students in underserved school districts. Between 2014 and 2018, we partnered with 14 elementary and 5 secondary schools in low-income Latino communities to increase students' leisure time moderate to vigorous physical activity (MVPA). Schools received consultation and technical assistance on their wellness policy, and some created wellness committees. Schools selected 1-2 PA/nutrition promotion activities for the academic year. Following the System for Observing Play and Leisure Activity in Youth protocol, we conducted a pre- vs. post- analysis of observations of school time student PA (levels of MVPA, energy expenditure, proportion of areas in which games and sports were prominent) in 4936 pre-intervention play areas and 4404 post-intervention areas before school, during lunch recess, and after school. We utilized linear and logistic regression analyses to test pre/post changes in these dependent variables using school area characteristics, period of observation, and temperature as covariates. Following our intervention, MVPA levels before school, during lunch recess, and after school increased significantly from 19.8% at baseline to 25.6% among elementary girls and from 25.4% to 33.2% among elementary boys. Decomposition of these effects suggested that the benefits were partially mediated by increased adult playground supervision. We did not observe any significant changes in PA levels among secondary school girls or boys. Our school-level intervention aimed at promoting PA was associated with modest but meaningful increases in leisure-time PA among elementary, but not secondary, school students. The effects were attributable in part to increased adult supervision on the playground., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Introduction: To examine the association of a novel disease-specific health plan, known as the Diabetes Health Plan (DHP), with emergency room (ER) and hospital utilization among patients with diabetes and pre-diabetes., Research Design and Methods: Quasi-experimental design, with employer group as the unit of analysis, comparing changes in any ER and inpatient hospital utilization over a 3-year period. Inverse probability weighting was used to control for differences between employers purchasing DHP versus standard plans. Estimated differences in utilization are calculated as average treatment effects on the treated. We used employees and dependents from employer groups contracting with a large, national private insurer between 2009 and 2012. Eligibility and claims data from continuously covered employees and dependents with diabetes and pre-diabetes (n=74 058) were aggregated to the employer level. The analysis included 9 DHP employers (n=7004) and 183 control employers (n=67 054)., Results: DHP purchase was associated with 2.4 and 1.8 percentage points absolute reduction in mean rates of any ER utilization, representing 13% and 10% relative reductions at 1 and 2 years post-DHP (p=0.012 and p=0.046, respectively). There was no significant association between DHP purchase and hospital utilization., Conclusion: Employers purchasing diabetes-specific health benefit designs may experience lower rates of resource-intensive services such as ER utilization., Competing Interests: Competing interests: TM received support from the Department of Veterans Affairs under grants QUE15-272, QUE15-286, and CSP2002, the NIH/National Istitute of Diabetes and Digestive and Kidnet Disease (NIDDK) under grant 1R01DK124503-01 and the Centers for Disease Control and Prevention (CDC) under grant U18DP006140.CMM and KD received support from the University of California at Los Angeles (UCLA), by the NIH/NIDDK under grant R18DK105464, the CDC under grant U18DP006140, and from the Patient-Centered Outcomes Research Institute (PCORI) under grant SDM-2018C2-13543. CMM also received support from NIH/National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute under grant UL1TR001881. CMM holds the Barbara A Levey and Gerald S Levey Endowed Chair in Medicine, which partially supported her work. CMM is a member of the United States Preventive Services Task Force (USPSTF). KD also received support from the Terasaki Family Foundation under grant 20191425. CMM, KD and NS received support from the Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly under National Institutes of Health (NIH)/NIA under grant P30AG021684., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by several neutralizing antibodies (NAbs) and is of interest for vaccine design. In this study, we identified novel MPER peptide mimotopes and evaluated their reactivity with HIV + plasma antibodies to characterize the diversity of the immune responses to MPER during natural infection. We utilized phage display technology to generate novel mimotopes that fit antigen-binding sites of MPER NAbs 4E10, 2F5 and Z13. Plasma antibodies from 10 HIV + patients were mapped by phage immunoprecipitation, to identify unique patient MPER binding profiles that were distinct from, and overlapping with, those of MPER NAbs. 4E10 mimotope binding profiles correlated with plasma neutralization of HIV-2/HIV-1 MPER chimeric virus, and with overall plasma neutralization breadth and potency. When administered as vaccines, 4E10 mimotopes elicited low titer NAb responses in mice. HIV mimotopes may be useful for detailed analysis of plasma antibody specificity., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Training in high-spending regions correlates with higher spending patterns among practicing physicians. This study aimed to evaluate whether trainees' exposure to a high-value care culture differed based on type of health system in which they trained., Method: In 2016, 517 internal medicine residents at 12 California graduate medical education programs (university, community, and safety-net medical centers) completed a cross-sectional survey assessing perceptions of high-value care culture within their respective training program. The authors used multilevel linear regression to assess the relationship between type of medical center and High-Value Care Culture Survey (HVCCS) scores. The correlation between mean institutional HVCCS and Centers for Medicare and Medicaid Services' Value-Based Purchasing (VBP) scores was calculated using Spearman rank coefficients., Results: Of 517 residents, 306 (59.2%), 83 (16.1%), and 128 (24.8%) trained in university, community, and safety-net programs, respectively. Across all sites, the mean HVCCS score was 51.2 (standard deviation [SD] 11.8) on a 0-100 scale. Residents reported lower mean HVCCS scores if they were from safety-net-based training programs (β = -4.4; 95% confidence interval: -8.2, -0.6) with lower performance in the leadership and health system messaging domain (P < .001). Mean institutional HVCCS scores among university and community sites positively correlated with institutional VBP scores (Spearman r = 0.71; P < .05)., Conclusions: Safety-net trainees reported less exposure to aspects of high-value care culture within their training environments. Tactics to improve the training environment to foster high-value care culture include training, increasing access to data, and improving open communication about value.

Background: School initiatives aimed at increasing physical activity (PA) may improve the health of children in low-income communities., Methods: Assessors completed 5909 observations of students' PA during leisure periods using a validated instrument in 19 schools in low-income Latino communities. We examined relationships between school environment factors (eg, presence of playground equipment) and levels of moderate-to-vigorous physical activity (MVPA)., Results: Overall, 16.4% of students were engaged in vigorous activity, lower than reported in prior analyses. Consistent with earlier reports, boys were more engaged in vigorous PA than girls (18.6% vs 13.2%). Playground equipment, such as balls and jump ropes, were present in 27.5% of activity areas. Supervision was present in 83.1% of observations; however, staff members were only observed leading organized activity in 1.7%. Playground equipment was associated with higher rates of MVPA, particularly among elementary boys (p < .0001). Staff supervision was not associated with MVPA, possibly because staff members rarely led organized activity., Conclusions: We found low rates of leisure time PA among students in this low-income Latino community. The presence of playground equipment was favorably associated with activity levels. Increasing the availability of playground equipment might promote activity among children in similar populations., (© 2019, American School Health Association.)

Background: Given the national emphasis on affordability, healthcare systems expect that their clinicians are motivated to provide high-value care. However, some hospitalists are reimbursed with productivity bonuses, and little is known about the effects of these reimbursements on the local culture of high-value care delivery., Objective: To evaluate if hospitalist reimbursement models are associated with high-value culture in university, community, and safety-net hospitals., Design, Setting, Patients: Internal medicine hospitalists from 12 hospitals across California completed a cross-sectional survey assessing their perceptions of high-value care culture within their institutions. Sites represented university, community, and safety-net centers with different performances as reflected by the Centers of Medicare and Medicaid Service's Value-based Purchasing (VBP) scores., Measurement: Demographic characteristics and High-Value Care Culture Survey (HVCCSTM) scores were evaluated using descriptive statistics, and associations were assessed through multilevel linear regression., Results: Of the 255 hospitalists surveyed, 147 (57.6%) worked in university hospitals, 85 (33.3%) in community hospitals, and 23 (9.0%) in safety-net hospitals. Across all 12 sites, 166 (65.1%) hospitalists reported payment with salary or wages, and 77 (30.2%) with salary plus productivity adjustments. The mean HVCCS score was 50.2 (SD 13.6) on a 0-100 scale. Hospitalists reported lower mean HVCCS scores if they reported payment with salary plus productivity (β = -6.2, 95% CI -9.9 to -2.5) than if they reported payment with salary or wages., Conclusions: Hospitalists paid with salary plus productivity reported lower high-value care culture scores for their institutions than those paid with salary or wages. High-value care culture and clinician reimbursement schemes are potential targets of strategies for improving quality outcomes at low cost., (© 2018 Society of Hospital Medicine.)

Background: Organisational culture affects physician behaviours. Patient safety culture surveys have previously been used to drive care improvements, but no comparable survey of high-value care culture currently exists. We aimed to develop a High-Value Care Culture Survey (HVCCS) for use by healthcare leaders and training programmes to target future improvements in value-based care., Methods: We conducted a two-phase national modified Delphi process among 28 physicians and nurse experts with diverse backgrounds. We then administered a cross-sectional survey at two large academic medical centres in 2015 among 162 internal medicine residents and 91 hospitalists for psychometric evaluation., Results: Twenty-six (93%) experts completed the first phase and 22 (85%) experts completed the second phase of the modified Delphi process. Thirty-eight items achieved ≥70% consensus and were included in the survey. One hundred and forty-one residents (83%) and 73 (73%) hospitalists completed the survey. From exploratory factor analyses, four factors emerged with strong reliability: (1) leadership and health system messaging (α=0.94); (2) data transparency and access (α=0.80); (3) comfort with cost conversations (α=0.70); and (4) blame-free environment (α=0.70). In confirmatory factor analysis, this four-factor model fit the data well (Bentler-Bonett Normed Fit Index 0.976 and root mean square residual 0.056). The leadership and health system messaging (r=0.56, p<0.001), data transparency and access (r=0.15, p<0.001) and blame-free environment (r=0.37, p<0.001) domains differed significantly between institutions and positively correlated with Value-Based Purchasing Scores., Conclusions: Our results provide support for the reliability and validity of the HVCCS to assess high-value care culture among front-line clinicians. HVCCS may be used by healthcare groups to identify target areas for improvements and to monitor the effects of high-value care initiatives., Competing Interests: Competing interests: RG is the Director of Outreach and Evaluation and the Director of the Teaching Value in Healthcare Learning Network at Costs of Care. She is supported by the VA Office of Academic Affiliations through the VA/Robert Wood Johnson Clinical Scholars Program. CM receives royalties from McGraw Hill for the textbook ‘Understanding Value-based Healthcare’, outside of the submitted work and is the Director of Implementation at Costs of Care. RDH was supported in part by grants from the NIA (No. P30-AG021684) and the NIMHD (No. P20-MD000182). CHB is the Vice Dean for Education at the David Geffen School of Medicine at UCLA and the chair of the American Board of Internal Medicine. RW reports that he is a member of the Lucian Leape Institute of the National Patient Safety Foundation (for which he receives no compensation); is currently chairing an advisory board to England's National Health Service reviewing the NHS’ digital health strategy (no compensation); has a contract to UCSF from the Agency for Healthcare Research and Quality to edit a patient-safety website; receives compensation from John Wiley and Sons for writing a blog; receives royalties from Lippincott Williams & Wilkins and McGraw-Hill for writing/editing several books; received a stipend and stock options for having previously served on the Board of Directors of IPC Healthcare; receives stock options for serving on the board of Accuity Medical Management Systems; serves on the scientific advisory boards for Amino.com, PatientSafe Solutions, QPID Health, Twine and EarlySense (for which he receives stock options); and holds the Benioff endowed chair in hospital medicine from Marc and Lynne Benioff. RG and CM had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

MHC class I dependent CD8(+) T cells are essential for protection induced by radiation-attenuated Plasmodium sporozoites (RAS) in murine malaria models. Apart from the mechanism of activation of CD8(+) T cells specific for the circumsporozoite protein, the major sporozoite antigen (Ag), CD8(+) T cells specific for other exoerythrocytic Ags that have been shown to mediate protection have not been thoroughly investigated. Specifically, mechanisms of processing and presentation of exoerythrocytic Ags, which includes liver stage (LS) Ags, remain poorly understood. We hypothesize that as exogenous proteins, LS Ags are processed by mechanisms involving either the TAP-dependent phagosomal-to-cytosol or TAP-independent vacuolar pathway of cross-presentation. We used TAP-deficient mice to investigate whether LS Ag mediated induction of naïve CD8(+) T cells and their recall during sporozoite challenge occur by the TAP-dependent or TAP-independent pathways. On the basis of functional attributes, CD8(+) T cells were activated via the TAP-independent pathway during immunizations with Plasmodium berghei RAS; however, IFN-γ(+) CD8(+) T cells previously induced by P. berghei RAS in TAP-deficient mice failed to be recalled against sporozoite challenge and the mice became parasitemic. On the basis of these observations, we propose that TAP-associated Ag processing is indispensable for sterile protection induced with P. berghei RAS., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

Aim: Identify what factors rural women perceived to influence their surgical choice for EBC., Background: Higher rates of mastectomy still remain for women with early breast cancer (EBC) in rural areas. While access to radiotherapy is a commonly identified barrier, there is growing debate around other factors which are also important influences on surgical choice., Methods: Qualitative study with 70 interviews with women diagnosed with EBC in rural Gippsland, Australia. Twenty-nine women had a mastectomy and 41 had breast conserving surgery (BCS)., Results: Patient led psychosocial and surgeon led factors influenced surgical choice. Psychosocial factors were a greater influence for the mastectomy group. These included a high fear of cancer recurrence and radiotherapy, negative views of the body and breast, a family history of cancer, wanting to avoid the negative treatment experiences they had seen significant others go through, and not wanting to travel for treatment. Surgeon led factors were a greater influence for the BCS group, in particular, the direct recommendation made by the surgeon for BCS. For both groups, urgency to act was a shared psychosocial factor. Trust and confidence in the expertise and reputation of the surgeon and their consultation style were surgeon led factors shared by the groups., Conclusions: To ensure women achieve the best treatment outcome, patients and clinicians need to work together to identify how important and influential the various factors are for the women and, if necessary, to seek support to ensure informed decisions are made., (© 2014 John Wiley & Sons Ltd.)

Objective: To determine opinions of faculty members with clinical appointments, clinical veterinarians, residents, and interns at a US veterinary teaching hospital regarding antimicrobial use and antimicrobial-resistant infections., Design: Cross-sectional survey., Sample: 71 veterinarians., Procedures: An online questionnaire was sent to all veterinarians with clinical service responsibilities at the North Carolina State University veterinary teaching hospital (n = 167). The survey included 23 questions regarding demographic information, educational experiences, current prescribing practices, and personal opinions related to antimicrobial selection, antimicrobial use, restrictions on antimicrobial use, and antimicrobial resistance., Results: Of the 167 veterinarians eligible to participate, 71 (43%) responded. When respondents were asked to rate their level of concern (very concerned = 1; not concerned = 5) about antimicrobial-resistant infections, most (41/70 [59%]) assigned a score of 1, with mean score for all respondents being 1.5. Most survey participants rated their immediate colleagues (mean score, 1.9) as more concerned than other veterinary medical professionals (mean score, 2.3) and their clients (mean score, 3.4). Fifty-nine of 67 (88%) respondents felt that antimicrobials were overprescribed at the hospital, and 32 of 69 (46%) respondents felt uncomfortable prescribing at least one class of antimicrobials (eg, carbapenems or glycopeptides) because of public health concerns., Conclusions and Clinical Relevance: Findings indicated that veterinarians at this teaching hospital were concerned about antimicrobial resistance, thought antimicrobials were overprescribed, and supported restricting use of certain antimicrobial classes in companion animals. Findings may be useful in educating future veterinarians and altering prescribing habits and antimicrobial distribution systems in veterinary hospitals.

Purpose: A collaborative pharmacist-primary care provider (PharmD-PCP) team approach to medication-therapy management (MTM), with pharmacists initiating and changing medications at separate office visits, holds promise for the cost-effective management of hypertension, but has not been evaluated in many systematic trials. The primary objective of this study was to examine blood pressure (BP) control in hypertensive patients managed by a newly formed PharmD-PCP MTM team versus usual care in a university-based primary care clinic., Methods: This randomized, pragmatic clinical trial was conducted in hypertensive patients randomly selected for PharmD-PCP MTM or usual care. In the PharmD-PCP MTM group, pharmacists managed drug-therapy initiation and monitoring, medication adjustments, biometric assessments, laboratory tests, and patient education. In the usual-care group, patients continued to see their PCPs. Participants were aged ≥ 18 years, were diagnosed with hypertension, had a most recent BP measurement of ≥ 140/≥ 90 mm Hg (≥ 130/≥ 80 mm Hg if codiagnosed with diabetes mellitus), were on at least 1 antihypertensive medication, and were English speaking. The primary outcome was the difference in the mean change from baseline in systolic BP at 6 months. Secondary outcomes included the percentage achieving therapeutic BP goal and the mean changes from baseline in diastolic BP and low- and high-density lipoprotein cholesterol., Findings: A total of 166 patients were enrolled (69 men; mean age, 67.7 years; PharmD-PCP MTM group, n = 75; usual-care group, n = 91). Mean reduction in SBP was significantly greater in the PharmD-PCP MTM group at 6 months (-7.1 [19.4] vs +1.6 [21.0] mm Hg; P = 0.008), but the difference was no longer statistically significant at 9 months (-5.2 [16.9] vs -1.7 [17.7] mm Hg; P = 0.22), based on an intent-to-treat analysis. In the intervention group, greater percentages of patients who continued to see the MTM pharmacist versus those who returned to their PCP were at goal at 6 months (81% vs 44%) and at 9 months (70% vs 52%). No significant between-group differences in changes in cholesterol were detected at 6 and 9 months; however, the mean baseline values were near recommended levels. The PharmD-PCP MTM group had significantly fewer PCP visits compared with the usual-care group (1.8 [1.5] vs 4.2 [1.0]; P < 0.001)., Implications: A PharmD-PCP collaborative MTM service was more effective in lowering BP than was usual care at 6 months in all patients and at 9 months in patients who continued to see the pharmacist. Incorporating pharmacists into the primary care team may be a successful strategy for managing medication therapy, improving patient outcomes and possibly extending the capacity of primary care. ClinicalTrials.gov identifier: NCT01973556., (Published by Elsevier Inc.)

To describe the steps needed for a successful implementation of an e-health programme (the Mobile Wound Care system) in rural Victoria, Australia and to provide recommendations for future e-health initiatives. Wound care is a major burden on the health care system. Optimal wound care was found to be impeded by issues that included the limited access to health care providers, incomplete and inconsistent documentation and limited access to expert review. This study trialled the use of a shared electronic wound reporting and imaging system in combination with an expert remote wound consultation service for the management of patients with chronic and acute wounds in Gippsland. The trial sites included four rural Home and Community Health Care providers. Considerable effort was put into designing a best practice e-health care programme. There was support from managers and clinicians at regional and local levels to address an area of health care considered a priority. Various issues contributing to the successful implementation of the wound care project were identified: the training model, quality of data collected, demands associated with multiple sites across a vast geographic region, computer access, hardware and computer literacy., (© 2013 The Author. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Measuring the prevalence of wounds within health care systems is a challenging and complex undertaking. This is often compounded by the clinicians' training, the availability of the required data to collect, incomplete documentation and lack of reporting of this type of data across the various health care settings. To date, there is little published data on wound prevalence across regions or states. This study aims to identify the number and types of wounds treated in the Gippsland area using the Mobile Wound Care (MWC™) program. The MWC program has enabled clinicians in Gippsland to collect data on wounds managed by district nurses from four health services. The main outcomes measured were patient characteristics, wound characteristics and treatment characteristics of wounds in Gippsland. These data create several clinical and research opportunities. The identification of predominant wound aetiologies in Gippsland provides a basis on which to determine a regional wound prospective and the impact of the regional epidemiology. Training that incorporates best practice guidelines can be tailored to the most prevalent wound types. Clinical pathways that encompass the Australian and New Zealand clinical practice guidelines for the management of venous leg ulcers can be introduced and the clinical and economical outcomes can be quantitatively measured. The MWC allows healing times (days) to be benchmarked both regionally and against established literature, for example, venous leg ulcers., (© 2013 The Author. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objectives: Despite recommendations for triennial cervical cancer screening for low-risk women 30 years and older, annual screening remains common. We studied how often women receiving care from an academically affiliated medical group were screened, and patient and provider factors associated with overuse and underuse. We also explored the impact of changing measurement intervals on computed screening frequency., Design: The study included women 30 years and older continuously enrolled over a 3-year period and excluded women with history of abnormal screening and conditions of high risk for cervical cancer., Methods: Administrative and laboratory data were merged to link Papanicolaou (pap) test results with patient and ordering provider characteristics. We used logistic regression to analyze multivariate models for overuse and underuse, and modified measurement intervals to test sensitivity to early and late pap smears., Results: The 8018 women had a mean age of 48years and 95% had an ambulatory physician visit during the observation period. Thirty-four percent of women received guideline-based screening, 45% had overuse, and 21% had underuse. Factors independently associated with overuse included younger age, more medical visits, contraceptive management visits, and gynecology provider specialty. Underuse was associated with older age, fewer medical visits, and increased comorbidity.Overuse was 47% if unsatisfactory paps were not considered and was reduced to 35% if the observation interval was reduced from 36 to 30 months., Conclusions: Overuse and underuse of cervical cancer screening are common and clinician and patient factors are identifiable to target quality improvement interventions. Modifying the measurement interval may improve the measure.

Ag-specific memory T cell responses elicited by infections or vaccinations are inextricably linked to long-lasting protective immunity. Studies of protective immunity among residents of malaria endemic areas indicate that memory responses to Plasmodium Ags are not adequately developed or maintained, as people who survive episodes of childhood malaria are still vulnerable to either persistent or intermittent malaria infections. In contrast, multiple exposures to radiation-attenuated Plasmodium berghei sporozoites (Pb γ-spz) induce long-lasting protective immunity to experimental sporozoite challenge. We previously demonstrated that sterile protection induced by Pb γ-spz is MHC class I-dependent and CD8 T cells are the key effectors. IFN-γ(+) CD8 T cells that arise in Pb γ-spz-immunized B6 mice are found predominantly in the liver and are sensitive to levels of liver-stage Ag depot and they express CD44(hi)CD62L(lo) markers indicative of effector/effector memory phenotype. The developmentally related central memory CD8 T (TCM) cells express elevated levels of CD122 (IL-15Rβ), which suggests that CD8 TCM cells depend on IL-15 for maintenance. Using IL-15-deficient mice, we demonstrate in this study that although protective immunity is inducible in these mice, protection is short-lived, mainly owing to the inability of CD8 TCM cells to survive in the IL-15-deficient milieu. We present a hypothesis consistent with a model whereby intrahepatic CD8 TCM cells, being maintained by IL-15-mediated survival and basal proliferation, are conscripted into the CD8 effector/effector memory T cell pool during subsequent infections.

Objective: This study examined rural women's satisfaction with the interaction and communication with their surgeon during diagnosis and treatment planning for early breast cancer. Differences in satisfaction were investigated between treatment groups (mastectomy and breast conservation surgery) and demographic variables (age, marital status, education level, employment status and place of residence). Practice was compared with clinical practice guidelines., Design: The study was designed as a cross-sectional survey., Setting: The study was set in Eastern regional Victoria, Australia., Participants: Seventy women diagnosed with early breast cancer participated in the study., Main Outcome Measures: The main outcome measures used by the study were satisfaction in three areas of practice: (i) telling a woman she has breast cancer; (ii) providing information and involving the woman in the decision-making; and (iii) preparing the woman for specific management., Results: No differences in satisfaction were found between treatment groups and demographic variables. Overall, women in this study were highly satisfied (>93%) with the interaction and communication with their surgeon. Women reported that the surgeon created a supportive environment for discussion, that they were provided with adequate information and referrals, and that they were actively involved in the decision-making. Practice could have been improved for women who were alone at diagnosis as women without a partner made a quicker decision about treatment., Conclusion: Rural women in Victoria Australia were largely satisfied with the interaction and communication with their surgeon during diagnosis and treatment planning for early breast cancer. Current practice was predominately in line with clinical practice guidelines., (© 2012 The Authors. Australian Journal of Rural Health © National Rural Health Alliance Inc.)

This community-partnered study was developed and fielded in partnership with key community stakeholders and describes age- and race-related variation in delays in care and preventive service utilization between middle-aged and older adults living in South Los Angeles. The survey sample included adults aged 50 and older who self-identified as African American or Latino and lived in ZIP codes of South Los Angeles (N=708). Dependent variables were self-reported delays in care and use of preventive services. Insured participants aged 50 to 64 were more likely to report any delay in care (adjusted predicted percentage (APP)=18%, 95% confidence interval (CI)=14-23) and problems obtaining needed medical care (APP=15%, 95% CI=12-20) than those aged 65 and older. Uninsured participants aged 50 to 64 reported even greater delays in care (APP=45%, 95% CI=33-56) and problems obtaining needed medical (APP=33%, 95% CI=22-45) and specialty care (APP=26%, 95% CI=16-39) than those aged 65 and older. Participants aged 50 to 64 were generally less likely to receive preventive services, including influenza and pneumococcal vaccines and colonoscopy than older participants, but women were more likely to receive mammograms. Participants aged 50 to 64 had more problems obtaining recommended preventive care and faced more delays in care than those aged 65 and older, particularly if they were uninsured. Providing insurance coverage for this group may improve access to preventive care and promote wellness., (© 2010, Copyright the Authors. Journal compilation © 2010, The American Geriatrics Society.)

Background: Some Medicare Part D enrollees whose drug expenditures exceed a threshold enter a coverage gap with full cost-sharing, increasing their risk for reduced adherence and adverse outcomes., Objective: To examine comorbidities and demographic characteristics associated with gap entry and exit., Design: We linked 2005-2006 pharmacy, outpatient, and inpatient claims to enrollment and Census data. We used logistic regression to estimate associations of 2006 gap entry and exit with 2005 medical comorbidities, demographics, and Census block characteristics. We expressed all results as predicted percentages., Patients: 287,713 patients without gap coverage, continuously enrolled in a Medicare Advantage Part D (MAPD) plan serving eight states. Patients who received a low-income subsidy, could not be geocoded, or had no 2006 drug fills were excluded., Results: Of enrollees, 15.9% entered the gap, 2.6% within the first 180 days; among gap enterers, only 6.7% exited again. Gap entry was significantly associated with female gender and all comorbidities, particularly dementia (39.5% gap entry rate) and diabetes (28.0%). Among dementia patients entering the gap, anti-dementia drugs (donepezil, memantine, rivastigmine, and galantamine) and atypical antipsychotic medications (risperidone, quetiapine, and olanzapine) together accounted for 40% of pre-gap expenditures. Among diabetic patients, rosiglitazone accounted for 7.2% of pre-gap expenditures. Having dementia was associated with twice the risk of gap exit., Conclusions: Certain chronically ill MAPD enrollees are at high risk of gap entry and exposure to unsubsidized medication costs. Clinically vulnerable populations should be counseled on how to best manage costs through drug substitution or discontinuation of specific, non-essential medications.

Background: Animal-assisted therapy improves physiological and psychosocial variables in healthy and hypertensive patients., Objectives: To determine whether a 12-minute hospital visit with a therapy dog improves hemodynamic measures, lowers neurohormone levels, and decreases state anxiety in patients with advanced heart failure., Methods: A 3-group randomized repeated-measures experimental design was used in 76 adults. Longitudinal analysis was used to model differences among the 3 groups at 3 times. One group received a 12-minute visit from a volunteer with a therapy dog; another group, a 12-minute visit from a volunteer; and the control group, usual care. Data were collected at baseline, at 8 minutes, and at 16 minutes., Results: Compared with controls, the volunteer-dog group had significantly greater decreases in systolic pulmonary artery pressure during (-4.32 mm Hg, P = .03) and after (-5.78 mm Hg, P = .001) and in pulmonary capillary wedge pressure during (-2.74 mm Hg, P = .01) and after (-4.31 mm Hg, P = .001) the intervention. Compared with the volunteer-only group, the volunteer-dog group had significantly greater decreases in epinephrine levels during (-15.86 pg/mL, P = .04) and after (-17.54 pg/mL, P = .04) and in norepinephrine levels during (-232.36 pg/mL, P = .02) and after (-240.14 pg/mL, P = .02) the intervention. After the intervention, the volunteer-dog group had the greatest decrease from baseline in state anxiety sum score compared with the volunteer-only (-6.65 units, P =.002) and the control groups (-9.13 units, P < .001)., Conclusions: Animal-assisted therapy improves cardiopulmonary pressures, neurohormone levels, and anxiety in patients hospitalized with heart failure.

Multi-factorial immune mechanisms underlie protection induced with radiation-attenuated Plasmodia sporozoites (gamma-spz). Spz pass through Kupffer cells (KC) before invading hepatocytes but the involvement of KC in protection is poorly understood. In this study we investigated whether gamma-spz-immune KC respond to infectious spz in a manner that is distinct from the response of naive KC to infectious spz. KC were isolated from (1) naive, (2) spz-infected, (3) gamma-spz-immune, and (4) gamma-spz-immune-challenged C57BL/6 mice and examined for the expression of MHC class I and II, CD40 and CD80/CD86, IL-10 and IL-12 responses and antigen-presenting cell (APC) function. KC from gamma-spz-immune-challenged mice up-regulated class I and costimulatory molecules and produced elevated IL-12p40, relative to naive KC. In contrast, KC from naive mice exposed to infectious spz down-modulated class I and IL-12p40 was undetectable. Accordingly, KC from spz-infected mice had reduced APC function, while KC from gamma-spz-immune-challenged mice exhibited augmented APC activity. The nearly opposite responses are consistent with the fact that spz challenge of gamma-spz-immune mice results in long-lasting sterile protection, while infection of naive mice always results in malaria.

Murine hydatid cysts of Echinococcus granulosus were incubated in vitro in the presence of nitric oxide produced from S-nitroso-N-acetylpenicillamine (SNAP) or interferon-gamma activated peritoneal macrophages. In both situations, evidence of cyst damage and death was observed by microscopy in over 77% of cysts after 3 days, indicating that intact hydatid cysts could be susceptible to a Th1 driven macrophage attack. A crude extract of the laminated layer from cysts was found to be able to reduce the production of nitric oxide from activated macrophages in vitro and in vivo and this may have been due to phagocytosis of laminated layer fragments by the macrophages. The results indicate that, although cysts may be susceptible to the effects of nitric oxide, the laminated layer may be involved in downregulating nitric oxide production.

2429 samples of foodstuffs were examined for the presence of verocytotoxigenic Escherichia coli O157 (VTEC O157) by means of immunomagnetic separation (IMS) over a 2-year period commencing April 1997. Specimens comprised 1190 raw meats, 500 raw milks and 739 raw-milk cheeses. The meat and cheese samples were purchased from retail premises in south-east Scotland; raw milk samples were obtained directly from farms. In addition, total E. coli counts were performed on milk and cheese samples, and the pH of cheese specimens measured. The water activity (Aw) was also measured for a representative sample of each cheese type, and for all of the samples with high levels of E. coli. VTEC O157 was isolated from two samples of beef burger, both manufactured on the premises of the same butchers shop. Control studies with artificially inoculated foodstuffs demonstrated a sensitivity of detection of < 5 organisms 25 g(-1). These findings, which contrast with the results of similar studies elsewhere in the UK, suggest that other sources of infection may be important in explaining the high rates of infection with this organism in south-east Scotland.