The IDEAL framework for surgical robotics: development, comparative evaluation and long-term monitoring.

The next generation of surgical robotics is poised to disrupt healthcare systems worldwide, requiring new frameworks for evaluation. However, evaluation during a surgical robot's development is challenging due to their complex evolving nature, potential for wider system disruption and integration with complementary technologies like artificial intelligence. Comparative clinical studies require attention to intervention context, learning curves and standardized outcomes. Long-term monitoring needs to transition toward collaborative, transparent and inclusive consortiums for real-world data collection. Here, the Idea, Development, Exploration, Assessment and Long-term monitoring (IDEAL) Robotics Colloquium proposes recommendations for evaluation during development, comparative study and clinical monitoring of surgical robots-providing practical recommendations for developers, clinicians, patients and healthcare systems. Multiple perspectives are considered, including economics, surgical training, human factors, ethics, patient perspectives and sustainability. Further work is needed on standardized metrics, health economic assessment models and global applicability of recommendations.

Benefits and harms of perioperative high fraction inspired oxygen for surgical site infection prevention: a protocol for a systematic review and meta-analysis of individual patient data of randomised controlled trials.

INTRODUCTION: The use of high fraction of inspired oxygen (FiO2) intraoperatively for the prevention of surgical site infection (SSI) remains controversial. Promising results of early randomised controlled trials (RCT) have been replicated with varying success and subsequent meta-analysis are equivocal. Recent advancements in perioperative care, including the increased use of laparoscopic surgery and pneumoperitoneum and shifts in fluid and temperature management, can affect peripheral oxygen delivery and may explain the inconsistency in reproducibility. However, the published data provides insufficient detail on the participant level to test these hypotheses. The purpose of this individual participant data meta-analysis is to assess the described benefits and harms of intraoperative high FiO2compared with regular (0.21-0.40) FiO2 and its potential effect modifiers. METHODS AND ANALYSIS: Two reviewers will search medical databases and online trial registries, including MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and WHO regional databases, for randomised and quasi-RCT comparing the effect of intraoperative high FiO2 (0.60-1.00) to regular FiO2 (0.21-0.40) on SSI within 90 days after surgery in adult patients. Secondary outcome will be all-cause mortality within the longest available follow-up. Investigators of the identified trials will be invited to collaborate. Data will be analysed with the one-step approach using the generalised linear mixed model framework and the statistical model appropriate for the type of outcome being analysed (logistic and cox regression, respectively), with a random treatment effect term to account for the clustering of patients within studies. The bias will be assessed using the Cochrane risk-of-bias tool for randomised trials V.2 and the certainty of evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. Prespecified subgroup analyses include use of mechanical ventilation, nitrous oxide, preoperative antibiotic prophylaxis, temperature (<35°C), fluid supplementation (<15 mL/kg/hour) and procedure duration (>2.5 hour). ETHICS AND DISSEMINATION: Ethics approval is not required. Investigators will deidentify individual participant data before it is shared. The results will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42018090261.

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.

Analgesic Efficacy of Adjuvant Medications in the Pediatric Caudal Block for Infraumbilical Surgery: A Network Meta-Analysis of Randomized Controlled Trials.

Various adjuvants are added to local anesthetics in caudal block to improve analgesia. The comparative analgesic effectiveness and relative rankings of these adjuvants are unknown. This network meta-analysis (NMA) sought to evaluate the comparative analgesic efficacy and relative ranking of caudal adjuvants added to local anesthetics (versus local anesthetics alone) in pediatric infra-umbilical surgery. We searched the United States National Library of Medicine database (MEDLINE), PubMed, and Excerpta Medica database (Embase) for randomized controlled trials (RCTs) comparing caudal adjuvants (clonidine, dexmedetomidine, ketamine, magnesium, morphine, fentanyl, tramadol, dexamethasone, and neostigmine) among themselves, or to no adjuvant (control). We performed a frequentist NMA and employed Cochrane's 'Risk of Bias' tool to evaluate study quality. We chose the duration of analgesia (defined as 'the time from caudal injection to the time of rescue analgesia') as our primary outcome. We also assessed the number of analgesic dose administrations and total dose of acetaminophen within 24 h. The duration of analgesia [87 randomized control trials (RCTs), 5285 patients] was most prolonged by neostigmine [mean difference: 513 min, (95% confidence interval, CI: 402, 625)]. Dexmedetomidine reduced the frequency of analgesic dose administrations within 24 h [29 RCTs, 1765 patients; -1.2 dose (95% CI: -1.6, -0.9)] and the total dose of acetaminophen within 24 h [18 RCTs, 1156 patients; -350 mg (95% CI: -467, -232)] the most.  Among caudal adjuvants, neostigmine (moderate certainty), tramadol (low certainty), and dexmedetomidine (low certainty) prolonged the duration of analgesia the most. Dexmedetomidine also reduced the analgesic frequency and consumption more than other caudal adjuvants (moderate certainty).

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.

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.

Measurement and prognosis of frail patients undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis.

OBJECTIVES: Our objectives were to review the literature to identify frailty instruments in use for transcatheter aortic valve implantation (TAVI) recipients and synthesise prognostic data from these studies, in order to inform clinical management of frail patients undergoing TAVI. METHODS: We systematically reviewed the literature published in 2006 or later. We included studies of patients with aortic stenosis, diagnosed as frail, who underwent a TAVI procedure that reported mortality or clinical outcomes. We categorised the frailty instruments and reported on the prevalence of frailty in each study. We summarised the frequency of clinical outcomes and pooled outcomes from multiple studies. We explored heterogeneity and performed subgroup analysis, where possible. We also used Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to assess the overall certainty of the estimates. RESULTS: Of 49 included studies, 21 used single-dimension measures to assess frailty, 3 used administrative data-based measures, and 25 used multidimensional measures. Prevalence of frailty ranged from 5.67% to 90.07%. Albumin was the most commonly used single-dimension frailty measure and the Fried or modified Fried phenotype were the most commonly used multidimensional measures. Meta-analyses of studies that used either the Fried or modified Fried phenotype showed a 30-day mortality of 7.86% (95% CI 5.20% to 11.70%) and a 1-year mortality of 26.91% (95% CI 21.50% to 33.11%). The GRADE system suggests very low certainty of the respective estimates. CONCLUSIONS: Frailty instruments varied across studies, leading to a wide range of frailty prevalence estimates for TAVI recipients and substantial heterogeneity. The results provide clinicians, patients and healthcare administrators, with potentially useful information on the prognosis of frail patients undergoing TAVI. This review highlights the need for standardisation of frailty measurement to promote consistency. PROSPERO REGISTRATION NUMBER: CRD42018090597.

Global perioperative surgery research: A call to Latin America / Investigación global sobre el perioperatorio quirúrgico: un llamado a América Latina

Every year, around 300 million surgical procedures are performed worldwide 1,2, with an estimated 4% early postoperative mortality rate. 3,4 However, little is known about global quality of surgery, specifically in middle-income countries. Colombia, similar to other Latin American countries, has an interesting diversity of healthcare needs. In urban settings, the healthcare offered is among the best in Latin America, with top-quality hospitals and educational programs comparable to those in the USA or Europe. In contrast, in most rural areas of Latin America, including some of the most remote locations in the world (like the Pacific Coast or the Amazon forest), a frail and fragmented healthcare system prevails, similar to the conditions in very low-income countries. At least 7.1 million people (15.1% of the population) lack hospital access within a 2-hour drive, and despite these characteristics, the early reported postoperative mortality is low - 0.74%.

Cada año se realizan alrededor de 300 millones de intervenciones quirúrgicas en todo el mundo 1,2, con una tasa estimada de mortalidad postoperatoria temprana del 4%. 3,4 Sin embargo, poco se sabe sobre la calidad global de la cirugía, específicamente en los países de ingresos medios. Colombia, al igual que otros países latinoamericanos, presenta una interesante diversidad de necesidades de atención médica. En los entornos urbanos, la oferta sanitaria se encuentra entre las mejores de América Latina, con hospitales de primera calidad y programas educativos comparables a los de Estados Unidos o Europa. En cambio, en la mayoría de las zonas rurales de América Latina, incluidas algunas de las localidades más remotas del mundo (como la costa del Pacífico o la selva amazónica), prevalece un sistema sanitario frágil y fragmentado, similar a las condiciones de los países de muy bajos ingresos. Al menos 7,1 millones de personas (el 15,1% de la población) carecen de acceso a un hospital a menos de 2 horas de viaje, y a pesar de estas características, la mortalidad postoperatoria temprana reportada es baja: 0,74%.

Efficacy and safety of caudal dexmedetomidine in pediatric infra-umbilical surgery: a meta-analysis and trial-sequential analysis of randomized controlled trials.

BACKGROUND: Dexmedetomidine is used as a local-anesthetics adjuvant in caudal block to prolong analgesia in pediatric infra-umbilical surgery. OBJECTIVE: We evaluated the analgesic efficacy and safety of the addition of caudal dexmedetomidine to local anesthetics (vs local anesthetics alone) in pediatric infra-umbilical surgery. EVIDENCE REVIEW: We searched 10 databases for randomized controlled trials (RCTs) of pediatric patients undergoing infra-umbilical surgery, comparing caudal block with and without dexmedetomidine as local anesthetic adjuvant. We performed a frequentist random-effects meta-analysis (R statistical package). We analyzed continuous outcomes as a ratio of means (ROM) and dichotomous data as relative risk (RR), along with 95% CI. We included 19 RCTs (n=1190 pediatric patients) in the meta-analysis. The primary outcome was duration of analgesia (defined as 'the time from caudal injection to the time at which the study-specific pain score was greater than a cut-off threshold'). FINDINGS: Data from 19 included RCTs (n=1190) suggested that compared with control (mean duration 346 min), the addition of caudal dexmedetomidine significantly prolonged the duration of analgesia (ratio of means 2.14, 95% CI 1.83 to 2.49, p<0.001; 'moderate' evidence). Trial-sequential analysis showed adequate 'information size' for the primary outcome. Caudal dexmedetomidine also reduced the number of analgesic administrations ('low' evidence), total acetaminophen dose ('moderate' evidence) and the risk of emergence delirium ('moderate' evidence). There were no significant differences in adverse effects such as hypotension, bradycardia, post-operative nausea and vomiting, urinary retention and respiratory depression. CONCLUSIONS: Our results suggest that the addition of dexmedetomidine to local anesthetic in caudal block significantly improves the duration of analgesia and reduces the analgesic requirements, while maintaining a similar risk-profile compared with local anesthetic alone. Further data on neurological safety are needed.

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.

Platelet Transfusion in Cardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Blood transfusion is a well-established independent risk factor for mortality in patients undergoing cardiac surgery but the impact of platelet transfusion is less clear. We performed a systematic review and meta-analysis of observational studies comparing outcomes of patients who received platelet transfusion after cardiac surgery. METHODS: We searched MEDLINE and EMBASE databases to January 2019 for studies comparing perioperative outcomes in patients undergoing cardiac surgery with and without platelet transfusion. RESULTS: There were nine observational studies reporting 101,511 patients: 12% with and 88% without platelet transfusion. In unmatched/unadjusted studies, patients who received platelet transfusion were older, with greater incidence of renal, peripheral, and cerebrovascular disease, myocardial infarction, left ventricular dysfunction, and anemia. They were more likely to have nonelective, combined surgery; preoperative hemodynamic instability and endocarditis; and more likely to be receiving clopidogrel preoperatively. Perioperative complications were significantly increased without adjusting for these baseline differences. After pooling only matched/adjusted data, differences were not found between patients who did receive platelets and patients who did not in operative mortality (risk ratio [RR] 1.26; 95% confidence interval [CI], 0.69 to 2.32, P = .46, five studies), stroke (RR 0.94; 95% CI, 0.62 to 1.45; P = .79; five studies), myocardial infarction (RR 1.29; 95% CI, 0.95 to 1.77; P = .11; three studies), reoperation for bleeding (RR 1.20; 95% CI, 0.46 to 3.18; P = .71; three studies), infection (RR 1.02; 95% CI, 0.86 to 1.20; P = .85; six studies); and perioperative dialysis (RR 0.91; 95% CI, 0.63 to 1.32; P = .62; three studies). CONCLUSIONS: After accounting for baseline differences, platelet transfusion was not linked with perioperative complications in cardiac surgery patients. Given the small number of observational studies, these findings should be considered hypothesis generating.

Antithrombotic treatment after coronary artery bypass graft surgery: systematic review and network meta-analysis.

OBJECTIVE: To assess the effects of different oral antithrombotic drugs that prevent saphenous vein graft failure in patients undergoing coronary artery bypass graft surgery. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, Web of Science, CINAHL, and the Cochrane Library from inception to 25 January 2019. ELIGIBILITY CRITERIA: for selecting studies Randomised controlled trials of participants (aged ≥18) who received oral antithrombotic drugs (antiplatelets or anticoagulants) to prevent saphenous vein graft failure after coronary artery bypass graft surgery. MAIN OUTCOME MEASURES: The primary efficacy endpoint was saphenous vein graft failure and the primary safety endpoint was major bleeding. Secondary endpoints were myocardial infarction and death. RESULTS: This review identified 3266 citations, and 21 articles that related to 20 randomised controlled trials were included in the network meta-analysis. These 20 trials comprised 4803 participants and investigated nine different interventions (eight active and one placebo). Moderate certainty evidence supports the use of dual antiplatelet therapy with either aspirin plus ticagrelor (odds ratio 0.50, 95% confidence interval 0.31 to 0.79, number needed to treat 10) or aspirin plus clopidogrel (0.60, 0.42 to 0.86, 19) to reduce saphenous vein graft failure when compared with aspirin monotherapy. The study found no strong evidence of differences in major bleeding, myocardial infarction, and death among different antithrombotic therapies. The possibility of intransitivity could not be ruled out; however, between-trial heterogeneity and incoherence were low in all included analyses. Sensitivity analysis using per graft data did not change the effect estimates. CONCLUSIONS: The results of this network meta-analysis suggest an important absolute benefit of adding ticagrelor or clopidogrel to aspirin to prevent saphenous vein graft failure after coronary artery bypass graft surgery. Dual antiplatelet therapy after surgery should be tailored to the patient by balancing the safety and efficacy profile of the drug intervention against important patient outcomes. STUDY REGISTRATION: PROSPERO registration number CRD42017065678.

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.

Intraoperative evoked potential monitoring for detecting cerebral injury during adult aneurysm clipping surgery: a systematic review and meta-analysis of diagnostic test accuracy.

OBJECTIVES: We aim to evaluate the diagnostic test accuracy (DTA) of intraoperative evoked potential (EP) monitoring to detect cerebral injury during clipping of cerebral aneurysms. DESIGN: Systematic review. DATA SOURCES: Major electronic databases including MEDLINE, EMBASE, LILACS. ELIGIBILITY CRITERIA: We included studies that reported the DTA of intraoperative EP monitoring during intracranial aneurysm clipping procedures in adult patients. DATA EXTRACTION AND SYNTHESIS: After quality assessment, we performed a meta-analysis using the bivariate random effects model, and calculated the possible range of DTA point estimates using a new best-case/worst-case scenario approach to quantify the impact of rescue intervention on DTA. RESULTS: A total of 35 studies involving 4011 patients were included. The quality of the primary studies was modest and the heterogeneity across studies was high. The pooled sensitivity and specificity for predicting postoperative neurological deficits for the somatosensory evoked potential (SSEP) monitoring was 59% (95% CI: 39% to 76%; I2: 76%) and 86% (95% CI: 77% to 92%; I2: 94%), for motor evoked potential (MEP) monitoring was 81% (95% CI: 58% to 93%; I2: 54%) and 90% (95% CI: 86% to 93%; I2: 81%), and for combined SSEP and MEP monitoring was 92% (95% CI: 62% to 100%) and 88% (95% CI: 83% to 93%). The best-case/worst-case range for the pooled point estimates for sensitivity and specificity for SSEP was 50%-63% and 81%-100%, and for MEP was 59%-74% and 93%-100%, and for combined SSEP and MEP was 89%-94% and 83%-100%. CONCLUSIONS: Due to the modest quality and high heterogeneity of the existing primary studies, it is not possible to confidently support or refute the diagnostic value of EP monitoring in cerebral aneurysm clipping surgery. However, combined SSEP and MEP appears to provide the best DTA for predicting postoperative stroke. Contrary to popular assertion, the modest sensitivity of SSEP monitoring is not explained by the use of rescue intervention. PROSPERO REGISTRATION NUMBER: CRD42015016884.

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.

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.

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.

Nuclear Insulin-Like Growth Factor Binding Protein-3 As a Biomarker in Triple-Negative Breast Cancer Xenograft Tumors: Effect of Targeted Therapy and Comparison With Chemotherapy.

Triple-negative breast cancer (TNBC) typically has a worse outcome than other breast cancer subtypes, in part owing to a lack of approved therapeutic targets or prognostic markers. We have previously described an oncogenic pathway in basal-like TNBC cells, initiated by insulin-like growth factor binding protein-3 (IGFBP-3), in which the epidermal growth factor receptor (EGFR) is transactivated by sphingosine-1-phosphate (S1P) resulting from sphingosine kinase (SphK)-1 activation. Oncogenic IGFBP-3 signaling can be targeted by combination treatment with the S1P receptor modulator and SphK inhibitor, fingolimod, and the EGFR kinase inhibitor, gefitinib (F + G). However, the interaction of this treatment with chemotherapy has not been documented. Since we observed nuclear localization of IGFBP-3 in some TNBC tumors, this study aimed to evaluate the prognostic significance of nuclear IGFBP-3 in pre-clinical models of basal-like TNBC treated with F + G and doxorubicin. Orthotopic xenograft tumors were grown in nude mice from the human basal-like TNBC cell lines MDA-MB-468 and HCC1806, and were treated with gefitinib, 25 mg/Kg, plus fingolimod, 5 mg/Kg, 3-times weekly. In some studies, doxorubicin was also administered once weekly for 6 weeks. Tumor tissue proteins were quantitated by immunohistochemistry (IHC). Interaction between doxorubicin and F + G was also studied in proliferation assays in vitro. In both tumor models, tissue staining for IGFBP-3 was predominantly nuclear. Combination of F + G significantly enhanced mouse survival, decreased nuclear IGFBP-3 and Ki67 staining, and increased apoptosis (cleaved caspase-3) staining. Kaplan-Meier survival analysis showed that a high tumor IGFBP-3 IHC score (>median), like a high Ki67 score, was significantly associated with shorter survival time, whereas a high apoptosis score was associated with prolonged survival. Studied in vitro in both cell lines, low-dose doxorubicin that had little effect alone, strongly enhanced the cytostatic effect of low-dose F + G combination. However, in both in vivo models, doxorubicin at maximum-tolerated dose neither inhibited tumor growth when administered alone, nor enhanced the significant inhibitory effect of F + G. We conclude that doxorubicin may not add benefit to the inhibitory effect of F + G unless its dose-limiting toxicity can be overcome. Nuclear IGFBP-3 appears to have potential as a prognostic marker in TNBC and could be evaluated for clinical utility.