Reverse Total Shoulder Arthroplasty Is the Most Cost-effective Treatment Strategy for Proximal Humerus Fractures in Older Adults: A Cost-utility Analysis.

BACKGROUND: Proximal humerus fractures are the second-most common fragility fracture in older adults. Although reverse total shoulder arthroplasty (RTSA) is a promising treatment strategy for proximal humerus fractures with favorable clinical and quality of life outcomes, it is associated with much higher, and possibly prohibitive, upfront costs relative to nonoperative treatment and other surgical alternatives. QUESTIONS/PURPOSES: (1) What is the cost-effectiveness of open reduction internal fixation (ORIF), hemiarthroplasty, and RTSA compared with the nonoperative treatment of complex proximal humerus fractures in adults older than 65 years from the perspective of a single-payer Canadian healthcare system? (2) Which factors, if any, affect the cost-effectiveness of ORIF, hemiarthroplasty, and RTSA compared with nonoperative treatment of proximal humerus fractures including quality of life outcomes, cost, and complication rates after each treatment? METHODS: This cost-utility analysis compared RTSA, hemiarthroplasty, and ORIF with the nonoperative management of complex proximal humerus fractures in adults older than 65 years over a lifetime time horizon from the perspective of a single-payer healthcare system. Short-term and intermediate-term complications in the 2-year postoperative period were modeled using a decision tree, with long-term outcomes estimated through a Markov model. The model was initiated with a cohort of 75-year-old patients who had a diagnosis of a comminuted (three- or four-part) proximal humerus fractures; 90% of the patients were women. The mean age and gender composition of the model's cohort was based on a systematic review conducted as part of this analysis. Patients were managed nonoperatively or surgically with either ORIF, hemiarthroplasty, or RTSA. The three initial surgical treatment options of ORIF, hemiarthroplasty, and RTSA resulted in uncomplicated healing or the development of a complication that would result in a subsequent surgical intervention. The model reflects the complications that result in repeat surgery and that are assumed to have the greatest impact on clinical outcomes and costs. Transition probabilities and health utilities were derived from published sources, with costs (2020 CAD) sourced from regional costing databases. The primary outcome was the incremental cost-utility ratio, which was calculated using expected quality-adjusted life years (QALYs) gained and costs. Sensitivity analyses were conducted to explore the impact of changing key model parameters. RESULTS: Based on both pairwise and sequential analysis, RTSA was found to be the most cost-effective strategy for managing complex proximal humerus fractures in adults older than 65 years. Compared with nonoperative management, the pairwise incremental cost-utility ratios of hemiarthroplasty and RTSA were CAD 25,759/QALY and CAD 7476/QALY, respectively. ORIF was dominated by nonoperative management, meaning that it was both more costly and less effective. Sequential analysis, wherein interventions are compared from least to most expensive in a pairwise manner, demonstrated ORIF to be dominated by hemiarthroplasty, and hemiarthroplasty to be extendedly dominated by RTSA. Further, at a willingness-to-pay threshold of CAD 50,000/QALY, RTSA had 66% probability of being the most cost-effective treatment option. The results were sensitive to changes in the parameters for the probability of revision RTSA after RTSA, the treatment cost of RTSA, and the health utilities associated with the well state for all treatment options except ORIF, although none of these changes were found to be clinically realistic based on the existing evidence. CONCLUSION: Based on this economic analysis, RTSA is the preferred treatment strategy for complex proximal humerus fractures in adults older than 65 years, despite high upfront costs. Based on the evidence to date, it is unlikely that the parameters this model was sensitive to would change to the degree necessary to alter the model's outcome. A major strength of this model is that it reflects the most recent randomized controlled trials evaluating the management of this condition. Therefore, clinicians should feel confident recommending RTSA for the management of proximal humerus fractures in adults older than 65 years, and they are encouraged to advocate for this intervention as being a cost-effective practice, especially in publicly funded healthcare systems wherein resource stewardship is a core principle. Future high-quality trials should continue to collect both clinical and quality of life outcomes using validated tools such as the EuroQOL-5D to reduce parameter uncertainty and support decision makers in understanding relevant interventions' value for money. LEVEL OF EVIDENCE: Level III, economic and decision analysis.

Comparative Efficacy of Nonoperative Treatments for Greater Trochanteric Pain Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: An evolved understanding of the pathophysiology of greater trochanteric pain syndrome has led to a number of proposed nonoperative management strategies. The objective of this review was to compare the efficacy of the various nonoperative treatments for greater trochanteric pain syndrome (GTPS). DESIGN: Systematic review and network meta-analysis. SETTING: PubMed, Embase, CENTRAL, SCOPUS, and Web of Science were searched to January 2020. PATIENTS: Patients undergoing nonoperative treatment for GTPS. INTERVENTIONS: Nonoperative treatment strategies for GTPS including injections of corticosteroids, platelet-rich plasma, hyaluronic acid, dry needling, and structured exercise programs and extracorporeal shockwave therapy. MAIN OUTCOME MEASURES: Pain and functional outcomes. Bayesian random-effects model was performed to assess the direct and indirect comparison of all treatment options. RESULTS: Thirteen randomized controlled trials and 1034 patients were included. For pain scores at 1 to 3 months follow-up, both platelet-rich plasma (PRP) and shockwave therapy demonstrated significantly better pain scores compared with the no treatment control group with PRP having the highest probability of being the best treatment at both 1 to 3 months and 6 to 12 months. No proposed therapies significantly outperformed the no treatment control group for pain scores at 6 to 12 months. Structured exercise had the highest probability of being the best treatment for improvements in functional outcomes and was the only treatment that significantly improved functional outcome scores compared with the no treatment arm at 1 to 3 months. CONCLUSION: Current evidence suggests that PRP and shockwave therapy may provide short-term (1-3 months) pain relief, and structured exercise leads to short-term (1-3 months) improvements in functional outcomes.

Basketball vs. Hockey-The Changing Face of Sport-Related Injuries in Canada.

OBJECTIVE: To characterize and compare the incidence of basketball-related, soccer-related, and hockey-related injuries over a 10-year period. DESIGN: Cohort analysis of sport-related injuries using multiple Ontario healthcare databases. SETTING: Emergency department visits in Ontario, Canada. PATIENTS: Any patient who sustained musculoskeletal injuries sustained while playing basketball, soccer, or hockey between 2006 and 2017 were identified. ASSESSMENT OF RISK FACTORS: Sport of injury, age, sex, rurality index, marginalization status, and comorbidity score. MAIN OUTCOME MEASURES: Annual Incidence Density Rates of injury were calculated for each sport, and significance of trends was analyzed by assessing overlap of 95% confidence intervals. RESULTS: One lakhs eighty five thousand eighty hundred sixty-eight patients (median age: 16 years, interquartile range 13-26) received treatment for sport-related injuries (basketball = 55 468; soccer = 67 021; and hockey = 63 379). The incidence of basketball-related and soccer-related injuries increased from 3.4 (3.3-3.5) to 5.6 (5.5-5.7) and 4.4 (4.3-4.5) to 4.9 (4.8-5) per 10 000 person years, respectively, whereas the incidence of hockey-related injuries decreased from 4.7 (4.6-4.8) to 3.7 (3.6-3.8). Patients with basketball injuries were more marginalized (3.01 ± 0.74) compared with patients with soccer and hockey injuries (2.90 ± 0.75 and 2.72 ± 0.69, respectively). CONCLUSIONS: Accurate regional epidemiologic information regarding sports injuries can be used to guide policy development for municipal planning and sport program development. The trends and demographic patterns described highlight general and sport-specific injury patterns in Ontario. Populations with the highest incidence of injury, most notably adolescents and men older than 50, may represent an appropriate population for injury risk prevention.

Light scattering in TIRF microscopy: A theoretical study of the limits to surface selectivity.

In TIRF microscopy, the sample resides near a surface in an evanescent optical field that, ideally, decreases in intensity with distance from the surface in a pure exponential fashion. In practice, multiple surfaces and imperfections in the optical system and refractive index (RI) inhomogeneities in the sample (often living cells) produce propagating scattered light that degrades the exponential purity. RI inhomogeneities cannot easily be avoided. How severe is the consequent optical degradation? Starting from Maxwell's equations, we derive a first-order perturbative approximation of the electric field strength of light scattered by sample RI inhomogeneities of several types under coherent evanescent field illumination. The approximation provides an expression for the scattering field of any arbitrary RI inhomogeneity pattern. The scattering is not all propagating; some is evanescent and remains near the scattering centers. The results presented here are only a first-order approximation, and they ignore multiple scattering and reflections off the total internal reflection (TIR) surface. For simplicity, we assume that the RI variations in the z direction are insignificant within the depth of the evanescent field and consider only scattering of excitation light, not fluorescence emission light. The general conclusion of most significance from this study is that TIR scattering from a sample with RI variations typical of those on a cell culture alters the effective thickness of the illumination to only ∼50% greater than it would be without scattering. The qualitative surface selectivity of TIR fluorescence is largely retained even in the presence of scattering. Quantitatively, however, scattering will cause a deviation from the incident exponential decay at shorter distances, adding a slower decaying background. Calculations that assume a pure exponential decay will be approximations, and scattering should be taken into account. TIR scattering is only slightly dependent on polarization but is strongly reduced for the highest accessible incidence angles.

What Is the Relative Effectiveness of the Various Surgical Treatment Options for Distal Radius Fractures? A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Many acceptable treatment options exist for distal radius fractures (DRFs); however, a simultaneous comparison of all methods is difficult using conventional study designs. QUESTIONS/PURPOSES: We performed a network meta-analysis of randomized controlled trials (RCTs) on DRF treatment to answer the following questions: Compared with nonoperative treatment, (1) which intervention is associated with the best 1-year functional outcome? (2) Which intervention is associated with the lowest risk of overall complications? (3) Which intervention is associated with the lowest risk of complications requiring operation? METHODS: Ten databases were searched from inception to July 25, 2019. Search and analysis reporting adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Included studies were English-language RCTs that assessed at least one surgical treatment arm for adult patients with displaced DRFs, with less than 20% loss to follow-up. We excluded RCTs reporting on patients with open fractures, extensive bone loss, or ipsilateral upper extremity polytrauma. Seventy RCTs (n = 4789 patients) were included. Treatments compared were the volar locking plate, bridging external fixation, nonbridging external fixation, dynamic external fixation, percutaneous pinning, intramedullary fixation, dorsal plating, fragment-specific plating, and nonoperative treatment. Subgroup analyses were conducted for intraarticular fractures, extraarticular fractures, and patients with an average age greater than 60 years. Mean (range) patient age was 59 years (56 to 63) and was similar across all treatment groups except for dynamic external fixation (44 years) and fragment-specific plating (47 years). Distribution of intraarticular and extraarticular fractures was approximately equal among the treatment groups other than that for intramedullary fixation (73% extraarticular), fragment-specific plating (66% intraarticular) [13, 70], and dorsal plating (100% intraarticular). Outcomes were the DASH score at 1 year, total complications, and reoperation. The minimum clinically important different (MCID) for the DASH score was set at 10 points. The analysis was performed using Bayesian methodology with random-effects models. Rank orders were generated using surface under the cumulative ranking curve values. Evidence quality was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology. Most studies had a low risk of bias due to randomization and low rates of incomplete follow-up, unclear risk of bias due to selective reporting, and high risk of bias due to lack of patient and assessor blinding. Studies assessing bridging external fixation and/or nonoperative treatment arms had a higher overall risk of bias while studies with volar plating and/or percutaneous pinning treatment arms had a lower risk of bias. RESULTS: Across all patients, there were no clinically important differences in terms of the DASH score at 1 year; although differences were found, all were less than the MCID of 10 points. Volar plating was ranked the highest for DASH score at 1 year (mean difference -7.34 [95% credible interval -11 to -3.7) while intramedullary fixation, with low-quality evidence, also showed improvement in DASH score (mean difference -7.75 [95% CI -14.6 to -0.56]). The subgroup analysis revealed that only locked volar plating was favored over nonoperative treatment for patients older than 60 years of age (mean difference -6.4 [95% CI -11 to -2.1]) and for those with intraarticular fractures (mean difference -8.4 [95% CI -15 to -2.0]). However, its clinical importance was uncertain as the MCID was not met. Among all patients, intramedullary fixation (odds ratio 0.09 [95% CI 0.02 to 0.84]) and locked volar plating (OR 0.14 [95% CI 0.05 to 0.39]) were associated with a lower complication risk compared with nonoperative treatment. For intraarticular fractures, volar plating was the only treatment associated with a lower risk of complications than nonoperative treatment (OR 0.021 [95% CI < 0.01 to 0.50]). For extraarticular fractures, only nonbridging external fixation was associated with a lower risk of complications than nonoperative treatment (OR 0.011 [95% CI < 0.01 to 0.65]), although the quality of evidence was low. Among all patients, the risk of complications requiring operation was lower with intramedullary fixation (OR 0.06 [95% CI < 0.01 to 0.85) than with nonoperative treatment, but no treatment was favored over nonoperative treatment when analyzed by subgroups. CONCLUSION: We found no clinically important differences favoring any surgical treatment option with respect to 1-year functional outcome. However, relative to the other options, volar plating was associated with a lower complication risk, particularly in patients with intraarticular fractures, while nonbridging external fixation was associated with a lower complication risk in patients with extraarticular fractures. For patients older than 60 years of age, nonoperative treatment may still be the preferred option because there is no reliable evidence showing a consistent decrease in complications or complications requiring operation among the other treatment options. Particularly in this age group, the decision to expose patients to even a single surgery should be made with caution. LEVEL OF EVIDENCE: Level I, therapeutic study.

Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Skeletal Metastases from Lung Cancer? A Systematic Review and Network Meta-analysis.

BACKGROUND: Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-related deaths. Metastatic bone disease occurs in 20% to 40% of patients with lung cancer, and these patients often present with pain or skeletal-related events (SREs) that are associated with decreased survival. Bone-modifying agents such as denosumab or bisphosphonates are routinely used; however, to our knowledge, there has been no quantitative synthesis of randomized controlled trial data to determine the most effective pharmacologic treatment of metastatic bone disease because of lung cancer. QUESTIONS/PURPOSES: We aimed to perform a network meta-analysis of randomized trials to identify the bone-modifying agent that is associated with the (1) highest overall survival, (2) longest time to SRE, (3) lowest SRE incidence, and (4) greatest likelihood of pain resolution. METHODS: We conducted our study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and pre-registered the analysis on PROSPERO (ID: CRD42019124364). We performed a librarian-assisted search of MEDLINE, PubMed, EMBASE, Cochrane Library, and Chinese databases including China National Knowledge Infrastructure and Wanfang Data. We included randomized controlled trials reporting outcomes specifically for patients with lung cancer treated with a bisphosphonate or denosumab. SREs included pathologic fractures, spinal cord compression, hypercalcemia of malignancy, or pain resulting in surgical intervention or radiation therapy. We excluded trials exclusively reporting surrogate outcomes such as changes in bone turnover markers. Screening, data extraction, risk of bias evaluation, and Grading of Recommendations Assessment, Development, and Evaluation evaluations were performed in duplicate. We included 131 randomized controlled trials that evaluated 11,105 patients with skeletal metastases from lung cancer. The network meta-analysis was performed using a frequentist model and the R statistical software. Results are reported as relative risks or mean differences, and the I2 value is reported for heterogeneity. The P-score, a measure of ranking certainty that accounts for standard error, is reported for each outcome. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for the incidence of SRE, and low for pain resolution. RESULTS: For overall survival, denosumab was ranked above zoledronic acid and estimated to confer a mean of 3.3 months (95% CI 0.3-6.3) of increased overall survival compared with untreated patients (P-score = 89%). For the time to SRE, denosumab was ranked first with a mean of 9.1 additional SRE-free months (95% CI 6.7-11.5) compared with untreated patients (P-score = 99%), while zoledronic acid conferred an additional 4.8 SRE-free months (95% CI 3.6-6.1). Reduction in the incidence of SREs was not different between patients treated with denosumab (relative risk 0.54; 95% CI 0.33-0.87) and those treated with zoledronic acid (relative risk 0.56; 95% CI 0.46-0.67). Patients treated with the combination of ibandronate and systemic therapy were more likely to experience successful pain resolution than untreated patients (relative risk 2.4; 95% CI 1.8-3.2). CONCLUSION: In this comprehensive synthesis of all available randomized controlled trial evidence guiding the pharmacologic treatment of bone metastases from lung cancer, denosumab was ranked above zoledronic acid for overall survival and time to SRE and was not different for reducing the incidence of SRE. Both were superior to no treatment for each of these outcomes. Given this, we encourage physicians to consider the use of denosumab or zoledronic acid in treating this patient population. The combination of ibandronate and systemic therapy was the most effective at reducing pain because of metastases. No cost-effectiveness analysis has yet been performed for denosumab and zoledronic acid on patients with metastatic lung cancer, and this represents an avenue for future research. LEVEL OF EVIDENCE: Level I, therapeutic study.

Safety and early results of Subchondroplasty® for the treatment of bone marrow lesions in osteoarthritis: a systematic review.

PURPOSE: Subchondroplasty® is a novel minimally invasive procedure for painful subchondral bone marrow lesions (BMLs). The aim of this systematic review was to characterize the clinical outcomes of the Subchondroplasty® procedure, a novel minimally invasive procedure for the treatment of BMLs. The hypothesis tested was that patients experience improvements in pain and functional outcomes following the Subchondroplasty® procedure. METHODS: MEDLINE, Embase, Web of Science, and Clinicaltrials.gov were searched from database inception to search date (June 10, 2020) for all clinical studies which discussed Subchondroplasty®. Two reviewers independently screened 45 unique results and 17 studies were included in the final analysis. Data were collected regarding patient demographics, indications, pain, functional scores, conversion to TKA, and complications of the procedure. RESULTS: All but one study were level IV evidence; the mean MINORS score was 9 ± 2. There were 756 patients included, 45.1% were female, and the mean age was 54 years (range 20-85). Thirteen studies investigated the effect Subchondroplasty® to the knee, while four studied the impact on the foot and ankle. Median length of follow-up was 12 months. The most common indication for Subchondroplasty® was joint pain with corresponding BML. Major contraindications to Subchondroplasty® included severe OA, joint instability, and malalignment. Mean pain score on visual analogue scale (VAS) prior to Subchondroplasty® was 7.8 ± 0.6, but decreased to 3.4 ± 0.7 postoperatively. All studies investigating functional scores reported improvement following Subchondroplasty® (IKDC 31.7 ± 1.9-54.0 ± 4.2 and KOOS 38.1 ± 0.6-70.0 ± 4.1). There were consistently high levels of patient satisfaction; 87 ± 8% of patients would be willing to undergo the procedure again. Seven cases of complications were reported, most seriously osteomyelitis and avascular necrosis. Conversion to knee arthroplasty ranged from 12.5 to 30% with length of follow-up ranging from 10 months to 7 years. CONCLUSIONS: Existing low-quality studies show Subchondroplasty® to benefit patients with BMLs through reduction in pain and improvement in function, along with a high degree of satisfaction following the procedure. The low short-to-medium term conversion rate to arthroplasty suggests that Subchondroplasty® may play a role in delaying more invasive and expensive procedures in patients with BMLs. Subchondroplasty® is a novel procedure that has promising initial findings, but requires further high-quality, comparative studies with long-term follow-up to better understand the outcomes of the procedure and impact clinical practice recommendations. LEVEL OF EVIDENCE: Systematic Review of Level III and IV Studies, Level IV.

Reporting Outcomes and Outcome Measures in Thumb Carpometacarpal Joint Osteoarthritis: A Systematic Review.

PURPOSE: In the thumb carpometacarpal (CMC) joint osteoarthritis (OA) literature, there is substantial heterogeneity in outcome and outcome measure reporting. This could be rectified by a standardized core outcome set (COS). This study aimed to identify a comprehensive list of outcomes and outcome measures for thumb CMC joint OA, which represents the first step in developing a COS. METHODS: A computerized search of MEDLINE, EMBASE, Cochrane, and CINAHL was performed to identify randomized controlled trials, as well as observational studies involving at least 50 participants aged greater than 18 years undergoing surgery for thumb CMC joint OA. Reported outcomes and outcome measures were extracted from these trials and summarized. RESULTS: This search yielded 3,498 unique articles, 97 of which were used for analysis. A total of 33 unique outcomes and 25 unique outcome measures were identified. The most frequently used outcomes were complications (78), postoperative pain (73), radiologic outcomes (64), and grip strength (63). Within each reported outcome, there was substantial variation in how the outcome was measured. Of the 25 unique outcome measures, 10 were validated. Of the remaining 15, 12 were created ad hoc by the author. The Disabilities of the Arm, Shoulder, and Hand questionnaire was the most commonly reported outcome measure (34%). CONCLUSIONS: There is a lack of consensus on critical outcomes after surgery for thumb CMC joint OA. A standardized COS created by stakeholder consensus would improve the consistency and therefore the quality of future research. CLINICAL RELEVANCE: This systematic review of outcomes represents the first step in developing a core outcome set for thumb CMC joint OA.

How should we lengthen post-traumatic limb defects? a systematic review and comparison of motorized lengthening systems, combined internal and external fixation and external fixation alone.

PURPOSE: Various external fixation systems for lower extremity long bone deformities have been used to various degrees of success, while newer mechanical lengthening nail (MLN) systems offer the potential for improved patient outcomes. Proponents of MLNs argue that they reduce the number of operations, infectious complications, and improve quality of life; however, the evidence to support these claims is scant. This systematic review aims to evaluate the optimal lengthening system for treating post-traumatic long bone deformity. METHODS: The systematic review was conducted in accordance with PRISMA guidelines. PUBMED, EMBASE, CINAHL, and the Cochrane Library were searched for comparative studies of lengthening techniques among adult patients with axial deformities. Studies were screened and data extracted in duplicate. Treatment groups were pooled into external fixation (EF) alone, combined internal and external fixation (CIF), and mechanical lengthening nail (MLN). Outcomes were mean lengthening achieved, lengthening index, and reported complications. RESULTS: Thirteen studies with 725 patients (mean age: 29.6 years, 74% male) were included. Nearly all of the studies were either prospective or retrospective cohort studies (n = 12), with one randomized controlled trial of moderate study quality. The mean limb lengthening achieved, lengthening index, and rate of reoperation were similar among the MLN, EF, and CIF groups. CONCLUSION: The purported decreased the duration of lengthening and the risk of reoperation associated with MLNs was not demonstrated in this review. Patients with post-traumatic leg length deformities remain a challenging patient population to treat, with intervention being associated with high rates of infectious complications and need for revision operations.

What Is the Best Evidence for Management of Displaced Midshaft Clavicle Fractures? A Systematic Review and Network Meta-analysis of 22 Randomized Controlled Trials.

BACKGROUND: Displaced mid-third clavicle fractures are common, and their management remains unclear. Although several meta-analyses have compared specific operative techniques with nonoperative management, it is not possible to compare different operative constructs with one another using a standard meta-analysis. Conversely, a network meta-analysis allows comparisons among more than two treatment arms, using both direct and indirect comparisons between interventions across many trials. To our knowledge, no network meta-analysis has been performed to compare the multiple treatment options for displaced clavicle fractures. QUESTIONS/PURPOSES: We performed a network meta-analysis of randomized, controlled trials (RCTs) to determine from among the approaches used to treat displaced midshaft clavicle fractures: (1) the intervention with the highest chance of union at 1 year, (2) the intervention with the lowest risk of revision surgery, and (3) the intervention with the highest functional outcome scores. Secondarily, we also (4) compared the surgical subtypes in the available RCTs on the same above endpoints. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were reviewed for relevant randomized controlled trials published up to July 25, 2018. Two hundred and eighty four papers were reviewed, with 22 meeting inclusion criteria of RCTs with appropriate randomization techniques, adult population, minimum of 1 year follow-up and including at least one operative treatment arm. In total, 1002 patients were treated with a plate construct, 378 with an intramedullary device, and 585 patients were managed nonoperatively. Treatment subtypes included locked intramedullary devices (56), unlocked intramedullary devices (322), anterior plating (89), anterosuperior plating (150), superior plating (449) or plating not otherwise specified (314). We performed a network meta-analysis to compare and rank the treatments for displaced clavicle fractures. We considered the following outcomes: union achievement, revision surgery risk and functional outcomes (DASH and Constant Scores). The minimal clinically important difference (MCID) was considered for both Constant and DASH scores to be at 8 points, representing the average of MCID scores reported for both DASH and Constant in the evidence, respectively. RESULTS: Union achievement was lower in patients treated nonoperatively (88.9%), and higher in patients treated operatively (96.7%, relative risk [RR] 1.128 [95% CI 1.1 to 1.17]; p < 0.001), Number needed to treat (NNT) = 10). Union achievement increased with any plate construct (97.8%, RR 1.13 [95% CI 1.1 to 1.7]; p < 0.0001, NNT = 9) and with anterior or anterosuperior plates (99.3%, RR 1.14 [95% CI 1.1 to 1.8]; p < 0.0001, NNT = 8). Risk of reoperation, when considering planned removal of hardware, was similar across all treatment arms. Lastly, operative treatment outperformed nonoperative treatment with minor improvements in DASH and Constant scores, though not approaching the MCID. At the subtype level, anterosuperior plating ranked highest in DASH and Constant functional scores with mean differences reaching 10-point improvement for Constant scores (95% CI 4.4 to 2.5) and 7.6 point improvement for DASH (95% CI 5.2 to 20). CONCLUSIONS: We found that surgical treatment led to a greater likelihood of union at 1 year of follow-up among adult patients with displaced mid-third clavicle fractures. In aggregate, surgical treatment did not increase functional scores by amounts that patients were likely to consider clinically important. Use of specific subtypes of plating (anterior, anterosuperior) resulted in improvements in the Constant score that were slightly above the MCID but did not reach the MCID for the DASH score, suggesting that any outcomes-score benefits favoring surgery were likely to be imperceptible or small. In light of these findings, we believe patients can be informed that surgery for this injury can increase the likelihood of union incrementally (about 10 patients would need to undergo surgery to avoid one nonunion), but they should not expect better function than they would achieve without surgery; most patients can avoid surgery altogether with little absolute risk of nonunion. Patients who opt for surgery must be told that the decision should be weighed against complications and the possibility of undergoing a second procedure for hardware removal. Patients opting not to have surgery for acute midshaft clavicle fractures can be told that nonunion occurs in slightly more than 10% of patients, and that these can be more difficult to manage than acute fractures. LEVEL OF EVIDENCE: Level I, therapeutic study.

Early Discharge After Total Hip and Knee Arthroplasty-An Observational Cohort Study Evaluating Safety in 330,000 Patients.

BACKGROUND: There has been considerable interest in recent years for early discharge after arthroplasty. We endeavored to evaluate the safety of same-day discharge given the rapid uptake of this practice approach. METHODS: This is a retrospective observational cohort study of the American College of Surgeons National Surgical Quality Improvement Program registry database. We included patients who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA) between 2015 and 2018. We categorized length of stay (LOS) as same-day discharge (LOS = 0 days), accelerated discharge (LOS = 1 day), and routine discharge (LOS = 2-3 days). For each LOS cohort, we determined the incidence of major complications within 30 days (surgical site infection [SSI], reoperation, readmission, deep vein thrombosis [DVT], and PE) and evaluated risk using multivariate logistic regression analysis if incidence was >1%. Patients undergoing THA and TKA were evaluated independently. RESULTS: The final study cohort consisted of 333,212 patients, including 124,150 who underwent THA (37%) and 209,062 who had TKA (63%). In the THA same-day discharge cohort, the incidence of superficial SSI (0.2%), deep/organ space SSI (0.3%), DVT (0.2%), and PE (0.2%) was low. The risk of reoperation was comparable to routine discharge (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.61-1.09; P = .17) and readmission rate was significantly lower (OR, 0.60; 95% CI, 0.48-0.76; P < .001). The risk of reoperation and readmission was also lower in the accelerated discharge cohort compared to routine discharge. In the TKA same-day discharge cohort, the risk of superficial SSI (0.3%), deep/organ space SSI (0.3%), reoperation (0.8%), DVT (0.4%), and PE (0.5%) was low. The risk of readmission after same-day discharge was comparable to routine discharge (OR, 0.85; 95% CI, 0.71-1.01; P = .07). In the accelerated discharge cohort, there was a small reduction in readmission risk (OR, 0.87; 95% CI, 0.81-0.93; P < .001). CONCLUSION: This large, observational, real-world study suggests that same-day and accelerated discharge management is safe clinical practice for patients undergoing total joint arthroplasty, yielding a similar risk of major acute 30-day complications. Further clinical trials evaluating long-term major outcomes, including patient-reported outcomes and experiences, would offer further and definitive insight into this practice approach.

Refractive Index Imaging of Cells with Variable-Angle Near-Total Internal Reflection (TIR) Microscopy.

The refractive index in the interior of single cells affects the evanescent field depth in quantitative studies using total internal reflection (TIR) fluorescence, but often that index is not well known. We here present method to measure and spatially map the absolute index of refraction in a microscopic sample, by imaging a collimated light beam reflected from the substrate/buffer/cell interference at variable angles of incidence. Above the TIR critical angle (which is a strong function of refractive index), the reflection is 100%, but in the immediate sub-critical angle zone, the reflection intensity is a very strong ascending function of incidence angle. By analyzing the angular position of that edge at each location in the field of view, the local refractive index can be estimated. In addition, by analyzing the steepness of the edge, the distance-to-substrate can be determined. We apply the technique to liquid calibration samples, silica beads, cultured Chinese hamster ovary cells, and primary culture chromaffin cells. The optical technique suffers from decremented lateral resolution, scattering, and interference artifacts. However, it still provides reasonable results for both refractive index (~1.38) and for distance-to-substrate (~150 nm) for the cells, as well as a lateral resolution to about 1 µm.

Protein mobility within secretory granules.

We investigated the basis for previous observations that fluorescent-labeled neuropeptide Y (NPY) is usually released within 200 ms after fusion, whereas labeled tissue plasminogen activator (tPA) is often discharged over many seconds. We found that tPA and NPY are endogenously expressed in small and different subpopulations of bovine chromaffin cells in culture. We measured the mobility of these proteins (tagged with fluorophore) within the lumen of individual secretory granules in living chromaffin cells, and related their mobilities to postfusion release kinetics. A method was developed that is not limited by standard optical resolution, in which a bright flash of strongly decaying evanescent field (∼64 nm exponential decay constant) produced by total internal reflection (TIR) selectively bleaches cerulean-labeled protein proximal to the glass coverslip within individual granules. Fluorescence recovery occurred as unbleached protein from distal regions within the 300 nm granule diffused into the bleached proximal regions. The fractional bleaching of tPA-cerulean (tPA-cer) was greater when subsequently probed with TIR excitation than with epifluorescence, indicating that tPA-cer mobility was low. The almost equal NPY-cer bleaching when probed with TIR and epifluorescence indicated that NPY-cer equilibrated within the 300 ms bleach pulse, and therefore had a greater mobility than tPA-cer. TIR-fluorescence recovery after photobleaching revealed a significant recovery of tPA-cer (but not NPY-cer) fluorescence within several hundred milliseconds after bleaching. Numerical simulations, which take into account bleach duration, granule diameter, and the limited number of fluorophores in a granule, are consistent with tPA-cer being 100% mobile, with a diffusion coefficient of 2 × 10(-10) cm(2)/s (∼1/3000 of that for a protein of similar size in aqueous solution). However, the low diffusive mobility of tPA cannot alone explain its slow postfusion release. In the accompanying study, we suggest that, additionally, tPA itself stabilizes the fusion pore with dimensions that restrict its own exit.

Lumenal protein within secretory granules affects fusion pore expansion.

It is often assumed that upon fusion of the secretory granule membrane with the plasma membrane, lumenal contents are rapidly discharged and dispersed into the extracellular medium. Although this is the case for low-molecular-weight neurotransmitters and some proteins, there are numerous examples of the dispersal of a protein being delayed for many seconds after fusion. We have investigated the role of fusion-pore expansion in determining the contrasting discharge rates of fluorescent-tagged neuropeptide-Y (NPY) (within 200 ms) and tissue plasminogen activator (tPA) (over many seconds) in adrenal chromaffin cells. The endogenous proteins are expressed in separate chromaffin cell subpopulations. Fusion pore expansion was measured by two independent methods, orientation of a fluorescent probe within the plasma membrane using polarized total internal reflection fluorescence microscopy and amperometry of released catecholamine. Together, they probe the continuum of the fusion-pore duration, from milliseconds to many seconds after fusion. Polarized total internal reflection fluorescence microscopy revealed that 71% of the fusion events of tPA-cer-containing granules maintained curvature for >10 s, with approximately half of the structures likely connected to the plasma membrane by a short narrow neck. Such events were not commonly observed upon fusion of NPY-cer-containing granules. Amperometry revealed that the expression of tPA-green fluorescent protein (GFP) prolonged the duration of the prespike foot ∼2.5-fold compared to NPY-GFP-expressing cells and nontransfected cells, indicating that expansion of the initial fusion pore in tPA granules was delayed. The t1/2 of the main catecholamine spike was also increased, consistent with a prolonged delay of fusion-pore expansion. tPA added extracellularly bound to the lumenal surface of fused granules. We propose that tPA within the granule lumen controls its own discharge. Its intrinsic biochemistry determines not only its extracellular action but also the characteristics of its presentation to the extracellular milieu.

A Suprapatellar Approach, When Compared With an Infrapatellar Approach, Yields Less Anterior Knee Pain and Better Patellofemoral Joint Function, for Intramedullary Nailing of Diaphyseal Tibial Fractures: Results of a Randomized Controlled Trial.

OBJECTIVES: To assess if a suprapatellar (SP) approach, when compared with an infrapatellar (IP) approach, yielded less patient-reported anterior knee pain and higher patellofemoral joint function at 6 weeks and 12 months postoperatively, when treating tibial fractures with intramedullary nailing. DESIGN: Prospective, parallel-group randomized control trial. SETTING: Tertiary level 1 trauma care center, Brisbane, Australia. PATIENTS SELECTION CRITERIA: Skeletally mature patients with an acute diaphyseal tibial fracture (AO/OTA 41A2/3, 42 A1-43A3) amenable to an intramedullary nailing were included. Exclusion criteria were periprosthetic fractures, nonunions, and presence of a contralateral injury that would restrict weight-bearing. OUTCOME MEASURES AND COMPARISONS: Anterior knee pain through the visual analog scale (VAS) and patellofemoral function using the Kujala scale at 6 weeks and 12 months were compared between those treated with a SP and IP approach. RESULTS: Ninety-five tibia fractures were included in the randomized trial, with complete follow-up data for 44 and 46 tibia fractures in the SP and IP groups, respectively. The SP cohort exhibited better patellofemoral knee function at both 6 weeks (Kajula 53.0 for SP vs. 43.2 for IP, P < 0.01) and 12 months (Kujala 92.0 for SP vs. 81.3 for IP, P < 0.01) postoperatively and a reduction in anterior knee pain at 12 months postoperatively (VAS 0.7 SP vs. 2.9 IP, P < 0.01). CONCLUSIONS: This randomized trial demonstrated clinically meaningful differences in patellofemoral function, for a SP versus IP approach, with a greater than 10 point discrepancy in Kujala score at both 6 weeks and 12 months. In addition, there was a clinically important difference in VAS knee pain scores for patients at 12 months, but not at 6 weeks, postoperatively. These results contribute to the growing body of evidence demonstrating the functional and clinical benefits of the SP approach. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A PACAP-activated network for secretion requires coordination of Ca2+ influx and Ca2+ mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells. However, the mechanisms by which PACAP acts are poorly understood. Here, it is shown that PACAP induces sustained increases in cytosolic Ca2+ which are disrupted when Ca2+ influx through L-type channels is blocked or internal Ca2+ stores are depleted. PACAP liberates stored Ca2+ via inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby functionally coupling Ca2+ mobilization to Ca2+ influx and supporting Ca2+-induced Ca2+-release. These Ca2+ influx and mobilization pathways are unified by an absolute dependence on phospholipase C epsilon (PLCε) activity. Thus, the persistent secretory response that is a defining feature of PACAP activity, in situ, is regulated by a signaling network that promotes sustained elevations in intracellular Ca2+ through multiple pathways.

A PACAP-activated network for secretion requires coordination of Ca 2+ influx and Ca 2+ mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells. However, the mechanisms by which PACAP acts are poorly understood. Here, it is shown that PACAP induces sustained increases in cytosolic Ca 2+ which are disrupted when Ca 2+ influx through L-type channels is blocked or internal Ca 2+ stores are depleted. PACAP liberates stored Ca 2+ via inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby functionally coupling Ca 2+ mobilization to Ca 2+ influx and supporting Ca 2+ -induced Ca 2+ -release. These Ca 2+ influx and mobilization pathways are unified by an absolute dependence on phospholipase C epsilon (PLCε) activity. Thus, the persistent secretory response that is a defining feature of PACAP activity, in situ , is regulated by a signaling network that promotes sustained elevations in intracellular Ca 2+ through multiple pathways.

Transtibial osseointegration following unilateral traumatic amputation: An observational study of patients with at least two years follow-up.

IMPORTANCE: Most patients use a traditional socket prosthesis (TSP) to ambulate independently following transtibial amputation. However, these patients generally require prosthesis repairs more than twice annually and an entirely new prosthesis every two years. Furthermore, transtibial amputation patients have four times the skin ulceration rate of transfemoral patients, prompting more frequent prosthesis refitting and diminished use. Trans-Tibial osseointegration (TTOI) is a promising technique to address the limitations of TSP, but remains understudied with only four cohorts totaling 41 total procedures reported previously. Continued concerns regarding the risk of infection and questions as to functional capacity postoperatively have slowed adoption of TTOI worldwide. OBJECTIVE: This study reports the changes in mobility, quality of life (QOL), and the safety profile of the largest described cohort of patients with unilateral TTOI following traumatic amputation. DESIGN: Retrospective observational cohort study. The cohort consisted of patients with data outcomes collected before and after osseointegration intervention. SETTING: A large, tertiary referral, major metropolitan center. PARTICIPANTS: Twenty-one skeletally mature adults who had failed socket prosthesis rehabilitation, with at least two years of post-osseointegration follow-up. MAIN OUTCOMES AND MEASURES: Mobility was evaluated by K-level, Timed Up and Go (TUG), and Six Minute Walk Test (6MWT). QOL was assessed by survey: daily prosthesis wear hours, prosthesis problem experience, general contentment with prosthesis, and Short Form 36 (SF36). Adverse events included any relevant unplanned surgery such as for infection, fracture, implant loosening, or implant failure. RESULTS: All patients demonstrated statistically significant improvement post osseointegration surgery with respect to K-level, TUG, 6MWT, prosthesis wear hours, prosthesis problem experience, general prosthesis contentment score, and SF36 Physical Component Score (p < 0.01 for all). Three patients had four unplanned surgeries: two soft tissue refashionings, and one soft tissue debridement followed eventually by implant removal. No deaths, postoperative systemic complications, more proximal amputations, or periprosthetic fractures occurred. CONCLUSIONS AND RELEVANCE: TTOI is likely to confer mobility and QOL improvements to patients dissatisfied with TSP rehabilitation following unilateral traumatic transtibial amputation. Adverse events are relatively infrequent and not further disabling. Judicious use of TTOI seems reasonable for properly selected patients. LEVEL OF EVIDENCE: 2 (Therapeutic investigation, Observational study with dramatic effect).

Research priorities for the management of major trauma: an international priority setting partnership with the James Lind Alliance.

OBJECTIVE: The objective of this study is to determine research priorities for the management of major trauma, representing the shared priorities of patients, their families, carers and healthcare professionals. DESIGN/SETTING: An international research priority-setting partnership. PARTICIPANTS: People who have experienced major trauma, their carers and relatives, and healthcare professionals involved in treating patients after major trauma. The scope included chest, abdominal and pelvic injuries as well as major bleeding, multiple injuries and those that threaten life or limb. METHODS: A multiphase priority-setting exercise was conducted in partnership with the James Lind Alliance over 24 months (November 2021-October 2023). An international survey asked respondents to submit their research uncertainties which were then combined into several indicative questions. The existing evidence was searched to ensure that the questions had not already been sufficiently answered. A second international survey asked respondents to prioritise the research questions. A final shortlist of 19 questions was taken to a stakeholder workshop, where consensus was reached on the top 10 priorities. RESULTS: A total of 1572 uncertainties, submitted by 417 respondents (including 132 patients and carers), were received during the initial survey. These were refined into 53 unique indicative questions, of which all 53 were judged to be true uncertainties after reviewing the existing evidence. 373 people (including 115 patients and carers) responded to the interim prioritisation survey and 19 questions were taken to a final consensus workshop between patients, carers and healthcare professionals. At the final workshop, a consensus was reached for the ranking of the top 10 questions. CONCLUSIONS: The top 10 research priorities for major trauma include patient-centred questions regarding pain relief and prehospital management, multidisciplinary working, novel technologies, rehabilitation and holistic support. These shared priorities will now be used to guide funders and teams wishing to research major trauma around the globe.