Capability After Total Knee Arthroplasty for Osteoarthritis Is Strongly Associated With Preoperative Symptoms of Depression.

BACKGROUND: Primary total knee arthroplasty (TKA) aims to improve the level of capability (ability to perform valued life activities) associated with knee osteoarthritis (OA). However, some evidence suggests a substantial proportion of patients remain dissatisfied with their outcomes after this procedure. We sought to better understand the association between mental health, specifically symptoms of depression, with postoperative outcomes. Symptoms of depression are shown to be common among orthopaedic populations in general and can be briefly and conveniently evaluated using the Patient Health Questionnaire-2 (PHQ-2) in a less burdensome manner compared with longer mental health surveys. This study assesses the association between preoperative depressive symptoms (PHQ-2) and levels of capability at 6 weeks and 6 months after TKA. METHODS: We conducted a prospective cohort study involving 114 patients with knee OA across five clinics in California and Texas scheduled for TKA. Participants completed a preoperative PHQ-2 and Knee Injury and OA Outcome Score for Joint Replacement (KOOS JR) survey at 6 weeks and 6 months post-TKA. We analyzed these data using bivariate and multivariable regression. RESULTS: Preoperative PHQ-2 scores were significantly associated with lower KOOS JR scores at 6 weeks and 6 months post-TKA. Latino/Hispanic race was also associated with lower KOOS JR scores at 6 weeks. The association between preoperative depressive symptoms and level of capability after TKA were more pronounced at 6 months compared with 6 weeks. CONCLUSION: Preoperative symptoms of depression are strongly associated with reduced capability after TKA and can be screened for using the PHQ-2-a brief tool that can be feasibly incorporated into clinical workflows. User-friendly assessment of depressive symptoms can assist orthopaedic surgeons in identifying and addressing mental health at the outset during the management of knee OA.

Effect of a Question-Building Intervention on Patient Activation in Integrated Musculoskeletal Care.

Patient activation, the propensity for patients to engage in adaptive health behaviors, is a modifiable factor associated with health outcomes and treatment compliance. The authors evaluated the effect of a question-building intervention (QBI) on patient activation among patients with musculoskeletal symptoms and a low baseline level of activation. Patients seeking treatment for musculoskeletal pain were recruited at the beginning of their outpatient clinic appointment, and they completed the Patient Activation Measure 10-item version (PAM-10) and a demographic questionnaire. Those identified as low activating, based on the initial PAM-10 scores, completed a QBI protocol before their consultation with their provider. A follow-up PAM-10 survey was administered at the end of the visit. A paired sample Student's t test was used to evaluate preintervention and postintervention PAM-10 scores. Fisher's exact test and an unpaired t test were used to assess the association between demographic variables and achievement of minimal clinically important difference (MCID) for PAM-10. Of 194 patients who consented to participate, 60 were identified as low activating and completed the QBI. A paired Student's t test showed a statistically significant increase in mean PAM-10 scores from preintervention (47.3±7.4) to postintervention (54.8±16.8; P<.001). No statistically significant differences were shown in the likelihood of achieving MCID for PAM-10 scores for the sociodemographic variables that were tested. Low-activating patients may benefit from a simple question-formulating intervention before consultation with an orthopedic provider. [Orthopedics. 2021;44(5):e661-e667.].

PROMIS PF correlates with HOOS, JR in patients with hip pain.

BACKGROUND: Patient-reported outcome measures (PROMs) are increasingly integrated into reporting requirements tied to reimbursement. There may be advantages to computer adaptive tests that apply to many different anatomical regions and diseases, provided that important information is not lost. QUESTIONS: 1) Does the Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS PF) computer adaptive test correlate with the Hip injury and Osteoarthritis Outcome Score for Joint Replacement (HOOS, JR: a hip-specific PROM); 2) Is there any difference in the amount of variation explained by various factors (e.g. age, BMI, presence of concomitant knee pain) for both measures? METHODS: In this prospective, cross-sectional study of 213 patients, we assessed the Pearson correlation of PROMIS PF and HOOS, JR. To investigate the variation explained by various patient-level factors, we constructed two multivariable linear regression models. RESULTS: We found a large correlation between PROMIS PF and HOOS, JR (r 0.58, P < 0.001). Disabled or unemployed status was independently associated with both lower PROMIS PF and HOOS, JR scores (regression coefficient [ß] -3.4; 95% confidence interval [CI] -5.8 to -1.0; P = 0.006 and ß -11; 95% CI -17 to -5.0; P < 0.001, respectively). Private rather than public insurance was associated with both higher PROMIS PF and HOOS, JR scores (ß 4.5; 95% CI 2.2 to 6.8; P < 0.001 and ß 6.4; 95% CI 0.49 to 12; P = 0.034, respectively). No floor or ceiling effects were observed for PROMIS PF. HOOS, JR scores showed 4.2% floor and 0.5% ceiling effect. CONCLUSIONS: This study adds to the evidence that general measures of physical limitations may provide similar information as joint- or region-specific measures. LEVEL OF EVIDENCE: Level III.

Pyriform Costal Cartilage Graft Improves Cleft-Side Alar Asymmetry in Secondary Cleft Rhinoplasty.

OBJECTIVE: The asymmetry of a retrusive cleft-side ala positioned posterior, lateral, and inferior relative to the noncleft ala is exacerbated by ipsilateral deficiency of the pyriform aperture. We describe use of pyriform costal cartilage grafts for enhanced structural foundation and alar symmetry in secondary cleft rhinoplasty. DESIGN: Retrospective case series. PATIENTS: All pyriform aperture paranasal augmentation secondary cleft rhinoplasty cases performed between May 2013 and February 2018 were included. Clinical photos were analyzed, and these results are provided in addition to a detailed description of the augmentation technique. RESULTS: Twelve total cleft patients, 10 (83.3%) unilateral cleft lip and palate, 1 (8.3%) unilateral cleft lip, and 1 cleft palate (8.3%) were included. Age averaged 18.6 ± 6.0 years with 3 (25.0%) males and 9 (75.0%) females. Costal cartilage grafting to the pyriform aperture through the gingivobuccal sulcus was used to reposition the alar base and nasal sill to a more anatomic anterior position, thereby enhancing symmetry in secondary cleft rhinoplasty. Average rib graft donor site incision was 2.5 cm. Follow-up ranged from 3.2 to 48.2 months, average 15.3 ± 14.4 months. No complications related to the pyriform cartilage graft were observed, other than one minor intraoperative breach of parietal pleura. CONCLUSIONS: We observed improvement in the anatomic contour of the cleft-side ala with costal cartilage grafting to the pyriform rim. This resulted in improved cleft-side alar form and thus overall alar symmetry. These results were obtained consistently, without significant complications. This technique is safe and provides a powerful tool to reposition the ala in secondary cleft rhinoplasty. Further studies will quantify the enhancement in nasal base symmetry.

Patient-Reported Outcome Measures and Patient Activation: What Are Their Roles in Orthopedic Trauma?

The rise of patient-reported outcome (PRO) measurement across medicine has been swift and now extends to the world of orthopedic trauma. However, PRO measures (PROMs) applied to trauma patients pose special considerations; measuring "episodes of care" is less straightforward, injuries are heterogeneous in their severity, and the patient's initial visit is "postinjury." Obtaining baseline scores and assessing the impact of a traumatic event on mental health are key considerations. Currently, few, if any, trauma registries include PROs; though general and condition-specific PROMs plus the patient empowerment measure of Patient Activation represent meaningful inputs for the clinical decision-making process. To be useful in trauma care, PROMs should be psychometrically sound and validated, be used for capturing function, screen for mental state and substance use, and give the clinician a sense of the patient's "activation" (engagement in their own health). Although the implementation of routine PRO collection can seem daunting, clinicians can use a multitude of electronic resources to access validated measures and simplify the implementation process. Computer-adaptive testing has evolved to help minimize patient burden, and PROM collection must maximize efficiency. Once established as part of your practice, PROs become an important tool to track recovery, identify mental health issues, engage in the prevention of future injury, and enable care of the whole patient.

Integrated Practice Units: What Are They and How Can They Be Applied to Orthopaedic Trauma?

Musculoskeletal professionals are looking for opportunities to provide integrated patient-centered models of care. Integrated practice units (IPUs) are structurally and functionally organized around the patient's medical condition over a full cycle of care with a comprehensive range of services delivered by dedicated multidisciplinary teams. Although IPUs have been developed for chronic orthopaedic conditions, such as hip and knee osteoarthritis, relatively little has been explored in relation to orthopaedic trauma. Development of novel IPUs for managing musculoskeletal injuries may help surgeons to better contend with the substantial burden associated with these conditions on the quality of life of individual patients and society at large. This review explores the challenges and unmet needs unique to orthopaedic trauma that could be bridged by high-value, integrated patient-centered models of care. It also provides a framework for the design and implementation of IPUs and the rationale of this framework in 3 major populations: ambulatory trauma, fragility fractures, and complex polytrauma. To conclude, in this review, we consider the mechanism and impact of alternative payment models in this setting.

Global Contributions to Aesthetic Surgery Journal Over the Past Decade.

BACKGROUND: The Aesthetic Surgery Journal (ASJ) is a world-renowned publication with valuable contributions from around the globe. OBJECTIVES: To better characterize the journal's evolving representation of global contributions to aesthetic surgery, the authors examined the author affiliations of all articles published in ASJ over the last decade. METHODS: A PubMed search was performed for all journal articles published in ASJ from January 2008 to August 2018. For each article, the first author's primary affiliation as indexed in MEDLINE was recorded as the source country. Data were tabulated by source country and year. The authorless errata, corrigenda, and Cosmetic Surgery National Data Bank Statistics were excluded from analysis. RESULTS: A total of 1746 articles were published during this period, contributed from 49 distinct countries. All continents other than Antarctica were represented. Higher income countries where aesthetic surgery is more prevalent produced 87% of published articles. The total number of published articles in ASJ has climbed from 77 annually in 2008 to 318 in 2018 as of August. In 2008, 27.3% of articles were from non-US countries, whereas in 2018 this increased to 43.7%. In particular, Turkey, the United Kingdom, Australia, Brazil, and Italy demonstrate steady increases in contributions over the 10-year period. CONCLUSIONS: Publications in ASJ have increased in number over the past decade, and the journal has become increasingly global in its network of contributing authors. The increased global contribution to the ASJ may enhance readers' experience both in the United States and in the world beyond.

δ-Opioid receptor activation modified microRNA expression in the rat kidney under prolonged hypoxia.

Hypoxic/ischemic injury to kidney is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs are differentially involved in hypoxic/ischemic events and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering the microRNA (miRNA) expression in kidney under hypoxic condition. We selected 31 miRNAs based on microarray data for quantitative PCR analysis. Among them, 14 miRNAs were significantly altered after prolonged hypoxia, DOR activation or a combination of both. We found that 1) DOR activation alters miRNA expression profiles in normoxic conditions; 2) hypoxia differentially alters miRNA expression depending on the duration of hypoxia; and 3) DOR activation can modify hypoxia-induced changes in miRNA expression. For example, 10-day hypoxia reduced the level of miR-212 by over 70%, while DOR activation could mimic such reduction even in normoxic kidney. In contrast, the same stress increased miR-29a by >100%, which was reversed following DOR activation. These first data suggest that hypoxia comprehensively modifies the miRNA profile within the kidney, which can be mimicked or modified by DOR activation. Ascertaining the targeted pathways that regulate the diverse cellular and molecular functions of miRNA may provide new insights into potential therapies for hypoxic/ischemic injury of the kidney.

The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p-glycoprotein-mediated drug resistance in the injured spinal cord.

There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. Pathological Pgp upregulation in diseases such as cancer causes heightened resistance to a broad variety of therapeutic drugs. Importantly, several drugs that have been evaluated for the treatment of SCI, such as riluzole, are known substrates of Pgp. We therefore examined whether Pgp-mediated pharmacoresistance diminishes delivery of riluzole to the injured spinal cord. Following moderate contusion injury at T10 in male Sprague-Dawley rats, we observed a progressive, spatial spread of increased Pgp expression from 3 days to 10 months post-SCI. Spinal cord uptake of i.p.-delivered riluzole was significantly reduced following SCI in wild type but not Abcb1a-knockout rats, highlighting a critical role for Pgp in mediating drug resistance following SCI. Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord.

δ-opioid receptor activation and microRNA expression of the rat cortex in hypoxia.

Prolonged hypoxic/ischemic stress may cause cortical injury and clinically manifest as a neurological disability. Activation of the δ-opioid receptor (DOR) may induce cortical protection against hypoxic/ischemic insults. However, the mechanisms underlying DOR protection are not clearly understood. We have recently found that DOR activation modulates the expression of microRNAs (miRNAs) in the kidney exposed to hypoxia, suggesting that DOR protection may involve a miRNA mechanism. To determine if the miRNAs expressed in the cortex mediated DOR neuroprotection, we examined 19 miRNAs that were previously identified as hypoxia- and DOR-regulated miRNAs in the kidney, in the rat cortex treated with UFP-512, a potent and specific DOR agonist under hypoxic condition. Of the 19 miRNAs tested, 17 were significantly altered by hypoxia and/or DOR activation with the direction and amplitude varying depending on hypoxic duration and times of DOR treatment. Expression of several miRNAs such as miR-29b, -101b, -298, 324-3p, -347 and 466b was significantly depressed after 24 hours of hypoxia. Similar changes were seen in normoxic condition 24 hours after DOR activation with one-time treatment of UFP-512. In contrast, some miRNAs were more tolerant to hypoxic stress and showed significant reduction only with 5-day (e.g., miR-31 and -186) or 10-day (e.g., miR-29a, let-7f and -511) exposures. In addition, these miRNAs had differential responses to DOR activation. Other miRNAs like miRs-363* and -370 responded only to the combined exposure to hypoxia and DOR treatment, with a notable reduction of >70% in the 5-day group. These data suggest that cortical miRNAs are highly yet differentially sensitive to hypoxia. DOR activation can modify, enhance or resolve the changes in miRNAs that target HIF, ion transport, axonal guidance, free radical signaling, apoptosis and many other functions.

Spinal cord injury causes sustained disruption of the blood-testis barrier in the rat.

There is a high incidence of infertility in males following traumatic spinal cord injury (SCI). Quality of semen is frequently poor in these patients, but the pathophysiological mechanism(s) causing this are not known. Blood-testis barrier (BTB) integrity following SCI has not previously been examined. The objective of this study was to characterize the effects of spinal contusion injury on the BTB in the rat. 63 adult, male Sprague Dawley rats received SCI (n = 28), laminectomy only (n = 7) or served as uninjured, age-matched controls (n = 28). Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), BTB permeability to the vascular contrast agent gadopentate dimeglumine (Gd) was assessed at either 72 hours-, or 10 months post-SCI. DCE-MRI data revealed that BTB permeability to Gd was greater than controls at both 72 h and 10 mo post-SCI. Histological evaluation of testis tissue showed increased BTB permeability to immunoglobulin G at both 72 hours- and 10 months post-SCI, compared to age-matched sham-operated and uninjured controls. Tight junctional integrity within the seminiferous epithelium was assessed; at 72 hours post-SCI, decreased expression of the tight junction protein occludin was observed. Presence of inflammation in the testes was also examined. High expression of the proinflammatory cytokine interleukin-1 beta was detected in testis tissue. CD68(+) immune cell infiltrate and mast cells were also detected within the seminiferous epithelium of both acute and chronic SCI groups but not in controls. In addition, extensive germ cell apoptosis was observed at 72 h post-SCI. Based on these results, we conclude that SCI is followed by compromised BTB integrity by as early as 72 hours post-injury in rats and is accompanied by a substantial immune response within the testis. Furthermore, our results indicate that the BTB remains compromised and testis immune cell infiltration persists for months after the initial injury.

Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century.

OBJECTIVES: To provide a review of the world literature and discuss the clinical role of subcutaneous immunoglobulin (SCIG) therapy for primary antibody deficiency. DATA SOURCES: English-language publications on SCIG therapy were identified through MEDLINE and through the reference list of the initially identified publications. STUDY SELECTION: Articles pertaining to SCIG for the treatment of immunodeficiency, particularly primary antibody deficiency, were selected. RESULTS: SCIG therapy has been shown to be effective and safe for the treatment of primary immunodeficiency. The risk of systemic reactions during infusion is generally reported to be less than 1%. Many patients prefer SCIG over conventional intravenous immunoglobulin therapy because of increased convenience and independence associated with SCIG therapy. Publications show SCIG therapy to be advantageous in selected patient populations, such as children, pregnant women, and patients with poor intravenous access. CONCLUSION: SCIG therapy has been widely used in some European countries for a number of years, but a Food and Drug Administration-approved product was only recently introduced into the United States in 2006. SCIG therapy offers unique advantages that are applicable to many patients receiving immunoglobulin therapy for primary immunodeficiency.

Transfection of cultured eukaryotic cells using cationic lipid reagents.

The development of high-efficiency methods for the introduction of functional genetic material into eukaryotic cells using cationic lipids has accelerated biological research in the studies of gene expression, control of cell growth, and cell lineage. Transfection mediated by cationic lipids is commonly used in industrial protein production as well as in some clinical gene therapy protocols. This unit describes how to perform transfection of adherent and suspension cells, insect cells, and RNA transfection using cationic lipid reagents.

A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development.

The cardiac conduction system is an anatomically discrete segment of specialized myocardium that initiates and propagates electrical impulses to coordinate myocardial contraction. To define the molecular composition of the mouse ventricular conduction system we used microdissection and transcriptional profiling by serial analysis of gene expression (SAGE). Conduction-system-specific expression for Id2, a member of the Id gene family of transcriptional repressors, was identified. Analyses of Id2-deficient mice demonstrated structural and functional conduction system abnormalities, including left bundle branch block. A 1.2 kb fragment of the Id2 promoter proved sufficient for cooperative regulation by Nkx2-5 and Tbx5 in vitro and for conduction-system-specific gene expression in vivo. Furthermore, compound haploinsufficiency of Tbx5 and Nkx2-5 or Tbx5 and Id2 prevented embryonic specification of the ventricular conduction system. We conclude that a molecular pathway including Tbx5, Nkx2-5, and Id2 coordinates specification of ventricular myocytes into the ventricular conduction system lineage.

Upstream stimulatory factor represses the induction of carnitine palmitoyltransferase-Ibeta expression by PGC-1.

Transcriptional regulation of carnitine palmitoyltransferase-1beta (CPT-1beta) is coordinated with contractile gene expression through cardiac-enriched transcription factors, GATA4 and SRF. Metabolic modulation of CPT-1beta promoter activity has been described with the stimulation of gene expression by oleate that is mediated through the peroxisome proliferator-activated receptor (PPAR) pathway. The coactivator, peroxisomal proliferator-activated receptor gamma coactivator (PGC-1), enhances gene expression through interactions with nuclear hormone receptors and the myocyte enhancer factor 2 (MEF2) family. PGC-1 and MEF2A synergistically activate CPT-1beta promoter activity. This stimulation is enhanced by mutation of the E-box sequences that flank the MEF2A binding site. These elements bind the upstream stimulatory factors (USF1 and USF2), which activate transcription in CV-1 fibroblasts. However, overexpression of the USF proteins in myocytes depresses CPT-1beta activity and significantly reduces MEF2A and PGC-1 synergy. Co-immunoprecipitation studies demonstrate that PGC-1 and USF2 proteins can physically interact. Our studies demonstrate that PGC-1 stimulates CPT-1beta gene expression through MEF2A. USF proteins have a novel role in repressing the expression of the CPT-1beta gene and modulating the induction by the coactivator, PGC-1.

A region in the first exon/intron of rat carnitine palmitoyltransferase Ibeta is involved in enhancement of basal transcription.

Carnitine palmitoyltransferase-Ibeta (CPT-Ibeta) catalyses the transfer of long-chain fatty acids to the enzymes of beta-oxidation of muscle and heart. Transcriptional control of this regulatory protein is relevant to disorders of fatty acid oxidation and the switch to glucose metabolism that occurs in cardiac pathology. The presence of a transcriptional enhancer sequence in the first untranslated exon and first intron of the CPT-Ibeta gene was identified using deletional and mutational analysis, and by ligation of an oleate responsive element (fatty acid response element) to a minimal promoter. The enhancer sequences are contained in the first 40 bases downstream of the transcription start site and increase CPT-Ibeta reporter gene expression independent of any 5' cis-acting elements. Deletion of the first 40 bases of the 3'-untranslated region does not affect the up-regulation of transcription by 10 microM phenylephrine. However, mutation and/or deletion of bases between +11 and +30 dramatically decreases reporter gene expression. Electrophoretic mobility-shift assays reveal two DNA (+11 to +36)-protein complexes that appear cardiac specific. The exon/intron element enhances activation of the heterologous thymidine kinase promoter in a position- and orientation-dependent manner. Therefore we have identified a novel region in the first exon/intron of the CPT-Ibeta gene that acts as a non-classical transcriptional enhancer downstream of regulatory elements characterized previously in the 5'-flanking region of the minimal promoter.