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Risk of bias (RoB) assessment is essential to the systematic review methodology. The new version of the Cochrane RoB tool for randomized trials (RoB 2) was published in 2019 to address limitations identified since the first version of the tool was published in 2008 and to increase the reliability of assessments. This study analyzed the frequency of usage of the RoB 2 and the adequacy of reporting the RoB 2 assessments in non-Cochrane reviews published in 2020. This meta-research study included non-Cochrane systematic reviews of interventions published in 2020. For the reviews that used the RoB 2 tool, we analyzed the reporting of the RoB 2 assessment. Among 3880 included reviews, the Cochrane RoB 1 tool was the most frequently used (N = 2228; 57.4%), followed by the Cochrane RoB 2 tool (N = 267; 6.9%). From 267 reviews that reported using the RoB 2 tool, 213 (79.8%) actually used it. In 26 (12.2%) reviews, erroneous statements were used to indicate the RoB 2 assessment. Only 20 (9.4%) reviews presented a complete RoB 2 assessment with a detailed table of answers to all signaling questions. The judgment of risk of bias by the RoB 2 tool was not justified by a comment in 158 (74.2%) reviews. Only in 33 (14.5%) of reviews the judgment in all domains was justified in the accompanying comment. In most reviews (81.7%), the RoB was inadequately assessed at the study level. In conclusion, the majority of non-Cochrane reviews published in 2020 still used the Cochrane RoB 1 tool. Many reviews used the RoB 2 tool inadequately. Further studies about the uptake and the use of the RoB 2 tool are needed.

Orthodontic therapy is associated with a more significant accumulation of dentobacterial plaque and impaired oral hygiene, which increase the risk of developing dental caries and periodontal disease. Therefore, it is crucial to educate orthodontic patients about proper oral hygiene maintenance and oral health before and during treatment. The aim of this pilot study was to implement evidence-based best practices related to oral hygiene in adult orthodontic patients and improve compliance. In addition to evaluating oral hygiene practices, another goal of the project was to assess the knowledge of orthodontic patients regarding oral health. Questionnaires with seven pre- (before) and post-test criteria (90 day after implementation) were developed based on the best evidence available. This project was conducted in a private dental clinic in Split, Croatia, and included 45 patients. The baseline audit showed a gap between clinical practice and the best evidence. Three criteria achieved a high compliance baseline, while after implementation, there were substantial improvements in compliance for all. The everyday use of mouthwash improved from 17.8% at baseline to 66.7% at follow-up, as did the use of interdental aids, which increased from 55.6% to 91.1%. Statistically significant differences were found in the total score for oral health knowledge between the baseline (6.67 ± 1.74) and the follow-up audit (7.78 ± 0.56, p ≤ 0.001). The strategies developed in this project were effective in providing essential information to adult orthodontic patients and improving compliance with evidence. Guidelines on this topic should be designed to assist orthodontists and patients in maintaining oral health and oral hygiene.

BackgroundWhether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.MethodsIn a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated.ResultsAt a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group.ConclusionsAmong patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35-0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSIONThe combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATIONClinicalTrials.gov NCT03201458.FUNDINGNational Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI's Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.

Objective: To assess the methodological quality and characteristics of systematic reviews (SRs) of interventional studies in orthodontics and assess how the certainty of the evidence is reported using the GRADE approach. Material and Methods: Six electronic databases were searched, followed by a hand search of the reference lists of eligible studies (PROSPERO #CRD42020180852). The required study design was randomized and nonrandomized studies of interventions published between January 2019 and May 2020. The Assessing the Methodological Quality of Systematic Reviews (AMSTAR 2) tool was used for the quality appraisal of the included SRs. Paired reviewers independently screened the studies, extracted data, and appraised the methodological quality. Results: The study included 46 SRs; 19.5% had moderate to high methodological quality, and the remaining had low to critically low methodological quality. Fifty-four percent of the reviews assessed the certainty of evidence using the GRADE approach, and 34.8% followed all GRADE criteria. Conclusion: Most reviews had a good judgment of the AMSTAR2 items, although some critical items contributed to decreased overall quality. Half of the reviews used the GRADE approach to assess the certainty of the evidence, and this approach should be included in future systematic reviews of interventions.

Some Cochrane reviews were declared stable or closed, that is, not in need of updating. For some of them, it has been declared that conclusions will not (or it is unlikely they will) change with further studies. We explored whether there is a discernable decision-making pattern for decisions about the conclusiveness and stabilization of these reviews. We analyzed Cochrane reviews published until April 2020 labeled as stable or closed. We extracted the rationale leading to the decision declaring that the conclusion is not expected to change with further studies. Furthermore, we assessed whether the reviews used GRADE analysis. We extracted data from summary of findings (SoF) tables on the direction of effect, statistical significance, and I[superscript 2] values for the first and primary outcomes in SoFs, conclusions in the abstract and review, and implications for practice and future research. We included 40 stable/closed Cochrane reviews. Rationales for their stabilization did not enable any insight into the Cochrane's decision-making algorithm for considering the evidence as conclusive. Among 191 outcomes presented in the SoFs, 70% were rated with either low or very low certainty evidence. None of the reviews mentioned in the text that the review should be stabilized or closed, or that there is sufficient evidence on the subject. Reasons for stabilizing/closing Cochrane reviews were unclear, and we could not discern any pattern of "conclusive review" traits. Definition of systematic review conclusiveness is still lacking, which may contribute to research waste.

Objectives To describe how systematic reviews with network meta-analyses (NMAs) that used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) NMA approach addressed intransitivity when assessing certainty of evidence.Design Systematic survey.Data sources Medline, Embase and Cochrane Database of Systematic Reviews from September 2014 to October 2022.Eligibility criteria Systematic reviews of randomised controlled trials with aggregate data NMAs that used the GRADE NMA approach for assessing certainty of evidence.Data extraction and synthesis We documented how reviewers described methods for addressing intransitivity when assessing certainty of evidence, how often they rated down for intransitivity and their explanations for rating down.Results Of the 268 eligible systematic reviews, 44.8% (120/268) mentioned intransitivity when describing methods for assessing the certainty of evidence. Of these, 28.3% (34/120) considered effect modifiers and from this subset, 67.6% (23/34) specified the effect modifiers; however, no systematic review noted how they chose the effect modifiers. 15.0% (18/120) mentioned looking for differences between the direct comparisons that inform the indirect estimate. No review specified a threshold for difference in effect modifiers between the direct comparisons that would lead to rating down for intransitivity. Reviewers noted rating down indirect evidence for intransitivity in 33.1% of systematic reviews, and noted intransitivity for network estimates in 23.0% of reviews. Authors provided an explanation for rating down for intransitivity in 59.6% (31/52) of the cases in which they rated down. Of the 31 in which they provided an explanation, 74.2% (23/31) noted they detected differences in effect modifiers and 67.7% (21/31) specified in what effect modifiers they detected differences.Conclusions A third of systematic reviews with NMAs using the GRADE approach rated down for intransitivity. Limitations in reporting of methods to address intransitivity proved considerable. Whether the problem is that reviewers neglected to address rating down for transitivity at all, or whether they did consider but not report, is not clear. At minimum systematic reviews with NMAs need to improve their reporting practices regarding intransitivity; it may well be that they need to improve their practice in transitivity assessment. How to best address intransitivity may remain unclear for many reviewers thus additional GRADE guidance providing practical instructions for addressing intransitivity may be desirable.

Abstract Background Lack of knowledge about systematic reviews (SRs) could prevent individual healthcare workers (HCWs) from using SRs as a source of information in their clinical practice or discourage them from participating in such research. In this study, we aimed to explore in-depth the opinion of a sample of HCWs about the newly created online educational intervention designed to improve knowledge about SRs. Methods We created a brief online educational intervention on SRs, consisting of 11 textual modules. We evaluated it among practicing HCWs who graduated from a university-level health sciences program using a mixed-methods pilot study that consisted of pre- and post-intervention questionnaires and qualitative evaluation via semi-structured interviews. We assessed participants’ knowledge about SR methodology before and after the intervention, and compared the responses. We sought their opinions about the characteristics of SRs. Also, the participants were presented with four scientific abstracts, where they were asked to distinguish whether those abstracts presented summaries of a systematic or a non-systematic review. Results Twelve participants took part in the study. In the pilot study, the participants’ knowledge about SRs was improved after the intervention compared to the baseline. Participants provided positive feedback regarding the educational intervention. Suggestions to improve the educational intervention were to provide more details about the forest plot, add more digital content or images, provide more details about the methodological steps of an SR, add descriptions about practical applications of SRs and provide links to additional educational materials. The participants suggested that HCWs could be motivated to take part in such an education if it is offered as continuing medical education (CME) course or credit for academic/career advancement. Conclusion HCWs provided positive feedback about the newly designed online educational intervention on SRs; they considered it an appropriate tool for learning about SRs and resulted in increased knowledge about SRs. In addition, participants gave suggestions for improving education, which can be used to tailor the education for end-users. In future studies, it would be useful to examine the effectiveness of the modified educational intervention on increasing knowledge in a larger sample and in the form of a randomized controlled trial.

Neratinib was developed as an irreversible catalytic inhibitor of ERBB2, which also acts to inhibit ERBB1 and ERBB4. Neratinib is U.S. Food and Drug Administration (FDA)-approved as a neo-adjuvant therapy for use in HER2+ breast cancer. More recently, chemical biology analyses and the authors’ own bench work have demonstrated that neratinib has additional targets, which open up the possibility of using the drug in cell types that either lack ERBB receptor family expression or who rely on survival signalling downstream of growth factor receptors. Neratinib rapidly disrupted mutant RAS nanoclustering, which was followed by mutant rat sarcoma virus proteins translocating via LC3-associated phagocytosis into the cytosol where they were degraded by macroautophagy. Neratinib catalytically inhibited the MAP4K mammalian STE20-like protein kinase 4 and also caused its degradation via macroautophagy. This resulted in ezrin dephosphorylation and the plasma membrane becoming flaccid. Neratinib disrupted the nanoclustering of RAC1, which was associated with dephosphorylation of PAK1 and Merlin, and with increased phosphorylation of the Merlin binding partners large tumour suppressor kinase 1/2, YAP, and TAZ. YAP and TAZ exited the nucleus. Neratinib retained its anti-tumour efficacy against NSCLC cells made resistant to either afatinib or to osimertinib. Collectively, these findings argue that the possibilities for the further development of neratinib as cancer therapeutic in malignancies that do not express or over-express members of the ERBB receptor family are potentially wide-ranging.

Background: It is challenging to keep systematic reviews (SR) current and updated. Cochrane designated some of its SRs as "stable," that is, not in need of updating. The issue of stabilizing an SR is an important in research synthesis, because it could help reduce research waste. The aim of this study was to analyze publicly available justifications for stabilizing a Cochrane review, with the ultimate goal of helping to make decisions about whether the update of any SR is warranted. Methods: We analyzed Cochrane reviews labeled as stable in Archie, Cochrane's system for managing the editorial/publishing process. From the "What's new" section of the reviews in the Cochrane Library, we extracted justification for stabilization. Results: We included 545 Cochrane reviews labeled in Archie as stable on October 28, 2019. The most common of the five reasons for stabilization was that "last search did not identify any potentially relevant studies likely to change conclusions" (N=99; 18%), followed by "research area no longer active" (N=86; 16%), "review is or will be superseded" (N=41; 7.5%), "evidence is conclusive" (N=35; 6.4%), and "intervention no longer in general use" (N=34; 6.2%). For the 269 (49%) Cochrane reviews, we considered that the justification for stabilization was not clearly described, that is, sufficiently informative. Conclusions: Cochrane reviews would benefit from more transparency and consistency in publicly available justifications for stabilizing reviews. Further work in this field will help make decisions about the futility of further research and deciding on enough evidence in the field of research synthesis.

Abstract Background Navigating the rapidly growing body of scientific literature on the SARS-CoV-2 pandemic is challenging, and ongoing critical appraisal of this output is essential. We aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic. Methods Nine databases (Medline, EMBASE, Cochrane Library, CINAHL, Web of Sciences, PDQ-Evidence, WHO’s Global Research, LILACS, and Epistemonikos) were searched from December 1, 2019, to March 24, 2020. Systematic reviews analyzing primary studies of COVID-19 were included. Two authors independently undertook screening, selection, extraction (data on clinical symptoms, prevalence, pharmacological and non-pharmacological interventions, diagnostic test assessment, laboratory, and radiological findings), and quality assessment (AMSTAR 2). A meta-analysis was performed of the prevalence of clinical outcomes. Results Eighteen systematic reviews were included; one was empty (did not identify any relevant study). Using AMSTAR 2, confidence in the results of all 18 reviews was rated as “critically low”. Identified symptoms of COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%) and gastrointestinal complaints (5–9%). Severe symptoms were more common in men. Elevated C-reactive protein and lactate dehydrogenase, and slightly elevated aspartate and alanine aminotransferase, were commonly described. Thrombocytopenia and elevated levels of procalcitonin and cardiac troponin I were associated with severe disease. A frequent finding on chest imaging was uni- or bilateral multilobar ground-glass opacity. A single review investigated the impact of medication (chloroquine) but found no verifiable clinical data. All-cause mortality ranged from 0.3 to 13.9%. Conclusions In this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic were of questionable usefulness. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards.

Heart rate (HR) lowering during acute coronary syndrome (ACS) is beneficial as it reduces myocardial oxygen consumption. However, the role of ivabradine as an HR-lowering agent in the setting of ACS is not clear. We aimed to systematically review and synthesize the current evidence on the role of ivabradine use in the ACS. A systematic review was conducted for eligible randomized clinical trials and quasi-experimental studies, between 2009 and 2020, that investigated the use of ivabradine in ACS. Various clinical endpoints were evaluated such as major adverse cardiovascular events, efficacy in HR control, impact on left ventricular (LV) dimensions and function, and overall safety. Eleven publications were included encompassing a total of 1833 patients. The mean age of the examined cohort was 57 ± 11 years and 80 % were men. Seven studies were in the setting of ST-segment elevation myocardial infarction (MI) while the remaining studies also included patients with unstable angina and non-ST-segment elevation MI. Ivabradine was administered as a peroral drug with dosing from 2.5 to 7.5 mg b.i.d. Overall, the addition of ivabradine was superior to the control arm concerning HR control with a good safety profile. Beneficial effects on LV function and potential impact on infarct size reduction were observed as well. The use of ivabradine appeared to not affect short-term mortality. In conclusion, the use of ivabradine for HR control is safe, feasible, and efficacious for HR control in the ACS. Further studies are required to elucidate other potentially beneficial effects of ivabradine.

Abstract Background Bias in randomized controlled trials (RCTs) can lead to underestimation or overestimation of the true effects of interventions. Surgical RCTs may suffer from the risk of bias (RoB) that is avoidable in trials of other interventions, and vice versa. We aimed to compare the adequacy of RoB assessments in surgical versus non-surgical RCTs included in Cochrane reviews and to assess the most common differences in those RoB assessments. Due to specificities of surgical trials, i.e. difficulties associated with blinding of surgical interventions, we hypothesized that assessments of surgical trials may be more adequate, compared to RCTs of non-surgical interventions. Methods This was a methodological study, analyzing methods of published Cochrane systematic reviews. Data were extracted from RoB tables in Cochrane reviews (judgments and accompanying explanatory comment) for the following four RoB domains used in the 2011 Cochrane RoB tool: randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessors. We defined adequate assessments as those that were in line with instructions from the Cochrane Handbook for Systematic Reviews of Interventions. The prevalence of adequate assessments was compared in surgical versus non-surgical trials. The most common differences in both groups of reviews were presented. Results In 729 analyzed Cochrane reviews, there were 10,537 included trials. The prevalence of adequate RoB judgments made by Cochrane authors ranged from 87.9, 95%CI (87.3 to 88.6%) for randomization to 70.7, 95%CI (69.8 to 71.5%) for blinding of participants and personnel. For all analyzed RoB domains, the prevalence of adequate RoB domains was higher in surgical trials than in non-surgical trials. For two RoB domains assessing blinding, this difference between surgical and non-surgical trials was statistically significant (P

The number of pregnant women with cancer is on the rise. These patients and their providers encounter complex medical management decisions. Standard-of-care systemic therapy and radiological imaging can impair fetal development and affect viability. Conversely, insufficient monitoring and treatment can lead to cancer progression, compromising the health of the patient. Personalized and tumor-informed circulating tumor DNA (ctDNA) testing (Signatera™, bespoke mPCR NGS assay) is a validated, noninvasive blood test that can accurately assess cancer progression and tumor response to treatment ahead of radiological imaging, across solid tumors. In this case series of four patients, we explore the clinical utility of longitudinal ctDNA testing in the medical management of pregnant patients with solid tumors, to aid in informed decision-making for patients and providers.

We have extended our analyses of HDAC inhibitor biology in sarcoma. The multi-kinase inhibitor axitinib interacted with multiple HDAC inhibitors to kill sarcoma cells. Axitinib and HDAC inhibitors interacted in a greater than additive fashion to inactivate AKT, mTORC1 and mTORC2, and to increase Raptor S722/S792 phosphorylation. Individually, all drugs increased phosphorylation of ATM S1981, AMPKα T172, ULK1 S317 and ATG13 S318 and reduced ULK1 S757 phosphorylation; this correlated with enhanced autophagic flux. Increased phosphorylation of ULK1 S317 and of Raptor S722/S792 required ATM-AMPK signaling. ULK1 S757 is a recognized site for mTORC1 and knock down of either ATM or AMPKα reduced the drug-induced dephosphorylation of this site. Combined exposure of cells to axitinib and an HDAC inhibitor significantly reduced the expression of HDAC1, HDAC2, HDAC3, HDAC4, HDAC6 and HDAC7. No response was observed for HDACs 10 and 11. Knock down of ULK1, Beclin1 or ATG5 prevented the decline in HDAC expression, as did expression of a constitutively active mTOR protein. Axitinib combined with HDAC inhibitors enhanced expression of Class I MHCA and reduced expression of PD-L1 which was recapitulated via knock down studies, particularly of HDACs 1 and 3. In vivo, axitinib and the HDAC inhibitor entinostat interacted to significantly reduce tumor growth. Collectively our findings support the exploration of axitinib and HDAC inhibitors being developed as a novel sarcoma therapy.