Is the level of consent to a national research registry associated with patient outcomes following traumatic spinal cord injury? A population-based study from the Rick Hansen Spinal Cord Injury Registry (RHSCIR).

OBJECTIVE: We examined the impact of consenting to the Rick Hansen Spinal Cord Injury Registry (RHSCIR) on outcomes: acute length of stay (LOS), in-hospital mortality, medical complications (pressure injuries and pneumonia), and the final discharge destination following a spinal cord injury (SCI) using the national RHSCIR dataset. DESIGN: A retrospective cohort study was conducted using RHSCIR participant data from 2014 to 2019. Participants approached for enrollment were grouped into 1) PC: provided full consent including community follow-up (CFU) interviews, 2) DWC: declined CFU interviews but accepted minimal data collection that may include initial/final interviews and/or those who later withdrew consent, and 3) DC: declined consent to any participation. As no data was collected for the DC group, descriptive, bivariate, and multivariable regression analysis was limited to the PC and DWC groups. RESULTS: Of 2811 participants, 2101 (74.7%) were PC, 553 (19.7%) were DWC, and 157 (5.6%) were DC. DWC participants had significantly longer acute LOS, more acute pneumonias/pressure injuries, and were less likely to be discharged home than PC participants. All these associations - except pneumonia - remained significant in the multivariable analyses. CONCLUSION: Not participating fully in RHSCIR was associated with more complications and longer hospital stays.

Biased signalling in analgesic research and development.

Ligand bias offers a novel means to improve the therapeutic profile of drugs. With regard to G protein-coupled receptors involved in analgesia, it could be advantageous to develop such drugs if the analgesic effect is mediated by a different cellular signalling pathway than the adverse effects associated with the drug. Whilst this has been explored over a number of years for the µ receptor, it remains unclear whether this approach offers significant benefit for the treatment of pain. Nevertheless, the development of biased ligands at other G protein-coupled receptors in the CNS does offer some promise for the development of novel analgesic drugs in the future. Here we summarise and discuss the recent evidence to support this.

COVID-19 in non-hospitalised adults caused by either SARS-CoV-2 sub-variants Omicron BA.1, BA.2, BA.4/5 or Delta associates with similar illness duration, symptom severity and viral kinetics, irrespective of vaccination history.

BACKGROUND: SARS-CoV-2 variant Omicron rapidly evolved over 2022, causing three waves of infection due to sub-variants BA.1, BA.2 and BA.4/5. We sought to characterise symptoms and viral loads over the course of COVID-19 infection with these sub-variants in otherwise-healthy, vaccinated, non-hospitalised adults, and compared data to infections with the preceding Delta variant of concern (VOC). METHODS: In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive polymerase chain reaction (PCR) or lateral flow test, self-swabbed on alternate weekdays until day 10. We compared participant-reported symptoms and viral load trajectories between infections caused by VOCs Delta and Omicron (sub-variants BA.1, BA.2 or BA.4/5), and tested for relationships between vaccine dose, symptoms and PCR cycle threshold (Ct) as a proxy for viral load using Chi-squared (χ2) and Wilcoxon tests. RESULTS: 563 infection episodes were reported among 491 participants. Across infection episodes, there was little variation in symptom burden (4 [IQR 3-5] symptoms) and duration (8 [IQR 6-11] days). Whilst symptom profiles differed among infections caused by Delta compared to Omicron sub-variants, symptom profiles were similar between Omicron sub-variants. Anosmia was reported more frequently in Delta infections after 2 doses compared with Omicron sub-variant infections after 3 doses, for example: 42% (25/60) of participants with Delta infection compared to 9% (6/67) with Omicron BA.4/5 (χ2 P < 0.001; OR 7.3 [95% CI 2.7-19.4]). Fever was less common with Delta (20/60 participants; 33%) than Omicron BA.4/5 (39/67; 58%; χ2 P = 0.008; OR 0.4 [CI 0.2-0.7]). Amongst infections with an Omicron sub-variants, symptoms of coryza, fatigue, cough and myalgia predominated. Viral load trajectories and peaks did not differ between Delta, and Omicron, irrespective of symptom severity (including asymptomatic participants), VOC or vaccination status. PCR Ct values were negatively associated with time since vaccination in participants infected with BA.1 (ß = -0.05 (CI -0.10-0.01); P = 0.031); however, this trend was not observed in BA.2 or BA.4/5 infections. CONCLUSION: Our study emphasises both the changing symptom profile of COVID-19 infections in the Omicron era, and ongoing transmission risk of Omicron sub-variants in vaccinated adults. TRIAL REGISTRATION: NCT04750356.

Radiologic and Clinical Evaluation of Posterolateral Versus Transforaminal Interbody Fusion in Degenerative Lumbar Spondylolisthesis.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The primary objective is to compare foraminal height (FH) and disk height (DH) differences in posterolateral (PLF) and transforaminal interbody fusions (TLIFs) and secondarily correlate these measurements with patient-reported outcomes. BACKGROUND: The impact FH has on patient outcomes in degenerative lumbar spinal fusion surgery is unknown. Postoperative FH change and how it relates to patient-reported outcomes in posteriorly based procedures has not been well evaluated. METHODS: A retrospective review of a subset of patients from a prospective cohort from the Canadian Spine Outcomes and Research Network was undertaken. Radiographic assessment preoperatively, at 3 months and 1 year, with standing lumbar spine radiographs were completed. FH and DH were recorded at each time interval, differences between groups were compared, and correlations with patient-reported outcomes were assessed. RESULTS: One hundred nine patients were included (23 PLF and 86 TLIF). At 3-month follow-up, the change in FH was greater in the TLIF group (mean difference =2.3; 95% CI: 0.8-3.5, P =0.002). The change in FH remained significantly different at 12 months (mean difference=1.6, 95% CI: 0.2, 3.0 mm, P =0.028). The change in DH was greater in the TLIF group, with a mean difference between groups of 4.1 mm (95% CI: 2.5, 5.7, P <0.001) and 3.6 mm (95% CI: 2.0, 5.3, P <0.001). A positive change in FH correlated with less back pain, less disability, and improved physical function in the TLIF group ( P <0.05). CONCLUSIONS: Patients treated with PLF lost FH over time. An increased difference in FH at 1 year was associated with improved function and less back pain in the TLIF group.

Characterizing mJOA-defined post-surgical recovery patterns in patients with degenerative cervical myelopathy.

Background: Degenerative cervical myelopathy is a spinal disorder resulting in progressive cord compression and neurological deficits that are assessed using the modified Japanese Orthopedic Association (mJOA) questionnaire. It is difficult to predict which patients will recover neurological function after surgery, making it challenging for clinicians to set postoperative patient expectations. In this study, we used mJOA subscores to identify patterns of recovery and recovery timelines in patients with moderate and severe myelopathy. Methods: Fifty-three myelopathy patients were enrolled and completed the mJOA questionnaire both pre-surgery, and six weeks and six months post-surgery. Pearson chi-square tests were performed to assess relationships of both recovery patterns and recovery timelines with severity of disease. Results: Moderate myelopathy patients were significantly more likely than severe myelopathy patients to experience full recovery of upper extremity, lower extremity, and sensory domains. Disease severity did not significantly impact the timeline during which recovery occurs. Overall, >90% of patients experienced at least partial recovery by six months post surgery, 80% of which demonstrated it within the first six weeks. Conclusions: This study shows the more severe the disease experienced by myelopathy patients, the more likely they will be left with permanent disabilities despite surgery. Early identification and treatment are therefore necessary to prevent worsening quality of life and increased costs of functional dependence. The recovery timelines for each subscore are similar and provide new values to guide patient expectations in their potential post-operative recovery. The overall recovery timeline is more generalizable though potentially lacking the specificity patients seek.

Combined analyses of within-host SARS-CoV-2 viral kinetics and information on past exposures to the virus in a human cohort identifies intrinsic differences of Omicron and Delta variants.

The emergence of successive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) during 2020 to 2022, each exhibiting increased epidemic growth relative to earlier circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics-such as varying levels of immunity-can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform Coronavirus Disease 2019 (COVID-19) planning and response and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both interindividual variation in Ct values and complex host characteristics-such as vaccination status, exposure history, and age-we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least 5 prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs. Trial Registration: The Legacy study is a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening for SARS-CoV-2 at University College London Hospitals or at the Francis Crick Institute (NCT04750356) (22,23). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469). The Legacy study was approved by London Camden and Kings Cross Health Research Authority Research and Ethics committee (IRAS number 286469) and is sponsored by University College London Hospitals. Written consent was given by all participants.

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

"We do it ourselves": strengths and opportunities for improving the practice of harm reduction.

BACKGROUND: Unprecedented increases in substance-related overdose fatalities have been observed in Texas and the U.S. since the onset of the COVID-19 pandemic and have made clear there is considerable need to reduce harms associated with drug use. At the federal level, initiatives have called for widespread dissemination and implementation of evidence-based harm reduction practices to reduce overdose deaths. Implementation of harm reduction strategies is challenging in Texas. There is a paucity of literature on understanding current harm reduction practices in Texas. As such, this qualitative study aims to understand harm reduction practices among people who use drugs (PWUD), harm reductionists, and emergency responders across four counties in Texas. This work would inform future efforts to scale and spread harm reduction in Texas. METHODS: Semi-structured qualitative interviews were conducted with N = 69 key stakeholders (25 harm reductionists; 24 PWUD; 20 emergency responders). Interviews were transcribed verbatim, coded for emergent themes, and analyzed using Applied Thematic Analysis with Nvivo 12. A community advisory board defined the research questions, reviewed the emergent themes, and assisted with interpretation of the data. RESULTS: Emergent themes highlighted barriers to harm reduction at micro and macro levels, from the individual experience of PWUD and harm reductionists to systemic issues in healthcare and the emergency medical response system. Specifically, (1) Texas has existing strengths in overdose prevention and response efforts on which to build, (2) PWUD are fearful of interacting with healthcare and 911 systems, (3) harm reductionists are in increasing need of support for reaching all PWUD communities, and (4) state-level policies may hinder widespread implementation and adoption of evidence-based harm reduction practices. CONCLUSIONS: Perspectives from harm reduction stakeholders highlighted existing strengths, avenues for improvement, and specific barriers that currently exist to harm reduction practices in Texas.

The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Carfentanil is a ß-arrestin-biased agonist at the µ opioid receptor.

BACKGROUND AND PURPOSE: The illicit use of fentanyl-like drugs (fentanyls), which are µ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls. EXPERIMENTAL APPROACH: For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with µ opioid receptors, to assess Gi protein activation and ß-arrestin 2 recruitment. Agonist-induced cell surface receptor loss was assessed using an enzyme-linked immunosorbent assay, whilst agonist-induced G protein-coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the µ opioid receptor were determined in silico using molecular dynamics simulations. KEY RESULTS: Relative to the reference ligand DAMGO, carfentanil was ß-arrestin-biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein-coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias. CONCLUSIONS AND IMPLICATIONS: Carfentanil is a ß-arrestin-biased opioid drug at the µ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls.

Lung adenocarcinoma promotion by air pollutants.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 µm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1ß. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.

A novel G protein-biased agonist at the µ opioid receptor induces substantial receptor desensitisation through G protein-coupled receptor kinase.

BACKGROUND AND PURPOSE: G protein-biased µ opioid receptor agonists have the potential to induce less receptor desensitisation and tolerance than balanced opioids. Here, we investigated if the cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a G protein-biased µ agonist and characterised its ability to induce rapid receptor desensitisation in mammalian neurones. EXPERIMENTAL APPROACH: The signalling and trafficking properties of opioids were characterised using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay and phosphosite-specific immunoblotting in human embryonic kidney 293 cells. Desensitisation of opioid-induced currents were studied in rat locus coeruleus neurones using whole-cell patch-clamp electrophysiology. The mechanism of Compound 1-induced µ receptor desensitisation was probed using kinase inhibitors. KEY RESULTS: Compound 1 has similar intrinsic activity for G protein signalling as morphine. As predicted for a G protein-biased µ agonist, Compound 1 induced minimal agonist-induced internalisation and phosphorylation at intracellular µ receptor serine/threonine residues known to be involved in G protein-coupled receptor kinase (GRK)-mediated desensitisation. However, Compound 1 induced robust rapid µ receptor desensitisation in locus coeruleus neurons, to a greater degree than morphine. The extent of Compound 1-induced desensitisation was unaffected by activation or inhibition of protein kinase C (PKC) but was significantly reduced by inhibition of GRK. CONCLUSION AND IMPLICATIONS: Compound 1 is a novel G protein-biased µ agonist that induces substantial rapid receptor desensitisation in mammalian neurons. Surprisingly, Compound 1-induced desensitisation was demonstrated to be GRK dependent despite its G protein bias. Our findings refute the assumption that G protein-biased agonists will evade receptor desensitisation and tolerance. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Patient-Reported Outcomes Following Surgery for Lumbar Disc Herniation: Comparison of a Universal and Multitier Health Care System.

STUDY DESIGN: Ambispective cohort study. OBJECTIVE: Canada has a government-funded universal health care system. The United States utilizes a multitier public and private system. The objective is to investigate differences in clinical outcomes between those surgically treated for lumbar disc herniation in a universal health care and multitier health system. METHODS: Surgical lumbar disc herniation patients enrolled in the Canadian Spine Outcome Research Network (CSORN) were compared with the surgical cohort enrolled in the Spine Patients Outcome Research Trial (SPORT) study. Baseline demographics and spine-related patient-reported outcomes (PROs) were compared at 3 months and 1 year post-operatively. RESULTS: The CSORN cohort consisted of 443 patients; the SPORT cohort had 763 patients. Patients in the CSORN cohort were older (46.4 ± 13.5 vs 41.0 ± 10.8, P < .001) and were more likely to be employed (69.5% vs 60.3%, P = .003). The CSORN cohort demonstrated significantly greater rates of satisfaction after surgery at 3 months (87.2% vs 64.8%, P < .0001) and 1 year (85.6% vs 69.6%, P < .0001). Improvements in back and leg pain followed similar trajectories in the two cohorts, but there was less improvement on ODI in the CSORN cohort (P < .01). On multivariable logistic regression, the CSORN cohort was a significant independent predictor of patient satisfaction at 1-year follow-up (P < .001). CONCLUSIONS: Despite less improvement on ODI, patients enrolled in CSORN, as part of a universal health care system, reported higher rates of satisfaction at 3 months and 1 year post-operatively compared to patients enrolled within a multitier health system.

Acute Physiological and Perceptual Responses to Rest Redistribution With Heavier Loads in Resistance-Trained Men.

ABSTRACT: Chae, S, Hill, DW, Bailey, CA, Moses, SA, McMullen, SM, and Vingren, JL. Acute physiological and perceptual responses to rest redistribution with heavier loads in resistance-trained men. J Strength Cond Res 37(5): 994-1000, 2023-The purpose of this study was to explore the effect of rest redistribution with heavier loads (RR + L) on physiological and perceptual responses in resistance-trained men. Eight men who had back squat (BS) 1 repetition maximum (1RM) to body mass ratio; 1.8 ± 0.2 completed 2 BS exercise sessions in a counterbalanced and a randomized order; RR + L: 4 sets of (2 × 5) repetitions with 90-second interset rest and 30-second intraset rest using 75% BS 1RM and traditional sets (TS): 4 sets of 10 repetitions with 120-second interset rest using 70% BS 1RM. Blood samples were collected before exercise, immediately post exercise, and 5, 15, and 30 minutes post exercise for the analysis of growth hormone (GH), total testosterone (TT), cortisol (C), and blood lactate (BL), whereas rating of perceived exertion (RPE) and heart rate (HR) were measured immediately after each set of the BS exercise. While neither main effect of condition nor interaction existed, there was a significant ( p < 0.05) main effect of time point (and set) for GH, TT, C, BL, RPE, and HR. Volume load was greater for RR + L compared with TS (4,074.9 ± 786.7 kg vs. 3,796.3 ± 714.8 kg). In conclusion, RR + L increases volume load by approximately 7% but does not seem to influence GH ( g = -0.15), TT ( g = -0.09), BL ( g = -0.22), RPE ( g = 0.14), and HR ( g = -0.08) responses. Practitioners may consider using RR + L to increase volume load without increasing acute fatigue responses.

Evaluating Instability in Degenerative Lumbar Spondylolisthesis: Objective Variables Versus Surgeon Impressions.

The subjective degenerative spondylolisthesis instability classification (S-DSIC) system attempts to define preoperative instability associated with degenerative lumbar spondylolisthesis (DLS). The system guides surgical decision-making based on numerous indicators of instability that surgeons subjectively assess and incorporate. A more objective classification is warranted in order to decrease variation among surgeons. In this study, our objectives included (1) proposing an objective version of the DSIC system (O-DSIC) based on the best available clinical and biomechanical data and (2) comparing subjective surgeon perceptions (S-DSIC) with an objective measure (O-DSIC) of instability related to DLS. Methods: In this multicenter cohort study, we prospectively enrolled 408 consecutive adult patients who received surgery for symptomatic DLS. Surgeons prospectively categorized preoperative instability using the existing S-DSIC system. Subsequently, an O-DSIC system was created. Variables selected for inclusion were assigned point values based on previously determined evidence quality. DSIC types were derived by point summation: 0 to 2 points was considered stable, Type I); 3 points, potentially unstable, Type II; and 4 to 5 points, unstable, Type III. Surgeons' subjective perceptions of instability (S-DSIC) were retrospectively compared with O-DSIC types. Results: The O-DSIC system includes 5 variables: presence of facet effusion, disc height preservation (≥6.5 mm), translation (≥4 mm), a kyphotic or neutral disc angle in flexion, and low back pain (≥5 of 10 intensity). Type I (n = 176, 57.0%) and Type II (n = 164, 53.0%) were the most common DSIC types according to the O-DSIC and S-DSIC systems, respectively. Surgeons categorized higher degrees of instability with the S-DSIC than the O-DSIC system in 130 patients (42%) (p < 0.001). The assignment of DSIC types was not influenced by demographic variables with either system. Conclusions: The O-DSIC system facilitates objective assessment of preoperative instability related to DLS. Surgeons assigned higher degrees of instability with the S-DSIC than the O-DSIC system in 42% of cases. Level of Evidence: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.