Aged skeletal stem cells generate an inflammatory degenerative niche.

Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.

Failed 2-Stage Revision Knee Arthroplasty for Periprosthetic Joint Infection-Patient Characteristics and Outcomes.

BACKGROUND: Chronic prosthetic joint infection (PJI) is most frequently treated with 2-stage revision in conjunction with antibiotic treatment. The aims of this study were 1) to investigate the characteristics of patients who have recurrent infection following 2-stage revision for PJI and 2) to identify risk factors associated with treatment failure. METHODS: A multicenter retrospective review of 90 total knee arthroplasty (TKA) patients who underwent 2-stage revision for treatment of PJI from March 1, 2003 to July 31, 2019, and had recurrent PJI was conducted. The minimum follow-up was 12 months (median follow up of 2.4 years). Microorganisms, subsequent revision, PJI control status, and final joint status were collected. The infection-free survival after initial 2-stage revision was plotted utilizing the Kaplan-Meier method. RESULTS: Mean survival time to reinfection was 21.3 months (range, 0.3 to 160.5). There were 14 recurrent infections that were acute PJIs treated with debridement, antibiotics, and implant retention (DAIR), while 76 were chronic and treated with repeat 2-stage revision. The most common pathogen identified for both index and recurrent PJI was coagulase-negative Staphylococci. Pathogen persistence was observed in 14 (22.2%) of recurrent PJIs. In total, 61 (67.8%) patients possessed a prosthetic reimplantation at their most recent follow-up, and 29 (35.6%) patients required intervention following repeat 2-stage. CONCLUSION: Overall, 31.1% of the patients obtained infection control after treatment of a failed 2-stage revision due to PJI. The high rate of pathogen persistence and the relatively low survival time to recurrence suggests a need to more closely monitor PJIs cases within 2 years.

What Are the Functional Outcomes and Pain Scores after Medial Clavicle Fracture Treatment?

BACKGROUND: Medial clavicle fractures are uncommon, occurring in older and multiply injured patients. The management of these fractures and the factors that predispose toward poor outcomes are controversial. Furthermore, the functional outcomes of treatment are not well characterized or correlated with fracture patterns. QUESTIONS/PURPOSES: (1) To determine minimum 1-year functional outcomes using QuickDASH scores and pain scores after medial clavicle fractures and (2) to identify factors associated with these outcome variables. METHODS: In an institutional review board-approved, retrospective study, we identified adult patients with medial clavicle fractures at two tertiary care referral centers in a single metropolitan area in the United States from January 2010 to March 2019. Our initial query identified 1950 patients with clavicle fractures, from which 74 adult patients with medial clavicle fractures and at least 1 year of follow-up were identified. We attempted to contact these eligible patients by telephone for functional outcomes and pain scores. Twenty-six patients were deceased according to the most recent Social Security Death Index data and public obituaries, three declined participation, and 14 could not be reached, leaving 42% of the total (31 of 74) and 65% (31 of 48) of living patients included in the analysis. Demographic characteristics, fracture characteristics, and clinical and radiographic union as assessed by plain radiography and CT were collected through record review. Twenty-nine patients were treated nonoperatively and two patients underwent open reduction internal fixation. Sixty-eight percent (21 of 31) of the included patients also had radiographic follow-up at least 6 weeks postoperatively; two patients had persistent nonunion at a mean of 5 ± 3 years after injury. Our primary response variable was the QuickDASH score at a minimum of 1 year (median [range] 5 years [2 to 10]). Our secondary response variable was the pain score on a 10-point Likert scale. A bivariate analysis was performed to identify factors associated with these response variables. The following explanatory variables were studied: age, gender, race, dominant hand injury, employment status, manual labor occupation, primary health insurance, social deprivation, BMI, diabetes mellitus, smoking status, American Society of Anesthesiologists physical status classification, Charlson Comorbidity Index, nonisolated injury, high-energy mechanism of injury, nondisplaced fracture, fracture comminution, superior-inferior fracture displacement, medial-lateral fracture shortening, and surgical treatment of the medial clavicle fracture. RESULTS: The mean QuickDASH score was 12 ± 15, and the mean pain score was 1 ± 1 at a mean of 5 ± 3 years after injury. The mortality rate of the cohort was 15% (11 of 74) at 1 year, 22% (16 of 74) at 3 years, and 34% (25 of 74) at 5 years after injury. With the numbers available, no factors were associated with the QuickDASH score or pain score, but it is likely we were underpowered to detect potentially important differences. CONCLUSION: Medial clavicle fractures have favorable functional outcomes and pain relief at minimum 1-year follow-up among those patients who survive the trauma, but a high proportion will die within 3 years of the injury. This likely reflects both the frailty of a predominantly older patient population and the fact that these often are high-energy injuries. The outcome measures in our cohort were not associated with fracture displacement, shortening, or comminution; however, our sample size was underpowered on these points, and so these findings should be considered preliminary. Further studies are needed to determine the subset of patients with this injury who would benefit from surgical intervention. LEVEL OF EVIDENCE: Level IV, therapeutic study.

A triple helix stabilizes the 3' ends of long noncoding RNAs that lack poly(A) tails.

The MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) locus is misregulated in many human cancers and produces an abundant long nuclear-retained noncoding RNA. Despite being transcribed by RNA polymerase II, the 3' end of MALAT1 is produced not by canonical cleavage/polyadenylation but instead by recognition and cleavage of a tRNA-like structure by RNase P. Mature MALAT1 thus lacks a poly(A) tail yet is expressed at a level higher than many protein-coding genes in vivo. Here we show that the 3' ends of MALAT1 and the MEN ß long noncoding RNAs are protected from 3'-5' exonucleases by highly conserved triple helical structures. Surprisingly, when these structures are placed downstream from an ORF, the transcript is efficiently translated in vivo despite the lack of a poly(A) tail. The triple helix therefore also functions as a translational enhancer, and mutations in this region separate this translation activity from simple effects on RNA stability or transport. We further found that a transcript ending in a triple helix is efficiently repressed by microRNAs in vivo, arguing against a major role for the poly(A) tail in microRNA-mediated silencing. These results provide new insights into how transcripts that lack poly(A) tails are stabilized and regulated and suggest that RNA triple-helical structures likely have key regulatory functions in vivo.

Can Patients Forecast Their Postoperative Disability and Pain?

BACKGROUND: Forecasting is a construct in which experiences and beliefs inform a projection of future outcomes. Current efforts to predict postoperative patient-reported outcome measures such as risk-stratifying models, focus on studying patient, surgeon, or facility variables without considering the mindset of the patient. There is no evidence assessing the association of a patient's forecasted postoperative disability with realized postoperative disability. Patient-forecasted disability could potentially be used as a tool to predict postoperative disability. QUESTIONS/PURPOSES: (1) Do patient-forecasted disability and pain correlate with patient-realized disability and pain after hand surgery? (2) What other factors are associated with patient ability to forecast disability and pain? METHODS: We completed a prospective, longitudinal study to assess the association between forecasted and realized postoperative pain and disability as a predictive tool. One hundred eighteen patients of one hand/upper extremity surgeon were recruited from November 2016 to February 2018. Inclusion criteria for the study were patients undergoing hand or upper extremity surgery, older than 18 years of age, and English fluency and literacy. We enrolled 118 patients; 32 patients (27%) dropped out as a result of incomplete postoperative questionnaires. The total number of patients eligible was not tracked. Eighty-six patients completed the preoperative and postoperative questionnaires. Exclusion criteria included patients unable to give informed consent, children, patients with dementia, and nonEnglish speakers. Before surgery, patients completed a questionnaire that asked them to forecast their upper extremity disability (DASH [the shortened Disabilities of the Arm, Shoulder and Hand] [QuickDASH]) and pain VAS (pain from 0 to 10) for 2 weeks after their procedure. The questionnaire also queried the following psychologic factors as explanatory variables, in addition to other demographic and socioeconomic variables: the General Self Efficacy Scale, the Pain Catastrophizing Scale, and the Patient Health Questionnaire Depression Scale. At the 2-week followup appointment, patients completed the QuickDASH and pain VAS to assess their realized disability and pain scores. Bivariate analysis was used to test the association of forecasted and realized disability and pain reporting Pearson correlation coefficients. Unpaired t-tests were performed to test the association of demographic variables (for example, men vs women) and the association of forecasted and realized disability and pain levels. One-way analysis of variance was used for variables with multiple groups (for example, annual salary and ethnicity). All p values < 0.05 were considered statistically significant. RESULTS: Forecasted postoperative disability was moderately correlated with realized postoperative disability (r = 0.59; p < 0.001). Forecasted pain was weakly correlated with realized postoperative pain (r = 0.28; p = 0.011). A total of 47% of patients (n = 40) were able to predict their disability score within the MCID of their realized disability score. Symptoms of depression also correlated with increased realized postoperative disability (r = 0.37; p < 0.001) and increased realized postoperative pain (r = 0.42; p < 0.001). Catastrophic thinking was correlated with increased realized postoperative pain (r = 0.31; p = 0.004). Patients with symptoms of depression realized greater pain postoperatively than what they forecasted preoperatively (r = -0.24; p = 0.028), but there was no association between symptoms of depression and patients' ability to forecast disability (r = 0.2; p = 0.058). Patient age was associated with a patient's ability to forecast disability (r = .27; p = 0.011). Catastrophic thinking, self-efficacy, and number of prior surgical procedures were not associated with a patient's ability to forecast their postoperative disability or pain. CONCLUSIONS: Patients undergoing hand surgery can moderately forecast their postoperative disability. Surgeons can use forecasted disability to identify patients who may experience greater disability compared with benchmarks, for example, forecast and experience high QuickDASH scores after surgery, and inform preoperative discussions and interventions focused on expectation management, resilience, and mindset. LEVEL OF EVIDENCE: Level III, prognostic study.

The Role of Patient Research in Patient Trust in Their Physician.

PURPOSE: Trust is foundational to the patient-physician relationship. However, there is limited information on the patient characteristics and behaviors that are related to patient trust. We investigated whether the time patients spend researching their physician and/or symptoms before a clinic visit was correlated with patient trust in their hand surgeon. METHODS: We conducted a prospective study of new patients (n = 134) who presented to a hand surgery clinic. We tested the null hypothesis that time spent researching the physician or symptom does not correlate with physician trust. Secondarily, we tested the association of a maximizing personality (a decision-making personality type defined as one who exhaustively searches for the "best option" as opposed to a "satisficer" who settles for the "good enough" decision) with time spent researching the hand surgeon and patient symptoms, general self-efficacy (one's ability to manage adversity), and patient trust. Patients completed a questionnaire assessing demographics, patient researching behavior, general self-efficacy (GSE-6), maximizing personality (Maximization Short Form), and physician trust (Trust in Physician Form). RESULTS: The average age of our cohort was 50 ± 17 years, and men and women were equally represented. Patients spent more time researching their symptoms (median, 60 min; range, 5-1,201 min) than they did researching their physician (median, 20 min; range, 1-1,201 min). There was no correlation between time spent by patients seeking information on their hand surgeon and/or symptoms with patient trust in their physician. However, female patients were significantly more trusting of their physician than male patients. CONCLUSIONS: Most patients research their symptoms before clinic, whereas about half research their physicians before meeting them. Time spent seeking information before clinic was not correlated with patient trust in their physician. However, in our study, female patients were more likely to trust their hand surgeon than male patients. Thus, modifying physician behavior rather than patient characteristics may be a stronger driver of patient trust. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an "on-demand" drug delivery system to modulate inflammation.

Chronic inflammation is associated with up-regulation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and excessive inflammatory cytokine secretion by M1 macrophages. The anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory and tissue-regenerative M2 phenotype, thus reducing inflammation and enhancing tissue regeneration. We have generated NF-κB responsive, or constitutively active IL-4 expression lentiviral vectors transduced into murine bone marrow-derived mesenchymal stromal cells (MSCs). MSCs with a constitutively active IL-4 expression vector produced large quantities of IL-4 continuously, whereas IL-4 secretion was significantly induced by lipopolysaccharide (LPS) in the NF-κB sensing MSCs. In contrast, LPS had no effect on MSCs with IL-4 secretion driven by a constitutively active promoter. We also found that intermittent and continuous LPS treatment displayed distinct NF-κB activation profiles, and this regulation was independent of IL-4 signaling. The supernatant containing IL-4 from the LPS-treated MSCs suppressed M1 marker (inducible nitric oxide synthase [iNOS] and tumor necrosis factor alpha [TNFα]) expression and enhanced M2 marker (Arginase 1, CD206 and IL1 receptor antagonist [IL1Ra]) expression in primary murine macrophages. The IL-4 secretion at the basal, non-LPS induced level was sufficient to suppress TNFα and enhance Arginase 1 at a lower level, but had no significant effects on iNOS, CD206 and IL1Ra expression. Finally, IL-4 secretion at basal or LPS-induced levels significantly suppressed osteogenic differentiation of MSCs. Our findings suggest that the IL-4 secreting MSCs driven by NF-κB sensing or constitutive active promoter have great potential for mitigating the effects of chronic inflammation and promoting earlier tissue regeneration.

Safety Factors and Patterns of Bicycle Trauma in a Tertiary Level 1 Trauma Center in Boston, Massachusetts: A Retrospective Review and Survey Study.

Objectives: Increasing bicycle ridership is accompanied by ongoing bicycle-related accidents in many urban cities. There is a need for improved understanding of patterns and risks of urban bicycle usage. We describe the injuries and outcomes of bicycle-related trauma in Boston, Massachusetts, and determine accident-related factors and behaviors associated with injury severity. Methods: We conducted a retrospective review via chart review of 313 bicycle-related injuries presenting to a Level 1 trauma center in Boston, Massachusetts. These patients were also surveyed regarding accident-related factors, personal safety practices, and road and environmental conditions during the accident. Results: Over half of all cyclists biked for commuting and recreational purposes (54%), used a road without a bike lane (58%), and a majority wore a helmet (91%). The most common injury pattern involved the extremities (42%) followed by head injuries (13%). Bicycling for commuting rather than recreation, cycling on a road with a dedicated bicycle lane, the absence of gravel or sand, and use of bicycle lights were all factors associated with decreased injury severity (p<0.05). After any bicycle injury, the number of miles cycled decreased significantly regardless of cycling purpose. Conclusion: Our results suggest that physical separation of cyclists from motor vehicles via bicycle lanes, regular cleaning of these lanes, and usage of bicycle lights are modifiable factors protective against injury and injury severity. Safe bicycling practices and understanding of factors involved in bicycle-related trauma can reduce injury severity and guide effective public health initiatives and urban planning.

Testing in a Prespecified Subgroup and the Intent-to-Treat Population.

In many settings, testing has been proposed to assess the effect of an experimental regimen within a biomarker-positive subgroup where it is biologically plausible that benefit is stronger in such patients, and in the overall population that also includes biomarker-negative subjects less likely to benefit from that regimen. A statistically favorable result in the biomarker-positive subgroup would lead to a claim for that subgroup, whereas a statistically favorable result for the overall population would lead to a claim that includes both biomarker subgroups. The latter setting is problematic when biomarker-negative patients truly do not benefit from the experimental regimen. When it is prespecified that biomarker-negative patients should not be included in the primary analysis of treatment effect in biomarker-positive patients because of the likelihood that treatment effects would differ between the 2 subgroups, it is logically inconsistent to include biomarker-positive patients in the primary analysis of treatment effect in biomarker-negative patients.

A Physician Assistant Is Associated With Higher Patient Satisfaction With Outpatient Orthopedic Surgery.

Patient satisfaction is increasingly used to assess the quality of care and determine physician reimbursement. Patient characteristics influence patient satisfaction, but the effect of physician practice parameters on satisfaction has not been studied in detail. Outpatient satisfaction scores from 11,059 patients who rated 24 orthopedic surgeons from a single institution were studied. Practice-related parameters were collected in a provider-reported survey. Univariate logistic regressions were used to test the associations between each provider characteristic and the likelihood of receiving a 5-star rating on a selection of 16 Press Ganey patient satisfaction questions. The presence of a physician assistant in the clinic positively affected the 5-star rating for all but 1 of the patient satisfaction questions examined, including overall satisfaction (odds ratio [OR], 1.38; 95% CI, 1.03-1.85; P=.031); the likelihood of being recommended to others (OR, 1.57; 95% CI, 1.16-2.14; P=.004); and friendliness/courtesy (OR, 1.58; 95% CI, 1.17-2.13; P=.003). However, having a fellow or nurse practitioner in the clinic, treating children, productivity (measured as total relative value units), taking trauma call, and provider distance from home were not associated with higher scores for any of the Press Ganey patient satisfaction questions. Having a physician assistant in the clinic is an actionable, practice-specific characteristic that positively affects patient satisfaction on many levels and may ultimately improve the perception of care. [Orthopedics. 2022;45(5):e252-e256.].

Selecting the Next Class: The "Virtual Orthopaedic Rotation".

INTRODUCTION: When the COVID-19 pandemic forced the cancellation of visiting subinternships, we pivoted to create a virtual orthopaedic rotation (VOR). The purpose of this study was to assess the effect of the VOR on the residency selection process and determine the role of such a rotation in the future. METHODS: A committee was convened to create a VOR to replace visiting orthopaedic rotations for medical students who are interested in pursuing a career in orthopaedic surgery. The VOR was reviewed and sanctioned by our medical school, but no academic credit was granted. We conducted three 3-week VOR sessions. During each session, virtual rotators participated in regularly scheduled educational conferences and attended an invitation-only daily conference in the evenings that was designed for a medical student audience. In addition, students were paired with faculty and resident mentors in a structured mentorship program. Students' orthopaedic knowledge was assessed using prerotation and postrotation tests. RESULTS: From July to September 2020, 61 students from 37 distinct medical schools participated in the VOR. Notable improvements were observed in prerotation and postrotation orthopaedic knowledge test scores. In postrotation surveys, both students and faculty expressed high satisfaction with the curriculum but less certainty about how well they got to know each other. In the subsequent residency application cycle, 27.9% of the students who participated in the VOR were selected to interview, compared with 8.7% of the total application pool. DISCUSSION: The VOR was a valuable substitute for in-person clinical rotations during the COVID-19 pandemic. Although not likely to be a replacement for conventional away rotations, the VOR is a possible adjunct to in-person clinical rotations in the future.

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in µm), crypt depth (CrD, in µm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Musculoskeletal Education in Medical Schools: a Survey in California and Review of Literature.

INTRODUCTION: Though musculoskeletal complaints account for roughly one-quarter of primary care and emergency department visits, only 2% of US medical school curriculum is devoted to musculoskeletal disease. Many graduating students demonstrate poor knowledge and report low confidence in treating musculoskeletal disorders. This study defines the current state of musculoskeletal curriculum of medical schools in detail to identify variations and potential shortcomings. METHODS: All eleven medical schools in California were invited to participate in an in-depth survey detailing the design and content of their musculoskeletal curriculum. RESULTS: A response rate of 100% was achieved. Overall, schools devoted an average of 58.7 h to musculoskeletal medicine, of which more than half was spent covering anatomy. The primary instructor for musculoskeletal medicine was a clinician in four schools (36.4%). Six schools offered a dedicated musculoskeletal physical exam course. No schools required students to complete a clinical rotation in musculoskeletal medicine. There was high variability among institutions when evaluating core subject coverage. DISCUSSION: There is large variation in the content and structure of musculoskeletal instruction among California medical schools. Increased curricular time, integration of preclinical and clinical experiences, greater specialist participation, and standardized objectives may provide more consistent and comprehensive musculoskeletal education. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-020-01144-3.

Do-Not-Resuscitate status is an independent risk factor for medical complications and mortality among geriatric patients sustaining hip fractures.

BACKGROUND: The purpose of this study was to compare outcomes after hip fracture surgery between DNR/DNI and full code cohorts to determine whether DNR/DNI status is an independent predictor of complications and mortality within one year. A significant number of geriatric hip fracture patients carry a code status designation of DNR/DNI (Do-Not-Resuscitate/Do-Not-Intubate). There is limited data addressing how this designation may influence prognosis. METHODS: A retrospective chart review of all geriatric hip fractures treated between 2002 and 2017 at a single level-I academic trauma center was performed. 434 patients were eligible for this study with 209 in the DNR/DNI cohort and 225 in the full code cohort. The independent variable was code-status and dependent variables included patient demographics, surgery performed, American Society of Anesthesiologists, score, Charlson Comorbidity Index, significant medical and surgical complications within one year of surgery, duration of follow-up by an orthopaedic surgeon, duration of follow-up by any physician, and mortality within 1 year of surgery. One-year complication rates were compared, and multiple logistic regression analyses were performed to analyze the relationship between independent and dependent variables. RESULTS: The DNR/DNI cohort experienced significantly more surgical complications compared to the full code cohort (14.8% vs 7.6%, p = 0.024). There was a significantly higher rate of medical complications and mortality in the DNR/DNI cohort (57.9% vs 36%, p < 0.001 and 19.1% vs 3.1%, p = 0.037, respectively). In the regression analysis, DNR/DNI status was an independent predictor of a medical complication (odds ratio 2.33, p = 0.004) and one-year mortality (odds ratio 9.69, p < 0.001), but was not for a surgical complication (OR 1.95, p = 0.892). CONCLUSIONS: In our analysis, DNR/DNI code status was an independent risk factor for postoperative medical complications and mortality within one year following hip fracture surgery. The results of our study highlight the need to recognize the relationship between DNR/DNI designation and medical frailty when treating hip fractures in the elderly population.

Provider Personal and Demographic Characteristics and Patient Satisfaction in Orthopaedic Surgery.

INTRODUCTION: Patient satisfaction has increasingly been used to assess physician performance and quality of care. Although there is evidence that patient satisfaction is associated with patient-reported health outcomes and communication-related measures, there is debate over the use of patient satisfaction in reimbursement policy. Patient characteristics that influence satisfaction have been studied, but the effects of personal and demographic characteristics of physicians on patient satisfaction have yet to be explored. METHODS: Outpatient satisfaction scores from 11,059 patients who rated 25 orthopaedic surgeons from a single institution were studied. In this study, we sought to explore the relationship between nonmodifiable physician characteristics, such as sex and race, and patient satisfaction with outpatient orthopaedic surgery care, as expressed in the Press Ganey Satisfaction Scores. Univariate logistic regression models were used to test the associations between each provider characteristic and patient satisfaction on the Press Ganey patient satisfaction questionnaire. RESULTS: Three nonmodifiable physician personal and demographic characteristics were markedly associated with lower patient satisfaction scores across overall satisfaction, communication, and empathy domains: (1) female gender, (2) Asian ethnicity, and (3) being unmarried. Asian ethnicity reduced the odds of receiving a 5-star rating for likelihood to recommend the provider by nearly 40%, but none of these nonmodifiable physician personal and demographic characteristics affected the likelihood to recommend the practice. DISCUSSION: Sex, ethnicity, and marital status are nonmodifiable provider characteristics, each associated with markedly lower odds of receiving a 5-star rating on Press Ganey patient satisfaction survey. These data reveal inherent patient biases that negatively affect physician-patient interactions and may exacerbate the lack of diversity in orthopaedic surgery. More research is necessary before using patient satisfaction ratings to evaluate surgeons or as quality measures that affect reimbursement policies.

Increased NF-kB activity in osteoprogenitor-lineage cells impairs the balance of bone versus fat in the marrow of skeletally mature mice.

"Senile osteoporosis" is defined as significant aging-associated bone loss, and is accompanied by increased fat in the bone marrow. The proportion of adipocytes in bone marrow is inversely correlated with bone formation, and is associated with increased risk of fracture. NF-κB is a transcription factor that functions as a master regulator of inflammation and bone remodeling. NF-κB activity increases during aging; furthermore, constitutive activation of NF-κB significantly impairs skeletal development in neonatal mice. However, the effects of NF-κB activation using a skeletally mature animal model have not been examined. In the current study, an osteoprogenitor (OP)-specific, doxycycline-regulated NF-κB activated transgenic mouse model (iNF-κB/OP) was generated to investigate the role of NF-κB in bone remodeling in skeletally mature mice. Reduced osteogenesis in the OP-lineage cells isolated from iNF-κB/OP mice was only observed in the absence of doxycycline in vitro. Bone mineral density in the metaphyseal regions of femurs and tibias was reduced in iNF-κB/OP mice. No significant differences in bone volume fraction and cortical bone thickness were observed. Osmium-stained bone marrow fat was increased in epiphyseal and metaphyseal areas in the tibias of iNF-κB/OP mice. These findings suggest that targeting NF-κB activity as a therapeutic strategy may improve bone healing and prevent aging-associated bone loss in aged patients.

Effect of Aging on the Macrophage Response to Titanium Particles.

Macrophage-mediated inflammatory reaction to implant wear particles drives bone loss around total joint replacements (TJR). Although most TJR recipients are elderly, studies linking wear particle-activated macrophages and peri-implant osteolysis have not taken into account the multiple effects that aging has on the innate immune system and, in particular, on macrophages. To address this, we compared the wear particle responses of bone marrow macrophages obtained from young (2-month) and aged (18-month) mice. Macrophages were polarized to M0, M1, or M2 phenotypes in vitro, challenged with titanium particles, and their inflammatory response was characterized at multiple time points by quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. In addition, age-dependent changes in activation of transcription factor nuclear factor-κB were analyzed by a lentiviral vector-based luciferase reporter system. The particle stimulation experiment was further repeated using human primary macrophages isolated from blood donors of different ages. We found that the pro-inflammatory responses were generally higher in macrophages obtained from young mice, but differences between the age groups remained small and of uncertain biological significance. Noteworthily, M2 polarization effectively suppressed the particle-induced inflammation in both young and aged macrophages. These results suggest that aging of the innate immune system per se plays no significant role in the response of macrophages to titanium particles, whereas induction of M2 polarization appears a promising strategy to limit macrophage-mediated inflammation regardless of age. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:405-416, 2020.

Mesenchymal stem cell-macrophage crosstalk and bone healing.

Recent research has brought about a clear understanding that successful fracture healing is based on carefully coordinated cross-talk between inflammatory and bone forming cells. In particular, the key role that macrophages play in the recruitment and regulation of the differentiation of mesenchymal stem cells (MSCs) during bone regeneration has been brought to focus. Indeed, animal studies have comprehensively demonstrated that fractures do not heal without the direct involvement of macrophages. Yet the exact mechanisms by which macrophages contribute to bone regeneration remain to be elucidated. Macrophage-derived paracrine signaling molecules such as Oncostatin M, Prostaglandin E2 (PGE2), and Bone Morphogenetic Protein-2 (BMP2) have been shown to play critical roles; however the relative importance of inflammatory (M1) and tissue regenerative (M2) macrophages in guiding MSC differentiation along the osteogenic pathway remains poorly understood. In this review, we summarize the current understanding of the interaction of macrophages and MSCs during bone regeneration, with the emphasis on the role of macrophages in regulating bone formation. The potential implications of aging to this cellular cross-talk are reviewed. Emerging treatment options to improve facture healing by utilizing or targeting MSC-macrophage crosstalk are also discussed.

Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex.

OBJECTIVES: Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage-mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures. METHODS: A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion. RESULTS: We found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis. CONCLUSION: These results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific.Cite this article: K. Nathan, L. Y. Lu, T. Lin, J. Pajarinen, E. Jämsen, J-F. Huang, M. Romero-Lopez, M. Maruyama, Y. Kohno, Z. Yao, S. B. Goodman. Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone Joint Res 2019;8:481-488. DOI: 10.1302/2046-3758.810.BJR-2018-0231.R2.

Joint replacement surgery in homeless veterans.

Total joint arthroplasty (TJA) in a homeless patient is generally considered contraindicated. Here, we report our known medical and social (housing and employment) results of homeless veterans who had TJA. Thirty-seven TJAs were performed on 33 homeless patients (31 men) at our hospital between November 2000 and March 2014. This was 1.2% of all TJAs. Average age was 54 years. Average hospital stay was 4.1 days. There were no major inpatient complications. Thirty-four cases had at least 1-year follow-up in any clinic within the Veterans Affairs health care system. There were no known surgery-related reoperations or readmissions. At final follow-up, 24 patients had stable housing and 9 were employed. The extensive and coordinated medical and social services that were provided to veterans from the Department of Veterans Affairs contributed to our positive results.