Minimum false-positive risk of primary outcomes and impact of reducing nominal P-value threshold from 0.05 to 0.005 in anaesthesiology randomised clinical trials: a cross-sectional study.

BACKGROUND: Reproducibility of research is poor; this may be because many articles report statistically significant findings that are false positives. Two potential solutions are to lower the P-value for statistical significance testing from 0.05 to 0.005 and to report the minimum false-positive risk (minFPR). This study determined these metrics for randomised controlled trials (RCTs) in general anaesthesiology journals. METHODS: We identified superiority RCTs published between January 1, 2019 and March 15, 2021 from seven leading anaesthesia journals. P-values for primary outcomes were collected, and minFPRs for these outcomes were calculated using a formula assuming a 50% prior probability of an intervention being effective (minFPR50). The primary outcomes were the percentage of RCTs maintaining statistical significance at P<0.005 and minFPR50. RESULTS: We included 318 RCTs. P-values below 0.05 were reported in 205/318 (64%) of RCTs. Of these 205 RCTs, 119/205 (58%) maintained statistical significance at the P<0.005 threshold. The mean (standard deviation) minFPR50 was 22% (20). At P=0.005, the minFPR50 was approximately 5%. CONCLUSIONS: These proposed metrics aimed at mitigating reproducibility concerns would call a significant portion of the anaesthesiology literature into question. We found a minFPR of 22% and determined that 42% of primary outcomes would not maintain statistical significance if the P-value threshold changed from 0.05 to 0.005. These findings could partially explain the lack of reproducibility of research findings.

Epidemiological, methodological, and statistical characteristics of network meta-analysis in anaesthesia: a systematic review.

BACKGROUND: Network meta-analyses (NMAs) combine direct and indirect estimates to provide mixed (or network) estimates of effect sizes. The scientific rigour of the conduct and reporting of anaesthesia NMAs is unknown. This review assessed the epidemiological, methodological, and statistical characteristics of anaesthesia NMAs. METHODS: We searched four databases for anaesthesia NMAs and developed a 64-item checklist to evaluate NMAs. For 29 binary items, we defined compliance as 'the ratio of NMAs that was awarded a 'yes' for that item, divided by the total number of NMAs. The compliance of such binary items was reclassified as very low (≤25%), low (26-50%), fair (51-75%), and high (>75%). We amalgamated findings from 29 key items to provide specific recommendations (post hoc). We compared the compliance of NMAs in anaesthesia across 26 items, with that of cancer NMAs and Cochrane NMAs, and analysed improvement over time (post hoc). RESULTS: Among 62 included NMAs, compliance was low (26-50%) for protocol registration, use of PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for NMA), publication bias assessment, evidence appraisal, reporting of Bayesian methodology and consistency evaluation. Compliance was very low (≤25%) for bias assessment, biostatistician involvement, search specialist, and use of predefined important differences. CONCLUSIONS: Anaesthesia NMAs need improvement in their conduct and reporting. Anaesthesia journals should mandate the registration of protocols and reporting of NMAs using PRISMA-NMA. Authors should carefully assess publication bias, and use updated bias assessment tools, and evidence appraisal methods designed for NMAs. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021227608.

Methodological and reporting quality assessment of network meta-analyses in anesthesiology: a systematic review and meta-epidemiological study.

PURPOSE: The scientific rigour of the conduct and reporting of anesthesiology network meta-analyses (NMAs) is unknown. This systematic review and meta-epidemiological study assessed the methodological and reporting quality of NMAs in anesthesiology. METHODS: We searched four databases, including MEDLINE, PubMed, Embase, and the Cochrane Systematic Reviews Database, for anesthesiology NMAs published from inception to October 2020. We assessed the compliance of NMAs against A Measurement Tool to Assess Systematic Reviews (AMSTAR-2), Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Network Meta-Analyses (PRISMA-NMA), and PRISMA checklists. We measured the compliance across various items in AMSTAR-2 and PRISMA checklists and provided recommendations to improve quality. RESULTS: Using the AMSTAR-2 rating method, 84% (52/62) of NMAs were rated "critically low." Quantitatively, the median [interquartile range] AMSTAR-2 score was 55 [44-69]%, while the PRISMA score was 70 [61-81]%. Methodological and reporting scores showed a strong correlation (R = 0.78). Anesthesiology NMAs had a higher AMSTAR-2 score and PRISMA score if they were published in higher impact factor journals (P = 0.006 and P = 0.01, respectively) or followed PRISMA-NMA reporting guidelines (P = 0.001 and P = 0.002, respectively). Network meta-analyses from China had lower scores (P < 0.001 and P < 0.001, respectively). Neither score improved over time (P = 0.69 and P = 0.67, respectively). CONCLUSION: The current study highlights numerous methodological and reporting deficiencies in anesthesiology NMAs. Although the AMSTAR tool has been used to assess the methodological quality of NMAs, dedicated tools for conducting and assessing the methodological quality of NMAs are urgently required. STUDY REGISTRATION: PROSPERO (CRD42021227997); first submitted 23 January 2021.

RéSUMé: OBJECTIF: La rigueur scientifique de la conduite et de la communication des méta-analyses en réseau (MAR) en anesthésiologie est inconnue. Cette revue systématique et étude méta-épidémiologique a évalué la qualité méthodologique et de communication des MAR en anesthésiologie. MéTHODE: Nous avons mené des recherches dans quatre bases de données, soit MEDLINE, PubMed, Embase et la base de données des revues systématiques Cochrane, pour trouver des MAR en anesthésiologie publiées depuis la création de ces bases de données jusqu'en octobre 2020. Nous avons évalué la conformité des MAR par rapport à trois outils, soit : AMSTAR-2 (outil de mesure pour évaluer les revues systématiques), PRISMA-NMA et les listes de contrôle PRISMA. Nous avons mesuré la conformité de divers éléments des listes de contrôle AMSTAR-2 et PRISMA et formulé des recommandations pour améliorer la qualité. RéSULTATS: En utilisant la méthode de notation AMSTAR-2, 84 % (52/62) des MAR ont reçu la cote « extrêmement faible ¼. Quantitativement, le score médian [écart interquartile] sur l'AMSTAR-2 était de 55 [44-69] %, tandis que le score PRISMA était de 70 [61-81] %. Les scores méthodologiques et de communication ont montré une forte corrélation (R = 0,78). Les MAR en anesthésiologie avaient un score AMSTAR-2 et un score PRISMA plus élevés si elles étaient publiées dans des revues à facteur d'impact plus élevé (P = 0,006 et P = 0,01, respectivement) ou avaient suivi les lignes directrices de PRISMA-NMA en matière de communication des résultats (P = 0,001 et P = 0,002, respectivement). Les méta-analyses en réseau provenant de Chine avaient des scores plus faibles (P < 0,001 et P < 0,001, respectivement). Aucun des deux scores ne s'est amélioré au fil du temps (P = 0,69 et P = 0,67, respectivement). CONCLUSION: La présente étude met en évidence de nombreuses lacunes méthodologiques et de communication dans les MAR en anesthésiologie. Bien que l'outil AMSTAR ait été utilisé pour évaluer la qualité méthodologique des MAR, il est urgent de disposer d'outils spécialisés pour mener des MAR et en évaluer la qualité méthodologique. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021227997); soumis pour la première fois le 23 janvier 2021.

Interpreting frequentist hypothesis tests: insights from Bayesian inference.

Randomized controlled trials are one of the best ways of quantifying the effectiveness of medical interventions. Therefore, when the authors of a randomized superiority trial report that differences in the primary outcome between the intervention group and the control group are "significant" (i.e., P ≤ 0.05), we might assume that the intervention has an effect on the outcome. Similarly, when differences between the groups are "not significant," we might assume that the intervention does not have an effect on the outcome. Nevertheless, both assumptions are frequently incorrect.In this article, we explore the relationship that exists between real treatment effects and declarations of statistical significance based on P values and confidence intervals. We explain why, in some circumstances, the chance an intervention is ineffective when P ≤ 0.05 exceeds 25% and the chance an intervention is effective when P > 0.05 exceeds 50%.Over the last decade, there has been increasing interest in Bayesian methods as an alternative to frequentist hypothesis testing. We provide a robust but nontechnical introduction to Bayesian inference and explain why a Bayesian posterior distribution overcomes many of the problems associated with frequentist hypothesis testing.Notwithstanding the current interest in Bayesian methods, frequentist hypothesis testing remains the default method for statistical inference in medical research. Therefore, we propose an interim solution to the "significance problem" based on simplified Bayesian metrics (e.g., Bayes factor, false positive risk) that can be reported along with traditional P values and confidence intervals. We calculate these metrics for four well-known multicentre trials. We provide links to online calculators so readers can easily estimate these metrics for published trials. In this way, we hope decisions on incorporating the results of randomized trials into clinical practice can be enhanced, minimizing the chance that useful treatments are discarded or that ineffective treatments are adopted.

RéSUMé: Les études randomisées contrôlées constituent l'un des meilleurs moyens de quantifier l'efficacité des interventions médicales. Par conséquent, lorsque les autrices et auteurs d'une étude randomisée superiorité signalent que les différences dans le critère d'évaluation principal entre le groupe d'intervention et le groupe témoin sont « significatives ¼ (c.-à-d. P ≤ 0,05), nous pourrions supposer que l'intervention a un effet sur le critère d'évaluation. De même, lorsque les différences entre les groupes ne sont « pas significatives ¼, nous pourrions supposer que l'intervention n'a pas d'effet sur le critère d'évaluation. Pourtant, ces deux hypothèses s'avèrent souvent incorrectes.Dans cet article, nous explorons la relation qui existe entre les effets réels d'un traitement et les déclarations de signification statistique fondées sur les valeurs P et les intervalles de confiance. Nous expliquons pourquoi, dans certaines circonstances, la probabilité qu'une intervention soit inefficace lorsque P ≤ 0,05 dépasse 25 % et la probabilité qu'une intervention soit efficace lorsque P > 0,05 dépasse 50 %.Au cours de la dernière décennie, nous avons assisté à un intérêt croissant pour les méthodes bayésiennes comme alternative aux tests d'hypothèses fréquentistes. Nous proposons une introduction robuste mais non technique à l'inférence bayésienne et expliquons pourquoi une distribution postérieure bayésienne surmonte bon nombre des problèmes associés aux tests d'hypothèses fréquentistes.Malgré l'intérêt actuel pour les méthodes bayésiennes, les tests d'hypothèses fréquentistes restent la méthode par défaut pour l'inférence statistique en recherche médicale. Par conséquent, nous proposons une solution provisoire au « problème de signification ¼ basée sur des mesures bayésiennes simplifiées (par exemple, facteur de Bayes, risque de faux positifs) qui peuvent être rapportées en même temps que les mesures traditionnelles des valeurs P et des intervalles de confiance. Nous calculons ces paramètres pour quatre études multicentriques bien connues. Nous fournissons des liens vers des calculatrices en ligne afin que les lectrices et lecteurs puissent facilement estimer ces mesures pour les études publiées. De cette façon, nous espérons que les décisions sur l'intégration des résultats des études randomisées dans la pratique clinique pourront être améliorées, minimisant ainsi le risque que des traitements utiles soient rejetés ou que des traitements inefficaces soient adoptés.

Performance of administrative database frailty instruments in predicting clinical outcomes and cost for patients undergoing transcatheter aortic valve implantation: a historical cohort study.

PURPOSE: Frailty instruments may improve prognostic estimates for patients undergoing transcatheter aortic valve implantation (TAVI). Few studies have evaluated and compared the performance of administrative database frailty instruments for patients undergoing TAVI. This study aimed to examine the performance of administrative database frailty instruments in predicting clinical outcomes and costs in patients who underwent TAVI. METHODS: We conducted a historical cohort study of 3,848 patients aged 66 yr or older who underwent a TAVI procedure in Ontario, Canada from 1 April 2012 to 31 March 2018. We used the Johns Hopkins Adjusted Clinical Group (ACG) frailty indicator and the Hospital Frailty Risk Score (HFRS) to assign frailty status. Outcomes of interest were in-hospital mortality, one-year mortality, rehospitalization, and healthcare costs. We compared the performance of the two frailty instruments with that of a reference model that adjusted baseline covariates and procedural characteristics. Accuracy measures included c-statistics, Akaike information criterion (AIC), Bayesian information criterion (BIC), integrated discrimination improvement (IDI), net reclassification index (NRI), bias, and accuracy of cost estimates. RESULTS: A total of 863 patients (22.4%) were identified as frail using the Johns Hopkins ACG frailty indicator and 865 (22.5%) were identified as frail using the HFRS. Although agreement between the frailty instruments was fair (Kappa statistic = 0.322), each instrument classified different subgroups as frail. Both the Johns Hopkins ACG frailty indicator (rate ratio [RR], 1.13; 95% confidence interval [CI], 1.06 to 1.20) and the HFRS (RR, 1.14; 95% CI, 1.07 to 1.21) were significantly associated with increased one-year costs. Compared with the reference model, both the Johns Hopkins ACG frailty indicator and HFRS significantly improved NRI for one-year mortality (Johns Hopkins ACG frailty indicator: NRI, 0.160; P < 0.001; HFRS: NRI, 0.146; P = 0.001) and rehospitalization (Johns Hopkins ACG frailty indicator: NRI, 0.201; P < 0.001; HFRS: NRI, 0.141; P = 0.001). These improvements in NRI largely resulted from classification improvement among those who did not experience the event. With one-year mortality, there was a significant improvement in IDI (IDI, 0.003; P < 0.001) with the Johns Hopkins ACG frailty indicator. This improvement in performance resulted from an increase in the mean probability of the event among those with the event. CONCLUSION: Preoperative frailty assessment may add some predictive value for TAVI outcomes. Use of administrative database frailty instruments may provide small but significant improvements in case-mix adjustment when profiling hospitals for certain outcomes.

RéSUMé: OBJECTIF: L'utilisation d'indicateur de fragilité pourrait améliorer l'évaluation pronostique des patients bénéficiant d'un remplacement valvulaire aortique par voie percutanée (procédure TAVI). Peu d'études ont évalué et comparé la performance des instruments d'évaluation de la fragilité développés à partir de données administratives chez les patients bénéficiant d'un TAVI. Nous avions pour objectif d'examiner la performance des instruments d'évaluation de la fragilité développés à partir de données administratives dans la prédiction des issues cliniques et des coûts chez les patients ayant bénéficié d'un TAVI. MéTHODE: Nous avons réalisé une étude de cohorte historique auprès de 3848 patients âgés de 66 ans ou plus qui ont bénéficié d'une procédure TAVI en Ontario, Canada, du 1er avril 2012 au 31 mars 2018. Nous avons utilisé l'indicateur de fragilité ACG (Adjusted Clinical Group) de Johns Hopkins et le score de risque de fragilité à l'hôpital (HFRS) pour définir la fragilité. Les critères d'évaluation étaient la mortalité hospitalière, la mortalité à un an, la réhospitalisation et les coûts des soins de santé. Nous avons comparé la performance des deux instruments d'évaluation de la fragilité à celle d'un modèle de référence qui ajustait les covariables de base et les caractéristiques procédurales. Les mesures d'exactitude comprenaient l'analyse statistique c, le critère d'information d'Akaike (AIC), le critère d'information bayésien (BIC), l'amélioration de la discrimination intégrée (IDI), l'indice NRI (net reclassification index), le biais et l'exactitude des estimations de coûts. RéSULTATS: Au total, 863 patients (22,4 %) ont été identifiés comme fragiles à l'aide de l'indicateur de fragilité ACG de Johns Hopkins, et 865 (22,5 %) ont été identifiés comme fragiles à l'aide du HFRS. Bien que l'agrément entre les instruments d'évaluation de la fragilité ait été acceptable (statistique de Kappa = 0,322), chaque instrument a classé des sous-groupes différents comme étant fragiles. L'indicateur de fragilité ACG de Johns Hopkins (rapport de taux [RR], 1,13; intervalle de confiance à 95 % [IC], 1,06 à 1,20) et le HFRS (RR, 1,14; IC 95 %, 1,07 à 1,21) étaient associés de façon significative à une augmentation des coûts sur un an. Par rapport au modèle de référence, l'indicateur de fragilité ACG de Johns Hopkins améliorent de façon significative le NRI pour la mortalité (l'indicateur de fragilité ACG de Johns Hopkins: NRI, 0.160; P < 0.001; HFRS: NRI, 0.146; P = 0.001) et la réhospitalisation (l'indicateur de fragilité ACG: NRI, 0.201; P < 0.001; HFRS: NRI, 0.141; P = 0.001) à un an. Ces améliorations du NRI résultent en grande partie de l'amélioration de la classification chez ceux qui n'ont pas bénéficié d'un TAVI. En ce qui a trait à la mortalité à un an, il y a eu une amélioration significative de l'IDI (IDI, 0,003; P < 0,001) avec l'indicateur de fragilité ACG de Johns Hopkins. Cette amélioration de la performance résultait d'une augmentation de la probabilité moyenne de TAVI chez les personnes ayant vécu l'événement. CONCLUSION: L'évaluation préopératoire de la fragilité peut ajouter une certaine valeur prédictive aux issues cliniques suivant une procédure de TAVI. L'utilisation d'instruments d'évaluation de la fragilité développés à partir de données administratives peut apporter des améliorations mineures mais significatives pour l'ajustement de risque lors de l'évaluation des hôpitaux en fonction de certaines issues cliniques.

IDEAL-D Framework for Device Innovation: A Consensus Statement on the Preclinical Stage.

OBJECTIVE: To extend the IDEAL framework for device innovation, IDEAL-D, to include the preclinical stage of development (stage 0). BACKGROUND: In previous work, the IDEAL collaboration has proposed frameworks for new surgical techniques and complex therapeutic technologies, the central tenet being that development and evaluation can and should proceed together in an ordered and logical manner that balances innovation and safety. METHODS: Following agreement at the IDEAL Collaboration Council, a multidisciplinary working group was formed comprising 12 representatives from healthcare, academia, industry, and a patient advocate. The group conducted a series of discussions following the principles used in the development of the original IDEAL framework. Importantly, IDEAL aims for maximal transparency, optimal validity in the evaluation of primary effects, and minimization of potential risk to patients or others. The proposals were subjected to further review and editing by members of the IDEAL Council before a final consensus version was adopted. RESULTS: In considering which studies are required before a first-in-human study, we have: (1) classified devices according to what they do and the risks they carry, (2) classified studies according to what they show about the device, and (3) made recommendations based on the principle that the more invasive and high risk a device is, the greater proof required of their safety and effectiveness before progression to clinical studies (stage 1). CONCLUSIONS: The proposed recommendations for preclinical evaluation of medical devices represent a proportionate and pragmatic approach that balances the de-risking of first-in-human translational studies against the benefits of rapid translation of new devices into clinical practice.

Evaluation of spin in the abstracts of systematic reviews and meta-analyses relating to postoperative nausea and vomiting.

INTRODUCTION: Spin - the beautification of study results to emphasise benefits or minimise harms - is a deceptive reporting strategy with the potential to affect clinical decision-making adversely. Few studies have investigated the extent of spin in systematic reviews. Here, we sought to address this gap by evaluating the presence of the nine most severe forms of spin in the abstracts of systematic reviews on treatments for postoperative nausea and vomiting (PONV). PONV has the potential to increase hospital costs and patient burden, adversely affecting outcomes. METHODS: We developed search strategies for MEDLINE and Embase to identify systematic reviews focused on PONV. Following title and abstract screening of the reviews identified during the initial search, those that met inclusion criteria were evaluated for the presence of spin and received a revised AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews) appraisal by two investigators in a masked, duplicate manner. Study characteristics for each review were also extracted in duplicate. RESULTS: Our systematic search returned 3513 studies, of which 130 systematic reviews and meta-analyses were eligible for data extraction. We found that 29.2% of included systematic reviews contained spin (38/130). Eight of the nine types of spin were identified, with spin type 3 ('selective reporting of or overemphasis on efficacy outcomes or analysis favouring the beneficial effect of the experimental intervention') being the most common. Associations were found between spin and funding source. Spin was more likely in the abstracts of privately funded than nonfunded studies, odds ratio (OR) 2.81 [95% confidence interval (CI), 0.66 to 11.98]. In the abstracts of studies not mentioning funding spin was also more likely than in nonfunded studies, OR 2.30 (95% CI, 0.61 to 8.70). Neither of these results were statistically significant. Significance was found in the association between the presence of spin and AMSTAR-2 ratings: 'low' quality studies were less likely to contain spin than 'high' quality, OR 0.24 (95% CI, 0.07 to 0.88): 'critically low' studies were also less likely to contain spin than 'high' quality studies, OR 0.21 (95% CI, 0.07 to 0.65). There were no other associations between spin and the remaining extracted study characteristics or AMSTAR-2 ratings. CONCLUSION: Spin was present in greater than 29% of abstracts of systematic reviews and meta-analyses regarding PONV. Various stakeholders must take steps to improve the reporting quality of abstracts on PONV.

Global surgery, obstetric, and anaesthesia indicator definitions and reporting: An Utstein consensus report.

BACKGROUND: Indicators to evaluate progress towards timely access to safe surgical, anaesthesia, and obstetric (SAO) care were proposed in 2015 by the Lancet Commission on Global Surgery. These aimed to capture access to surgery, surgical workforce, surgical volume, perioperative mortality rate, and catastrophic and impoverishing financial consequences of surgery. Despite being rapidly taken up by practitioners, data points from which to derive the indicators were not defined, limiting comparability across time or settings. We convened global experts to evaluate and explicitly define-for the first time-the indicators to improve comparability and support achievement of 2030 goals to improve access to safe affordable surgical and anaesthesia care globally. METHODS AND FINDINGS: The Utstein process for developing and reporting guidelines through a consensus building process was followed. In-person discussions at a 2-day meeting were followed by an iterative process conducted by email and virtual group meetings until consensus was reached. The meeting was held between June 16 to 18, 2019; discussions continued until August 2020. Participants consisted of experts in surgery, anaesthesia, and obstetric care, data science, and health indicators from high-, middle-, and low-income countries. Considering each of the 6 indicators in turn, we refined overarching descriptions and agreed upon data points needed for construction of each indicator at current time (basic data points), and as each evolves over 2 to 5 (intermediate) and >5 year (full) time frames. We removed one of the original 6 indicators (one of 2 financial risk protection indicators was eliminated) and refined descriptions and defined data points required to construct the 5 remaining indicators: geospatial access, workforce, surgical volume, perioperative mortality, and catastrophic expenditure. A strength of the process was the number of people from global institutes and multilateral agencies involved in the collection and reporting of global health metrics; a limitation was the limited number of participants from low- or middle-income countries-who only made up 21% of the total attendees. CONCLUSIONS: To track global progress towards timely access to quality SAO care, these indicators-at the basic level-should be implemented universally as soon as possible. Intermediate and full indicator sets should be achieved by all countries over time. Meanwhile, these evolutions can assist in the short term in developing national surgical plans and collecting more detailed data for research studies.

Identifying a Basket of Surgical Procedures to Standardize Global Surgical Metrics: An International Delphi Study.

OBJECTIVE: We aimed to define a globally applicable list of surgical procedures, or "basket," which could represent a health system's capacity to provide surgical care and standardize global surgical measurement. SUMMARY OF BACKGROUND DATA: Six indicators have been proposed to assess access to safe, affordable, timely surgical and anesthesia care, with a focus on laparotomy, cesarean section, and treatment of open fracture. However, comparability, particularly for these procedures, has been limited by a lack of definitional clarity and their overly broad scope. METHODS: We conducted a 3 round international expert Delphi exercise between April and June 2019 using REDCap to identify a set of procedures representative of surgical capacity. To be included, procedures had to be important for treating common conditions, well-defined, and impactful (ie, well-recognized clinical or functional benefit). Procedures were eliminated or prioritized in each round, and those noted as "extremely" or "very important" by ≥50% of respondents in round 3 were included in the final "basket." RESULTS: Altogether 331 respondents from 78 countries participated in the Delphi process. A final basket of 32 procedures representing disease categories in trauma, cancer, congenital anomalies, maternal/reproductive health, aging, and infection were identified for inclusion to assess surgical capacity. CONCLUSIONS: This surgical basket facilitates a more standardized assessment of a country's surgical system. Further testing and refinement will likely be needed, but this basket can be used immediately to guide ongoing monitoring and evaluation of global surgery capacities to improve and strengthen surgery and anesthesia care.

IGFBP-3 interacts with NONO and SFPQ in PARP-dependent DNA damage repair in triple-negative breast cancer.

Women with triple-negative breast cancer (TNBC) are generally treated by chemotherapy but their responsiveness may be blunted by DNA double-strand break (DSB) repair. We previously reported that IGFBP-3 forms nuclear complexes with EGFR and DNA-dependent protein kinase (DNA-PKcs) to modulate DSB repair by non-homologous end-joining (NHEJ) in TNBC cells. To discover IGFBP-3 binding partners involved in chemoresistance through stimulation of DSB repair, we analyzed the IGFBP-3 interactome by LC-MS/MS and confirmed interactions by coimmunoprecipitation and proximity ligation assay. Functional effects were demonstrated by DNA end-joining in vitro and measurement of γH2AX foci. In response to 20 µM etoposide, the DNA/RNA-binding protein, non-POU domain-containing octamer-binding protein (NONO) and its dimerization partner splicing factor, proline/glutamine-rich (SFPQ) formed complexes with IGFBP-3, demonstrated in basal-like TNBC cell lines HCC1806 and MDA-MB-468. NONO binding to IGFBP-3 was also shown in a cell-free biochemical assay. IGFBP-3 complexes with NONO and SFPQ were blocked by inhibiting EGFR with gefitinib or DNA-PKcs with NU7026, and by the PARP inhibitors veliparib and olaparib, which also reduced DNA end-joining activity and delayed the resolution of the γH2AX signal (i.e. inhibited DNA DSB repair). Downregulation of the long noncoding RNA in NHEJ pathway 1 (LINP1) by siRNA also blocked IGFBP-3 interaction with NONO-SFPQ. These findings suggest a PARP-dependent role for NONO and SFPQ in IGFBP-3-dependent DSB repair and the involvement of LINP1 in the complex formation. We propose that targeting of the DNA repair function of IGFBP-3 may enhance chemosensitivity in basal-like TNBC, thus improving patient outcomes.

A novel, point-of-care, whole-blood assay utilizing dielectric spectroscopy is sensitive to coagulation factor replacement therapy in haemophilia A patients.

BACKGROUND: Reliable monitoring of coagulation factor replacement therapy in patients with severe haemophilia, especially those with inhibitors, is an unmet clinical need. While useful, global assays, eg thromboelastography (TEG), rotational thromboelastometry (ROTEM) and thrombin generation assay (TGA), are cumbersome to use and not widely available. OBJECTIVE: To assess the utility of a novel, point-of-care, dielectric microsensor - ClotChip - to monitor coagulation factor replacement therapy in patients with haemophilia A, with and without inhibitors. METHODS: The ClotChip Tpeak parameter was assessed using whole-blood samples from children with severe haemophilia A, with (n = 6) and without (n = 12) inhibitors, collected pre- and postcoagulation factor replacement therapy. ROTEM, TGA and chromogenic FVIII assays were also performed. Healthy children (n = 50) served as controls. RESULTS: ClotChip Tpeak values exhibited a significant decrease for samples collected postcoagulation factor replacement therapy as compared to baseline (pretherapy) samples in patients with and without inhibitors. A difference in Tpeak values was also noted at baseline among severe haemophilia A patients with inhibitors as compared to those without inhibitors. ClotChip Tpeak parameter exhibited a very strong correlation with clotting time (CT) of ROTEM, endogenous thrombin potential (ETP) and peak thrombin of TGA, and FVIII clotting activity. CONCLUSIONS: ClotChip is sensitive to coagulation factor replacement therapy in patients with severe haemophilia A, with and without inhibitors. ClotChip Tpeak values correlate very well with ROTEM, TGA and FVIII assays, opening up possibilities for its use in personalized coagulation factor replacement therapy in haemophilia.

Clinical impact of disinvestment in hydroxyethyl starch for patients undergoing coronary artery bypass surgery: a retrospective observational study.

PURPOSE: To examine the effect of discontinuing hydroxyethyl starch (HES) solutions on length of hospital stay, transfusion, risk of death, acute kidney injury (AKI), and dialysis. METHODS: We conducted a historical cohort study of linked administrative and clinical databases in patients undergoing coronary artery bypass surgery (CABG) on cardiopulmonary bypass. We used propensity scores to match patients who did not receive HES (after discontinuation) with patients exposed to HES (before discontinuation) and also controlled for albumin exposure. Hospital length of stay (the primary outcome) was analyzed using Fine-Gray proportional hazard regression, with hospital discharge as the outcome and death as a competing risk. Adverse outcomes were compared between matched patients using conditional logistic regression. RESULTS: We compared 1,085 propensity score-matched pairs (n = 2,170) from a pool of 2,757 patients. Discontinuation of HES was associated with shorter length of hospital stay, as evidenced by an increased probability of discharge (hazard ratio, 1.24; 95% confidence interval [CI], 1.14 to 1.35) and a reduced risk of red blood cell transfusion (odds ratio [OR], 0.68; 95% CI, 0.55 to 0.84), plasma transfusion (OR, 0.48; 95% CI, 0.34 to 0.66), and platelet transfusion (OR, 0.62; 95% CI, 0.44 to 0.87). Discontinuation of HES was not associated with in-hospital mortality (OR, 0.74; 95% CI, 0.36 to 1.54), AKI (OR, 0.84; 95% CI, 0.57 to 1.25), or dialysis (OR, 0.83; 95% CI, 0.25 to 2.73). CONCLUSIONS: For patients undergoing CABG on cardiopulmonary bypass, discontinuation of HES was associated with reduced hospital length of stay and reduced blood product transfusion, without measurable change in renal failure, dialysis rate, or in-hospital mortality. Our results should be interpreted with caution, though we found no evidence of harms associated with discontinuing HES. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT02329158); registered 31 December, 2014.

Is the Risk of Infection Lower with Sutures than with Staples for Skin Closure After Orthopaedic Surgery? A Meta-analysis of Randomized Trials.

BACKGROUND: Two previous meta-analyses comparing staples versus sutures have led to conflicting relative risks for surgical site infection between skin closure methods after orthopaedic surgery. Consequently, the choice of sutures or staples for skin closure continues to be a subject of conversation. Recently, additional randomized trials have been published, and an updated meta-analysis is needed to inform this debate. QUESTIONS/PURPOSES: To determine using a meta-analysis of randomized trials (1) whether there is a difference in surgical site infection (SSI) between staples and sutures for skin closure after orthopaedic surgery, and (2) whether that finding remains the same when the analysis is limited to randomized trials with a low risk of bias. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) comparing staples with sutures for skin closure after orthopaedic surgery was conducted. We excluded barbed sutures, surgical zippers, and skin adhesives from this meta-analysis. Medline, Embase, CINAHL, Cochrane Library, and Global Index Medicus were searched from date of inception to October 18, 2017. The sole outcome of interest was SSI as defined by the original study authors, with preference given to Center for Disease Control and Prevention (CDC) definitions whenever possible, recognizing that this may result in the pooling of more common minor events with rarer, more severe events, and in so doing, overestimate between-group differences. Because of this, subgroup analysis was planned based on severity of infection. Relative risk was calculated using a random-effects model (relative risk [RR], 95% confidence interval [CI]). Heterogeneity was estimated using I. Publication bias was explored using visual inspection of the funnel plot and Egger's test. Subgroup analysis was planned for type of orthopaedic surgery, suture material, SSI category, and country development index. Subgroup interaction p values were calculated. The Cochrane risk of bias tool was used to assess study quality. Sensitivity analysis was planned to assess whether the results changed when the analysis was limited to studies with low risk of bias. In total, 17 RCTs (2446 patients) were eligible, of which five RCTs (501 patients) were at low risk of bias. RESULTS: In the primary analysis, patients randomized to staples had a higher risk of SSI versus those who received sutures for skin closure (RR, 2.05; 95% CI,1.38-3.06; I = 0%). However, most of the events were driven by superficial SSI, and only two deep infections were explicitly reported in total (one in each group). After a post-hoc sensitivity analysis excluded a highly influential trial with high risk of bias, the results were highly fragile, relying on a difference of only four additional events in the staples group. When we limited the analysis to RCTs with low risk of bias, no difference was found between sutures and staples in terms of SSI (RR, 1.45; 95% CI, 0.31-6.79; I = 46%). Effect sizes were consistent across subgroups (p value for subgroup interaction was not significant for elective versus trauma; hip versus knee arthroplasty; suture material; high versus middle- versus low-income settings). CONCLUSIONS: Even in this relatively large meta-analysis, existing RCTs do not provide definitive evidence of a difference in SSI risk when staples are used instead of sutures for skin closure after orthopaedic surgery. Currently, the total body of evidence remains weak and, even when limiting to only low risk of bias studies, it is not possible to rule in or rule out clinically important differences between staples and sutures. Until randomized studies of adequate power and followup duration are performed to definitively inform this issue, the choice between staples versus sutures should be based on other factors such as local availability, surgeon preference, and cost. LEVEL OF EVIDENCE: Level I, therapeutic study.

Should Transfusion Trigger Thresholds Differ for Critical Care Versus Perioperative Patients? A Meta-Analysis of Randomized Trials.

OBJECTIVE: To address the significant uncertainty as to whether transfusion thresholds for critical care versus surgical patients should differ. DESIGN: Meta-analysis of randomized controlled trials. SETTING: Medline, EMBASE, and Cochrane Library searches were performed up to 15 June 2016. PATIENTS: Trials had to enroll adult surgical or critically ill patients for inclusion. INTERVENTIONS: Studies had to compare a liberal versus restrictive threshold for the transfusion of allogeneic packed RBCs. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 30-day all-cause mortality, sub-grouped by surgical and critical care patients. Secondary outcomes included myocardial infarction, stroke, renal failure, allogeneic blood exposure, and length of stay. Odds ratios and weighted mean differences were calculated using random effects meta-analysis. To assess whether subgroups were significantly different, tests for subgroup interaction were used. Subgroup analysis by trials enrolling critically ill versus surgical patients was performed. Twenty-seven randomized controlled trials (10,797 patients) were included. In critical care patients, restrictive transfusion resulted in significantly reduced 30-day mortality compared with liberal transfusion (odds ratio, 0.82; 95% CI, 0.70-0.97). In surgical patients, a restrictive transfusion strategy led to the opposite direction of effect for mortality (odds ratio, 1.31; 95% CI, 0.94-1.82). The subgroup interaction test was significant (p = 0.04), suggesting that the effect of restrictive transfusion on mortality is statistically different for critical care (decreased risk) versus surgical patients (potentially increased risk or no difference). Regarding secondary outcomes, for critically ill patients, a restrictive strategy resulted in reduced risk of stroke/transient ischemic attack, packed RBC exposure, transfusion reactions, and hospital length of stay. In surgical patients, restrictive transfusion resulted in reduced packed RBC exposure. CONCLUSIONS: The safety of restrictive transfusion strategies likely differs for critically ill patients versus perioperative patients. Further trials investigating transfusion strategies in the perioperative setting are necessary.

Cost-Effectiveness of First-Line Sevelamer and Lanthanum versus Calcium-Based Binders for Hyperphosphatemia of Chronic Kidney Disease.

BACKGROUND: Phosphate binders are used to treat hyperphosphatemia among patients with chronic kidney disease (CKD). OBJECTIVES: To conduct an economic evaluation comparing calcium-free binders sevelamer and lanthanum with calcium-based binders for patients with CKD. METHODS: Effectiveness data were obtained from a recent meta-analysis of randomized trials. Effectiveness was measured as life-years gained and translated to quality-adjusted life-years (QALYs) using utility weights from the literature. A Markov model consisting of non-dialysis-dependent (NDD)-CKD, dialysis-dependent (DD)-CKD, and death was developed to estimate the incremental costs and effects of sevelamer and lanthanum versus those of calcium-based binders. A lifetime horizon was used and both costs and effects were discounted at 1.5%. All costs are presented in 2015 Canadian dollars from the Canadian public payer perspective. Results of probabilistic sensitivity analysis were presented using cost-effectiveness acceptability curves. Sensitivity analyses were conducted for risk pooling methods, omission of dialysis costs, and persistence of drug effects on mortality. RESULTS: Sevelamer resulted in an incremental cost-effectiveness ratio of $106,522/QALY for NDD-CKD and $133,847/QALY for DD-CKD cohorts. Excluding dialysis costs, sevelamer was cost-effective in the NDD-CKD cohort ($5,847/QALY) and the DD-CKD cohort ($11,178/QALY). Lanthanum was dominated regardless of whether dialysis costs were included. CONCLUSIONS: Existing evidence does not clearly support the cost-effectiveness of non-calcium-containing phosphate binders (sevelamer and lanthanum) relative to calcium-containing phosphate binders in DD-CKD patients. Our study suggests that sevelamer may be cost-effective before dialysis onset. Because of the remaining uncertainty in several clinically relevant outcomes over time in DD-CKD and NDD-CKD patients, further research is encouraged.

Fibrinogen Concentrate in Cardiovascular Surgery: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Postoperative bleeding remains a frequent complication after cardiovascular surgery and may contribute to serious morbidity and mortality. Observational studies have suggested a relationship between low endogenous plasma fibrinogen concentration and increased risk of postoperative blood loss in cardiac surgery. Although the transfusion of fibrinogen concentrate has been increasing, potential benefits and risks associated with perioperative fibrinogen supplementation in cardiovascular surgery are not fully understood. METHODS: PubMed, Cochrane Library, Ovid MEDLINE, Embase, Web of Science, and China National Knowledge Infrastructure were searched on January 15, 2017, with automated updates searched until February 15, 2018, to identify all randomized controlled trials (RCTs) of fibrinogen concentrate, whether for prophylaxis or treatment of bleeding, in adults undergoing cardiovascular surgery. All RCTs comparing fibrinogen infusion versus any other comparator (placebo/standard of care or another active comparator) in adult cardiovascular surgery and reporting at least 1 predefined clinical outcome were included. The random-effects model was used to calculate risk ratios and weighted mean differences (95% confidence interval [CI]) for dichotomous and continuous variables, respectively. Subgroup analyses by fibrinogen dose and by baseline risk for bleeding were preplanned. RESULTS: A total of 8 RCTs of fibrinogen concentrate in adults (n = 597) of mixed risk or high risk undergoing cardiovascular surgery were included. Compared to placebo or inactive control, perioperative fibrinogen concentrate did not significantly impact risk of all-cause mortality (risk ratio, 0.41; 95% CI, 0.12-1.38; I = 10%; P = .15). Fibrinogen significantly reduced incidence of allogeneic red blood cell transfusion (risk ratio, 0.64; 95% CI, 0.49-0.83; I = 0%; P = .001). No significant differences were found for other clinical outcomes. Subgroup analyses were unremarkable when analyzed according to fibrinogen dose, time of infusion initiation, mean cardiopulmonary bypass time, and rotational thromboelastometry/fibrinogen temogram use (all P values for subgroup interaction were nonsignificant). CONCLUSIONS: Current evidence remains insufficient to support or refute routine perioperative administration of fibrinogen concentrate in patients undergoing cardiovascular surgery. Fibrinogen concentrate may reduce the need for additional allogeneic blood product transfusion in cardiovascular surgery patients at high risk or with evidence of bleeding. However, no definitive advantage was found for reduction in risk of mortality or other clinically relevant outcomes. The small number of clinical events within existing randomized trials suggests that further well-designed studies of adequate power and duration to measure all-cause mortality, stroke, myocardial infarction, reoperation, and thromboembolic events should be conducted. Future studies should also address cost-effectiveness relative to standard of care.

Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade.

BACKGROUND: New molecular targets are needed for women with triple-negative breast cancer (TNBC). This pre-clinical study investigated the combination of the EGFR inhibitor gefitinib with the sphingosine kinase (SphK) inhibitor FTY720 (Fingolimod), aiming to block tumorigenic signaling downstream of IGFBP-3, which is abundantly expressed in basal-like TNBC. METHODS: In studies of breast cancer cell growth in culture, proliferation was monitored by IncuCyte live-cell imaging, and protein abundance was determined by western blotting. In vivo studies of mammary tumor growth used two models: orthotopic xenograft tumors derived from three basal-like TNBC cell lines, grown in immune-deficient mice, and syngeneic murine 4T1 tumors grown in immune-competent mice. Protein abundance in tumor tissue was assessed by immunohistochemistry. RESULTS: Quantitated by live-cell imaging, the inhibitor combination showed synergistic cytostatic activity in basal-like cell lines across several TNBC molecular subtypes, the synergy being decreased by IGFBP-3 downregulation. Suppression of the tumorigenic mediator CD44 by gefitinib was potentiated by FTY720, consistent with CD44 involvement in the targeted pathway. In MDA-MB-468 and HCC1806 orthotopic TNBC xenograft tumors in nude mice, the drug combination inhibited tumor growth and prolonged mouse survival, although this effect was not significant for the gefitinib-resistant cell line HCC70. Combination treatment of murine 4T1 TNBC tumors in syngeneic BALB/c mice was more effective in immune-competent than immune-deficient (nude) mice, and a relative loss of tumor CD3 (T-cell) immunoreactivity caused by FTY720 treatment alone was alleviated by the drug combination, suggesting that, even at an FTY720 dose causing relative lymphopenia, the combination is still effective in an immune-competent setting. Immunohistochemistry of xenograft tumors showed significant enhancement of caspase-3 cleavage and suppression of Ki67 and phospho-EGFR by the drug combination, but SphK1 downregulation occurred only in MDA-MB-468 tumors, so is unlikely to be integral to treatment efficacy. CONCLUSIONS: Our data indicate that targeting IGFBP-3-dependent signaling pathways through gefitinib-FTY720 co-therapy may be effective in many basal-like breast cancers, and suggest tissue IGFBP-3 and CD44 measurement as potential biomarkers of treatment efficacy.

The efficacy and safety of sevelamer and lanthanum versus calcium-containing and iron-based binders in treating hyperphosphatemia in patients with chronic kidney disease: a systematic review and meta-analysis.

Background: It remains unclear which phosphate binders should be preferred for hyperphosphatemia management in chronic kidney disease (CKD). Methods: We performed a systematic review and meta-analysis of randomized trials comparing sevelamer or lanthanum with other phosphate binders in CKD. Results: Fifty-one trials (8829 patients) were reviewed. Compared with calcium-based binders, all-cause mortality was nonsignificantly lower with sevelamer {risk ratio [RR] 0.62 [95% confidence interval (CI) 0.35-1.08]} and lanthanum [RR 0.73 (95% CI 0.18-3.00)], but risk of bias was concerning. Compared with calcium-based binders, sevelamer reduced the risk of hypercalcemia [RR 0.27 (95% CI 0.17-0.42)], as did lanthanum [RR 0.12 (95% CI 0.05-0.32)]. Sevelamer reduced hospitalizations [RR 0.50 (95% CI 0.31-0.81)], but not lanthanum [RR 0.80 (95% CI 0.34-1.93)]. The presence/absence of other clinically relevant outcomes was infrequently reported. Compared with calcium-based binders, sevelamer reduced serum calcium, low-density lipoprotein and coronary artery calcification, but increased intact parathyroid hormone. The clinical relevance of these changes is unknown since corresponding clinical outcomes were not reported. Lanthanum had less favorable impact on biochemical parameters. Sevelamer hydrochloride and sevelamer carbonate were similar in three studies. Sevelamer was similar to lanthanum (three studies) and iron-based binders (three studies). Conclusion: Sevelamer was associated with a nonsignificant reduction in mortality and significantly lower hospitalization rates and hypercalcemia compared with calcium-based binders. However, differences in important outcomes, such as cardiac events, fractures, calciphylaxis, hyperchloremic acidosis and health-related quality of life remain understudied. Lanthanum and iron-based binders did not show superiority for any clinically relevant outcomes. Future studies that fail to measure clinically important outcomes (the reason why phosphate binders are prescribed in the first place) will be wasteful.

A systematic review of transthoracic and transesophageal echocardiography in non-cardiac surgery: implications for point-of-care ultrasound education in the operating room.

PURPOSE: Point-of-care ultrasound (POCU) is an evolving field in anesthesia. Therefore a systematic review of common diagnoses made by POCU during non-cardiac surgery was conducted. The information obtained from the review may be used to develop POCU curricula for the perioperative setting during non-cardiac surgery. SOURCE: A systematic review was conducted for perioperative use of transthoracic /transesophageal echocardiography (TTE/TEE) in high-risk patients or in other patients experiencing periods of hemodynamic instability. The diagnoses included segmental wall motion abnormalities (SWMAs), low left ventricular ejection fraction (LVEF), hypovolemia, air embolism, cardiac/aortic thrombus, pulmonary embolus (PE), aortic valve disease, mitral valve disease, tricuspid valve disease, right ventricular (RV) failure, pericardial disease, and patent foramen ovale. PRINCIPAL FINDINGS: Three hundred twenty-one studies were found using our search terms, and thirteen studies were retained that met our inclusion criteria for review. The studies included 968 patients analyzed as either preoperative exams in high-risk patients (n = 568) or intraoperative exams during times of hemodynamic compromise/cardiac arrest (n = 400). The most common diagnoses in the preoperative exam group were low ejection fraction (25.4%), aortic valve disease (24.4%), mitral valve disease (20.0%), RV failure (6.6%), and hypovolemia (6.3%). In the intraoperative exam group, the most common diagnoses were hypovolemia (33.2%), low ejection fraction (20.5%), RV failure (13.1%), SWMAs (10.1%), and PE (5.8%). CONCLUSION: In this systematic review examining the use of TTE or TEE in non-cardiac surgery, the most frequent diagnoses were valvulopathy, low LVEF, hypovolemia, PE, SWMAs, and RV failure. This information should be used to inform evidence-based curricula for POCU in anesthesiology.