Clinician Views of Proactive Tobacco Treatment Programs: A Qualitative Evaluation.

INTRODUCTION: Proactive tobacco treatment programs are an evidence-based strategy to recruit patients who smoke to make supported quit attempts. However, such programs are rarely implemented. We performed a qualitative assessment of clinicians to inform the creation of a proactive outreach program for patients with chronic obstructive pulmonary disease (COPD) who smoke. METHODS: Informed by the Consolidated Framework for Implementation Research, we conducted semi-structured interviews to assess clinician views of proactive outreach, including barriers, program structure, and the use of technology. Clinicians included primary and specialty care physicians, nurses and advanced practice providers, pharmacists, respiratory therapists, a psychologist, and relevant members of leadership. Interviews were transcribed and analyzed using directed content analysis. RESULTS: Clinicians in all roles identified that proactive outreach could be an effective use of resources to help patients with COPD who smoke quit with several advantages over the current state. Clinicians disagreed on the priority population (e.g., younger patients, sicker patients), and to some extent on whether proactive outreach is a clinical priority. Though they supported that technology could be part of the outreach program, most advocated for multiple avenues (phone calls, drop-in clinic, texting), as these patients were perceived to be low technology utilizers. The primary implementation barriers were competing priorities and cost, as well as unclear billing and staffing models. CONCLUSIONS: Clinicians support proactive outreach for patients with COPD, but the optimal way to structure, staff, and fund such programs remains unclear. Health systems should leverage implementation strategies to speed uptake of these potentially life-saving programs.

Recovery Curves for Lisfranc ORIF Using PROMIS Physical Function and Pain Interference.

OBJECTIVES: To determine the postoperative trajectory and recovery of patients who undergo Lisfranc open reduction and internal fixation using Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) and pain interference (PI). DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENT SELECTION CRITERIA: Patients who underwent Lisfranc open reduction and internal fixation between January 2002 and December 2022 with documented PROMIS PF and/or PI scores after surgery. OUTCOME MEASURES AND COMPARISONS: PROMIS PF and PI were mapped over time up to 1 year after surgery. A subanalysis was performed to compare recovery trajectories between high-energy and low-energy injuries. RESULTS: A total of 182 patients were included with average age of 38.7 (SD 15.9) years (59 high-energy and 122 low-energy injuries). PROMIS PF scores at 0, 6, 12, 24, and 48 weeks were 30.2, 31.4, 39.2, 43.9, and 46.7, respectively. There was significant improvement in PROMIS PF between 6 and 12 weeks ( P < 0.001), 12-24 weeks ( P < 0.001), and 24-48 weeks ( P = 0.022). A significant difference in PROMIS PF between high and low-energy injuries was seen at 0 week (28.4 vs. 31.4, P = 0.010). PROMIS PI scores at 0, 6, 12, 24, and 48 weeks were 62.2, 58.5, 56.6, 55.7, and 55.6, respectively. There was significant improvement in PROMIS PI 0-6 weeks ( P = 0.016). A significant difference in PROMIS PI between high-energy and low-energy injuries was seen at 48 weeks with scores of (58.6 vs. 54.2, P = 0.044). CONCLUSIONS: After Lisfranc open reduction and internal fixation, patients can expect improvement in PF up to 1 year after surgery, with the biggest improvement in PROMIS PF scores between 6 and 12 weeks and PROMIS PI scores between 0 and 6 weeks after surgery. Regardless the energy type, Lisfranc injuries seem to regain comparable PF by 6-12 months after surgery. However, patients with higher energy Lisfranc injuries should be counseled that these injuries may lead to worse PI at 1 year after surgery as compared with lower energy injuries. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Variation in Reporting of Incidental Findings on Initial Lung Cancer Screening and Associations With Clinician Assessment.

PURPOSE: The aim of this study was to quantify the distribution, frequency, and clinical significance of incidental findings (IFs) on initial lung cancer screening (LCS) and the association of report characteristics with subsequent assessment. METHODS: Health records of patients undergoing initial LCS from 2015 to 2018 in the Minneapolis VA Health Care System were retrospectively reviewed for demographics, Lung CT Screening Reporting & Data System coding, IFs, and subsequent clinical assessment. IFs were considered potentially significant if they were likely to require any follow-up. High-risk significant IFs (SIFs) were potentially malignant. The primary outcome was the SIF being addressed. Outcomes were analyzed using a mixed-effects model. RESULTS: Patients (n = 901) were primarily male (94.1%) smokers (62.1%) with a mean age of 65.2 years. IFs were extremely common (93.9%), with an average of 2.6 IFs per scan (n = 2,296). Seven hundred eighty-six IFs (34.2%) were deemed likely SIFs, of which 58 (7.4%) were high risk. Two hundred twenty-two (28.2%) were addressed by clinicians, of which 104 (13.2%) underwent testing. Reporting of SIFs varied among radiologists, with at least one SIF in the impression in 24% to 78% of low-dose CT studies with the S modifier, used to indicate the presence of a SIF, applied to 0% to 51% of reports. In the mutually adjusted model, radiologist recommendation (adjusted odds ratio [OR], 4.67; 95% confidence interval [CI], 2.23-9.76), high-risk finding (adjusted OR, 4.35; 95% CI, 1.81-10.45), and reporting in the impression (adjusted OR, 2.58; 95% CI, 1.28-5.18) were associated with increased odds of the SIF's being addressed. CONCLUSIONS: Radiologists vary in their reporting of IFs on LCS. Further standardization of reporting of SIFs may improve this process, with the simultaneous goals of generating appropriate testing when needed and minimizing low-value care.

Use of Information and Communication Technology among Patients with Chronic Obstructive Pulmonary Disease Who Smoke: A Mixed Methods Study.

Rationale: Although overall use is on the rise, certain patient populations have persistently low technology use. Objectives: To inform the creation of a proactive tobacco treatment program, we assessed access to, use of, and barriers surrounding information and communication technology (ICT) among patients with chronic obstructive pulmonary disease (COPD) who currently smoke, examining associations between key predictors and electronic health (e-health) literacy. Methods: Single-center mixed-methods study of veterans with COPD who smoke. Eligible participants who smoked were identified by the e-health record and mailed a survey. E-health literacy was assessed by the eHEALS (Electronic Health Literacy Scale; 8-40). Low technology use was defined as no Internet-capable device and use of ICT less than monthly. Qualitative participants were purposively selected from survey respondents and interviewed using a semistructured guide. Interviews were transcribed and analyzed using directed content analysis. We used a Bayesian three-component joint model to identify predictors of low technology use and low eHEALS. Results: Participants (N = 204) were older (mean age, 65.8), primarily White (76.4%), men (87.1%), and with low income (44.9% income under $20,000). Low technology use was reported by 25.5%, and many reported low use of specific types of ICT. For example, only 36.3% had reliable in-home Internet, fewer than half (46.6%) accessed e-mail at least weekly, 58.3% texted at least weekly, and few used the secure patient portal (13.2% accessed it monthly). The mean eHEALS was 24.6 (±8.7), indicating low to moderate e-health literacy. In the Bayesian analysis, low technology use was associated with lower eHEALS (estimate: -8.5 [95% confidence interval, -12.13 to -4.81]). Attainment of at least a college graduate-level education was associated with higher eHEALS (3.83 [0.43-7.24]). Participants reported barriers to use of ICT, including struggles navigating account security, frequently lost login information, mistrust of providing personal information to the Internet, and lack of familiarity with processes. Many perceived ICT as not useful or necessary. Conclusions: Many patients with COPD who smoke report barriers to engagement with health promotion programs offered electronically, which may perpetuate health disparities. Health promotion programs must account for the low use of ICT and e-health literacy to ensure equitable access across the population.

Development and Validation of a Health-Related Quality-of-Life Measure in Older Children and Adolescents with Early-Onset Scoliosis: Early-Onset Scoliosis Self-Report Questionnaire (EOSQ-SELF).

BACKGROUND: The 24-question Early-Onset Scoliosis Questionnaire (EOSQ-24) is a proxy measure assessing health-related quality of life (HRQoL) among patients with early-onset scoliosis (EOS). There exists an increasing need to assess HRQoL through a child's own perspective, particularly for older children and adolescents with EOS. The purpose of this study was to develop and validate a self-reported questionnaire, the Early-Onset Scoliosis Self-Report Questionnaire (EOSQ-SELF), to assess HRQoL in older children and adolescents with EOS. METHODS: A literature review, an expert focus group, and patient interviews were used to generate a preliminary survey of appropriate domains and question items. This survey was provided to English-speaking patients with EOS who were 8 to 18 years of age and capable of answering survey questions. Content validity was assessed for clarity and relevance of questions. Confirmatory factors analysis was performed to reduce the number of items and determine domains that fit items. Reliability was evaluated by measuring the internal consistency of items and test-retest reliability. Construct validity was evaluated by convergent, discriminant, and known-group validity. RESULTS: The literature review, expert focus group, and patient interviews identified 59 questions in 14 domains. Psychometric analysis reduced these to 30 questions across 12 domains: General Health, Pain/Discomfort, Pulmonary Function, Transfer, Physical Function/Daily Living, Participation, Fatigue/Energy Level, Sleep, Appearance, Relationships, Emotion, and Satisfaction. The final questionnaire was found to have good content and construct validity and adequate reliability. CONCLUSIONS: The EOSQ-SELF is a valid and reliable instrument for measuring self-reported HRQoL among older children and adolescents with EOS (ages 8 to 18 years). This will serve as an important research outcome measure and enhance clinical care by providing a better understanding of HRQoL for these patients. LEVEL OF EVIDENCE: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Validity of Categories Related to Gender Identity in ICD-11 and DSM-5 Among Transgender Individuals who Seek Gender-Affirming Medical Procedures.

BACKGROUND/OBJECTIVE: The most recent versions of the two main mental disorders classifications-the World Health Organization's ICD-11 and the American Psychiatric Association's DSM-5-differ substantially in their diagnostic categories related to transgender identity. ICD-11 gender incongruence (GI), in contrast to DSM-5 gender dysphoria (GD), is explicitly not a mental disorder; neither distress nor dysfunction is a required feature. The objective was compared ICD-11 and DSM-5 diagnostic requirements in terms of their sensitivity, specificity, discriminability and ability to predict the use of gender-affirming medical procedures. METHOD: A total of 649 of transgender adults in six countries completed a retrospective structured interview. RESULTS: Using ROC analysis, sensitivity of the diagnostic requirements was equivalent for both systems, but ICD-11 showed greater specificity than DSM-5. Regression analyses indicated that history of hormones and/or surgery was predicted by variables that are an intrinsic aspect of GI/GD more than by distress and dysfunction. IRT analyses showed that the ICD-11 diagnostic formulation was more parsimonious and contained more information about caseness than the DSM-5 model. CONCLUSIONS: This study supports the ICD-11 position that GI/GD is not a mental disorder; additional diagnostic requirements of distress and/or dysfunction in DSM-5 reduce the predictive power of the diagnostic model.

ANTECEDENTES/OBJETIVO: Las versiones más recientes de las clasificaciones de trastornos mentales ­CIE-11 de la Organización Mundial de la Salud y DSM­5 de la Asociación Psiquiátrica Americana­ difieren en sus categorías diagnósticas relacionadas con la identidad transgénero. La discordancia de género (DiscG) de la CIE-11, en contraste con la disforia de género (DisfG) del DSM-5, no es considerada un trastorno mental; el distrés y la disfunción no son características requeridas para el diagnóstico. El objetivo fue comparar los requisitos diagnósticos de la CIE-11 y el DSM-5 en términos de sensibilidad, especificidad y capacidad para discriminar casos y predecir el uso de procedimientos médicos de afirmación de género. MÉTODO: 649 adultos transgénero de seis países completaron una entrevista estructurada retrospectiva. RESULTADOS: De acuerdo con el análisis ROC, la sensibilidad de ambos sistemas fue equivalente, aunque la CIE-11 mostró mayor especificidad que el DSM-5. Los análisis de regresión indicaron que la historia de uso de hormonas o cirugía se predijo por variables intrínsecas a la DiscG/DisfG y no por el distrés o disfunción. Según los análisis de respuesta al ítem (TRi) la formación CIE-11 resulta más parsimoniosa y contiene mayor información sobre los casos. CONCLUSIONES: Se aporta evidencia a favor de que la DiscG/DisfG no es un trastorno mental; los criterios diagnósticos adicionales de distrés y/o disfunción del DSM-5 reducen su poder predictivo.

Risk Factors Associated with Surgical Site Infection in Pediatric Patients Undergoing Spinal Deformity Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Considerable variation exists in surgical site infection (SSI) prevention practices for pediatric patients undergoing spinal deformity surgery, but the incidence of SSI has been reported to remain high in the United States. The literature reports various risk factors associated with SSI but findings are inconsistent. The purpose of this systematic review and meta-analysis was to assess the published literature investigating associations between various risk factors and SSI in pediatric patients undergoing spinal surgery. METHODS: The systematic review and the meta-analysis were conducted according to Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) guidelines among peer-reviewed journals published in English between January 2000 and April 2019. Studies that involved pediatric patients with spinal deformity undergoing surgical procedures in North America and assessed risk factors for SSI were included. The quality of individual studies was assessed, and weighted risk ratios and mean differences were calculated for each risk factor. RESULTS: Of 763 potential articles identified, 13 met inclusion criteria; 7 studies were rated as average and 6, as poor quality based on the quality checklist. The meta-analysis demonstrated that the SSI risk increased by the following factors: 2.53 (95% confidence interval [CI], 1.26 to 5.10) for overweight to obese patients compared with patients with normal weight, 2.84 (95% CI, 1.67 to 4.81) for patients with a neuromuscular etiology compared with non-neuromuscular etiology, 1.69 (95% CI, 1.41 to 2.02) for patients with a gastrostomy tube (G-tube) compared with those without, 3.45 (95% CI, 2.08 to 5.72) for nonambulatory patients compared with ambulators, and 3.39 (95% CI, 2.38 to 4.83) for patients with pelvic instrumentation compared with those without. Patients who developed SSI also had 158.38 mL (95% CI, 46.78 to 269.97 mL) greater estimated blood loss compared with those who did not. CONCLUSIONS: Despite the limited quality of the available studies and wide variety of populations and outcome definitions, evidence suggests that overweight to obese status, neuromuscular etiology, use of a G-tube, nonambulatory status, instrumentation to the pelvis, and greater estimated blood loss are risk factors for SSI. The use of a common SSI definition and strong methodology are warranted for future studies. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete list of levels of evidence.

Establishing Consensus on the Best Practice Guidelines for Use of Halo Gravity Traction for Pediatric Spinal Deformity.

BACKGROUND: Although halo gravity traction (HGT) has been used to treat children with severe spinal deformity for decades, there is a distinct lack of high-quality evidence to speak to its merits or to dictate ideal manner of implementation. In addition, no guidelines exist to drive research or assist surgeons in their practice. The aim of this study was to establish best practice guidelines (BPG) using formal techniques of consensus building among a group of experienced pediatric spinal deformity surgeons to determine ideal indications and implementation of HGT for pediatric spinal deformity. METHODS: The Delphi process and nominal group technique were used to formally derive consensus among leaders in pediatric spine surgery. Initial work identified significant areas of variability in practice for which we sought to garner consensus. After review of the literature, 3 iterative surveys were administered from February through April 2018 to nationwide experts in pediatric spinal deformity. Surveys assessed anonymous opinions on ideal practices for indications, preoperative evaluation, protocols, and complications, with agreement of 80% or higher considered consensus. Final determination of consensus items and equipoise were established using the Nominal group technique in a facilitated meeting. RESULTS: Of the 42 surgeons invited, responses were received from 32, 40, and 31 surgeons for each survey, respectively. The final meeting included 14 experts with an average 10.5 years in practice and average 88 annual spinal deformity cases. Experts reached consensus on 67 items [indications (17), goals (1), preoperative evaluations (5), protocols (36), complications (8)]; these were consolidated to create final BPG in all categories, including statements to help dictate practice such as using at least 6 to 8 pins under 4 to 8 lbs of torque, with a small, tolerable starting weight and reaching goal weight of 50% TBW in ∼2 weeks. Nine items remained items of equipoise for the purposes of guiding future research. CONCLUSIONS: We developed consensus-based BPG for the use and implementation of HGT for pediatric spinal deformity. This can serve as a measure to help drive future research as well as give new surgeons a place to begin their practice of HGT. LEVEL OF EVIDENCE: Level V-expert opinion.

Reconstruction with Custom Unicondylar Hemiarthroplasty following Tumor Resection: A Case Series and Review of the Literature.

For patients with tumors of the distal femur, options for limb salvage include tumor resection followed by reconstruction. While reconstruction commonly involves a distal femoral replacement, careful selection of patients with tumor involvement limited to a single condyle may be candidates for reconstruction with distal femur hemiarthroplasty. In these procedures, resection spares considerably more native anatomy. Three consecutive patients who underwent resection and reconstruction at the distal femur with custom unicondylar hemiarthroplasty are presented in this case series at a mean follow-up of 45 months (range, 26-78). In two cases, prostheses were utilized as a secondary procedure after failure of initial reconstruction. In one case, the custom prosthesis was utilized as the primary method of reconstruction. Mean Musculoskeletal Tumor Society disease-specific scores were 26.7 (range, 25-28). All patients achieved a return to full weight bearing, activities of daily living, and functional range of motion. In appropriately selected patients with tumors of the distal femur, reconstruction with custom unicondylar hemiarthroplasty provides benefits including optimal function postoperatively via preservation of tumor-free bone and ligamentous structures. Additionally, maintenance of greater bone stock may confer benefits to patients with pathology at a high likelihood for recurrence and need for subsequent procedures.

The Association Between the Classification of Early-onset Scoliosis and Smith Complications After Initiation of Growth-friendly Spine Surgery: A Preliminary Study.

BACKGROUND: Early-onset scoliosis (EOS) is a complex, heterogeneous condition involving multiple etiologies, genetic associations, and treatment plans. In 2014, Williams and colleagues proposed a classification system of EOS (C-EOS) that categorizes patients by etiology, Cobb angle, and kyphosis. Shortly after, Smith and colleagues validated a classification system to report complications of growth-friendly spine instrumentation. Severity refers to the level of care and urgency required to treat the complication, and can be classified as device-related or disease-related complications. The purpose of this study was to investigate if C-EOS can be used as a reliable predictor of Smith complications to better risk stratify these young, surgical patients. METHODS: This study queried retrospective data from a large multicenter registry with regard to growth-friendly spine instrumentation in the EOS population. One-hundred sixteen patients were included in final data analysis to investigate the outcomes of their growth-friendly procedures according to the Smith complication classification system. RESULTS: There were 245 Smith complications distributed among 116 patients included in this study (2.1 complications per patient). The majority of the complications were device related requiring at least one unplanned trip to the operating room (Smith Device Complication IIA or IIB; 111 complications). There were no complications that caused abandonment of growth-friendly instrumentation (Smith Complication III) and no mortalities (Smith Complication IV). The most severely affected EOS group was the hyperkyphotic syndromic group with a major curve angle >50 degrees (S3+), with 3.4 complications per patient. The least affect EOS group was the hyperkyphotic congenital group with a major curve angle between 20 and 50 degrees, with 0.3 complications per patient. CONCLUSIONS: The C-EOS simplifies a complex pathology and the Smith complication classification scheme creates a language to discuss treatment of known complications of growth-friendly spine surgery. Although there is an association between more advanced C-EOS and Smith complications, there does not appear to be a correlation that can satisfy a risk stratification at this time. LEVEL OF EVIDENCE: Level II.

Paper #45: Development of a Risk Severity Score (RSS) Predicting Surgical Site Infection in Early Onset Scoliosis: Identifying High-Risk Patients.

The RSS was developed to quantify the risk of SSI when considering operative intervention in patients with early onset scoliosis undergoing spinal surgery. The tool includes neuromuscular etiology, myelomeningocele, spinal muscular atrophy, endocrine comorbidity, gastrointestinal comorbidity, pulmonary comorbidity, developmental delay, urinary incontinence, and ventriculoperitoneal shunt as predictive variables. The RSS can improve shared decision making with patients and families during preoperative counseling and aid policy makers and administrators in determining reliable and valid risk-adjusted outcome measures.

Continuing to lift the burden: using a continuous quality improvement approach to advance Aboriginal tobacco resistance and control.

Smoking remains the most preventable cause of early mortality and ill health in Aboriginal people. The Aboriginal Health & Medical Research Council of New South Wales has developed the Aboriginal Tobacco Resistance and Control (ATRAC) Yarning Tool with a range of key stakeholders, to contribute to reducing the prevalence of smoking in Aboriginal communities. The Yarning Tool was adapted from the ATRAC Framework and aims to promote the meaningful discussion, planning and strengthening of tobacco resistance and control activities using a continuous quality improvement (CQI) approach. CQI provides an opportunity to closer align current health service practice with evidence. The Yarning Tool was piloted using focus group testing across four Aboriginal Community Controlled Health Services (ACCHSs) and three Local Health Districts. Purposive sampling was used to ensure that services engaged were from a diverse range of settings, with representation from metropolitan, regional and rural areas, and services with varying degrees of tobacco control capacity. Overall, feedback on the Yarning Tool and its potential use was positive. Pilot participants consistently reported that the Yarning Tool brought staff from a range of positions together to focus on tackling tobacco for the service and community. The pilot participants agreed that the Yarning Tool could be practical for the planning and reviewing stages of a CQI activity, and recommended that the tool should be completed every 6 months. The Yarning Tool is a simple tool to guide the ATRAC Framework principles into practice, and provides a platform to support Aboriginal community-led efforts, and coordination and integration of tobacco control efforts. The tool shows promise as a mechanism to encourage ACCHSs and other relevant services to use a CQI approach to reduce tobacco use in Aboriginal communities.

A library of MiMICs allows tagging of genes and reversible, spatial and temporal knockdown of proteins in Drosophila.

Here, we document a collection of ∼7434 MiMIC (Minos Mediated Integration Cassette) insertions of which 2854 are inserted in coding introns. They allowed us to create a library of 400 GFP-tagged genes. We show that 72% of internally tagged proteins are functional, and that more than 90% can be imaged in unfixed tissues. Moreover, the tagged mRNAs can be knocked down by RNAi against GFP (iGFPi), and the tagged proteins can be efficiently knocked down by deGradFP technology. The phenotypes associated with RNA and protein knockdown typically correspond to severe loss of function or null mutant phenotypes. Finally, we demonstrate reversible, spatial, and temporal knockdown of tagged proteins in larvae and adult flies. This new strategy and collection of strains allows unprecedented in vivo manipulations in flies for many genes. These strategies will likely extend to vertebrates.

Protein tyrosine phosphatase α mediates profibrotic signaling in lung fibroblasts through TGF-ß responsiveness.

Fibrotic lung diseases represent a diverse group of progressive and often fatal disorders with limited treatment options. Although the pathogenesis of these conditions remains incompletely understood, receptor type protein tyrosine phosphatase α (PTP-α encoded by PTPRA) has emerged as a key regulator of fibroblast signaling. We previously reported that PTP-α regulates cellular responses to cytokines and growth factors through integrin-mediated signaling and that PTP-α promotes fibroblast expression of matrix metalloproteinase 3, a matrix-degrading proteinase linked to pulmonary fibrosis. Here, we sought to determine more directly the role of PTP-α in pulmonary fibrosis. Mice genetically deficient in PTP-α (Ptpra(-/-)) were protected from pulmonary fibrosis induced by intratracheal bleomycin, with minimal alterations in the early inflammatory response or production of TGF-ß. Ptpra(-/-) mice were also protected from pulmonary fibrosis induced by adenoviral-mediated expression of active TGF-ß1. In reciprocal bone marrow chimera experiments, the protective phenotype tracked with lung parenchymal cells but not bone marrow-derived cells. Because fibroblasts are key contributors to tissue fibrosis, we compared profibrotic responses in wild-type and Ptpra(-/-) mouse embryonic and lung fibroblasts. Ptpra(-/-) fibroblasts exhibited hyporesponsiveness to TGF-ß, manifested by diminished expression of αSMA, EDA-fibronectin, collagen 1A, and CTGF. Ptpra(-/-) fibroblasts exhibited markedly attenuated TGF-ß-induced Smad2/3 transcriptional activity. We conclude that PTP-α promotes profibrotic signaling pathways in fibroblasts through control of cellular responsiveness to TGF-ß.

Neutrophil transmigration triggers repair of the lung epithelium via beta-catenin signaling.

Injury to the epithelium is integral to the pathogenesis of many inflammatory lung diseases, and epithelial repair is a critical determinant of clinical outcome. However, the signaling pathways regulating such repair are incompletely understood. We used in vitro and in vivo models to define these pathways. Human neutrophils were induced to transmigrate across monolayers of human lung epithelial cells in the physiological basolateral-to-apical direction. This allowed study of the neutrophil contribution not only to the initial epithelial injury, but also to its repair, as manifested by restoration of transepithelial resistance and reepithelialization of the denuded epithelium. Microarray analysis of epithelial gene expression revealed that neutrophil transmigration activated ß-catenin signaling, and this was verified by real-time PCR, nuclear translocation of ß-catenin, and TOPFlash reporter activity. Leukocyte elastase, likely via cleavage of E-cadherin, was required for activation of ß-catenin signaling in response to neutrophil transmigration. Knockdown of ß-catenin using shRNA delayed epithelial repair. In mice treated with intratracheal LPS or keratinocyte chemokine, neutrophil emigration resulted in activation of ß-catenin signaling in alveolar type II epithelial cells, as demonstrated by cyclin D1 expression and/or reporter activity in TOPGAL mice. Attenuation of ß-catenin signaling by IQ-1 inhibited alveolar type II epithelial cell proliferation in response to neutrophil migration induced by intratracheal keratinocyte chemokine. We conclude that ß-catenin signaling is activated in lung epithelial cells during neutrophil transmigration, likely via elastase-mediated cleavage of E-cadherin, and regulates epithelial repair. This pathway represents a potential therapeutic target to accelerate physiological recovery in inflammatory lung diseases.

Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the ß-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of ß-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of ß-catenin signaling and induction of epithelial-mesenchymal transition.

Patient identification errors are common in a simulated setting.

STUDY OBJECTIVE: We evaluate the frequency and accuracy of health care workers verifying patient identity before performing common tasks. METHODS: The study included prospective, simulated patient scenarios with an eye-tracking device that showed where the health care workers looked. Simulations involved nurses administering an intravenous medication, technicians labeling a blood specimen, and clerks applying an identity band. Participants were asked to perform their assigned task on 3 simulated patients, and the third patient had a different date of birth and medical record number than the identity information on the artifact label specific to the health care workers' task. Health care workers were unaware that the focus of the study was patient identity. RESULTS: Sixty-one emergency health care workers participated--28 nurses, 16 technicians, and 17 emergency service associates--in 183 patient scenarios. Sixty-one percent of health care workers (37/61) caught the identity error (61% nurses, 94% technicians, 29% emergency service associates). Thirty-nine percent of health care workers (24/61) performed their assigned task on the wrong patient (39% nurses, 6% technicians, 71% emergency service associates). Eye-tracking data were available for 73% of the patient scenarios (133/183). Seventy-four percent of health care workers (74/100) failed to match the patient to the identity band (87% nurses, 49% technicians). Twenty-seven percent of health care workers (36/133) failed to match the artifact to the patient or the identity band before performing their task (33% nurses, 9% technicians, 33% emergency service associates). Fifteen percent (5/33) of health care workers who completed the steps to verify patient identity on the patient with the identification error still failed to recognize the error. CONCLUSION: Wide variation exists among health care workers verifying patient identity before performing everyday tasks. Education, process changes, and technology are needed to improve the frequency and accuracy of patient identification.

Sequence variants in three loci influence monocyte counts and erythrocyte volume.

Blood cells participate in vital physiological processes, and their numbers are tightly regulated so that homeostasis is maintained. Disruption of key regulatory mechanisms underlies many blood-related Mendelian diseases but also contributes to more common disorders, including atherosclerosis. We searched for quantitative trait loci (QTL) for hematology traits through a whole-genome association study, because these could provide new insights into both hemopoeitic and disease mechanisms. We tested 1.8 million variants for association with 13 hematology traits measured in 6015 individuals from the Australian and Dutch populations. These traits included hemoglobin composition, platelet counts, and red blood cell and white blood cell indices. We identified three regions of strong association that, to our knowledge, have not been previously reported in the literature. The first was located in an intergenic region of chromosome 9q31 near LPAR1, explaining 1.5% of the variation in monocyte counts (best SNP rs7023923, p=8.9x10(-14)). The second locus was located on chromosome 6p21 and associated with mean cell erythrocyte volume (rs12661667, p=1.2x10(-9), 0.7% variance explained) in a region that spanned five genes, including CCND3, a member of the D-cyclin gene family that is involved in hematopoietic stem cell expansion. The third region was also associated with erythrocyte volume and was located in an intergenic region on chromosome 6q24 (rs592423, p=5.3x10(-9), 0.6% variance explained). All three loci replicated in an independent panel of 1543 individuals (p values=0.001, 9.9x10(-5), and 7x10(-5), respectively). The identification of these QTL provides new opportunities for furthering our understanding of the mechanisms regulating hemopoietic cell fate.

Common variants in TMPRSS6 are associated with iron status and erythrocyte volume.

We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5 x 10(-20)), transferrin saturation (combined P = 2.2 x 10(-23)) and erythrocyte mean cell volume (MCV, combined P = 1.1 x 10(-10)). We also find suggestive evidence of association with blood hemoglobin levels (combined P = 5.3 x 10(-7)). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.

Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component.

OBJECTIVE: To conduct in vitro studies as well as a phase 2 clinical trial in patients with smoldering or indolent multiple myeloma to determine if interleukin 1 (IL-1) inhibitors can delay or prevent active myeloma. PATIENTS AND METHODS: Stromal cells were cocultured with IL-1beta-expressing myeloma cells in the presence of dexamethasone, IL-1 receptor antagonist (IL-1Ra), or both. Levels of interleukin 6 (IL-6) and of apoptosis were also quantified. Between November 19, 2002, and May 24, 2007, 47 patients were enrolled in the study and subsequently treated with IL-1Ra. In 25 (53%) of the 47 study patients, low-dose dexamethasone (20 mg/wk) was added. The primary end point was progression-free survival (PFS). RESULTS: In vitro, IL-1Ra was superior to dexamethasone at inhibiting IL-6 production; maximal IL-6 inhibition and apoptosis induction were achieved by addition of both IL-1Ra and dexamethasone. In the clinical trial, 3 patients achieved a minor response to IL-1Ra alone; 5 patients achieved a partial response and 4 patients a minor response after addition of dexamethasone. Seven patients showed a decrease in the plasma cell labeling index that paralleled a decrease in high-sensitivity C-reactive protein (hs-CRP) levels. The median overall PFS was 37.5 months. The median PFS for patients without (n=12) or with (n=35) a greater than 15% decrease in 6-month vs baseline hs-CRP levels was 6 months and more than 3 years, respectively (P=.002). Disease stability was maintained in 8 patients who received therapy for more than 4 years. CONCLUSION: In patients with smoldering or indolent multiple myeloma who were at risk of progression to active myeloma, treatment with IL-1 inhibitors decreased the myeloma proliferative rate and hs-CRP levels in those who responded, leading to a chronic disease state and an improved PFS. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00635154.