A retrospective cohort study of adverse event assessment during anesthesia-related procedures for cochlear implant candidacy assessment and cochlear implantation in infants and toddlers.

BACKGROUND: Cochlear implantation in children with sensorineural hearing loss is preferably performed at youngest age because early auditory input is essential to prevent neural plasticity decline. In contrast, the rate of anesthetic adverse events is increased during infancy. Therefore, to provide recommendations regarding an optimal pediatric implantation age, these possible anesthetic risks in infants need to be taken into account. AIMS: This study aimed at assessing the relation between the age at cochlear implant surgery and anesthetic and surgical adverse events. Secondary aims were to evaluate anesthetic and surgical adverse events in relation to (a) the number of preoperative anesthesia-related procedures for cochlear implant candidacy assessment and (b) the anesthetic maintenance agent (total intravenous anesthesia versus inhalation anesthesia) during implantation. METHODS: We executed a retrospective cohort study to evaluate cochlear implantation performed in infants and toddlers between January 2008 and July 2015 in a tertiary pediatric center. We compared anesthetic and surgical adverse events between age-at-implantation (0-12 and 12-24 months of age) groups. Furthermore, we assessed whether anesthetic adverse events occurred during preoperative anesthesia-related procedures for cochlear implant candidacy assessment. RESULTS: Forty-six cochlear implantations were performed in 43 patients requiring 42 preoperative anesthesia-related procedures. Nineteen cochlear implantations (41.3%) were performed during infancy. During implantation, the maintenance agent was either sevoflurane (n = 22) or propofol (n = 24). None of the patients encountered major anesthetic adverse events, whereas minor adverse events occurred during 34 cochlear implantations. Those attributed to surgery occurred following six implantations. Neither the age at implantation nor the anesthetic maintenance agent was significantly related to the occurrence of both types of adverse events. CONCLUSIONS: Adverse events occur independent of the age at implantation, the number of anesthetic preoperative procedures, and the type of anesthetic maintenance agent in patients who received a cochlear implant before 24 months of age.

Incorporating ceiling effects during analysis of speech perception data from a paediatric cochlear implant cohort.

OBJECTIVE: To compare speech perception between children with a different age at cochlear implantation. DESIGN: We evaluated speech perception by comparing consonant-vowel-consonant (auditory) (CVC(A)) scores at five-year follow-up of children implanted between 1997 and 2010. The proportion of children from each age-at-implantation group reaching the 95%CI of CVC(A) ceiling scores (>95%) was calculated to identify speech perception differences masked by ceiling effects. STUDY SAMPLE: 54 children implanted between 8 and 36 months. RESULTS: Although ceiling effects occurred, a CVC(A) score difference between age-at-implantation groups was confirmed (H (4) = 30.36; p < 0.001). Outperformance of early (<18 months) compared to later implanted children was demonstrated (p <0.001). A larger proportion of children implanted before 13 months compared to children implanted between 13 and 18 months reached ceiling scores. Logistic regression confirmed that age at implantation predicted whether a child reached a ceiling score. CONCLUSIONS: Ceiling effects can mask thorough delineation of speech perception. However, this study showed long-term speech perception outperformance of early implanted children (<18 months) either including or not accounting for ceiling effects during analysis. Development of long-term assessment tools not affected by ceiling effects is essential to maintain adequate assessment of young implanted infants.

A Systematic Review to Define the Speech and Language Benefit of Early (<12 Months) Pediatric Cochlear Implantation.

OBJECTIVE: This review aimed to evaluate the additional benefit of pediatric cochlear implantation before 12 months of age considering improved speech and language development and auditory performance. MATERIALS AND METHODS: We conducted a search in PubMed, EMBASE and CINAHL databases and included studies comparing groups with different ages at implantation and assessing speech perception and speech production, receptive language and/or auditory performance. We included studies with a high directness of evidence (DoE). RESULTS: We retrieved 3,360 articles. Ten studies with a high DoE were included. Four articles with medium DoE were discussed in addition. Six studies compared infants implanted before 12 months with children implanted between 12 and 24 months. Follow-up ranged from 6 months to 9 years. Cochlear implantation before the age of 2 years is beneficial according to one speech perception score (phonetically balanced kindergarten combined with consonant-nucleus-consonant) but not on Glendonald auditory screening procedure scores. Implantation before 12 months resulted in better speech production (diagnostic evaluation of articulation and phonology and infant-toddler meaningful auditory integration scale), auditory performance (Categories of Auditory Performance-II score) and receptive language scores (2 out of 5; Preschool Language Scale combined with oral and written language skills and Peabody Picture Vocabulary Test). CONCLUSIONS: The current best evidence lacks level 1 evidence studies and consists mainly of cohort studies with a moderate to high risk of bias. Included studies showed consistent evidence that cochlear implantation should be performed early in life, but evidence is inconsistent on all speech and language outcome measures regarding the additional benefit of implantation before the age of 12 months. Long-term follow-up studies are necessary to provide insight on additional benefits of early pediatric cochlear implantation.

Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine.

BACKGROUND: GATA transcription factors are essential for self-renewal of the small intestinal epithelium. Gata4 is expressed in the proximal 85% of small intestine while Gata6 is expressed throughout the length of small intestine. Deletion of intestinal Gata4 and Gata6 results in an altered proliferation/differentiation phenotype, and an up-regulation of SAM pointed domain containing ETS transcription factor (Spdef), a transcription factor recently shown to act as a tumor suppressor. The goal of this study is to determine to what extent SPDEF mediates the downstream functions of GATA4/GATA6 in the small intestine. The hypothesis to be tested is that intestinal GATA4/GATA6 functions through SPDEF by repressing Spdef gene expression. To test this hypothesis, we defined the functions most likely regulated by the overlapping GATA6/SPDEF target gene set in mouse intestine, delineated the relationship between GATA6 chromatin occupancy and Spdef gene regulation in Caco-2 cells, and determined the extent to which prevention of Spdef up-regulation by Spdef knockout rescues the GATA6 phenotype in conditional Gata6 knockout mouse ileum. RESULTS: Using publicly available profiling data, we found that 83% of GATA6-regulated genes are also regulated by SPDEF, and that proliferation/cancer is the function most likely to be modulated by this overlapping gene set. In human Caco-2 cells, GATA6 knockdown results in an up-regulation of Spdef gene expression, modeling our mouse Gata6 knockout data. GATA6 occupies a genetic locus located 40 kb upstream of the Spdef transcription start site, consistent with direct regulation of Spdef gene expression by GATA6. Prevention of Spdef up-regulation in conditional Gata6 knockout mouse ileum by the additional deletion of Spdef rescued the crypt cell proliferation defect, but had little effect on altered lineage differentiation or absorptive enterocytes gene expression. CONCLUSION: SPDEF is a key, immediate downstream effecter of the crypt cell proliferation function of GATA4/GATA6 in the small intestine.

Adverse events of open A1 pulley release for idiopathic trigger finger.

PURPOSE: To classify and report adverse events of trigger finger release in a large cohort of patients. METHODS: We retrospectively reviewed 1,598 trigger finger releases performed by 12 surgeons in 984 patients between 2001 and 2011. Adverse events were classified based on a system derived from the Centers for Disease Control and Prevention criteria and clinical experience. Risk factors for various adverse events were sought in bivariate and multivariable statistical analysis. RESULTS: At the latest follow-up, 66 patients (7%), or 84 operated trigger digits (5%), experienced a documented adverse event. The most common adverse events were recovery issues in 46 patients (3%) (such as postoperative symptoms treated with steroid injection or slow recovery of motion treated with hand therapy), wound problems in 30 patients (2%) (consisting of suture abscess, superficial infection, or wound separation), persistent postoperative triggering in 10 patients (0.6%), and recurrent triggering in 4 patients (0.3%). Diabetes mellitus was associated with wound problems, slow recovery of motion, and recurrence. Concomitant carpal tunnel release on the same side was associated with slow recovery. CONCLUSIONS: Fourteen patients, less than 1%, in this cohort experienced an adverse event, such as persistent or recurrent triggering, requiring secondary surgery. No nerve injury or deep infection occurred in our cohort. One in 15 patients experienced a minor transient or treatable adverse event, and patients with diabetes were at greater risk. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

A Systematic Literature Review to Compare Clinical Outcomes of Different Surgical Techniques for Second Branchial Cyst Removal.

OBJECTIVE: During the last 2 decades, new treatment methods have been developed for the surgical removal of second branchial cysts which result in less visible scars. The aim of this systematic review is to assess which surgical technique for second branchial arch cyst removal results in the lowest complication and recurrence rates with the highest scar satisfaction. METHODS: Two authors systematically reviewed the literature in the Cochrane, PubMed, and EMBASE databases (search date: 1975 to December 2nd, 2020) to identify studies comparing surgical outcomes of second branchial arch cyst removal. Authors appraised selected studies on directness of evidence and risk of bias. Results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Out of the 2442 retrieved articles, 4 articles were included in the current review including a total of 140 operated cysts. Only 2 studies included pre-operatively infected cysts. Follow up ranged from 3 to 24 months. Complication rates ranged from 0 to 27.3% (conventional: [0-10.4%]; endoscopic/retro-auricular: [0-27.3%]). None of the patients presented with postoperative recurrence. Significantly higher scar satisfaction was found in adult patients who underwent endoscopic or retro-auricular hairline incision cyst removal. CONCLUSION: No recurrence of disease occurred during (at least) 3 months of follow up using either conventional surgery or endoscopic/retro-auricular techniques. Although more (temporary) complications occur using endoscopic and retro-auricular techniques, patients report a significantly higher scar satisfaction 3 to 6 months after surgery in comparison to the conventional technique. Future studies are needed to support these findings.

Quality of life (QoL) evaluation of children using cochlear implants: agreement between pediatric and parent proxy-QoL reports.

Objectives: Cochlear implants are known to significantly improve the quality of life (QoL) of implanted children. However, variability exists between self-reported outcomes and parental-reported QoL questionnaires. We evaluated the QoL agreement between children and their parents following cochlear implantation and determined which factors lead to increased agreement. Methods: A cross-sectional study was performed including pediatric cochlear implant recipients and their parents. We evaluated postoperative QoL using The Pediatric Quality of Life Inventory (PedsQL). To assess agreement between pediatric and parental QoL perception, PedsQL intra-class correlations (ICCs) were calculated. Results: Thirty-five children and their parents completed QoL questionnaires. Children who were evaluated between 8-12 years of age reported highest absolute total and subscale PedsQL scores. Highest agreement was found amongst parents and children when: (1) children were between 8-12 years at QoL assessment (ICC: between 0.917[95%CI: 0.676-0.981] and 0.972[95%CI: 0.882-0.994]), and (2) when evaluating the physical health QoL domain (ICC: 0.964[95%CI: 0.849-0.992]). Conclusions: This study demonstrates high agreement (ICC > 0.8) between pediatric and parental QoL report in children aged between 8-12 years at QoL assessment. Therefore, results confirm that: (1) QoL agreement between pediatric self-report and parent proxy-report is high in chronically ill children and (2) children using cochlear implants can reliably report QoL between 8-12 years.

Low-Frequency Sensorineural Hearing Loss in Familial Hemophagocytic Lymphohistiocytosis Type 5.

INTRODUCTION: Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease affecting the cytotoxic pathway. Due to the recent advances in molecular diagnosis, immuno-chemo therapy, and hematopoietic stem cell transplantation treatment, FHL survival rates have drastically increased. CASE PRESENTATION: Herein, we describe a case of FHL type 5 presenting with low-frequency sensorineural hearing loss. Alongside our reported case, 6 additional patients were identified in the literature. Management and Outcome: The progressive nature of FHL disorder may cause bilateral, low-frequency, irreversible sensorineural hearing loss. This type of hearing loss should be considered among the long-term sequelea presenting with FHL5. DISCUSSION: We recommend audiological evaluation at initial FHL5 diagnosis to assess for hearing functions. Follow-up in audiology should be part of the long-term monitoring of patients with FHL5 as hearing loss could develop long after diagnosis.

Identification of Pure-Tone Audiologic Thresholds for Pediatric Cochlear Implant Candidacy: A Systematic Review.

Importance: Although current guidelines recommend cochlear implantation only for children with profound hearing impairment (HI) (>90 decibel [dB] hearing level [HL]), studies show that children with severe hearing impairment (>70-90 dB HL) could also benefit from cochlear implantation. Objective: To perform a systematic review to identify audiologic thresholds (in dB HL) that could serve as an audiologic candidacy criterion for pediatric cochlear implantation using 4 domains of speech and language development as independent outcome measures (speech production, speech perception, receptive language, and auditory performance). Evidence Review: PubMed and Embase databases were searched up to June 28, 2017, to identify studies comparing speech and language development between children who were profoundly deaf using cochlear implants and children with severe hearing loss using hearing aids, because no studies are available directly comparing children with severe HI in both groups. If cochlear implant users with profound HI score better on speech and language tests than those with severe HI who use hearing aids, this outcome could support adjusting cochlear implantation candidacy criteria to lower audiologic thresholds. Literature search, screening, and article selection were performed using a predefined strategy. Article screening was executed independently by 4 authors in 2 pairs; consensus on article inclusion was reached by discussion between these 4 authors. This study is reported according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Findings: Title and abstract screening of 2822 articles resulted in selection of 130 articles for full-text review. Twenty-one studies were selected for critical appraisal, resulting in selection of 10 articles for data extraction. Two studies formulated audiologic thresholds (in dB HLs) at which children could qualify for cochlear implantation: (1) at 4-frequency pure-tone average (PTA) thresholds of 80 dB HL or greater based on speech perception and auditory performance subtests and (2) at PTA thresholds of 88 and 96 dB HL based on a speech perception subtest. In 8 of the 18 outcome measures, children with profound HI using cochlear implants performed similarly to children with severe HI using hearing aids. Better performance of cochlear implant users was shown with a picture-naming test and a speech perception in noise test. Owing to large heterogeneity in study population and selected tests, it was not possible to conduct a meta-analysis. Conclusions and Relevance: Studies indicate that lower audiologic thresholds (≥80 dB HL) than are advised in current national and manufacturer guidelines would be appropriate as audiologic candidacy criteria for pediatric cochlear implantation.

Preliminary audiologic and peri-operative outcomes of the Sophono™ transcutaneous bone conduction device: A systematic review.

OBJECTIVE: To delineate the auditory functional improvement and peri-operative outcomes of the Sophono™ transcutaneous bone conduction device. METHODS: Eligible articles presenting patients implanted with the Sophono™ were identified through a comprehensive search of PubMed and Embase electronic databases. All relevant articles were reviewed to justify inclusion independently by 2 authors. Studies that successfully passed critical appraisal for directness of evidence and risk of bias were included. RESULTS: From a total of 125 articles, 8 studies encompassing 86 patients using 99 implants were selected. Most patients (79.1%) were children. Ear atresia (67.5%) was the most frequently reported indication for Sophono™ implantation. Overall pure tone average auditory improvement was 31.10 (±8.29) decibel. During a mean follow-up time of 12.48 months, 25 patients (29%) presented with post-operative complications from which 3 were deemed as serious implant-related adverse events (3.5%). CONCLUSIONS: The Sophono™ transcutaneous bone conduction device shows promising functional improvement, no intra-operative complications and minor post-operative skin related complications. If suitable, the device could be a proposed solution for the rehabilitation of hearing in children meeting eligibility criteria. A wearing schedule must be implemented in order to reduce magnet-related skin complications.

Evaluation of pediatric cochlear implant care throughout Europe: Is European pediatric cochlear implant care performed according to guidelines?

OBJECTIVES: International guidelines indicate that children with profound hearing loss should receive a cochlear implant (CI) soon after diagnosis in order to optimize speech and language rehabilitation. Although prompt rehabilitation is encouraged by current guidelines, delays in cochlear implantation are still present. This study investigated whether European countries establish timely pediatric CI care based on epidemiological, commercial, and clinical data. METHODS: An estimation of the number of pediatric CI candidates in European countries was performed and compared to epidemiological (Euro-CIU), commercial (Cochlear®), and clinical (institutional) age-at-implantation data. The ages at implantation of pediatric patients in eight countries (the Netherlands, Belgium, Germany, the United Kingdom, France, Turkey, Portugal, and Italy) between 2005 and 2015 were evaluated. RESULTS: From 2010 onwards, over 30% of the pediatric CI candidates were implanted before 24 months of age. Northern European institutions implanted children on average around 12 months of age, whereas southern European institutions implanted children after 18 months of age. The Netherlands and Germany implanted earliest (between 6 and 11 months). DISCUSSION: Implemented newborn hearing screening programs and reimbursement rates of CIs vary greatly within Europe due to local, social, financial, and political differences. However, internationally accepted recommendations are applicable to this heterogeneous European CI practice. Although consensus on early pediatric cochlear implantation exists, this study identified marked delays in European care. CONCLUSION: Regardless of the great heterogeneity in European practice, reasons for latency should be identified on a national level and possibilities to prevent avoidable future implantation delays should be explored to provide national recommendations.

Systematic Review on Surgical Outcomes and Hearing Preservation for Cochlear Implantation in Children and Adults.

OBJECTIVE: The mastoidectomy with facial recess approach (MFRA) is considered the reference standard for cochlear implantation. The suprameatal approach (SMA) was developed more recently and does not require mastoidectomy, which could influence postoperative outcomes. We aim to identify the optimal operative approach for cochlear implantation based on postoperative complications and hearing preservation in children and adults. DATA SOURCES: PubMed, EMBASE, Scopus, and Google Scholar. REVIEW METHODS: Studies comparing MFRA and SMA in children and adults were eligible for inclusion. Original reports with moderate relevance and validity were included. Relevance and validity were assessed with a self-modified critical appraisal tool. This review was reported in accordance to PRISMA guidelines. RESULTS: We retrieved 294 citations. Only retrospective nonrandomized studies were identified (level III evidence). Six articles were selected for full-text inclusion and 4 articles for data extraction. No article found a significant difference between MFRA and SMA with respect to postoperative complications in children and adults. One study found a significantly (P < .023) higher pediatric MFRA mastoiditis rate; however, meta-analysis did not indicate an overall effect. Hearing preservation was reported only in adults, and outcomes between techniques did not differ. CONCLUSION: No evidence was noted for lower complication rates or improved hearing preservation between the MFRA and SMA for cochlear implantation in children and adults. Pediatric data were available for children implanted above the age of 24 months only. Level I evidence is needed to resolve the uncertainty regarding differences in postoperative outcomes of pediatric and adult MFRA and SMA.

A systematic review on the surgical outcome of preauricular sinus excision techniques.

OBJECTIVES/HYPOTHESIS: Preauricular sinuses are benign congenital malformations of preauricular soft tissues. Complete excision using either sinectomy or supra-auricular approach is advised to prevent recurrence. Reported recurrence varies between 0 and 42%. We evaluated which surgical technique resulted in lowest complication and recurrence rates. STUDY DESIGN: PubMed, Embase, Scopus, Web of Science. METHODS: Two authors appraised studies on directness of evidence and risk of bias. Original data were extracted and pooled when I(2) was smaller than 50%. Results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Fourteen high directness of evidence studies were included. Reported complication rates were similar: sinectomy [0-31.4%] and supra-auricular approach (SAA) [0-18.2%]. Pooled recurrence rates showed that sinectomy resulted in significantly (P = .04) more recurrence 5.5% (95% confidence interval [CI] 3.6-8.3%) than SAA 2.2% (95% CI 0.7-7.0). Sinectomy using the microscope resulted in the lowest sinectomy recurrence rates (1.9%). SAA in combination with a Penrose drain resulted in 0% recurrence in revision cases. Drain use resulted in the lowest SAA recurrence rates; however, drain application was not advised due to higher complication rates (frequent wound infection [P = .003] and more [P = .002] and longer [P = .001] compression dressing use). CONCLUSION: SAA could be the preferable technique for preauricular sinus removal. If despite evidence, sinectomy is elected over SAA, microscope use can further decrease recurrence rates comparable to SAA levels. Level of included evidence (Ib-IV) indicates the need for a prospective study comparing surgical outcomes between techniques. Laryngoscope, 126:1535-1544, 2016.

The disease recurrence rate after the canal wall up or canal wall down technique in adults.

OBJECTIVES/HYPOTHESIS: To review which type of cholesteatoma surgery, canal wall up (CWU) or canal wall down (CWD), provides the lowest risk for residual and/or recurrent disease in adults with primary acquired cholesteatoma. DATA SOURCES: PubMed, Embase, CINAHL, the Cochrane Library, Scopus and Web of Science. STUDY DESIGN: We selected articles comparing CWU with CWD, reporting on disease recidivism (combined residual and recurrent disease) or independent residual or disease recurrence rates. We included studies with a moderate to high relevance. RESULTS: Our search yielded 2,060 articles. We selected seven studies that carried a moderate risk of bias. Six studies described higher disease recidivism after the CWU procedure [16.7-61.0%] compared to the CWD technique [0-13.2%]. Four studies showed statistical significant difference (P < .05). One study showed opposite results: recidivism was found in 7.8% CWU and in 22.1% CWD cases (P < .001). Studies showed CWU recidivism more likely to be residual disease, whereas CWD recidivism tended to be recurrent disease. CONCLUSION: The majority of included studies showed CWU to result in more disease recidivism compared to the CWD technique in adult patients with a primary acquired cholesteatoma. If recidivism risk is the most important factor to consider a certain surgical technique, we recommend application of the CWD procedure. However, many additional factors in patient care will define the best treatment decision, such as residual hearing and access to health care. Our recommendations are based on Level II evidence, which underlines the need for future high-level evidence studies.

Influence of Ossicular Chain Damage on Hearing After Chronic Otitis Media and Cholesteatoma Surgery: A Systematic Review and Meta-analysis.

IMPORTANCE: Physicians should ideally be able to provide patients with chronic otitis media and/or cholesteatoma specific information about postoperative hearing outcome, based on their level of preoperative ossicular chain damage (OCD). OBJECTIVE: To identify the influence of preoperative OCD on hearing outcomes in patients after chronic otitis media and/or cholesteatoma surgery. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library databases were systematically searched for available evidence, without any constraints, on December 13, 2014, for articles published between January 1, 1975, and December 13, 2014. STUDY SELECTION: We reviewed the literature for articles assessing the prognostic value of OCD on postoperative hearing outcome (air-bone gap [ABG] in decibels), using Austin-Kartush criteria or independent OCD classification systems. We assessed relevance and validity using a self-designed critical appraisal tool based on the Cochrane Collaboration's risk of bias tool. DATA EXTRACTION: Characteristics of study populations and postoperative ABGs in decibels were extracted from all included studies by 4 authors (E.F.B., M.N.G., N.J.K., A.S.H.J.L.). RESULTS: The tested hypothesis was formulated before data collection. Primary study outcome was defined as postoperative adult hearing outcomes after COM and/or cholesteatoma surgery defined as mean postoperative ABG. Our search yielded 5661 articles. Nine articles with high relevance were included. Pooled results of studies using the Austin-Kartush criteria showed a significant (P < .001) difference in mean ABG in favor of group B, when comparing group B (patients with malleus present, stapes absent; 11.1 [95% CI, 10.3-11.8] dB) to group C (patients with malleus absent, stapes present; 15.7 [95% CI, 14.6-16.7] dB) and group B to group D (patients with malleus absent, stapes absent; 16.5 [95% CI, 15.2-17.9] dB). Three studies using independent OCD classification criteria found no influence of stapes structure (intact stapes suprastructure, 13.5 [95% CI, 10.3-16.7], 15.1 [95% CI, 11.8-18.3], and 21.9 [95% CI, 15.0-28.8] dB vs absent stapes structure, 12.8 [95% CI, 9.5-16.1], 19.5 [95% CI, 14.9-24.1], and 30.2 [95% CI, 24.7-35.8] dB) on postoperative ABG. One study reported a significant (P = .04) difference in mean ABG between patients with present (18.9 [95% CI, 15.7-22.1] dB) and absent (24.4 [95% CI, 20.2-28.6] dB) malleus. CONCLUSIONS AND RELEVANCE: Pooled results of Austin-Kartush studies showed that in patients with COM, with or without cholesteatoma, the malleus status is a significant predictor of postoperative hearing outcome, independent of the stapes condition. Studies reporting on individual ossicle status supported this finding by showing that only malleus condition influenced postoperative hearing outcome. These findings are based on level IV evidence, which indicates the need for future high-level evidence studies.