The Epidemiology of Radial Tunnel Syndrome and Its Overlap With Lateral Epicondylitis.

PURPOSE: Radial tunnel syndrome (RTS) is characterized by nerve compression affecting the posterior interosseous nerve branch in the forearm, and its symptoms often overlap with those of lateral epicondylitis (LE). The purpose of this study was to examine the epidemiology of RTS, frequency of injections and surgical release, and overlap of RTS with LE. METHODS: We queried the PearlDiver database to identify RTS in patients older than 18 years. Demographic data, diagnostic or therapeutic injection within 30 days of diagnosis, surgical release within 1 year of diagnosis, and 90-day postoperative complication rates were evaluated. Using International Classification of Diseases, 10th Revision, laterality codes, we also determined the number of patients who had same-side RTS and LE and the proportion of patients who subsequently underwent simultaneous RT release and LE debridement. RESULTS: The prevalence of RTS in a representative United States insurance database was 0.091%, and the annual incidence was 0.0091%. There were 75,459 patients identified with an active RTS diagnosis. The mean age at the time of diagnosis was 52 years (range, 18-81 years), 55% were women, and 1,833 patients (2.4%) underwent RT release within 1 year. Fewer than 3% of the patients received an injection within 30 days of RTS diagnosis. The 90-day postoperative complication rates were low: 5% of the patients required hospital readmission and 2.1% underwent revision surgery. Approximately 5.7% of the patients with RTS also had a diagnosis of LE on the same side within 6 months of RTS diagnosis. In patients with ipsilateral RTS and LE who underwent surgery, 59.1% underwent simultaneous RT release and LE debridement, whereas 40.9% underwent isolated radial tunnel release. CONCLUSIONS: The analysis of a large insurance database showed that the diagnosis of RTS is rarely assigned, suggesting that the incidence of this nerve compression is low. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

Higher-Than-Expected Rates of Distal Radioulnar Joint Fixation in Radial Shaft Fractures: Location of Fracture Matters.

BACKGROUND: The purpose of this study was to evaluate rates of distal radioulnar joint (DRUJ) fixation based on location of the radial shaft fracture and risk factors associated with postoperative complications following radial shaft open reduction internal fixation (ORIF). METHODS: Adult patients who underwent isolated radial shaft ORIF from 2014 to 2018 were identified from American College of Surgeons National Surgical Quality Improvement Program database and stratified by fracture location and by the presence or absence of DRUJ fixation. Preoperative patient characteristics and postoperative complications were compared to determine risk factors associated with DRUJ fixation. RESULTS: We identified 1517 patients who underwent isolated radial shaft ORIF, of which 396 (26.1%) underwent DRUJ fixation. Preoperative patient characteristics and postoperative complications were similar between cohorts. Distal radioulnar joint fixation was performed in 50 (30.7%) of 163 distal radial shaft fractures, 191 (21.8%) of 875 midshaft fractures, and 3 (13.0%) of 23 proximal shaft fractures (P = .025). Risk factors for patients readmitted include male sex (odds ratio [OR] = 12.76, P = .009) and older age (OR = 4.99, P = .035). Risk factors for patients with any postoperative complication include dependent functional status (OR = 6.78, P = .02), older age (50-69 vs <50) (OR = 2.73, P = .05), and American Society of Anesthesiologists (ASA) ≥3 (OR = 2.45, P = .047). CONCLUSIONS: The rate of DRUJ fixation in radial shaft ORIF exceeded previously reported rates of concomitant DRUJ injury, especially among distal radial shaft fractures. More distally located radial shaft fractures are significantly associated with higher rates of DRUJ fixation. Male sex is a risk factor for readmission, whereas dependent functional status, older age, and ASA ≥3 are risk factors for postoperative complications.

Carpal Tunnel Release Performed during Distal Radius Fracture Surgery.

Background Carpal tunnel release (CTR) may be concomitantly performed along with distal radius fracture open reduction internal fixation (DRF ORIF) to prevent carpal tunnel syndrome; however, there is little to no literature investigating the rate, risk factors, and complications associated with CTR. Questions/Purposes The purpose was to determine (1) the rate of CTR performed at time of DRF ORIF, (2) factors associated with CTR, and (3) whether CTR was associated with any complications. Patients and Methods In this case-control study, adult patients who underwent DRF ORIF from 2014 to 2018 were identified from a national surgical database. Two cohorts were analyzed, (1) patients with CTR and (2) patients without CTR. Preoperative characteristics and postoperative complications were compared with determine factors associated with CTR. Results Of the 18,466 patients, 769 (4.2%) had CTR. Rates of CTR in patients with intra-articular fractures with two or three fragments were significantly higher than the rate of CTR for patients with extra-articular fractures. Underweight patients underwent CTR at a significantly lower rate compared with overweight and obese patients. The American Society of Anesthesiologists ≥3 was associated with a higher rate of CTR. Male and older patients were less likely to have CTR. Conclusion The rate of CTR at time of DRF ORIF was 4.2%. Intra-articular fractures with multiple fragments were strongly associated with CTR at time of DRF ORIF, while being underweight, elderly, and male were associated with lower rates of CTR. These findings should be considered when developing clinical guidelines to assess the need for CTR in patients undergoing DRF ORIF. This is a retrospective case control study and reflects level of evidence III.

Disparities in insecurity, social support, and family relationships in association with poor mental health among US adults during the COVID-19 pandemic.

The COVID-19 pandemic has had a significant impact on mental health. Identifying risk factors and susceptible subgroups will guide efforts to address mental health concerns during the pandemic and long-term management and monitoring after the pandemic. We aimed to examine associations of insecurity (concerns about food, health insurance, and/or money), social support, and change in family relationships with poor mental health and to explore disparities in these associations. An online survey was collected from 3952 US adults between May and August 2020. Symptoms of anxiety, depression, stress, and trauma-related disorders were assessed by the Generalized Anxiety Disorder 7-item scale, the Patient Health Questionnaire-9, the Perceived Stress Scale-4, and the Primary Care Post-Traumatic Stress Disorder Screen, respectively. Social support was measured by the Oslo Social Support Scale. Logistic regression was used and stratified analyses by age, race/ethnicity, and sex were performed. We found a higher prevalence of poor mental health among those who were younger, female, with lower socioeconomic status, and racial/ethnic minorities. Participants who were worried about money, health insurance, or food had higher odds of symptoms of anxiety (OR = 3.74, 95% CI: 3.06-4.56), depression (OR = 3.20, 95% CI: 2.67-3.84), stress (OR = 3.08, 95% CI: 2.67-3.57), and trauma-related disorders (OR = 2.93, 95% CI: 2.42-3.55) compared to those who were not. Compared to poor social support, moderate and strong social support was associated with lower odds of all four symptoms. Participants who had changes in relationships with parents, children, or significant others had worse mental health. Our findings identified groups at higher risk for poor mental health, which offers insights for implementing targeted interventions.

Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects.

This White Paper, written collaboratively by members of the Cardiac Safety Research Consortium from academia, industry, and regulatory agencies, discusses different methods to characterize the QT effects for drugs that have a substantial direct or indirect effect on heart rate. Descriptions and applications are provided for individualized QT-R-R correction, Holter bin, dynamic QT beat-to-beat, pharmacokinetic-pharmacodynamic modeling, and QT assessment at constant heart rate. Most of these techniques are optimally performed using continuous electrocardiogram data obtained in clinical studies designed to characterize a drug's effect on the QT interval. An important study design element is the collection of drug-free data over a range of heart rates seen on treatment. The range of heart rates is increased at baseline by using ambulatory electrocardiogram recordings in addition to those collected under semisupine, resting conditions. Discussions in this study summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further increase our knowledge and understanding of this topic.

Practice and challenges of thorough QT studies.

The drug-induced Torsade de Pointes (TdP) tachycardia is a known regulatory problem which led to the concept of the so-called thorough QT (TQT) studies now required for practically every new pharmaceutical compound. This review summarizes the concept of the TQT studies, their statistical evaluation, and related pharmacodynamic /pharmacokinetic modeling. The review also lists suggestions of how to make TQT studies more efficient and how to improve the interpretation of clinical data obtained during drug development to identify drugs prone to TdP induction more effectively.

Cardiovascular function in nonclinical drug safety assessment: current issues and opportunities.

There are several recent examples where clinically significant, safety-related, drug effects on hemodynamics or cardiac function were not apparent until large clinical trials were completed or the drugs entered the consumer market. Such late-stage safety issues can have significant impact on patient health and consumer confidence, as well as ramifications for the regulatory, pharmaceutical, and financial communities. This manuscript provides recommendations that evolved from a 2009 HESI workshop on the need for improved translation of nonclinical cardiovascular effects to the clinical arena. The authors conclude that expanded and improved efforts to perform sensitive yet specific evaluations of functional cardiovascular parameters in nonclinical studies will allow pharmaceutical companies to identify suspect drugs early in the discovery and development process while allowing promising drugs to proceed into clinical development.

The Fate of Patients After a Staged Nonunion Procedure for Known Infection.

OBJECTIVES: To determine the factors associated with successful union and eradication of infection in the setting of staged procedures to treat obviously infected nonunions of long bones. We hypothesize that patients with positive intraoperative cultures obtained at the time of definitive surgery for infected nonunions are more likely to have persistent nonunion than those with negative cultures. DESIGN: Multicenter retrospective review. SETTING: Eight academic Level 1 trauma centers. PATIENTS/PARTICIPANTS: Patients who underwent staged management for obviously infected nonunion of a long bone. MAIN OUTCOME MEASUREMENTS: For each patient, initial fracture management, management of retained implants, number of debridements, grafting, bacteriology, antibiotic course, bone defect management, soft-tissue coverage, and definitive surgery performed were reviewed. RESULTS: A total of 134 patients were treated with staged procedures for obviously infected nonunion of a long bone (mean age 49 years, 60% open fractures, and mean follow-up 22 months). During definitive procedures, 120 patients had intraoperative cultures taken with 43% having positive cultures. For culture-positive patients, 41 patients achieved eventual union and 10 had persistent nonunion. Of 69 culture-negative patients, 66 achieved eventual union and 3 had persistent nonunion. The number of patients with union versus persistent nonunion was statistically significant between culture-positive and culture-negative groups (P = 0.015). CONCLUSIONS: Management of infected nonunion in long bones with staged treatments before definitive fixation are beneficial but ultimately less effective when performed in the setting of positive bacterial cultures at the time of definitive management. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Cardiac Safety Research Consortium electrocardiogram warehouse: thorough QT database specifications and principles of use for algorithm development and testing.

This document examines the formation, structure, and principles guiding the use of electrocardiogram (ECG) data sets obtained during thorough QT studies that have been derived from the ECG Warehouse of the Cardiac Safety Research Consortium (CSRC). These principles are designed to preserve the fairness and public interest of access to these data, commensurate with the mission of the CSRC. The data sets comprise anonymized XML formatted digitized ECGs and descriptive variables from placebo and positive control arms of individual studies previously submitted on a proprietary basis to the US Food and Drug Administration by pharmaceutical sponsors. Sponsors permit the release of these studies into the public domain through the CSRC on behalf of the Food and Drug Administration's Critical Path Initiative and public health interest. For algorithm research protocols submitted to and approved by CSRC, unblinded "training" ECG data sets are provided for algorithm development and for initial evaluation, whereas separate blinded "testing" data sets are used for formal algorithm evaluation in cooperation with the CSRC according to methods detailed in this document.

Statistical characteristics of moxifloxacin-induced QTc effect.

Moxifloxacin has been the most commonly used positive control in "thorough" QTc (TQT) studies. In a TQT study, the assay sensitivity is often considered to be established if the baseline corrected mean difference in QTc between moxifloxacin and placebo is greater than 5 ms in common practice at one or more prespecified time points and the observed moxifloxacin induced QTc effect over time follows the proper pharmacokinetics profile. To better understand the statistical characteristics of moxifloxacin-induced QTc prolongation and to provide guidance for future studies, 20 TQT studies that involved moxifloxacin have been evaluated. We study the QTc profile of the baseline adjusted mean difference in QTc between moxifloxacin and placebo over time. Zhang (2008) proposed that the moxifloxacin induced QTc effect can be evaluated between 1 and 4 h after a single dose (400 mg) administration near the time (T(max)) of peak concentration instead of all time points (typically 9-12 time points) at which QT was measured for the study drug evaluation. After evaluating 20 TQT studies, we confirm that the maximum moxifloxacin effect occurs in the time window between 1 and 4 h post dose. We also investigate the variability of the data as well as correlations between time points and between regimens. These findings and results can be used as a reference for future studies.

Multiple comparisons of repeatedly measured response: issues of validation testing in thorough QT/QTc clinical trials.

In order to validate the results of a thorough QT/QTc clinical trial, ICH E14 recommended that a concurrent positive control treatment be included in the trial. Zhang (2008) recommended that the study results are validated if the positive control establishes assay sensitivity, i.e., has an effect on the mean QT/QTc interval of 5 ms or more. Zhang (2008) and Tsong et al. (2008) discussed the intersection-union test approach and an alternative global average test approach for testing assay sensitivity during the validation process. In this article, we further discuss the multiple comparison issues of the repeatedly measured QT difference between positive control treatment and placebo in the validation test. We describe and discuss several approaches for type I error rate adjustment that are applicable to the situation.

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis.

Development of pharmacotherapies that promote remyelination is a high priority for multiple sclerosis (MS), due to their potential for neuroprotection and restoration of function through repair of demyelinated lesions. A novel preparation of clean-surfaced, faceted gold nanocrystals demonstrated robust remyelinating activity in response to demyelinating agents in both chronic cuprizone and acute lysolecithin rodent animal models. Furthermore, oral delivery of gold nanocrystals improved motor functions of cuprizone-treated mice in both open field and kinematic gait studies. Gold nanocrystal treatment of oligodendrocyte precursor cells in culture resulted in oligodendrocyte maturation and expression of myelin differentiation markers. Additional in vitro data demonstrated that these gold nanocrystals act via a novel energy metabolism pathway involving the enhancement of key indicators of aerobic glycolysis. In response to gold nanocrystals, co-cultured central nervous system cells exhibited elevated levels of the redox coenzyme nicotine adenine dinucleotide (NAD+), elevated total intracellular ATP levels, and elevated extracellular lactate levels, along with upregulation of myelin-synthesis related genes, collectively resulting in functional myelin generation. Based on these preclinical studies, clean-surfaced, faceted gold nanocrystals represent a novel remyelinating therapeutic for multiple sclerosis.

Locking Hole Inserts: Effect of Insertion Torque on Fatigue Performance and Insert Loosening in Locking Plates.

OBJECTIVES: To evaluate the effect of locking hole inserts (LHIs) and their insertion torque on locking plate fatigue life. METHODS: Eighteen standard 3.5-mm locking plates were instrumented with LHIs (Smith & Nephew, Memphis, TN) of 1.70 or 3.96 Nm insertion torque, or without LHIs, whereas eleven 4.5-mm locking plates were instrumented with LHIs at 3.96 Nm insertion torque or without LHIs. Plates were cyclically loaded to failure (ie, plate fracture) in four-point bending. Number of cycles to plate failure were measured. RESULTS: The 3.5-mm plates with 1.70 Nm LHI insertion torque had a 52% increase in cycles to failure compared with plates without LHIs (114,300 ± 23,680 vs. 75,487 ± 15,746 cycles; P = 0.01). Increasing insertion torque to 3.96 Nm led to a further increase of 36% in fatigue life (155,177 ± 32,493 cycles; P = 0.02) and a 106% increase compared with plates without LHIs (P = 0.001). The 4.5-mm plates with 3.96 Nm insertion torque had a 48% increase in cycles to failure when compared with plates without LHIs (74,369 ± 10,181 vs. 50,214 ± 5544 cycles; P = 0.001). CONCLUSIONS: LHIs significantly extend plate fatigue length, which would be advantageous in the setting of delayed fracture healing. We recommend the use of LHIs in round locking holes over bony gaps whenever possible; however, we recognize that these findings are limited to implants manufactured by Smith & Nephew.

Testing for positive control activity in a thorough QTc study.

The ICH E14 guidance (ICH, 2005) recommend that a concurrent positive control should be included in a thorough QTc clinical trial to validate the study. The ICH E14 guidance (ICH, 2005) state that "The positive control should have an effect on the mean QTc interval of about 5 ms (i.e., an effect that is close to the QTc effect that represents the threshold of regulatory concern, around 5 ms)". This task may be carried out through some statistical tests. The current practice is to test at each time point where QT measurements are collected. This method is usually not efficient. In this article, I discuss two types of statistical procedures. The first one is a local statistical test to make a time-point-specific claim, i.e., to claim a mild QTc effect due to the positive control at some specific time points. A different approach, named as a global test, is also proposed, to make a general claim that the mean difference of the positive control and placebo after baseline adjustment will be about 5 ms without specifying at which time points. An example will be used to illustrate how to apply the two procedures. How to best allocate sample size in a parallel QTc study is also discussed in this paper.

Statistical issues including design and sample size calculation in thorough QT/QTc studies.

After several drugs were removed from the market in recent years because of death due to ventricular tachycardia resulting from drug-induced QT prolongation (Khongphatthanayothin et al., 1998; Lasser et al., 2002; Pratt et al., 1994; Wysowski et al., 2001), the ICH Regulatory agencies requested all sponsors of new drugs to conduct a clinical study, named a Thorough QT/QTc (TQT) study, to assess any possible QT prolongation due to the study drug. The final version of the ICH E14 guidance (ICH, 2005) for "The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs" was released in May 2005. The purpose of the ICH E14 guidance (ICH, 2005) is to provide recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. The guideline, however, is not specific on several issues. In this paper, we try to address some statistical issues, including study design, primary statistical analysis, assay sensitivity analysis, and the calculation of the sample size for a TQT study.

Statistical issues of QT prolongation assessment based on linear concentration modeling.

The ICH (2005) defined drug-induced prolongation of QT interval, i.e., the duration of depolarization and repolarization of ventricles, as evidenced by an upper bound of the 95% confidence interval around the mean effect on QTc (QT corrected for heart rate) of 10 ms. Furthermore, it defined that a negative thorough QT/QTc study is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms. This objective leads to the application of intersection-union tests by testing the mean difference between test treatment and placebo of QTc change from baseline at each of the matched time points at which the observations are collected. The nature of the higher false positive rate due to more observational time points leads to the concern of study efficiency. Based on the concept of clinical pharmacology, a concentration-response modeling approach is often adopted to assess the prolongation size of QTc interval induced by a drug without carefully examining the validity of the assumptions involved. In most of the applications, the model is assumed either to be linear, log-linear, or logistic. The supporter of the modeling often emphasizes the advantage of power improvement and reduction in estimation error. However, it has been often pointed out by statisticians and pharmacologists that modeling under an invalid uniformity assumption across study population often leads to severe bias in testing and estimation. In this article, we examine data sets of New Drug Applications to illustrate the bias and lack of validity of the linearity assumptions.

Utilization of Platelet-Rich Plasma for Musculoskeletal Injuries: An Analysis of Current Treatment Trends in the United States.

BACKGROUND: Platelet-rich plasma (PRP) has emerged as a popular biologic treatment for musculoskeletal injuries and conditions. Despite numerous investigations on the efficacy of PRP therapy, current utilization of this treatment within the United States is not widely known. PURPOSE: To investigate the national utilization of PRP, including the incidence and conditions for which it is used in the clinical setting, and to determine the current charges associated with this treatment. STUDY DESIGN: Descriptive epidemiology study. METHODS: Using a national database (PearlDiver) of private insurance billing records, we conducted a comprehensive search using Current Procedural Terminology (CPT) codes to identify patients who received PRP injections over a 2-year period (2010-2011). Associated International Classification of Diseases, 9th Revision (ICD-9) codes were identified to determine the specific conditions the injection was used to treat. The aggregate patient data were analyzed by yearly quarter, practice setting, geographic region, and demographics. PRP therapy charges were calculated and reported as per-patient average charges (PPACs). RESULTS: A total of 2571 patients who received PRP injections were identified; 51% were male and 75% were older than 35 years. The overall incidence ranged from 5.9 to 7.9 per 1000 patients over the study period. PRP was most commonly administered in hospitals (39%) and ambulatory surgical centers (37%) compared with in private offices (26%). The most common conditions treated were knee meniscus/plica disorders, followed by unspecified shoulder conditions, rotator cuff injuries, epicondylitis, and plantar fasciitis. Further evaluation revealed that 25% of all patients received injections for cartilage-related conditions, 25% meniscus, 25% unspecified, 12% tendon, 8% glenoid labrum, and 5% ligament. The PPAC for PRP treatment was US$1755 per injection. CONCLUSION: Despite a lack of consensus regarding PRP indications and efficacy, we observed widespread application of this treatment for a myriad of musculoskeletal injuries. Most treated patients were older than 35 years, and the most commonly treated conditions included cartilage and meniscus disorders. Given the current controversy surrounding this treatment, further studies are necessary to guide clinicians on the value of this therapy for each clinical diagnosis.

Lessons Learned From Hundreds of Thorough QT Studies.

BACKGROUND: The coherence between the relationship of QTc and drug plasma concentration (this relationship is measured through the slope) and ICH E14 findings based on hundreds of QT study reports was studied. RESULTS: Based on ICH E14 analysis, our findings indicate that if the slope was not positive, in most cases (86%) the corresponding QT studies were also negative. If the slope was positive, 92% of the corresponding QT studies were also positive. CONCLUSIONS: In exploring whether a thorough QT (TQT) study may be needed, we recommend that the relationship analysis between QTc and drug plasma concentration be performed when proper single ascending dose (SAD) and multiple ascending dose (MAD) studies are available. If the relationship cannot be detected and the 90% upper confidence interval at a fixed concentration level (50th or 75th percentile, or mean peak plasma concentration [Cmax]) is below a certain threshold level (eg, 10 milliseconds), then a TQT study might be unnecessary. If the relationship can be established and the 90% lower confidence interval at a fixed concentration level (eg, mean Cmax) is greater than 10 milliseconds, further investigation is needed. If the signal is real, one might choose intensive safety monitoring during later drug development instead of a TQT study for a good compound. However, there are still some gray areas in which this analysis alone cannot determine the potential QT liability of the drug, and a TQT type of study might be worth considering.