Harms reporting by systematic reviews for functional endoscopic sinus surgery: a cross-sectional analysis.

OBJECTIVES: To evaluate the completeness of harms reporting in systematic reviews (SRs) pertaining to functional endoscopic sinus surgery (FESS). METHODS: Using a cross-sectional study design, we performed a comprehensive search using MEDLINE (PubMed and Ovid), EMBASE, Epistemonikos, and the Cochrane Database of Systematic Reviews databases for SRs regarding FESS on May 15th, 2022. Returns were screened and data were extracted in a masked, duplicate manner. Following established methodology, we extracted general study characteristics, harms items, and overall methodological quality for each SR in our sample. Corrected covered area (CCA) was calculated for SR dyads. For data analysis, using Stata 16.1 we performed a bivariate analysis between variables. RESULTS: Fifty-five SR's were included in our sample after excluding 375 studies that did not meet our inclusion criteria. Of the included SRs, 19 (19/55, 34.5%) did not report harms and 39 (39/55, 70.9%) reported half of the harms items or fewer. Our study found that 23 (23/55, 41.8%) of SRs demonstrated a method of harms data collection, 26 (26/55, 47.3%) of SRs had patients available for harms analysis in their results, and 25 (25/55, 45.5%) of SRs had a balanced discussion of harms and benefits of FESS. Fifty-two SRs were appraised as "critically low" quality using AMSTAR-2. A significant association was found between completeness of harms reporting (Mahady) and whether harms were listed as a primary outcome. No other associations were statistically significant. Two SR dyads had CCAs between 20% and 50% overlap and were compared for unique and shared harms. CONCLUSIONS: Our study demonstrates gaps in harms reporting regarding FESS in SRs. We recommend future studies implement guidelines such as the STROCCS guidelines or the harms extension of the PRISMA guidelines to improve harms reporting. Accurate harms reporting may advance patient safety and promote a more objective risk-benefit analysis for physicians and patients.

The Use of Person-centered Language in Medical Research Articles Focusing on Hearing Loss or Deafness.

BACKGROUND: Hearing loss represents one of the most common disabilities worldwide. Despite its prevalence, there is a degree of stigmatization within the public's perception of, or attitude toward, individuals diagnosed with hearing loss or deafness. This stigmatization is propagated by the way hearing loss is referenced, especially in writing. Although the medical community is familiar with hearing loss, medical research is not consistently compliant with nonstigmatizing terminology, like person-centered language (PCL). This study aims to quantify the use of PCL in medical research related to hearing loss. METHODS: A cross-sectional analysis of articles related to hearing loss was performed using PubMed as the primary search engine. The search encompassed articles from January 1, 2016, to November 17, 2020. Journals had to have at least 20 search returns to be included in this study. The primary search resulted in 2392 articles from 31 journals. The sample was then randomized and the first 500 articles were chosen for data extraction. Article screening was performed systematically. Each article was evaluated for predetermined non-PCL terminology to determine adherence to the American Medical Association Manual of Style (AMAMS) guidelines. Articles were included if they involved research with human participants and were available in English. Commentaries and editorials were excluded. RESULTS: Four hundred eighty-two articles were included in this study. Results from this study indicate that 326 articles were not adherent to AMAMS guidelines for PCL (326/482; 68%). Emotional language (i.e., burden, suffer, afflicted) was employed to reference hearing loss in 114 articles (114/482; 24%). Non-PCL adherent labels (i.e., impaired and handicapped) were identified in 46% (221/482) of articles related to hearing loss or deafness. Sixty-seven articles (67/482; 14%) used person-first language in reference to the word "deaf" and 15 articles (15/482; 3%) used "deaf" as a label. CONCLUSIONS: Based on the findings from this cross-sectional analysis, the majority of medical research articles that address hearing loss contain terminology that does not conform to PCL guidelines, as established by AMAMS. Many respected organizations, like the American Medical Association, have encouraged the use of PCL in interactions between patient and medical provider. This encompasses communication in person and in writing. This recommendation stems from the understood role that language plays in how we build impressions of others, especially in a medical context. Implementing PCL to destigmatize language used in reference to deafness or hearing loss is essential to increase advocacy and protect the autonomy of these individuals.

The fragility of statistically significant results in otolaryngology randomized trials.

OBJECTIVES: The American Academy of Otolaryngology-Head and Neck Surgery regards randomized controlled trials as class A evidence. A novel method to determine the robustness of outcomes in trials is the fragility index. This index represents the number of patients whose status would have to change from a non-event to an event to make a statistically significant result non-significant. METHODS: Investigators included otolaryngology journals listed in the top 10 of one or both of Google Scholar Metrics and Clarivate Analytics' Journal rankings. For inclusion, a randomized controlled trial needed to report a one-to-one random assignment of participants to condition, contain two parallel arms or have used a two-by-two factorial design, and report at least one statistically significant dichotomous outcome. RESULTS: Sixty-nine trials met inclusion criteria. The median fragility index was three events (interquartile range 1-7.5). Median sample size was 72 (interquartile range 50-102.5). Modest correlations were observed between fragility index and total sample size (r = 0.27) and fragility index and event rate (r = 0.46). Investigators found no correlation between fragility index and impact factor or Science Citation Index. In 39% (27/69) of trials, the number lost to follow-up was equal to or greater than the fragility index. CONCLUSION: A median fragility index of 3 indicates that three people, on average, are needed to alter the outcomes in otolaryngology trials. This indicates that the results of two-group randomized controlled trials reporting binary endpoints published in otolaryngology journals may frequently be fragile.

Results of the First Prospective Multi-institutional Treatment Study in Children With Bilateral Wilms Tumor (AREN0534): A Report From the Children's Oncology Group.

OBJECTIVE: The Children's Oncology Group study AREN0534 aimed to improve event-free survival (EFS) and overall survival (OS) while preserving renal tissue by intensifying preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response. BACKGROUND: No prospective therapeutic clinic trials in children with bilateral Wilms tumors (BWT) exist. Historical outcomes for this group were poor and often involved prolonged chemotherapy; on NWTS-5, 4-year EFS for all children with BWT was 56%. METHODS: Patients were enrolled and imaging studies were centrally reviewed to assess for bilateral renal lesions. They were treated with 3-drug induction chemotherapy (vincristine, dactinomycin, and doxorubicin) for 6 or 12 weeks based on radiographic response followed by surgery and further chemotherapy determined by histology. Radiation therapy was provided for postchemotherapy stage III and IV disease. RESULTS: One hundred eighty-nine of 208 patients were evaluable. Four-year EFS and OS were 82.1% (95% CI: 73.5%-90.8%) and 94.9% (95% CI: 90.1%-99.7%. Twenty-three patients relapsed and 7 had disease progression. After induction chemotherapy 163 of 189 (84.0%) underwent definitive surgical treatment in at least 1 kidney by 12 weeks and 39% retained parts of both kidneys. Surgical approaches included: unilateral total nephrectomy with contralateral partial nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral total nephrectomy (10.5%), unilateral partial nephrectomy (4%), and bilateral total nephrectomies (2.5%). CONCLUSION: This treatment approach including standardized 3-drug preoperative chemotherapy, surgical resection within 12 weeks of diagnosis and response and histology-based postoperative therapy improved EFS and OS and preservation of renal parenchyma compared with historical outcomes for children with BWT.

A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity.

IRAK4 is a member of IL-1 receptor (IL-1R)-associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)-mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase-inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R-mediated nuclear factor kappaB activation, a reduction of LPS-, R848-, and IL-1-mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow-derived macrophages from IRAK4 kinase-inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus-induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.

Harms Reporting in Systematic Reviews of the Microvascular Free Flap in Head and Neck Reconstruction.

OBJECTIVE: To evaluate harms reporting in systematic reviews (SRs) of microvascular free flap (MFF) in head and neck reconstruction. DATA SOURCES: This cross-sectional analysis included searches from the following major databases from 2012 to June 1, 2022: MEDLINE (Pubmed and Ovid), Embase, Epistemonikos, and the Cochrane Database of Systematic Reviews. REVIEW METHODS: In a masked duplicate manner, screening was performed using Rayyan, and data were extracted using a pilot-tested Google form. A MeaSurement Tool to Assess systematic Reviews-2 (AMSTAR-2) was used to appraise the methodological quality of reviews and the corrected covered area was calculated to detect primary study overlap across all reviews. Reviews were then grouped in pairs of 2, called dyads, and the corrected covered area was calculated again for each individual dyad. Dyads with high overlap (≥50%) were further investigated for the accuracy of harms reporting. RESULTS: Our initial search yielded 268 records, with 50 SRs meeting the inclusion criteria. A total of 46 (92%) of the included reviews demonstrated 50% or more adherence to the items assessed in our harms checklist. Our corrected covered area tool revealed 0.6% primary study overlap across all reviews, and 1 dyad with high overlap (≥50%). No statistically significant relationship was observed between the completeness of harms reporting and reviews listing harms as a primary outcome, reviews reporting adherence to Preferred Reporting Items of Systematic Reviews and Meta-Analyses, or a review's AMSTAR rating. CONCLUSION: This study identifies how harms reporting in SRs of MFF reconstruction of the head and neck can be improved and provides suggestions with the potential to mitigate the paucity in current literature.

An assessment of transparency and reproducibility-related research practices in otolaryngology.

OBJECTIVES/HYPOTHESIS: Clinical research serves as the foundation for evidence-based patient care, and reproducibility of results is consequently critical. We sought to assess the transparency and reproducibility of research studies in otolaryngology by evaluating a random sample of publications in otolaryngology journals between 2014 and 2018. STUDY DESIGN: Review of published literature for reproducible and transparent research practices. METHODS: We used the National Library of Medicine catalog to identify otolaryngology journals that met the inclusion criteria (available in the English language and indexed in MEDLINE). From these journals, we extracted a random sample of 300 publications using a PubMed search for records published between January 1, 2014 and December 31, 2018. Specific indicators of reproducible and transparent research practices were evaluated in a blinded, independent, and duplicate manner using a pilot-tested Google form. RESULTS: Our initial search returned 26,498 records, from which 300 were randomly selected for analysis. Of these 300 records, 286 met inclusion criteria and 14 did not. Among the empirical studies, 2% (95% confidence interval [CI]: 0.4%-3.5%) of publications indicated that raw data were available, 0.6% (95% CI: 0.3%-1.6%) reported an analysis script, 5.3% (95% CI: 2.7%-7.8%) were linked to an accessible research protocol, and 3.9% (95% CI: 1.7%-6.1%) were preregistered. None of the publications had a clear statement claiming to replicate, or to be a replication of, another study. CONCLUSIONS: Inadequate reproducibility practices exist in otolaryngology. Nearly all studies in our analysis lacked a data or material availability statement, did not link to an accessible protocol, and were not preregistered. Taking steps to improve reproducibility would likely improve patient care. LEVEL OF EVIDENCE: NA Laryngoscope, 130: 1894-1901, 2020.

Registration Practices of Randomized Clinical Trials in Rhinosinusitis: A Cross-sectional Review.

IMPORTANCE: Randomized clinical trials (RCTs) play an important role in the development of clinical practice guidelines and in clinical decision making. Little is known about the registration practices of RCTs in the diagnosis and treatment of rhinosinusitis. OBJECTIVES: The primary outcome was the frequency of reported RCT registry numbers by authors of rhinosinusitis RCTs. A secondary outcome was the rates of selective reporting bias in RCTs that were prospectively registered. A tertiary outcome end point was the frequency of publication of RCTs registered on ClinicalTrials.gov. EVIDENCE REVIEW: Our sample was derived from a PubMed (MEDLINE) search performed on October 31, 2017, using the keywords "sinusitis OR rhinosinusitis OR rhinitis," and filtering by date (January 1, 2015, through October 31, 2017) and study type (RCT). Studies that were considered an RCT were included for the primary outcome analysis. All RCTs that were registered prior to or during patient enrollment were included for secondary outcome analysis. For the tertiary outcome, a search was performed on ClinicalTrials.gov on September 4, 2018, using the keywords "sinusitis OR rhinosinusitis," and filtering by date (January 1, 2013, through October 31, 2015). All analysis took place between October 29, 2018, and October 31, 2018. FINDINGS: A total of 179 RCTs were analyzed for our primary outcome: 94 (52.5%) included a registration number in their publication, and 70 (39.1%) were included for secondary outcome analysis of rates of selective reporting bias. Of these 70 RCTs, 22 (31%) were found to have at least 1 major discrepancy between trial registration and publication. For the tertiary outcome, 52 completed clinical trials were identified on ClinicalTrials.gov, of which 21 (40%) had listed publication in the registry. CONCLUSIONS AND RELEVANCE: We found that published rhinosinusitis RCTs frequently do not include a trial registration number and that registered RCTs frequently are not published. Furthermore, RCTs that are registered often display selective reporting of their outcomes and frequently favor positive results. We recommend strict adherence to RCT registration policies and the enforcement of accurate reporting to help strengthen the evidence behind clinical decision making.

Evaluation of spin in the abstracts of otolaryngology randomized controlled trials.

OBJECTIVE: Spin, the misrepresentation and distortion of research findings, has been shown to affect clinical decision making. Spin has been found in randomized controlled trials (RCTs) published in various fields of medicine, but no study has tested for the presence of spin in otolaryngology RCTs. The purpose of this study is to evaluate the abstracts of RCTs found in the otolaryngology literature for spin. METHODS: In this cross-sectional analysis, we analyzed the abstracts of RCTs for spin using a pilot-tested form. Double data extraction was performed by two blinded authors, and discrepancies were resolved using mutual discussion. RESULTS: Out of the 534 PubMed citations retrieved by our search string, 162 parallel-group RCTs with clearly defined primary and secondary endpoints were identified. Further analysis identified 47 trials with nonsignificant primary outcomes, which were then evaluated for spin. Spin was identified in 33 of the 47 (70%) abstracts. Spin was found in the results sections of 25 (53%) of the included abstracts and was found in the conclusion section of 27 (57%) of the abstracts. Spin was not present in the titles of any of the included studies. CONCLUSION: Spin was common in our sample of otolaryngology RCTs. Spin may potentially create false impressions about the true validity of a drug or intervention. Further research needs to test for potential clinical implications of spin in the otolaryngology literature. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018.

IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression.

NOTCH1 signalling contributes to defective remyelination by impairing differentiation of oligodendrocyte progenitor cells (OPCs). Here we report that IL-17 stimulation induces NOTCH1 activation in OPCs, contributing to Th17-mediated demyelinating disease. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NOTHC1 intracellular domain (NICD1). IL-17-induced NOTCH1 activation results in the interaction of IL-17R adaptor Act1 with NICD1, followed by the translocation of the Act1-NICD1 complex into the nucleus. Act1-NICD1 are recruited to the promoters of several NOTCH1 target genes (including STEAP4, a metalloreductase important for inflammation and cell proliferation) that are specifically induced in the spinal cord by Th17 cells. A decoy peptide disrupting the IL-17RA-NOTCH1 interaction inhibits IL-17-induced NOTCH1 activation and attenuates Th17-mediated experimental autoimmune encephalitis (EAE). Taken together, these findings demonstrate critical crosstalk between the IL-17 and NOTCH1 pathway, regulating Th17-induced inflammatory and proliferative genes to promote demyelinating disease.

Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells.

Recent data implicate elevated transforming growth factor-ß (TGFß) signalling in BRAF inhibitor drug-resistance mechanisms, but the potential for targeting TGFß signalling in cases of advanced melanoma has not been investigated. We show that mutant BRAFV600E confers an intrinsic dependence on TGFß/TGFß receptor 1 (TGFBR1) signalling for clonogenicity of murine melanocytes. Pharmacological inhibition of the TGFBR1 blocked the clonogenicity of human mutant BRAF melanoma cells through SMAD4-independent inhibition of mitosis, and also inhibited metastasis in xenografted zebrafish. When investigating the therapeutic potential of combining inhibitors of mutant BRAF and TGFBR1, we noted that unexpectedly, low-dose PLX-4720 (a vemurafenib analogue) promoted proliferation of drug-naïve melanoma cells. Pharmacological or pharmacogenetic inhibition of TGFBR1 blocked growth promotion and phosphorylation of SRC, which is frequently associated with vemurafenib-resistance mechanisms. Importantly, vemurafenib-resistant patient derived cells retained sensitivity to TGFBR1 inhibition, suggesting that TGFBR1 could be targeted therapeutically to combat the development of vemurafenib drug-resistance.