Combining multiple biomarkers linearly to minimize the Euclidean distance of the closest point on the receiver operating characteristic surface to the perfection corner in trichotomous settings.

The performance of individual biomarkers in discriminating between two groups, typically the healthy and the diseased, may be limited. Thus, there is interest in developing statistical methodologies for biomarker combinations with the aim of improving upon the individual discriminatory performance. There is extensive literature referring to biomarker combinations under the two-class setting. However, the corresponding literature under a three-class setting is limited. In our study, we provide parametric and nonparametric methods that allow investigators to optimally combine biomarkers that seek to discriminate between three classes by minimizing the Euclidean distance from the receiver operating characteristic surface to the perfection corner. Using this Euclidean distance as the objective function allows for estimation of the optimal combination coefficients along with the optimal cutoff values for the combined score. An advantage of the proposed methods is that they can accommodate biomarker data from all three groups simultaneously, as opposed to a pairwise analysis such as the one implied by the three-class Youden index. We illustrate that the derived true classification rates exhibit narrower confidence intervals than those derived from the Youden-based approach under a parametric, flexible parametric, and nonparametric kernel-based framework. We evaluate our approaches through extensive simulations and apply them to real data sets that refer to liver cancer patients.

Statistical assessment of the prognostic and the predictive value of biomarkers-A biomarker assessment framework with applications to traumatic brain injury biomarker studies.

Studies that investigate the performance of prognostic and predictive biomarkers are commonplace in medicine. Evaluating the performance of biomarkers is challenging in traumatic brain injury (TBI) and other conditions when both the time factor (i.e. time from injury to biomarker measurement) and different levels or doses of treatments are in play. Such factors need to be accounted for when assessing the biomarker's performance in relation to a clinical outcome. The Hyperbaric Oxygen in Brain Injury Treatment (HOBIT) trial, a phase II randomized control clinical trial seeks to determine the dose of hyperbaric oxygen therapy (HBOT) for treating severe TBI that has the highest likelihood of demonstrating efficacy in a phase III trial. Hyperbaric Oxygen in Brain Injury Treatment will study up to 200 participants with severe TBI. This paper discusses the statistical approaches to assess the prognostic and predictive performance of the biomarkers studied in this trial, where prognosis refers to the association between a biomarker and the clinical outcome while the predictiveness refers to the ability of the biomarker to identify patient subgroups that benefit from therapy. Analyses based on initial biomarker levels accounting for different levels of HBOT and other baseline clinical characteristics, and analyses of longitudinal changes in biomarker levels are discussed from a statistical point of view. Methods for combining biomarkers that are of complementary nature are also considered and the relevant algorithms are illustrated in detail along with an extensive simulation study that assesses the performance of the statistical methods. Even though the discussed approaches are motivated by the HOBIT trial, their applications are broader. They can be applied in studies assessing the predictiveness and prognostic ability of biomarkers in relation to a well-defined therapeutic intervention and clinical outcome.

Proximal Tibial Osteotomies: Indications, Techniques, and Outcomes.

High tibial osteotomy (HTO) is a surgical procedure that can be used as a primary or as an adjunctive treatment for a variety of knee pathologies, most commonly isolated medial compartment arthrosis in a knee with varus alignment. More recently, indications for HTO have been expanded to include its use in combination with cartilage preserving techniques, to offload the effected compartment, and in conjunction with ligamentous reconstruction. HTO also has utility in delaying total knee arthroplasty (TKA) in select patients with favorable literature on future TKA outcomes. Numerous techniques for HTO have been published, however, medial opening wedge and lateral closing wedge osteotomies remain the most common. The purpose of this article is to summarize HTO patient selection and indications, surgical techniques, common complications, and review outcomes from recent literature. (Journal of Surgical Orthopaedic Advances 32(3):148-155, 2023).

Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.

When amino acids vary during evolution, the outcome can be functionally neutral or biologically-important. We previously found that substituting a subset of nonconserved positions, "rheostat" positions, can have surprising effects on protein function. Since changes at rheostat positions can facilitate functional evolution or cause disease, more examples are needed to understand their unique biophysical characteristics. Here, we explored whether "phylogenetic" patterns of change in multiple sequence alignments (such as positions with subfamily specific conservation) predict the locations of functional rheostat positions. To that end, we experimentally tested eight phylogenetic positions in human liver pyruvate kinase (hLPYK), using 10-15 substitutions per position and biochemical assays that yielded five functional parameters. Five positions were strongly rheostatic and three were non-neutral. To test the corollary that positions with low phylogenetic scores were not rheostat positions, we combined these phylogenetic positions with previously-identified hLPYK rheostat, "toggle" (most substitution abolished function), and "neutral" (all substitutions were like wild-type) positions. Despite representing 428 variants, this set of 33 positions was poorly statistically powered. Thus, we turned to the in vivo phenotypic dataset for E. coli lactose repressor protein (LacI), which comprised 12-13 substitutions at 329 positions and could be used to identify rheostat, toggle, and neutral positions. Combined hLPYK and LacI results show that positions with strong phylogenetic patterns of change are more likely to exhibit rheostat substitution outcomes than neutral or toggle outcomes. Furthermore, phylogenetic patterns were more successful at identifying rheostat positions than were co-evolutionary or eigenvector centrality measures of evolutionary change.

Estimation and construction of confidence intervals for biomarker cutoff-points under the shortest Euclidean distance from the ROC surface to the perfection corner.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer with a 5-year survival rate of less than 5%. As in many other diseases, its diagnosis might involve progressive stages. It is common that in biomarker studies referring to PDAC, recruitment involves three groups: healthy individuals, patients that suffer from chronic pancreatitis, and PDAC patients. Early detection and accurate classification of the state of the disease are crucial for patients' successful treatment. ROC analysis is the most popular way to evaluate the performance of a biomarker and the Youden index is commonly employed for cutoff derivation. The so-called generalized Youden index has a drawback in the three-class case of not accommodating the full data set when estimating the optimal cutoffs. In this article, we explore the use of the Euclidean distance of the ROC to the perfection corner for the derivation of cutoffs in trichotomous settings. We construct an inferential framework that involves both parametric and nonparametric techniques. Our methods can accommodate the full information of a given data set and thus provide more accurate estimates in terms of the decision-making cutoffs compared with a Youden-based strategy. We evaluate our approaches through extensive simulations and illustrate them on a PDAC biomarker study.

Long-term Functional Outcomes of Nonoperatively Treated Highly Displaced Scapular Body and Neck Fractures.

Historically, extra-articular scapular body fractures were treated nonsurgically, but displaced fractures of the glenoid neck can lead to dysfunction. Controversy exists regarding which extra-articular scapular fractures should be treated surgically; however, nonsurgical management of severely displaced scapular body fractures can result in satisfactory outcomes. Inclusion criteria for this study were medial or lateral displacement greater than 2 cm, angular deformity between fracture fragments greater than 45°, or glenopolar angle less than 22°. Functional outcomes included Disabilities of the Arm, Shoulder and Hand (DASH) score, Short Form-36 (SF-36) score, and American Shoulder and Elbow Surgeons (ASES) shoulder score. Radiographs and computed tomography scans were available for all patients. Range of motion (ROM), strength, other injuries, and complications also were recorded. Twelve patients (10 males, 2 females) with a mean age of 45.6 years (range, 29-57 years) underwent follow-up for a mean of 54.1 months (range, 28.2-74.4 months). At latest follow-up, mean DASH score was 8.9 (range, 0-35), mean SF-36 score was 72.2 (range, 57.3-96.1), and mean ASES score was 85.9 (range, 46.7-100). Mean ROM and strength expressed as a percentage of the contralateral side ranged from 88% to 99% and 70% to 93%, respectively. At longest follow-up, 10 patients reported excellent satisfaction with their treatment. There were no radiographic non-unions. One patient with concomitant clavicle and acromion fractures treated surgically had a postoperative infection requiring operative irrigation and debridement. None of the patients required or sought additional treatment. Nonoperative treatment of highly displaced scapular body fractures resulted in good patient satisfaction, satisfactory long-term functional outcomes, and only minor loss of motion and strength. [Orthopedics. 2020;43(3):e177-e181.].

Survival Analysis of Revision Autologous Chondrocyte Implantation for Failed ACI.

BACKGROUND: Autologous chondrocyte implantation (ACI) provides a successful outcome for treating articular cartilage lesions. However, there have been very few reports on the clinical outcomes of revision ACI for failed ACI. PURPOSE: To evaluate clinical outcomes in patients who underwent revision ACI of the knee for failure of an initial ACI and to determine the factors affecting the survival rate. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A review of a prospectively collected data set was performed from patients who underwent revision ACI of the knee for failure of an initial ACI between 1995 and 2014 by a single surgeon. The authors evaluated 53 patients (53 knees; mean age, 38 years) over a mean 11.2-year follow-up (range, 2-20). A total of 62 cartilage lesions were treated for failed graft lesions after an initial ACI, and 31 new cartilage lesions were treated at revision ACI, as there was progression of disease. Overall, 93 cartilage lesions (mean, 1.8 lesions per knee) with a total surface area of 7.4 cm2 (range, 2.5-18 cm2) per knee were treated at revision ACI. Survival analysis was performed with the Kaplan-Meier method, with ACI graft failure or conversion to a prosthetic arthroplasty as the endpoint. The modified Cincinnati Knee Rating Scale, Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, and 36-Item Short Form Health Survey were used to evaluate clinical outcomes. Patients also self-reported knee function and satisfaction. Standard radiographs were evaluated with Kellgren-Lawrence grades. RESULTS: Survival rates were 71% and 53% at 5 and 10 years, respectively. Survival subanalysis revealed a trend that patients without previous cartilage repair procedures before an initial ACI had better survival rates than those with such procedures (81% vs 62% at 5 years, 64% vs 42% at 10 years, P = .0958). Patients with retained grafts showed significant improvement in pain and function, with a high level of satisfaction. At a mean 5.1 years postoperatively, 18 of 27 successful knees were radiographically assessed with no significant osteoarthritis progression. Outcomes for 26 patients were considered failures (mean, 4.9 years postoperatively), in which 15 patients had prosthetic arthroplasty (mean, 4.6 years) and the other 11 patients had revision cartilage repair (mean, 5.4 years) and thus could maintain their native knees. CONCLUSION: Results of revision ACI for patients who failed ACI showed acceptable clinical outcomes. Revision ACI may be an option for young patients after failed initial ACI, particularly patients without previous cartilage repair procedures and those who desire to maintain their native knees.

Can We Accurately Predict the Quadruple Hamstring Graft Diameter From Preoperative Magnetic Resonance Imaging?

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction with a quadruple hamstring (QH) autograft is a widely utilized procedure with good outcomes. A graft diameter less than 8 mm, however, has been associated with higher revision rates. Accurately determining the diameter of the hamstring tendon preoperatively can help surgeons plan accordingly. PURPOSE/HYPOTHESIS: The purpose of our study was to determine whether QH graft size can be reliably predicted from preoperative magnetic resonance imaging (MRI) measurements. We hypothesized that we can achieve a high predicted QH graft size correlation with regard to preoperative and intraoperative measurements. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: We evaluated patients undergoing ACL reconstruction using QH autografts. At the time of surgery, the semitendinosus tendon (ST) and gracilis tendon (GT) were harvested and sized and then sized as a QH graft. Preoperative individual ST and GT sizes were determined from T2-weighted fat-saturated MRI at 3 cm above the joint line using correlating axial and coronal images. We then used a predictive chart to predict what the size of the QH graft would be and compared this with the actual measurements. Pearson correlation coefficients between predicted and actual graft sizes were calculated. RESULTS: The predicted GT graft size was within 0.5 mm of the actual size in 45 of 60 (75%) patients and within 1 mm of the actual graft size in 59 of 60 (98%) patients. The predicted GT graft size from MRI measurements correlated with the actual GT graft size (r = 0.62, P < .00001). The predicted ST graft size was within 0.5 mm of the actual size in 45 of 60 (75%) patients and within 1 mm of the actual graft size in 56 of 60 (93%) patients. The predicted ST graft size from MRI measurements correlated with the actual ST graft size (r = 0.71, P < .00001). The predicted QH graft size was within 0.5 mm of the actual size in 52 of 60 (87%) patients and within 1 mm of the actual graft size in 60 of 60 (100%) patients. The predicted QH graft size from MRI measurements correlated with the actual QH graft size (r = 0.81, P < .00001). CONCLUSION: The current technique can reliably predict the size of a QH graft within 1 mm of the final graft size.

Short-Term Outcomes for the Biologic Treatment of Bone Marrow Edema of the Knee Using Bone Marrow Aspirate Concentrate and Injectable Demineralized Bone Matrix.

PURPOSE: To evaluate short-term outcomes for the biologic treatment of bone marrow edema (BME) of the knee using bone marrow aspirate concentrate (BMAC) and injectable demineralized bone matrix (iDBM). METHODS: We performed a review of prospectively collected data from patients who underwent treatment for bone marrow lesions (BMLs) of the knee using BMAC and iDBM (IntraOsseous BioPlasty; Arthrex, Naples, FL) between May 2017 and December 2018. Inclusion criteria included patients aged 18 to 65 years with the presence of BME on T2-weighted magnetic resonance imaging in the subchondral weightbearing region of the tibia or femoral condyle, with pain corresponding to the same compartment. The International Knee Documentation Committee (IKDC), pain visual analog scale (VAS), and 12-Item Short Form Health Survey (SF-12) scores were used to evaluate clinical outcomes. RESULTS: We evaluated 20 patients who were treated at a single academic medical institution over a mean 14.5-month follow-up (median, 14 months; range, 6-25 months). The average patient age was 51.7 years (range 38-62 years). Compared with preoperative values, the visual analog scale decreased from 7.0 to 1.3 (P = .008). The mean International Knee Documentation Committee scores improved from 29.2 to 66.1 (P = .063). Both the Physical and Mental Component Scores of the 12-Item Short Form Health Survey also showed improvement (Physical Component Score, P = .438; Mental Component Score, P = .563). Based on postoperative magnetic resonance imaging, 75% (3 of 4) of the BMLs demonstrated complete healing. The survival rate was 93% at 1-year follow-up. CONCLUSION: Biologic treatment of BME of the knee using BMAC and iDBM is an effective adjunct to arthroscopy that provides short-term pain relief for BMLs associated with degenerative conditions of the knee. This procedure is associated with clinically significant improvements in knee pain and function at a short-term follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Autologous Chondrocyte Implantation for Bipolar Chondral Lesions in the Tibiofemoral Compartment.

BACKGROUND: Treating bipolar chondral lesions in the tibiofemoral (TF) compartment with cartilage repair procedures is challenging, and a suitable treatment remains unclear. PURPOSE: To evaluate clinical outcomes after autologous chondrocyte implantation (ACI) for the treatment of bipolar chondral lesions in the TF compartment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We evaluated 57 patients who underwent ACI for the treatment of symptomatic bipolar chondral lesions in the TF compartment by a single surgeon between October 1995 and June 2014. One patient did not return for follow-up. Thus, 56 patients (58 knees) were included with a minimum of 2 years' follow-up. A mean of 3.1 lesions per knee were treated, representing a mean total surface area of 16.1 cm2 (range, 3.2-44.5 cm2) per knee. Bipolar lesions were present in the medial compartment (32 knees) and in the lateral compartment (26 knees). Patients were evaluated with the modified Cincinnati Knee Rating Scale, visual analog scale for pain, Western Ontario and McMaster Universities Osteoarthritis Index, and Short Form-36. Patients also answered questions regarding self-rated knee function and satisfaction with the procedure. Standard radiographs were evaluated with the Kellgren-Lawrence grading system. RESULTS: The survival rate was 80% at 5 years and 76% at 10 years. A significantly better survival rate was found in patients with the use of a collagen membrane than periosteum (97% vs 61% at 5 years, respectively; P = .0014). Of 46 knees with retained grafts, all functional scores significantly improved postoperatively, with a very high satisfaction rate (91%) at a mean of 8.3 ± 5.1 years (range, 2-20 years) after ACI. At last follow-up, 24 of 46 successful knees were radiographically assessed (mean, 5.5 ± 4.0 years [range, 2.0-18.7 years]) and showed no significant osteoarthritis progression ( P = .3173). Outcomes for 12 patients were considered as failures at a mean of 4.1 years. Of these, 9 patients were converted to partial or total knee arthroplasty at a mean of 4.4 years. Two patients underwent revision ACI at 5 and 17 months. The other 1 patient did not require revision surgery. CONCLUSION: Our study showed that ACI for the treatment of bipolar chondral lesions in the TF compartment provided successful clinical outcomes in patients with retained grafts and possibly prevented or delayed osteoarthritis progression at midterm to long-term follow-up. A collagen membrane is more encouraging than periosteum for bipolar lesions in the TF compartment. While addressing the predisposing factors affecting cartilage repair, ACI could be an adequate salvage procedure for bipolar chondral lesions in the TF compartment for the relatively young arthritic patient who wishes to avoid arthroplasty.

Bridging Public Health and Education: Results of a School-Based Physical Activity Program to Increase Student Fitness.

OBJECTIVE: Power Up for 30 (PU30) is a schoolwide intervention that encourages schools to provide an additional 30 minutes of physical activity during the school day, beyond physical education. The objective of this study was to evaluate the impact of PU30 on Georgia public elementary schools and their students. METHODS: A total of 719 of 1320 public elementary schools in Georgia that were sent a baseline survey about school physical activity during October 2013 to September 2014 completed the survey, 160 of which were asked to complete a second survey. In the interim (March to June 2015), half (80) of these schools implemented the PU30 program. The interim surveys, which were completed during March to June 2015, assessed opportunities for student physical activity and staff member professional development focused on student physical activity. RESULTS: Compared with schools that had not implemented the program, more schools using the PU30 program reported offering before- and after-school physical activity programs. Forty-four of 78 (57%) PU30 schools compared with 20 of 53 (38%) non-PU30 schools offered before-school physical activity programs. Likewise, more PU30 schools than non-PU30 schools offered after-school physical activity programs (35% vs 16%), and a greater proportion of students at PU30 schools compared with non-PU30 schools met fitness benchmarks: recess 5 days per week (91% [288 of 323] vs 80% [273 of 341]), offering ≥11 minutes per day of classroom-based physical activity (39% [53 of 136] vs 25% [47 of 189] for kindergarten through second grade; 20% [37 of 187] vs 6% [9 of 152] for grades 3 through 5), and receiving physical activity-related professional development time (42% [136 of 323] vs 14% [48 of 341]). CONCLUSIONS: The surveys provided a statewide picture of the physical activity opportunities offered to students and staff members in Georgia elementary schools and demonstrated the effective use of a comprehensive, multicomponent program to offer more school-based physical activity opportunities and to improve student fitness.

A 20-Year Follow-up After First-Generation Autologous Chondrocyte Implantation.

BACKGROUND: Treating articular cartilage defects is a demanding problem. Although several studies have reported durable and improved clinical outcomes after autologous chondrocyte implantation (ACI) over a long-term period, there is no report with over 20 years' follow-up. PURPOSE: To evaluate clinical outcomes after first-generation ACI for the treatment of knees with disabling, large single and multiple cartilage defects for which patients wished to avoid prosthetic arthroplasty, with a minimum of 20 years' follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors reviewed prospectively collected data from 23 patients (24 knees; mean age, 35.4 years [range, 13-52 years]) undergoing ACI for the treatment of symptomatic, full-thickness articular cartilage lesions. A mean of 2.1 lesions per knee were treated over a mean total surface area of 11.8 cm2 (range, 2.4-30.5 cm2) per knee. Kaplan-Meier survival analysis and functional outcome scores, including the modified Cincinnati Knee Rating System, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form-36 (SF-36), were used. Patients also self-reported an improvement in pain with a visual analog scale and a satisfaction survey. RESULTS: The 20-year survival rate was 63% (95% CI, 40%-78%). The evaluation of the 15 knees with retained grafts demonstrated that all clinical scores except the WOMAC subscore for stiffness and SF-36 mental component summary score improved significantly and were sustained to 20 years postoperatively. Ninety-three percent of these patients rated knee-specific outcomes as good or excellent. The outcomes for 9 of 24 knees were considered failures, including 5 undergoing revision ACI and 4 being converted to arthroplasty at a mean of 1.7 and 5.9 years, respectively. Only 1 of 5 knees that underwent revision ACI was converted to arthroplasty at 1.9 years after the index surgery, and the other 4 patients were able to maintain their biological knee. Overall, 20 years later, 79% of patients maintained their native knee, for which they initially sought treatment, and were satisfied when evaluated. CONCLUSION: First-generation ACI provided satisfactory survival rates and significant clinical improvements over a 20-year follow-up, which offers an important standard for comparison with newer-generation ACI technologies of the future.

Management of Patellofemoral Arthritis: From Cartilage Restoration to Arthroplasty.

The management of patellofemoral cartilage lesions is controversial and should begin with a comprehensive nonsurgical treatment plan. Patients with patellofemoral cartilage lesions in whom nonsurgical treatment fails may be candidates for surgical treatment. Surgical treatment strategies for the management of patellofemoral cartilage lesions are guided by the size, quality, and location of the defect. Recent advancements in cartilage restoration and arthroplasty techniques as well as appropriate patient selection and meticulous surgical technique have resulted in promising outcomes for patients with patellofemoral cartilage lesions who undergo surgical treatment.

Management of Patellofemoral Arthritis: From Cartilage Restoration to Arthroplasty.

The management of patellofemoral cartilage lesions is controversial and should begin with a comprehensive nonsurgical treatment plan. Patients with patellofemoral cartilage lesions in whom nonsurgical treatment fails may be candidates for surgical treatment. Surgical treatment strategies for the management of patellofemoral cartilage lesions are guided by the size, quality, and location of the defect. Recent advancements in cartilage restoration and arthroplasty techniques as well as appropriate patient selection and meticulous surgical technique have resulted in promising outcomes in patients with patellofemoral cartilage lesions who undergo surgical treatment.

Peritrochanteric Endoscopy.

Over the last decade, there have been significant advances in endoscopic techniques for peritrochanteric disorders of the hip. Endoscopic repair of gluteus medius and minimus tears has demonstrated good to excellent results in most patients who meet surgical indications with extremely low complication rates. Treatment of coxa saltans and other peritrochanteric disorders are also described, though the literature lacks sufficient evidence to guide treatment. As our understanding of peritrochanteric disorders evolves, endoscopic intervention will continue to progress with the development of improved technology to treat these disorders and ensure good outcomes.

Progressive Cardiomyopathy in a Patient With Elevated Cobalt Ion Levels and Bilateral Metal-on-Metal Hip Arthroplasties.

Systemic cobalt toxicity is a rare complication after metal-on-metal (MOM) total hip arthroplasty. Here we present a case of progressive cardiomyopathy, as evidenced by biopsy and cardiac magnetic resonance imaging (MRI), in a patient with bilateral MOM total hip arthroplasties. To our knowledge, it is one of the first cases in which cardiomyopathy resulting from systemic cobalt disease has been shown on MRI. While there is no guideline to unequivocally diagnose cobalt cardiomyopathy, the constellation of findings, including pathologic, biologic, blood levels, imaging, and surgical, all uniformly indicate a unifying diagnosis. The lack of improvement after removal of the prosthetic device supports a diagnosis of permanent myocardial damage, which is consistent with cardiomyopathy of advanced toxic etiology.

Recurrent carpal tunnel syndrome.

Carpal tunnel release is a common procedure with a high rate of alleviating the patient's symptoms. The incidence of recurrent or persistent carpal tunnel syndrome is rare, although likely underestimated. Complaints of worsening numbness, tingling, or weakness should alert the physician to possible nerve injury and need for early exploration. The overall results of revision carpal tunnel procedures are less successful than primary surgery; however, surgery should be performed when indicated, as it may alleviate or improve symptoms.