The interdomain interface in bifunctional enzyme protein 3/4A (NS3/4A) regulates protease and helicase activities
Hepatitis C (HCV) protein 3/4A (NS3/4A) is a bifunctional enzyme comprising two separate domains with protease and helicase activities, which are essential for viral propagation. Both domains are stable and have enzymatic activity separately, and the relevance and implications of having protease and helicase together as a single protein remains to be explored. Altered in vitro activities of isolated domains compared with the full-length NS3/4A protein suggest the existence of interdomain communication. The molecular mechanism and extent of this communication was investigated by probing the domain-domain interface observed in HCV NS3/4A crystal structures. We found in molecular dynamics simulations that the two domains of NS3/4A are dynamically coupled through the interface. Interestingly, mutations designed to disrupt this interface did not hinder the catalytic activities of either domain. In contrast, substrate cleavage and DNA unwinding by these mutants were mostly enhanced compared with the wild-type protein. Disrupting the interface did not significantly alter RNA unwinding activity; however, the full-length protein was more efficient in RNA unwinding than the isolated protease domain, suggesting a more direct role in RNA processing independent of the interface. Our findings suggest that HCV NS3/4A adopts an "extended" catalytically active conformation, and interface formation acts as a switch to regulate activity. We propose a unifying model connecting HCV NS3/4A conformational states and protease and helicase function, where interface formation and the dynamic interplay between the two enzymatic domains of HCV NS3/4A potentially modulate the protease and helicase activities in vivo.
Behavior problems among preschool children are common. They are important targets for intervention because early externalizing problems and self-regulation issues tend to persist without appropriate attention, and can affect later mental health and school achievement outcomes. However, few preschool curricula addressing social and emotional development exist, and evidence for effects are mixed. In this study, the Second Step Pre/Kindergarten Social and Emotional Learning curriculum was adapted and tested in a small cluster randomized pilot study of community preschool classrooms to determine if it could improve outcomes in: (1) individual children's teacher-rated behavior problems and prosocial skills; (2) classroom climate (classroom interactions and two measures of disruptive behavior); and (3) teacher interaction skills. Year 1 outcomes were modest and were accounted for by baseline differences. In Year 2, classroom climate, measured by independent observers, differed significantly in intervention classrooms, largely because of declines in control classrooms, and there was some evidence for better teacher interaction skills in intervention classrooms. The pattern of effects suggests important impacts on classroom quality worth investigating in a larger study. Both fidelity and implementation rates, as well as positive teacher responses to the curriculum, indicate potential for widespread adoption.
We report the performance of our approaches for protein-protein docking and interface analysis in CAPRI rounds 20-26. At the core of our pipeline was the ZDOCK program for rigid-body protein-protein docking. We then reranked the ZDOCK predictions using the ZRANK or IRAD scoring functions, pruned and analyzed energy landscapes using clustering, and analyzed the docking results using our interface prediction approach RCF. When possible, we used biological information from the literature to apply constraints to the search space during or after the ZDOCK runs. For approximately half of the standard docking challenges we made at least one prediction that was acceptable or better. For the scoring challenges we made acceptable or better predictions for all but one target. This indicates that our scoring functions are generally able to select the correct binding mode. (c) Proteins 2013;. (c) 2013 Wiley Periodicals, Inc.
A population-based dietary inflammatory index predicts levels of C-reactive protein in the Seasonal Variation of Blood Cholesterol Study (SEASONS)
OBJECTIVE: To perform construct validation of the population-based Dietary Inflammatory Index (DII) using dietary data from two different dietary assessments and serum high-sensitivity C-reactive protein (hs-CRP) as the construct validator.
DESIGN: Using data derived from (i) three 24 h dietary recalls (24HR) at baseline and at the end of each subsequent quarter (i.e. up to fifteen over a year) and (ii) a 7 d dietary recall (7DDR) measured at baseline and then quarterly, regression analyses were conducted to test the effect of the DII score on serum hs-CRP as dichotomous (3 mg/l), while controlling for important potential confounders.
SETTING: Existing data from the Seasonal Variation of Blood Cholesterol Study (SEASONS), a longitudinal observational study of healthy participants recruited in Worcester, MA, USA and participants were followed for 1 year.
SUBJECTS: Participants who had at least one hs-CRP measurement over her/his 1-year participation (n 495 for 24HR, n 559 for 7DDR).
RESULTS: Higher DII scores were associated with values of hs-CRP >3 mg/l (OR = 1.08; 95 % CI 1.01, 1.16, P = 0.035 for the 24HR; and OR = 1.10; 95 % CI 1.02, 1.19, P = 0.015 for the 7DDR).
CONCLUSIONS: The population-based DII was associated with interval changes in hs-CRP using both the 24HR and 7DDR. The success of this first-of-a-kind attempt at relating individuals' intakes of inflammation-modulating foods using this refined DII, and the finding that there is virtually no drop-off in predictive capability using a structured questionnaire in comparison to the 24HR standard, sets the stage for use of the DII in a wide variety of other epidemiological and clinical studies.
Factor H-Dependent Alternative Pathway Inhibition Mediated by Porin B Contributes to Virulence of Neisseria meningitidis
The identification of "factor H binding protein (fHbp)-null" invasive meningococcal isolates and the realization that widespread use of fHbp-based vaccines could herald selection of such strains prompted us to characterize novel mechanisms of alternative pathway (AP) inhibition on meningococci. Of seven strains engineered to lack four known AP-inhibiting molecules, capsular polysaccharide, lipooligosaccharide sialic acid, fHbp, and neisserial surface protein A (quadruple mutants), four strains inhibited human AP-mediated C3 deposition. All four expressed the porin B2 (PorB2) molecule, and three strains belonged to the hypervirulent ST-11 lineage. Consistent with reduced C3 deposition, the rate of C3a generation by a PorB2 isolate was lower than that by a PorB3 strain. Allelic replacement of PorB3 with PorB2, in both encapsulated and unencapsulated strains, confirmed the role of PorB2 in AP inhibition. Expression of PorB2 increased resistance to complement-dependent killing relative to that seen in an isogenic PorB3-expressing strain. Adult rabbit and mouse APs were unimpeded on all mutants, and human fH inhibited nonhuman C3 deposition on PorB2-expressing strains, which provided functional evidence for human fH-dependent AP regulation by PorB2. Low-affinity binding of full-length human fH to quadruple mutants expressing PorB2 was demonstrated. fH-like protein 1 (FHL-1; contains fH domains 1 through 7) and fH domains 6 and 7 fused to IgG Fc bound to one PorB2-expressing quadruple mutant, which suggested that fH domains 6 and 7 may interact with PorB2. These results associate PorB2 expression with serum resistance and presage the appearance of fHbp-null and hypervirulent ST-11 isolates that may evade killing by fHbp-based vaccines. IMPORTANCE The widespread use of antimeningococcal vaccines based on factor H (fH) binding protein (fHbp) is imminent. Meningococci that lack fHbp were recently isolated from persons with invasive disease, and these fHbp-null strains could spawn vaccine failure. Our report provides a molecular basis for an explanation of how fHbp-null strains may evade the host immune system. Meningococci possess several mechanisms to subvert killing by the alternative pathway (AP) of complement, including production of the fHbp and NspA fH binding proteins. Here we show that a meningococcal protein called porin B2 (PorB2) contributes to inhibition of the AP on the bacterial surface. A majority of the "fHbp-null" isolates identified, as well as all members of a "hypervirulent" lineage (called ST-11), express PorB2. Our findings highlight the potential for the emergence of fHbp-negative strains that are able to regulate the AP and may be associated with fHbp vaccine failure.
Patient-reported outcomes after total knee replacement vary on the basis of preoperative coexisting disease in the lumbar spine and other nonoperatively treated joints: the need for a musculoskeletal comorbidity index
BACKGROUND: Although the majority of patients report substantial gains in physical function following primary total knee replacement, the degree of improvement varies widely. To understand the potential role of preoperative pain due to other musculoskeletal conditions on postoperative outcomes, we quantified bilateral knee and hip pain and low back pain before primary total knee replacement and evaluated its association with physical function at six months after total knee replacement.
METHODS: A prospective cohort of 180 patients having primary unilateral total knee replacement reported joint-specific pain in right and left hips and knees (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain) as well as the low back (Oswestry Disability Index) before surgery. Participants also completed the Short Form-36 (SF-36), including the physical and mental component summary scores, before and at six months after surgery.
RESULTS: Of the 180 patients, 110 (61%) were women; the mean age was 65.1 years, the mean body mass index (BMI) was 32.5 kg/m2, and mean SF-36 physical component summary score reported before the total knee replacement was 33.1. Before total knee replacement, 56.1% of the patients reported no or mild pain in the nonoperatively treated knee, hips, and low back. In addition, 22.2% of the patients had moderate to severe pain in one location; 12.8%, in two locations; and 8.9%, in three or four locations. Women reported more moderate to severe pain than men did in the nonoperatively treated knee (30% versus 11%; p andlt; 0.004) and ipsilateral hip (26% versus 11%; p andlt; 0.02). At six months, the mean physical component summary score was lower among patients with a greater number of preoperative locations of moderate to severe pain. After adjusting for age, sex, BMI, and SF-36 mental component summary score, moderate to severe preoperative pain in the contralateral knee (p = 0.013), ipsilateral (p = 0.014) and contralateral hip (p = 0.026), and low back (p andlt; 0.001) was significantly associated with poorer function at six months after total knee replacement.
CONCLUSIONS: Preoperative musculoskeletal pain in the low back and nonoperatively treated lower extremity joints is associated with poorer physical function at six months after total knee replacement. The degree of functional improvement varies with the burden of musculoskeletal pain in other weight-bearing locations.
LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
BACKGROUND: In the largest overhaul to Medicare since its creation in 1965, the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 established Part D in 2006 to improve access to essential medication among disabled and older Americans. Despite previous evidence of a positive impact on the general Medicare population, Part D's overall effects on long-term care (LTC) are unknown.
OBJECTIVE: The purpose of this systematic review was to evaluate the literature regarding Part D's impact on the LTC context, specifically costs to LTC residents, providers and payers; prescription drug coverage and utilization; and clinical and administrative outcomes.
DATA SOURCES: Four electronic databases [PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Health Business Fulltext Elite and Science Citation Index Expanded], selected US government and non-profit websites, and bibliographies were searched for quantitative and qualitative studies characterizing Part D in the LTC context. Searches were limited to studies that may have been published between 1 January 2006 (date of Part D implementation) and 8 January 2013.
STUDY SELECTION: Systematic searches identified 1,624 publications for a three-stage (title, abstract and full-text) review. Included publications were in English language; based in the US; assessed Part D-related outcomes; and included or were directly relevant to LTC residents or settings. News articles, reviews, opinion pieces, letters or commentaries; case reports or case series; simulation or modeling studies; and summaries that did not report original data were excluded.
STUDY APPRAISAL AND SYNTHESIS METHODS: A standardized form was used to abstract study type, study design, LTC setting, sources of data, method of data collection, time periods assessed, unit of observation, outcomes and results. Methodological quality was assessed using modified criteria specific to quantitative and qualitative studies.
RESULTS: Eleven quantitative and eight qualitative studies met inclusion criteria. In the seven years since its implementation, Part D decreased out-of-pocket costs among enrolled nursing home residents and potentially increased costs borne by LTC facilities. Coverage of prescription drugs frequently used by older adults was adequate, except for certain drugs and alternative formulations of importance to LTC residents. The use of medications that raise safety concerns was decreased, but overall drug utilization may have been unaffected. Although there was uncertain impact on clinical outcomes, quantitative studies demonstrated evidence of unintended health consequences. Qualitative studies consistently revealed increased administrative burden among providers.
LIMITATIONS: Empirical evidence of Part D's LTC impact was sparse. Due to limitations in available types of data, quantitative studies were generically lacking in methodological rigor. Qualitative studies suffered from lack of clarity of reporting. As future studies use clinical Medicare data, study quality is expected to improve.
CONCLUSION: Although LTC-specific policies continue to evolve, it appears that the prescription drug benefit may require further modifications to more effectively provide for LTC residents' unique medication needs and improve their health outcomes. Adjustments may be needed for Part D to be more compatible with LTC prescription drug delivery processes.
Epigenetic Modifications Induced by Blimp-1 Regulate CD8(+) T Cell Memory Progression during Acute Virus Infection
The transcription factor Blimp-1 regulates the overall accumulation of virus-specific CD8(+) T cells during acute viral infections. We found that increased proliferation and survival of Blimp-1-deficient CD8(+) T cells resulted from sustained expression of CD25 and CD27 and persistent cytokine responsiveness. Silencing of Il2ra and Cd27 reduced the Blimp-1-deficient CD8(+) T cell response. Genome-wide chromatin immunoprecipitation (ChIP) sequencing analysis identified Il2ra and Cd27 as direct targets of Blimp-1. At the peak of the antiviral response, but not earlier, Blimp-1 recruited the histone-modifying enzymes G9a and HDAC2 to the Il2ra and Cd27 loci, thereby repressing expression of these genes. In the absence of Blimp-1, Il2ra and Cd27 exhibited enhanced histone H3 acetylation and reduced histone H3K9 trimethylation. These data elucidate a central mechanism by which Blimp-1 acts as an epigenetic regulator and enhances the numbers of short-lived effector cells while suppressing the development of memory-precursor CD8(+) T cells.
RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals
Double-stranded RNA (dsRNA) directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). Using a recently developed Drosophila in vitro system, we examined the molecular mechanism underlying RNAi. We find that RNAi is ATP dependent yet uncoupled from mRNA translation. During the RNAi reaction, both strands of the dsRNA are processed to RNA segments 21-23 nucleotides in length. Processing of the dsRNA to the small RNA fragments does not require the targeted mRNA. The mRNA is cleaved only within the region of identity with the dsRNA. Cleavage occurs at sites 21-23 nucleotides apart, the same interval observed for the dsRNA itself, suggesting that the 21-23 nucleotide fragments from the dsRNA are guiding mRNA cleavage.
Activation of NFAT signaling establishes a tumorigenic microenvironment through cell autonomous and non-cell autonomous mechanisms
NFAT (the nuclear factor of activated T cells) upregulation has been linked to cellular transformation intrinsically, but it is unclear whether and how tissue cells with NFAT activation change the local environment for tumor initiation and progression. Direct evidence showing NFAT activation initiates primary tumor formation in vivo is also lacking. Using inducible transgenic mouse systems, we show that tumors form in a subset of, but not all, tissues with NFATc1 activation, indicating that NFAT oncogenic effects depend on cell types and tissue contexts. In NFATc1-induced skin and ovarian tumors, both cells with NFATc1 activation and neighboring cells without NFATc1 activation have significant upregulation of c-Myc and activation of Stat3. Besides known and suspected NFATc1 targets, such as Spp1 and Osm, we have revealed the early upregulation of a number of cytokines and cytokine receptors, as key molecular components of an inflammatory microenvironment that promotes both NFATc1(+) and NFATc1(-) cells to participate in tumor formation. Cultured cells derived from NFATc1-induced tumors were able to establish a tumorigenic microenvironment, similar to that of the primary tumors, in an NFATc1-dependent manner in nude mice with T-cell deficiency, revealing an addiction of these tumors to NFATc1 activation and downplaying a role for T cells in the NFATc1-induced tumorigenic microenvironment. These findings collectively suggest that beyond the cell autonomous effects on the upregulation of oncogenic proteins, NFATc1 activation has non-cell autonomous effects through the establishment of a promitogenic microenvironment for tumor growth. This study provides direct evidence for the ability of NFATc1 in inducing primary tumor formation in vivo and supports targeting NFAT signaling in anti-tumor therapy.
Cytokinesis, the process in which cytoplasm is apportioned between dividing daughter cells, requires coordination of myosin II function, membrane trafficking and central spindle organization. Most known regulators act during late cytokinesis; a few, including the myosin II-binding proteins anillin and supervillin, act earlier. Anillin's role in scaffolding the membrane cortex with the central spindle is well established, but the mechanism of supervillin action is relatively uncharacterized. We show here that two regions within supervillin affect cell division: residues 831-1281, which bind central spindle proteins, and residues 1-170, which bind the myosin II heavy chain (MHC) and the long form of myosin light chain kinase (l-MLCK). MHC binding is required to rescue supervillin deficiency, and mutagenesis of this site creates a dominant-negative phenotype. Supervillin concentrates activated and total myosin II at the furrow, and simultaneous knockdown of supervillin and anillin additively increase cell division failure. Knockdown of either protein causes mislocalization of the other, and endogenous anillin increases upon supervillin knockdown. Proteomic identification of interaction partners recovered using a high-affinity GFP nanobody suggest that supervillin and anillin regulate the myosin II- and actin cortical cytoskeletons through separate pathways. We conclude that supervillin and anillin play complementary roles during vertebrate cytokinesis.
This self-directed learning module highlights the physician's role in the diagnosis and treatment of neuromuscular disorders in pediatric populations. It is part of the chapter on neuromuscular rehabilitation and electrodiagnosis in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article discusses both clinical and electrodiagnostic features of common neuromuscular disorders in pediatric populations. The diagnostic value of somatosensory evoked potential is reviewed in a case of traumatic spinal cord injury without radiographic abnormality. Therapeutic interventions of progressive muscular dystrophy are discussed, as well as the differential diagnosis of floppy infant syndrome, the most common pediatric electrodiagnostic referral. OVERALL ARTICLE OBJECTIVES: (a) To become familiar with electrodiagnosis and rehabilitation for common neuromuscular disorders in the pediatric population, (b) to undrstand electrodiagnostic findings of Guillain-Barre syndrome corresponding to pathophysiology, (c) to become familiar with somatosensory evoked potentials, and (d) to be able to make differential diagnosis of floppy infant syndrome based on clinical findings as well as electrodiagnosis.
Comparison of the flat torso versus the elevated torso shoulder pad removal techniques in a cadaveric cervical spine instability model
STUDY DESIGN: Controlled laboratory study in a cadaveric model.
OBJECTIVE: To determine if removing shoulder pads using the elevated torso technique generated less spinal segment motion than using the flat torso method.
SUMMARY OF BACKGROUND DATA: Guidelines for care of the injured football player with a suspected spinal injury recommend initial immobilization with shoulder pads and helmet in place. There is a need to develop a safe protocol, for shoulder pad removal that maintains optimum cervical stability.
METHODS: Five lightly embalmed cadavers were studied before and after a globally unstable segment was created at C5-C6. A trained group of medical staff conducted repeated measures trials for 2 pad removal protocols. The elevated torso technique, outlined by the NATA Inter-Association Task Force, is the same as the flat torso except an additional assistant is employed to lift the patient's shoulders 30 degrees to 40 degrees off the ground while the head holder maintains spinal alignment as the pads are removed. An electromagnetic tracking device captured angular and linear motions in 3 planes between the C5-C6 segments.
RESULTS: The elevated torso technique generated significantly less C5-C6 motion in flexion/extension (P = 0.015) and lateral bending (P = 0.001), with a trend toward decreased cervical motion in axial rotation (P = 0.052). When moving the spine-injured cadavers, linear translation was also slightly, but not significantly less when the elevated torso technique was used. In the intact spine, significantly less motion was seen in 5 of 6 measures when the elevated torso technique was used. However, the differences were not large enough to be clinically significant in an intact spine.
CONCLUSION: These findings support use of the elevated torso method to minimize cervical spine motion during shoulder pad removal when neither thoracic nor lumbar spinal injury is a concern.
Glomus tumors are rare, usually solitary lesions, most commonly presenting as a painful nodule in the subungual location of the digits. Glomus tumors have been reported in multiples and can be found in atypical locations, including the lower leg. We describe sonographic and magnetic resonance imaging (MRI) findings in a patient with multiple glomus tumors of the lower leg.
STUDY DESIGN: Meta-analysis.
OBJECTIVE: Meta-analysis of the data to determine the effect of magnetic resonance imaging (MRI) signal change on preoperative and postoperative Japanese Orthopedic Association (JOA) scores and on recovery rate after surgery.
SUMMARY OF BACKGROUND DATA: MRI signal changes are commonly found in myelopathy. There is often an increased T2 signal with or without a decreased T1 signal. The clinical significance of these signal changes remains debated.
METHODS: A comprehensive review of the literature was performed to identify all published studies with data on the presence of MRI signal change and JOA scores in myelopathic patients. T tests were performed to determine if there were significant differences between preoperative and postoperative JOA scores in patients with or without MRI signal change. The recovery rate was calculated for all patients undergoing surgery. T tests were performed to determine whether significant differences occurred in recovery rate in patients with or without MRI signal change.
RESULTS: A total of 16 studies were used for the meta-analysis. The total population included 886 patients: 659 with MRI signal change, and 227 without MRI signal change. Preoperative and postoperative JOA scores and the recovery rates were significantly better in patients without MRI signal changes (P < 0.05). The mean preoperative JOA scores were 10.63 and 11.37 for patients with and without MRI signal changes, respectively. The mean postoperative JOA scores were 13.37 and 14.19 for patients with and without MRI signal changes, respectively. The mean recovery rates were 43.87% and 49.31% for patients with and without MRI signal changes, respectively.
CONCLUSION: A meta-analysis of the literature revealed statistically better preoperative and postoperative JOA scores and recovery rates following surgery in myelopathic patients without MRI signal change. Although the data were statistically significant, the clinical significance of the differences might be less due to the relatively small differences in actual values.
STUDY DESIGN: This is a case report of a posterior extrusion of the polyethylene core from a CHARITE arthroplasty. This is the first reported case of posterior dislocation of the polyethylene and the revision strategies used to correct this problem.
OBJECTIVE: To report a novel failure mechanism and revision strategy for CHARITE total disc arthroplasty (TDA).
SUMMARY OF BACKGROUND DATA: Case report at a Level 1 tertiary care referral center in the northeastern United States. METHODS: This is a case report and review of the literature of a patient who sustained posterior dislocation of the polyethylene core from a CHARITE TDA several months after the index procedure.
RESULTS: Core dislocation is a known complication of TDA. However, of the known reported dislocations all have been anterior. This case describes the first known occurrence of posterior core dislocation and the revision strategy for this problem.
CONCLUSION: This case report highlights the first known case of a posterior dislocation of a CHARITE core. It is likely that altered biomechanical forces generated over time attributed to device failure. An instrumented posterior fusion with removal of the core is what ultimately led to a stable revision construct.
Incorporating Patient-reported Outcomes in Total Joint Arthroplasty Registries: Challenges and Opportunities
BACKGROUND: Total joint arthroplasty (TJA) registries traditionally have focused on implant longevity and rates of revision surgery. Registries would benefit from the addition of standardized patient-reported outcomes (PROs) such as pain relief and improved physical function. However, PROs have not been routinely adopted, and their incorporation into TJA registries presents challenges.
QUESTIONS/PURPOSES: We review current PRO use by existing national registries, challenges to integrating PROs in national registries, lessons from national registries that have integrated PROs, and suggestions to guide future adoption of PROs.
METHODS: We conducted a literature search of papers addressing PRO use in national knee and hip arthroplasty registries, resulting in 15 articles. These publications were supplemented by discussions with thought leaders from international registries.
WHERE ARE WE NOW?: Some national TJA registries are collecting PROs and valuable research is emerging. However, challenges exist, such as selecting suitable PROs, selection bias in countries without government-mandated participation for all hospitals, and challenges with missing data.
WHERE DO WE NEED TO GO?: The ideal system will incorporate PROs into TJA registries. In so doing, it will be important to choose suitable PROs and develop innovative methods to collect PROs to ensure complete data and sustainability.
HOW DO WE GET THERE?: New methods are required to meet the challenges related to registry design, logistics of PRO collection, and registry cost and sustainability. Modifications to the traditional hospital- and implant-centric design and new procedures to collect complete data from both patients and clinicians may be necessary. For instance, England and Wales, New Zealand, and Sweden developed methods to collect PROs after TJA directly from patients and a US TJA registry collects PROs as the primary outcome. Finally, to assure long-term sustainability, PRO data must be valuable to multiple stakeholders, including patients, clinicians, researchers, and policy makers.
Integrating Patient-reported Outcomes Into Orthopaedic Clinical Practice: Proof of Concept From FORCE-TJR
BACKGROUND: Good orthopaedic care requires a knowledge of the patient's history of musculoskeletal pain and associated limitations in daily function. Standardized measures of patient-reported outcomes (PROs) can provide this information. Integrating PROs into routine orthopaedic patient visits can provide key information to monitor changes in symptom severity over time, support shared clinical care decisions, and assess treatment effectiveness for quality initiatives and value-based reimbursement.
WHERE ARE WE NOW?: Although standardized, validated PRO surveys are routinely used in clinical and comparative effectiveness research, they are not consistently or efficiently collected in clinical practice.
WHERE DO WE NEED TO GO?: Ideally, PROs need to be collected directly from patients before their surgeon visit so the data are readily available to the surgeon and patient at the time of the office visit. In addition, PROs should be integrated in the electronic health record to monitor patient status over time.
HOW DO WE GET THERE?: PRO integration in clinical practice requires minor modifications to the office flow, some additional staff to facilitate collection, and the technical infrastructure to score, process, and store the responses. We document successful office procedures for collecting PROs in one busy orthopaedic clinic and some suggested methods to extend this model to the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) consortium of 121 surgeons where the process is centralized and staff obtained consent to send the PRO directly to the patient's home. Both methods are options for the broader adoption of office-based PROs.
Do clinical factors explain persistent sex disparities in the use of acute reperfusion therapy in STEMI in Sweden and Canada?
Aims: This study examined clinical factors associated with sex differences in the use of acute reperfusion therapy (fibrinolysis or primary percutaneous coronary intervention) in ST-elevation myocardial infarction (STEMI) patients, and the interaction between sex and these factors in Sweden and Canada.
Methods: Patients with STEMI in Sweden (n=32,676 from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) were compared with similar patients in Canada (n=3375 from the Canadian Global Registry of Acute Coronary Events) for the period 2004–2008.
Results: Unadjusted vs. age-adjusted odds ratios (OR) for no reperfusion (women vs. men) were for Sweden 1.57 (95% CI 1.49–1.64) vs. 1.14 (95% CI 1.08–1.20), and for Canada 1.61 (95% CI 1.39–1.87) vs. OR 1.18 (95% CI 1.01–1.39). Sex differences persisted after multivariable adjustments (including prehospital delay, atypical symptoms, diabetes), factors for which no interaction with sex was found. Among women <60 years, adjusting for atypical symptoms in Canada and angiographic data in Sweden made the greatest contribution to explaining observed sex differences.
Conclusions: In both countries, acute reperfusion therapy in STEMI was used less often in women than in men. Factors associated with these sex differences appear to differ between older and younger women. Targeted interventions are needed to optimize care for women with STEMI, as well as sex- and age-stratified reporting of quality indicators to assess their effectiveness.