Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis.

OBJECTIVES: While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. METHODS: We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. RESULTS: Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. CONCLUSION: Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

Implementation of Care Management: An Analysis of Recent AHRQ Research.

Care management (CM) is a promising team-based, patient-centered approach "designed to assist patients and their support systems in managing medical conditions more effectively." As little is known about its implementation, this article describes CM implementation and associated lessons from 12 Agency for Healthcare Research and Quality-sponsored projects. Two rounds of data collection resulted in project-specific narratives that were analyzed using an iterative approach analogous to framework analysis. Informants also participated as coauthors. Variation emerged across practices and over time regarding CM services provided, personnel delivering these services, target populations, and setting(s). Successful implementation was characterized by resource availability (both monetary and nonmonetary), identifying as well as training employees with the right technical expertise and interpersonal skills, and embedding CM within practices. Our findings facilitate future context-specific implementation of CM within medical homes. They also inform the development of medical home recognition programs that anticipate and allow for contextual variation.

A model for teaching and learning spinal thrust manipulation and its effect on participant confidence in technique performance.

BACKGROUND: Despite emerging evidence to support the use of high velocity thrust manipulation in the management of lumbar spinal conditions, utilization of thrust manipulation among clinicians remains relatively low. One reason for the underutilization of these procedures may be related to disparity in training in the performance of these techniques at the professional and post professional levels. PURPOSE: To assess the effect of using a new model of active learning on participant confidence in the performance of spinal thrust manipulation and the implications for its use in the professional and post-professional training of physical therapists. METHODS: A cohort of 15 DPT students in their final semester of entry-level professional training participated in an active training session emphasizing a sequential partial task practice (SPTP) strategy in which participants engaged in partial task practice over several repetitions with different partners. Participants' level of confidence in the performance of these techniques was determined through comparison of pre- and post-training session surveys and a post-session open-ended interview. RESULTS: The increase in scores across all items of the individual pre- and post-session surveys suggests that this model was effective in changing overall participant perception regarding the effectiveness and safety of these techniques and in increasing student confidence in their performance. Interviews revealed that participants greatly preferred the SPTP strategy, which enhanced their confidence in technique performance. CONCLUSION: Results indicate that this new model of psychomotor training may be effective at improving confidence in the performance of spinal thrust manipulation and, subsequently, may be useful for encouraging the future use of these techniques in the care of individuals with impairments of the spine. Inasmuch, this method of instruction may be useful for training of physical therapists at both the professional and post-professional levels.

Implementation of Patient-Centered Medical Homes in Adult Primary Care Practices.

There has been relatively little empirical evidence about the effects of patient-centered medical home (PCMH) implementation on patient-related outcomes and costs. Using a longitudinal design and a large study group of 2,218 Michigan adult primary care practices, our study examined the following research questions: Is the level of, and change in, implementation of PCMH associated with medical surgical cost, preventive services utilization, and quality of care in the following year? Results indicated that both level and amount of change in practice implementation of PCMH are independently and positively associated with measures of quality of care and use of preventive services, after controlling for a variety of practice, patient cohort, and practice environmental characteristics. Results also indicate that lower overall medical and surgical costs are associated with higher levels of PCMH implementation, although change in PCMH implementation did not achieve statistical significance.

Synthesis of bis-macrocyclic HCV protease inhibitor MK-6325 via intramolecular sp²-sp³ Suzuki-Miyaura coupling and ring closing metathesis.

A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp(2)-sp(3) Suzuki-Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.

Catalytic, asymmetric, and stereodivergent synthesis of non-symmetric ß,ß-diaryl-α-amino acids.

We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected ß,ß-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc ß,ß-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks.

Context matters: the experience of 14 research teams in systematically reporting contextual factors important for practice change.

PURPOSE: We aimed to advance the internal and external validity of research by sharing our empirical experience and recommendations for systematically reporting contextual factors. METHODS: Fourteen teams conducting research on primary care practice transformation retrospectively considered contextual factors important to interpreting their findings (internal validity) and transporting or reinventing their findings in other settings/situations (external validity). Each team provided a table or list of important contextual factors and interpretive text included as appendices to the articles in this supplement. Team members identified the most important contextual factors for their studies. We grouped the findings thematically and developed recommendations for reporting context. RESULTS: The most important contextual factors sorted into 5 domains: (1) the practice setting, (2) the larger organization, (3) the external environment, (4) implementation pathway, and (5) the motivation for implementation. To understand context, investigators recommend (1) engaging diverse perspectives and data sources, (2) considering multiple levels, (3) evaluating history and evolution over time, (4) looking at formal and informal systems and culture, and (5) assessing the (often nonlinear) interactions between contextual factors and both the process and outcome of studies. We include a template with tabular and interpretive elements to help study teams engage research participants in reporting relevant context. CONCLUSIONS: These findings demonstrate the feasibility and potential utility of identifying and reporting contextual factors. Involving diverse stakeholders in assessing context at multiple stages of the research process, examining their association with outcomes, and consistently reporting critical contextual factors are important challenges for a field interested in improving the internal and external validity and impact of health care research.

Assessment and measurement of patient-centered medical home implementation: the BCBSM experience.

PURPOSE: Our goal was to describe an approach to patient-centered medical home (PCMH) measurement based on delineating the desired properties of the measurement relative to assumptions about the PCMH and the uses of the measure by Blue Cross Blue Shield of Michigan (BCBSM) and health services researchers. METHODS: We developed and validated an approach to assess 13 functional domains of PCMHs and 128 capabilities within those domains. A measure of PCMH implementation was constructed using data from the validated self-assessment and then tested on a large sample of primary care practices in Michigan. RESULTS: Our results suggest that the measure adequately addresses the specific requirements and assumptions underlying the BCBSM PCMH program-ability to assess change in level of implementation; ability to compare across practices regardless of size, affiliation, or payer mix; and ability to assess implementation of the PCMH through different sequencing of capabilities and domains. CONCLUSIONS: Our experience illustrates that approaches to measuring PCMH should be driven by the measures' intended use(s) and users, and that a one-size-fits-all approach may not be appropriate. Rather than promoting the BCBSM PCMH measure as the gold standard, our study highlights the challenges, strengths, and limitations of developing a standardized approach to PCMH measurement.

The policy context of patient centered medical homes: perspectives of primary care providers.

BACKGROUND: Interest in the patient centered medical home (PCMH) model has increased significantly in recent years. Despite this attention, information is limited regarding the influence of policy context on implementation of the PCMH model. Using comparative, qualitative data, we identify several key policy impediments to PCMH implementation, and propose practical guidelines for addressing these issues. RESEARCH DESIGN: Qualitative, semi-structured in-person interviews with representatives of physician organizations and primary care practices pursuing PCMH. PARTICIPANTS: Practitioners and staff at 16 physician practices in Michigan, as well as key leaders of physician organizations. KEY RESULTS: We identified five primary policy issues cited by physicians and physician organization leaders as most impactful on their efforts to adopt PCMH: misalignment of current reimbursement schemes, administrative burden, conflicting criteria for PCMH designation, workforce policy issues, and uncertainty of health care reform. These policies were largely seen as barriers to their ability to implement PCMH. CONCLUSIONS: Providers' motivation to embrace PCMH, and their level of confidence regarding the results of such change, are greatly influenced by their perception of the external environment and the control they believe they have over this environment. Having policies in place that shape the path to PCMH in a manner that makes it as easy as possible for providers to accomplish the desired changes could well make the difference in whether successful transformation is achieved.

Physician organization-practice team integration for the advancement of patient-centered care.

The patient-centered medical home is being promoted as a cornerstone for transforming primary care. Physician organizations (POs) are playing a more prominent role by facilitating practices' transformation to the patient-centered medical home. Using a framework of organizational integration, we investigated the changing relationship between POs and practices through qualitative interviews. Through increased integration, POs can support both the big picture and day-to-day activities of practice transformation. Most PO-practice unit connections we identified reflected new areas of engagement-competencies that POs were not developing in the past-that are proving integral to the broad-scale practice change of patient-centered medical home implementation.

Journey toward a patient-centered medical home: readiness for change in primary care practices.

CONTEXT: Information is limited regarding the readiness of primary care practices to make the transformational changes necessary to implement the patient-centered medical home (PCMH) model. Using comparative, qualitative data, we provide practical guidelines for assessing and increasing readiness for PCMH implementation. METHODS: We used a comparative case study design to assess primary care practices' readiness for PCMH implementation in sixteen practices from twelve different physician organizations in Michigan. Two major components of organizational readiness, motivation and capability, were assessed. We interviewed eight practice teams with higher PCMH scores and eight with lower PCMH scores, along with the leaders of the physician organizations of these practices, yielding sixty-six semistructured interviews. FINDINGS: The respondents from the higher and lower PCMH scoring practices reported different motivations and capabilities for pursuing PCMH. Their motivations pertained to the perceived value of PCMH, financial incentives, understanding of specific PCMH requirements, and overall commitment to change. Capabilities that were discussed included the time demands of implementation, the difficulty of changing patients' behavior, and the challenges of adopting health information technology. Enhancing the implementation of PCMH within practices included taking an incremental approach, using data, building a team and defining roles of its members, and meeting regularly to discuss the implementation. The respondents valued external organizational support, regardless of its source. CONCLUSIONS: The respondents from the higher and lower PCMH scoring practices commented on similar aspects of readiness-motivation and capability-but offered very different views of them. Our findings suggest the importance of understanding practice perceptions of the motivations for PCMH and the capability to undertake change. While this study identified some initial approaches that physician organizations and practices have used to prepare for practice redesign, we need much more information about their effectiveness.

Evaluation of patient centered medical home practice transformation initiatives.

BACKGROUND: The patient-centered medical home (PCMH) has become a widely cited solution to the deficiencies in primary care delivery in the United States. To achieve the magnitude of change being called for in primary care, quality improvement interventions must focus on whole-system redesign, and not just isolated parts of medical practices. METHODS: Investigators participating in 9 different evaluations of Patient Centered Medical Home implementation shared experiences, methodological strategies, and evaluation challenges for evaluating primary care practice redesign. RESULTS: A year-long iterative process of sharing and reflecting on experiences produced consensus on 7 recommendations for future PCMH evaluations: (1) look critically at models being implemented and identify aspects requiring modification; (2) include embedded qualitative and quantitative data collection to detail the implementation process; (3) capture details concerning how different PCMH components interact with one another over time; (4) understand and describe how and why physician and staff roles do, or do not evolve; (5) identify the effectiveness of individual PCMH components and how they are used; (6) capture how primary care practices interface with other entities such as specialists, hospitals, and referral services; and (7) measure resources required for initiating and sustaining innovations. CONCLUSIONS: Broad-based longitudinal, mixed-methods designs that provide for shared learning among practice participants, program implementers, and evaluators are necessary to evaluate the novelty and promise of the PCMH model. All PCMH evaluations should as comprehensive as possible, and at a minimum should include a combination of brief observations and targeted qualitative interviews along with quantitative measures.

Skeletal versus skin traction before definitive management of pediatric femur fractures: a comparison of patient narcotic requirements.

BACKGROUND: Pediatric patients with femoral shaft fractures are often placed in traction as a temporizing measure before definitive management. The purpose of our study was to compare narcotic use in pediatric patients with isolated femoral shaft fractures that were initially treated with skeletal traction with similar patients that were initially treated with skin traction. The hypothesis was that narcotic use would not be significantly different between the groups. METHODS: Chart review at 2 institutions was carried out to identify pediatric patients with isolated femoral shaft fractures treated with either skeletal traction or skin traction. The patients' age, weight, and the amount and duration of narcotic use were recorded. A 2-sample t test was used for the comparison. RESULTS: Fifty-one patients were treated with skin traction and 24 patients were treated with skeletal traction. Patients in the skeletal traction group used more pain medication (0.0177 mg/kg/h in traction) than those in the skin traction group (0.0137 mg/kg/h in traction), but this was not statistically significant (P=0.1031). CONCLUSIONS: The findings support our hypothesis that the amount of narcotics used between the skeletal traction group and skin traction group would not be significantly different. In using narcotic requirement as a gross measure of patient comfort while in traction, it seems there may be no benefit to the patient to have invasive skeletal traction while awaiting definitive management of their fracture. LEVEL OF EVIDENCE: Retrospective comparative study, level III.

Minimally invasive sacroiliac arthrodesis: outcomes of a new technique.

STUDY DESIGN: Prospective cohort. OBJECTIVE: Comparing efficacy and outcomes of a new technique for sacroiliac arthrodesis. BACKGROUND: The sacroiliac joint has been described as a possible source of chronic low back pain. However, surgical treatment of sacroiliac pain and dysfunction is controversial. Arthrodesis is normally reserved as a salvage procedure when all others have failed to relieve pain and involves an extensive surgical exposure. We have developed a novel technique of sacroiliac arthrodesis using percutaneously inserted fusion cages filled with bone morphogenic protein. This study describes the radiographic and clinical outcomes of this procedure. METHODS: Thirteen consecutive patients underwent minimally invasive sacroiliac arthrodesis between February and December 2004 at a single teaching hospital and were prospectively followed. Six patients had bilateral fusions for a total of 19 joints. The average age was 53.1 (range 45 to 62). Average body mass index was 31.2 (range 21.9 to 46.9). Mean follow-up was 29.5 months (range 24 to 35). Diagnosis was confirmed using fluoroscopically guided intra-articular injections of local anesthetic and corticosteroid when their pain was relieved 2 or more hours. Arthrodesis was only performed on patients with positive injections who subsequently had their symptoms recur. Outcome measurements included radiographic assessment for fusion and improvement in visual analog pain scale for low back pain, leg pain, and dyspareunia. Computed tomography scan to evaluate implant placement was performed postoperatively and again at 6 months to assess fusion. RESULTS: The overall fusion rate was 89% (17/19 joints). Significant improvements were seen in final low back pain score on a visual analog scale (0 to 10) (average improvement 4.9, P< or =0.001). Leg pain improved an average of 2.4 (P=0.013). Dyspareunia improved an average of 2.6 (P=0.0028). One patient was revised to an open arthrodesis secondary to nonunion and persistent pain. There were no infections or neurovascular complications. CONCLUSIONS: Minimally invasive sacroiliac arthrodesis via a percutaneous posterior approach is a safe and efficacious procedure, leading to a high fusion rate and significant improvement in low back, leg pain, and dyspareunia.

Crystal-associated arthritis in the elderly.

Since the original recognition of these conditions in 1961, a great deal has been learned about the pathogenesis, clinical manifestations, and appropriate treatment of gout and pseudogout, and the role of crystals in osteoarthritis has been further defined. The variable manifestations of crystal-induced arthritis in elderly populations has led to a greater need for proper diagnosis and treatment strategies for these increasingly common forms of arthritis.

Population-based medical and disease management: an evaluation of cost and quality.

Reports by the Institute of Medicine and the Health Care Financing Administration have emphasized that the integration of medical care delivery, evidence-based medicine, and chronic care disease management may play a significant role in improving the quality of care and reducing medical care costs. The specific aim of this project is to assess the impact of an integrated set of care coordination tools and chronic disease management interventions on utilization, cost, and quality of care for a population of beneficiaries who have complementary health coverage through a plan designed to apply proactive medical and disease management processes. The utilization of health care services by the study population was compared to another population from the same geographic service area and covered by a traditional fee-for-service indemnity insurance plan that provided few medical or disease management services. Evaluation of the difference in utilization was based on the difference in the cost per-member-per-month (PMPM) in a 1-year measurement period, after adjusting for differences in fee schedules, case-mix and healthcare benefit design. After adjustments for both case-mix and benefit differences, the study group is $63 PMPM less costly than the comparison population for all members. Cost differences are largest in the 55-64 and 65 and above age groups. The study group is $115 PMPM lower than the comparison population for the age category of 65 years and older, after adjustments for case-mix and benefits. Health Plan Employer and Data Information Set (HEDIS)-based quality outcomes are near the 90th percentile for most indications. The cost outcomes of a population served by proactive, population-based disease management and complex care management, compared to an unmanaged population, demonstrates the potential of coordinated medical and disease management programs. Further studies utilizing appropriate methodologies would be beneficial.

Etanercept therapy for immune-mediated cochleovestibular disorders: a multi-center, open-label, pilot study.

OBJECTIVE: Immune-mediated cochleovestibular disorders (IMCVDs) continue to present a diagnostic and therapeutic challenge. Antirheumatic agents, commonly employed for IMCVDs, are associated with variable efficacy and sometimes with serious side effects. The objective of the current study was to preliminarily evaluate the efficacy of etanercept therapy for IMCVD. METHODS: In this open-label prospective pilot study, 23 patients with bilateral IMCVDs or symptoms of bilateral Meniere's disease were treated with etanercept (25 mg twice weekly, by subcutaneous injection) for 24 weeks. All participants showed progressive hearing loss within 3 months prior to the study and responded to prednisone therapy. Hearing improvement was defined as an improvement of sensorineural hearing from baseline, in at least one ear, of 15 dB or more in the pure-tone air conduction thresholds, or an increase of more than 12% in word identification score. When present, vertigo and tinnitus were assessed by frequency and severity of attack and a functional level scale. Limited serial positron emission tomography (PET) of the inner ear region was performed in 5 patients to assess disease activity. RESULTS: There were 12 female (52%) and 11 male patients with a mean age of 48 years. Hearing improved in 7 (30%) patients, was unchanged in 13 (57%), and worsened in 3 (13%). Of 21 patients with tinnitus, this symptom improved in 7 (33%), was unchanged in 10 (48%), and worsened in 3 (13%). Of 16 patients with vertigo, 8 (50%) were improved, 7 (47%) unchanged, and 1 (3%) worse at the end of the study. Etanercept was generally well tolerated. PET was positive on one ear of 2 of 5 patients, remained positive with treatment on 1 of these, and was initially positive in 1 deaf ear, becoming negative at followup. CONCLUSION: These prospective pilot data suggest that etanercept therapy is safe among patients with IMCVDs. However, these data do not suggest substantial efficacy of etanercept among patients with IMCVDs in improving hearing loss. There appeared to be stabilization or improvement of hearing in 87% in this group of patients with pretreatment intractable progressive hearing loss. However, the study endpoint of improvement in 70% of patients was not attained. This short-term effect of possible stabilization requires further study. PET scanning was not useful as a tool to evaluate hearing loss in a limited subset of patients.

Crystal-associated arthritis in the elderly.

Since the original descriptions of the involvement of crystals in arthritis, our understanding of the clinical syndromes of gout and pseudogout, and the role of basic calcium crystals in arthritis has increased. Gout is usually considered an affliction confined to middle-aged men, but has an increasing prevalence in older populations, with unique and often atypical features. Calcium pyrophosphate dihydrate crystal deposition disease is common in elderly patients. The diagnosis of both of these common forms of arthritis and the need to individualize therapy in patients with other medical problems remain important clinical challenges to the practicing physician.