Development and validation of a novel fetal vesico-amniotic shunt, the vortex shunt.

Fetal lower urinary tract obstruction (LUTO) is a severe malformation associated with an up to 80% mortality risk as well as significant renal and pulmonary morbidity in survivors. Fetal vesico-amniotic shunts (VAS) bypass the bladder obstruction, improve amniotic fluid volume and enhance in-utero pulmonary development. VAS has been shown to reduce respiratory morbidity and mortality in the neonatal period without proven benefit on long-term renal and bladder function. Clinically available shunts are associated with an up to 80% dislodgement rate, leading to repeat invasive procedures which increase fetal and maternal risks. We developed a novel "Vortex" shunt, which incorporates enhanced fixation to reduce dislodgement, a one-way valve to optimize in-utero bladder function, and enhanced sonographic echogenicity that optimizes the accurate deployment. Following the validation of these characteristics in initial benchtop experiments we have moved to feasibility studies in the fetal lamb model. We hope that the Vortex shunt may ultimately facilitate shunt deployment, reduce dislodgement risk, improve neonatal morbidity and mortality, and decrease the significant healthcare expenditures associated with long-term morbidity in LUTO survivors. In this manuscript, we review the natural history of LUTO, the risks and benefits of clinically available fetal shunts, and our development and early validation experiments.

Clusters of bacterial RNA polymerase are biomolecular condensates that assemble through liquid-liquid phase separation.

Once described as mere "bags of enzymes," bacterial cells are in fact highly organized, with many macromolecules exhibiting nonuniform localization patterns. Yet the physical and biochemical mechanisms that govern this spatial heterogeneity remain largely unknown. Here, we identify liquid-liquid phase separation (LLPS) as a mechanism for organizing clusters of RNA polymerase (RNAP) in Escherichia coli Using fluorescence imaging, we show that RNAP quickly transitions from a dispersed to clustered localization pattern as cells enter log phase in nutrient-rich media. RNAP clusters are sensitive to hexanediol, a chemical that dissolves liquid-like compartments in eukaryotic cells. In addition, we find that the transcription antitermination factor NusA forms droplets in vitro and in vivo, suggesting that it may nucleate RNAP clusters. Finally, we use single-molecule tracking to characterize the dynamics of cluster components. Our results indicate that RNAP and NusA molecules move inside clusters, with mobilities faster than a DNA locus but slower than bulk diffusion through the nucleoid. We conclude that RNAP clusters are biomolecular condensates that assemble through LLPS. This work provides direct evidence for LLPS in bacteria and demonstrates that this process can serve as a mechanism for intracellular organization in prokaryotes and eukaryotes alike.

Novel Umbilical Catheter Securement and Protection Device for Umbilical Line Securement during Laparotomy.

OBJECTIVE: Umbilical catheter malposition rate is high. We compared a Novel Umbilical Securement Device (NUSD) to standard methodologies for neonatal invasive care unit patients undergoing laparotomy. STUDY DESIGN: Retrospective study was performed on infants undergoing laparotomy from April 2019 to January 2023. Two neonatologists compared position of umbilical arterial catheter/umbilical venous catheter (UVC) on perioperative chest X-ray (CXRs) in patients with or without NUSD. RESULTS: Eighteen patients underwent laparotomy, of which 8 patients had NUSD (9 lines) and 10 patients did not (14 lines). In NUSD group, mean gestational age was 37 ± 4 weeks and mean birth weight was 2.3 ± 0.9 kg compared with 31 ± 8 weeks and 2.1 ± 1.4 kg in non-NUSD group, respectively. The mean age at surgery was 5 ± 7 and 5 ± 3 days, respectively. No malposition was seen in NUSD group, while 57% of UVCs (28% of lines) were malpositioned postoperatively in non-NUSD group (p = 0.048). CONCLUSION: NUSD is an umbilical catheter securement device with low malposition rate, specifically during perioperative period with heightened risk for dislodgement. KEY POINTS: · Umbilical catheters provide reliable access for neonates but have a high rate of malpositioning.. · NUSD is an umbilical catheter securement device with low malposition rate.. · NUSD can be kept in place during laparotomy and can decrease the risk of malpositioning..

A Novel Method for Administering Epinephrine during Neonatal Resuscitation.

OBJECTIVE: This study aimed to determine if prefilled epinephrine syringes will reduce time to epinephrine administration compared with conventional epinephrine during standardized simulated neonatal resuscitation. STUDY DESIGN: Timely and accurate epinephrine administration during neonatal resuscitation is lifesaving in bradycardic infants. Current epinephrine preparation is inefficient and error-prone. For other emergency use drugs, prefilled medication syringes have decreased error and administration time. Twenty-one neonatal intensive care unit nurses were enrolled. Each subject engaged in four simulated neonatal resuscitation scenarios involving term or preterm manikins using conventional epinephrine or novel prefilled epinephrine syringes specified for patient weight and administration route. All scenarios were video-recorded. Two investigators analyzed video recordings for time to epinephrine preparation and administration. Differences between conventional and novel techniques were evaluated using the Wilcoxon Signed Rank Tests. RESULTS: Twenty-one subjects completed 42 scenarios with conventional epinephrine and 42 scenarios with novel prefilled syringes. Epinephrine preparation was faster using novel prefilled epinephrine syringes (median = 17.0 s, interquartile range [IQR] = 13.3-22.8) compared with conventional epinephrine (median = 48.0 s, IQR = 40.5-54.9, n = 42, z = 5.64, p < 0.001). Epinephrine administration was also faster using novel prefilled epinephrine syringes (median = 26.9 s, IQR = 22.1-33.2) compared with conventional epinephrine (median = 57.6 s, IQR = 48.8-66.8, n = 42, z = 5.63, p < 0.001). In a poststudy survey, all subjects supported the clinical adoption of prefilled epinephrine syringes. CONCLUSION: During simulated neonatal resuscitation, epinephrine preparation and administration are faster using novel prefilled epinephrine syringes, which may hasten return of spontaneous circulation and be lifesaving for bradycardic neonates in clinical practice. KEY POINTS: · Currently, epinephrine administration in neonatal resuscitation is inefficient and error prone.. · Prefilled epinephrine syringes hasten medication administration in simulated neonatal resuscitation.. · Clinical use of prefilled epinephrine syringes may be lifesaving for bradycardic neonates..

The Value of Scientific Publications in Surgical Device Innovation.

BACKGROUND: Clinical trials represent a significant risk in the commercialization of surgical technologies. There is incentive for companies to mitigate their regulatory risk by targeting 510K over Premarket Approval (PMA) pathways in order to limit the scope, complexity and cost of clinical trials. As such, not all companies will publish clinical data in the scientific literature. PURPOSE: We set out to investigate the relationship between scientific publication by surgical device companies and the impact it has on company valuation. We hypothesize that publishing in the scientific literature correlates with success of the surgical device companies as measured by funding. RESEARCH DESIGN: We first obtained a list of surgical device startup companies and their financial deals using the Pitchbook database. Those companies were then cross referenced with the FDA database and the Dimensions database for product registrations and peer reviewed publications, respectively. Analysis was then performed using these query results. STUDY SAMPLE AND DATA COLLECTION: We obtained a list of US surgical device startups financing deals closed between 2010 and 2020 from the Pitchbook database. We queried the Pitchbook for deal dates from January 1, 2010 to January 1, 2020 for deal types spanning early stage investment to IPO. Deals were limited to those conducted in the United States and to the surgical device industry. We queried the FDA database for product registration information associated with each of the companies involved in the deals. We tabulated the number of journal articles associated with surgical device companies using the Dimensions Search API as well as a manual confirmation. RESULTS: Five hundred thirty five (535) deals from 222 companies were found in Pitchbook that met our criteria. Querying the FDA database resulted in 578 registrations associated with these companies. Publications per company ranged widely. CONCLUSIONS: Companies that are able to generate a more numerous publications had correspondingly higher valuations during funding rounds. A subset of outstanding companies were analyzed and at least four factors affect: direct value of publications, indirect valve of publications, survivorship bias, and adoption share; each of which will be discussed in this manuscript.

Development and in-vitro characterization of a novel fetal vesicoamniotic shunt - The Vortex shunt.

OBJECTIVES: To develop and test a novel vesicoamniotic shunt (VAS) to treat fetal lower urinary tract obstruction (LUTO), decrease dislodgement and optimize shunt deployment in-vitro. METHODS: Vesicoamniotic shunt design objectives included: (1) robust and atraumatic fixation elements, (2) kink resistant conduit to adjust to fetal movement and growth, (3) one-way pressure valve to facilitate bladder cycling, and (4) echogenic deployment visualization aids. The force to dislodge the novel Vortex shunt was compared with existing commercially available shunts in a bench-top porcine bladder model. Sonographic echogenicity was evaluated with ultrasound-guided deployment, and the shunt valve pressure measured. RESULTS: A prototype novel Vortex shunt was developed using braided nitinol "umbrella-type" ends with a kink-resistant stem incorporating an internal one-way valve. The peak force required to dislodge the Vortex shunt was significantly higher than commercially available shunts (p < 0.01). Shunt deployment in the bench-top model was easily confirmed with ultrasound guidance and the brisk decompression of the inflated porcine bladder thereafter. In-vitro valve gauge pressure testing mirrored bladder pressures in human LUTO cases. CONCLUSION: In-vitro testing shows that the Vortex shunt may improve deployment, sonographic visualization, kink resistance, and dynamic size adjustment. Validation in preclinical animal models are warranted and currently underway.

The Value of Surgical Data-Impact on the Future of the Surgical Field.

The combination of computing power, connectivity, and big data has been touted as the future of innovation in many fields, including medicine. There has been a groundswell of companies developing tools for improving patient care utilizing healthcare data, but procedural specialties, like surgery, have lagged behind in benefitting from data-based innovations, given the lack of data that is well structured. While many companies are attempting to innovate in the surgical field, some have encountered difficulties around collecting surgical data, given its complex nature. As there is no standardized way in which to interact with healthcare systems to purchase these data, the authors attempt to characterize the various ways in which surgical data are collected and shared. By surveying and conducting interviews with various surgical technology companies, at least 3 different methods to collect surgical data were identified. From this information, the authors conclude that an attempt to outline best practices should be undertaken that benefits all stakeholders.

Novel Neonatal Umbilical Catheter Protection and Stabilization Device in In vitro Model of Catheterized Human Umbilical Cords: Effect of Material and Venting on Bacterial Colonization.

OBJECTIVE: Umbilical central lines deliver life-saving medications and nutrition for neonates; however, complications associated with umbilical catheters (UCs) occur more frequently than in adults with central lines (i.e., line migration, systemic infection). We have developed a device for neonatal UC protection and stabilization to reduce catheter exposure to bacteria compared with the standard of care: "goal post" tape configuration. This study analyzes the effect of device venting and material on bacterial load of human umbilical cords in vitro. STUDY DESIGN: Catheters were inserted into human umbilical cord segments in vitro, secured with plastic or silicone vented prototype versus tape, and levels of bacterial colonization were compared between groups after 7 days of incubation. RESULTS: Nonvented plastic prototype showed increased bacterial load compared with goal post (p = 0.04). Colonization was comparable between the goal post and all vented plastic prototypes (p ≥ 0.30) and when compared with the vented silicone device (p = 1). CONCLUSION: A novel silicone device does not increase external bacterial colonization compared with the current standard of care for line securement, and may provide a safe, convenient alternative to standard adhesive tape for UC stabilization. Future studies are anticipated to establish safety in vivo, alongside benefits such as migration and infection reduction.

Use of the blood substitute HBOC-201 in critically ill patients during sickle crisis: a three-case series.

BACKGROUND: Red blood cell (RBC) transfusion is an important treatment modality during severe sickle cell crisis (SCC). SCC patients who refuse, or cannot accept, RBCs present a unique challenge. Acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) might be an alternative for critically ill patients in SCC with multiorgan failure due to life-threatening anemia. HBOC-201 (HbO2 Therapeutics) has been administered to more than 800 anemic patients in 22 clinical trials, but use of any HBOCs in critically ill sickle cell patients with organ failure is exceedingly rare. In the United States, HBOC-201 is currently only available for expanded access. CASE REPORT: We report three cases of HBOC-201 administered to critically ill sickle cell disease patients in SCC with multiorgan failure, either who refused RBCs (Jehovah's Witnesses) or for whom compatible RBCs were not available. RESULTS: Two patients received more than 20 units of HBOC-201, while the other received 6. The 27 units used in the third case equals the largest volume a patient has successfully received to date. All three patients survived to hospital discharge. CONCLUSION: These reports suggest that blood substitutes such as HBOC-201 can provide an oxygen bridge in SCC with multiorgan failure, until corpuscular Hb levels recover to meet metabolic demand, and highlight the compelling biochemical properties that warrant further investigation.

Trends and surgical outcomes of laparoscopic versus open pyloromyotomy.

BACKGROUND: Hypertrophic pyloric stenosis (HPS) is one of the most common pediatric illnesses necessitating surgical intervention. Controversy remains over the optimal surgical approach between laparoscopic pyloromyotomy (LP) and open pyloromyotomy (OP). LP has gained acceptance for management of HPS in an era of expanding minimal access surgical approaches to pediatric conditions. Several studies suggest advantages of LP over OP; however, selection bias and small sample sizes remain a concern. This study compares the outcomes of LP versus OP using propensity score methods. METHODS: The 2013-2015 ACS NSQIP Pediatric PUF was queried for all infants undergoing pyloromyotomy. The trend in the proportion of infants undergoing LP was described and perioperative outcomes between the OP and LP cohorts were compared using propensity score weighted regression models. RESULTS: 4847 infants were identified to have undergone surgical pyloromyotomy. The proportion of LP performed increased significantly from 59% in 2013 to 65.5% in 2015 (p < 0.001). LP was associated with lower overall complications (1.4% vs 2.9%) (ORadj 0.52, 95% CI 0.34-0.80), surgical site-related complications (1.1% vs 2.1%) (ORadj 0.52, 95% CI 0.32-0.84), and post-operative length of stay (1.5 days vs 1.9 days) (ORadj 0.89, 95% CI 0.81-0.98) without significant differences in related re-operation (0.9% vs 0.9%) (ORadj 1.01, 95% CI 0.52-1.93) or readmissions (1.4% vs 2.1%) (ORadj 0.73, 95% CI 0.46-1.17). CONCLUSIONS: Our study demonstrates that LP is increasingly utilized for management of hypertrophic pyloric stenosis and is associated with shorter length of stay, and lower odds of surgical site-specific and overall complications without differences in related re-operations. This study supports LP as a safe and effective method for management of HPS.

A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma.

Bendamustine in combination with rituximab (BR) has been associated with high response rates and acceptable toxicity in older patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Evaluation of BR is warranted in the front-line setting for DLBCL patients not eligible for anthracyclines or for the elderly. In this phase II study, we enrolled DLBCL patients aged ≥65 years who were poor candidates for R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to determine the efficacy and safety of BR in previously untreated stage II-IV DLBCL. Twenty-three patients were enrolled with a median age of 80 years. 52% of patients presented with poor functional status (Eastern Cooperative Oncology Group performance score of ≥2). The overall response rate was 78% with 12 complete responses (52%). At a median follow up of 29 months, the median overall survival was 10·2 months and the median progression-free survival was 5·4 months. The most common grade 3/4 adverse events were haematological. Combination therapy with BR demonstrates high response rates as front-line therapy in frail older patients with DLBCL, but survival rates were low. BR should be used with caution in future clinical trials involving older DLBCL patients with poor functional status.

Prenatal imaging and postnatal presentation, diagnosis and management of congenital lung malformations.

PURPOSE OF REVIEW: Congenital lung malformations (CLMs) vary in their clinical presentation and severity. Increases in prenatal diagnosis, observed regression of certain lesions, and prognostic uncertainty are driving an evolution in management. RECENT FINDINGS: There has been an increase in the early diagnosis of these malformations, a change that is attributable to the routine use of prenatal ultrasound. Although prenatal diagnosis of CLMs using ultrasound and MRI has increased, chest radiography and computed tomography still play important roles in diagnosis. The management of these lesions depends on the type of malformation and symptoms. The treatment of asymptomatic patients with lung malformations is controversial, because the prognosis of these lesions is largely unknown. Proponents of early intervention argue that the complications of CLM, which may include infection, pneumothorax, bleeding and malignant transformation, justify surgery. Advocates of conservative management note that some CLMs disappear postnatally, and that the long-term complication rate following surgery is unknown. There is a need to obtain natural history data regardless of the therapeutic recommendations. SUMMARY: This article reviews the prenatal radiographic features and postnatal clinical findings of various CLMs and the dilemmas regarding treatment.

Characterizing continuous positive airway pressure (CPAP) Belly Syndrome in preterm infants in the neonatal intensive care unit (NICU).

OBJECTIVE: Reproducibly define CPAP Belly Syndrome (CBS) in preterm infants and describe associated demographics, mechanical factors, and outcomes. STUDY DESIGN: A retrospective case-control study was conducted in infants <32 weeks gestation in the Stanford Children's NICU from January 1, 2020 to December 31, 2021. CBS was radiographically defined by a pediatric radiologist. Data analysis included descriptive statistics and comparator tests. RESULTS: Analysis included 41 infants with CBS and 69 infants without. CBS was associated with younger gestational age (median 27.7 vs 30 weeks, p < 0.001) and lower birthweight (median 1.00 vs 1.31 kg, p < 0.001). Infants with CBS were more likely to receive bilevel respiratory support and higher positive end expiratory pressure. Infants with CBS took longer to advance enteral feeds (median 10 vs 7 days, p = 0.003) and were exposed to more abdominal radiographs. CONCLUSIONS: Future CBS therapies should target small infants, prevent air entry from above, and aim to reduce time to full enteral feeds and radiographic exposure.

Impact of the COVID-19 pandemic on international cutaneous squamous cell carcinoma incidence: A systematic review and meta-analysis.

Background: Non-melanoma skin cancer (NMSC) is the most common cancer globally in white ethinicity populations, and cutaneous squamous cell carcinoma (cSCC) is the second most common subtype. The COVID-19 pandemic severely impacted public and private healthcare systems. Many studies have reported reduced cancer diagnoses during the pandemic. The impact of the COVID-19 pandemic on global cSCC and NMSC incidence is poorly reported. Objectives: The aim was to conduct a systematic review and meta-analysis to assess the impact of the COVID-19 pandemic on global cSCC and NMSC incidence rates, compared with 2019 incidence rates. Two primary outcome measures were used: crude incidence rate ratios (CIRR) and age-standardised incidence rate ratios (ASIRR). Methods: A structured search was undertaken on 23 March 2023 using grey literature and four electronic databases: MEDLINE, CINAHL, EMBASE and Web of Science. Studies published before January 2020 were excluded. A quality assessment was undertaken using A. Lomas quality assessment tool. CIRR outcomes were synthesised in a meta-analysis, while ASIRR outcomes were narratively synthesised. Results: Fourteen cancer registries were included, capturing data from 13 countries across Europe. Variation was observed in NMSC and cSCC incidence across the cancer registries. Pooled cSCC crude incidence rates in 2020 were equal to crude incidence rates in 2019 (cSCC-CIRR 1.00 (95% confidence interval (CI) 0.94-1.06). In 2021, the pooled result indicated a non-significant 8% increase in cSCC crude incidence rates, compared with 2019 (cSCC-CIRR 1.08 (95% CI 0.98-1.19). Significant reductions were reported in NMSC incidence across all meta-analyses in 2020 and 2021 compared with 2019. Heterogeneity was observed across most pooled estimates (I 2>75%). Conclusion: There was a lack of high quality data on cSCC incidence rates recorded during the pandemic outside of Europe. The COVID-19 pandemic resulted in no significant changes in cSCC incidence across Europe. By contrast, NMSC incidence fell across Europe following the pandemic. Significant reductions in pooled NMSC incidence rates may reflect a delay in basal cell carcinoma presentation, diagnosis and treatment. Although annual incidence rates for cSCC were not affected by the pandemic, delays in treatment may still have occurred, which may result in poorer outcomes yet to be fully understood.

The utility of Endoscopic Functional Luminal Imaging (EndoFLIP) in the diagnosis and management of children with achalasia.

BACKGROUND: Per-oral endoscopic myotomy (POEM) has is an alternative treatment to laparoscopic Heller myotomy for children with achalasia. The EndoFLIP functional luminal imaging system is used to measure esophagogastric junction (EGJ) distensibility pre- and post-POEM. Previous adult studies have established a correlation between obstructive symptoms and Distensibility Index (DI). Here we analyze the utility of EndoFLIP in diagnosis and management of achalasia in the largest study on pediatric POEM patients and hypothesize that DI may aid diagnosis and treatment of pediatric achalasia. METHODS: Demographics, preoperative basal and residual pressures measured on manometry, and EndoFLIP measurements pre- and post-POEM were recorded for children that underwent POEM. Pearson correlation coefficient and T-scores were used to assess for correlation between manometry measurements and pre-POEM DI. Linear regression was conducted to analyze the relationship between pre-POEM DI, Eckardt scores, and manometry pressures. RESULTS: Of 33 patients that underwent POEM and EndoFLIP since 2014 (21 male, 12 female), the median pre-POEM Eckardt score decreased from 7 to 1 post-POEM. The median basal pressure was 50 ± 25 mmHg, pre-POEM DI was 0.9 (0.8-1.6) mm2/mmHg and the post-POEM DI was 3.8 (3.2-4.4) mm2/mmHg. There was no correlation between DI and basal pressure or residual pressure, though there was a strong negative correlation between Eckardt scores and DI. CONCLUSION: The EndoFLIP system is a valuable tool in adult patients in diagnosing achalasia and defining the endpoint of the POEM procedure. We find that there is a role for EndoFLIP in the pediatric population in diagnosis and management of the disease. TYPE OF STUDY & LEVEL OF EVIDENCE: Study of diagnostic test; Level IV.

Using an Accelerated Undergraduate Needs Finding Course to Build Skills, Inspire Confidence, and Promote Interest in Health Technology Innovation.

Many undergraduate educational experiences in biomedical design lack clinical immersion-based needs finding training for students. Convinced of the merits of this type of training for undergraduates, but unable to offer a quarter-long course due to faculty and administrative constraints, we developed an accelerated block-plan course, during which students were dedicated solely to our class for 3 weeks. The course focused on the earliest stages of the health technology innovation process-conducting effective clinical observations and performing comprehensive need research and screening. We grounded the course in experiential learning theory (with hands-on, collaborative, and immersive experiences) and constructivist learning theory (where students integrated prior knowledge with new material on need-driven innovation). This paper describes the design of this intensive block-plan course and the teaching methods intended to support the achievement of five learning objectives. We used pre- and post-course surveys to gather self-reported data about the effect of the course on student learning. Despite the accelerated format, we saw statistically significant gains for all but one sub-measure across the learning objectives. Our experience supports key benefits of the block-plan model, and the results indicate that specific course design choices were effective in achieving positive learning outcomes. These design decisions include (1) opportunities for students to practice observations before entering the clinical setting; (2) a framework for the curriculum that reinforced important concepts iteratively throughout the program; (3) balanced coverage of preparation, clinical immersion, and need research; (4) extensive faculty and peer coaching; and (5) providing hands-on prototyping opportunities while staying focused on need characterization rather than solution development. Based on our experience, we expect that this model is replicable across institutions with limited bandwidth to support clinical immersion opportunities.

Optimizing Orthopaedic Trauma Implant Pricing Through a Data-Driven and Surgeon-Integrated Approach.

OBJECTIVE: To determine whether market-based pricing could be coupled with surgeon integration into negotiation strategies to achieve lower pricing levels for orthopaedic trauma implants. A secondary aim was to identify specific types of implants that may offer larger opportunities for cost savings. METHODS: Market pricing levels were reviewed from 2 industry implant databases. This information was used by surgeons and supply chain management at our institution to select appropriate target pricing levels (25th percentile) for commonly used orthopaedic trauma implants. Target price values were provided to the existing 12 vendors used by our institution with a clear expectation that vendors meet these thresholds. RESULTS: Benchmark modeling projected a potential savings of 20.0% over our prior annual spend on trauma implants. After 2 rounds of negotiation, savings amounted to 23.0% of prior annual spend. Total savings exceeded 1,000,000 USD with 11 of 12 vendors (91.7%) offering net savings. Total percent savings were highest for external fixators, drill bits, and K-wires. Plates and screws comprised the greatest proportion of our prior annual spend and achieved similar savings. CONCLUSION: A surgeon and supply chain coordinated effort led to major cost savings without a need for consolidation of vendors. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence.