Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward.

Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry.

Assessing the robustness of positive vascular surgery randomized controlled trials using their fragility index.

OBJECTIVE: The fragility index (FI) measures the robustness of statistically significant findings in randomized controlled trials (RCTs) by quantifying the minimum number of event conversions required to reverse a dichotomous outcome's statistical significance. In vascular surgery, many clinical guidelines and critical decision-making points are informed by a handful of key RCTs, especially regarding open surgical versus endovascular treatment. The objective of this study is to evaluate the FI of RCTs with statistically significant primary outcomes that compared open vs endovascular surgery in vascular surgery. METHODS: In this meta-epidemiological study and systematic review, MEDLINE, Embase, and CENTRAL were searched for RCTs comparing open versus endovascular treatments for abdominal aortic aneurysms, carotid artery stenosis, and peripheral arterial disease to December 2022. RCTs with statistically significant primary outcomes were included. Data screening and extraction were conducted in duplicate. The FI was calculated by adding an event to the group with the smaller number of events while subtracting a nonevent to the same group until Fisher's exact test produced a nonstatistically significant result. The primary outcome was the FI and proportion of outcomes where the loss to follow-up was greater than the FI. The secondary outcomes assessed the relationship of the FI to disease state, presence of commercial funding, and study design. RESULTS: Overall, 5133 articles were captured in the initial search with 21 RCTs reporting 23 different primary outcomes being included in the final analysis. The median FI (first quartile, third quartile) was 3 (3, 20) with 16 outcomes (70%) reporting a loss to follow-up greater than its FI. Mann-Whitney U test revealed that commercially funded RCTs and composite outcomes had greater FIs (median, 20.0 [5.5, 24.5] vs median, 3.0 [2.0, 5.5], P = .035; median, 21 [8, 38] vs median, 3.0 [2.0, 8.5], P = .01, respectively). The FI did not vary between disease states (P = .285) or between index and follow-up trials (P = .147). There were significant correlations between the FI and P values (Pearson r = 0.90; 95% confidence interval, 0.77-0.96), and the number of events (r = 0.82; 95% confidence interval, 0.48-0.97). CONCLUSIONS: A small number of event conversions (median, 3) are needed to alter the statistical significance of primary outcomes in vascular surgery RCTs evaluating open surgical and endovascular treatments. Most studies had loss to follow-up greater than its FI, which can call into question trial results, and commercially funded studies had a greater FI. The FI and these findings should be considered in future trial design in vascular surgery.

Development of an Artificial Intelligence Tool for Intraoperative Guidance During Endovascular Abdominal Aortic Aneurysm Repair.

BACKGROUND: Adverse events during surgery can occur in part due to errors in visual perception and judgment. Deep learning is a branch of artificial intelligence (AI) that has shown promise in providing real-time intraoperative guidance. This study aims to train and test the performance of a deep learning model that can identify inappropriate landing zones during endovascular aneurysm repair (EVAR). METHODS: A deep learning model was trained to identify a "No-Go" landing zone during EVAR, defined by coverage of the lowest renal artery by the stent graft. Fluoroscopic images from elective EVAR procedures performed at a single institution and from open-access sources were selected. Annotations of the "No-Go" zone were performed by trained annotators. A 10-fold cross-validation technique was used to evaluate the performance of the model against human annotations. Primary outcomes were intersection-over-union (IoU) and F1 score and secondary outcomes were pixel-wise accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The AI model was trained using 369 images procured from 110 different patients/videos, including 18 patients/videos (44 images) from open-access sources. For the primary outcomes, IoU and F1 were 0.43 (standard deviation ± 0.29) and 0.53 (±0.32), respectively. For the secondary outcomes, accuracy, sensitivity, specificity, NPV, and PPV were 0.97 (±0.002), 0.51 (±0.34), 0.99 (±0.001). 0.99 (±0.002), and 0.62 (±0.34), respectively. CONCLUSIONS: AI can effectively identify suboptimal areas of stent deployment during EVAR. Further directions include validating the model on datasets from other institutions and assessing its ability to predict optimal stent graft placement and clinical outcomes.

Evaluating YouTube as a Source of Education for Patients Undergoing Surgery: A Systematic Review.

OBJECTIVE: The objective of this systematic review is to characterize the peer-reviewed literature investigating YouTube as a source of patient education for patients undergoing surgery. SUMMARY BACKGROUND DATA: YouTube is the largest online video sharing platform and has become a substantial source of health information that patients are likely to access before surgery, yet there has been no systematic assessment of peer-reviewed studies. A comprehensive literature search was conducted using EMBASE, MEDLINE, and Ovid HealthStar from inception through to December of 2021. METHODS: All primary studies evaluating YouTube as a source of patient education relating to surgical procedures (general, cardiac, urology, otolaryngology, plastic, vascular) were included. Study screening and data extraction occurred in duplicate with two reviewers. Characteristics extracted included video length, view count, upload source, overall video educational quality, and quality of individual studies. RESULTS: Among 6,453 citations, 56 studies were identified that examined 6,797 videos with 547 hours of content and 1.39 billion views. There were 49 studies that evaluated the educational quality of the videos. A total of 43 quality assessment tools were used, with each study using a mean of 1.90 assessment tools. Per the global rating for assessments, 34/49 studies (69%) concluded that the overall quality of educational content was poor. CONCLUSIONS: While the impact of non-peer-reviewed YouTube videos on patient knowledge for surgery is unclear, the large amount of online content suggests that they are in demand. The overall educational content of these videos is poor, however, and there is substantial heterogeneity in the quality assessment tools used in their evaluation. A peer-reviewed and standardized approach to online education with video content is needed to better support patients.

Completeness of reporting in systematic reviews and meta-analyses in vascular surgery.

OBJECTIVE: Systematic reviews (SRs) and meta-analyses are essential in informing clinical guidelines and decision-making. Complete reporting of SRs through compliance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines promotes transparency, reproducibility, and consistency across the literature. The purpose of this meta-epidemiological study is to assess the completeness of reporting of SRs in the vascular surgery literature. METHODS: MEDLINE and Embase were used to search through four major vascular surgery journals and four high impact general medical journals for SRs published between 2018 and October 2022 evaluating clinical treatments for any pathology treated by a vascular surgeon. Data screening and extraction were conducted in duplicate. The reporting completeness of each included SR was measured with reference to the 27-item PRISMA checklist, and methodological quality was evaluated using the Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2) tool. Parametric tests were used to evaluate for associations between PRISMA score and study funding, protocol registration, publication in a higher impact factor journal, and AMSTAR 2 score. The protocol is available online: 10.17605/OSF.IO/VBC5N. RESULTS: Of 1653 articles captured in the initial search, 162 SRs were included in the final analysis. All SRs had more than one incomplete PRISMA item. The mean PRISMA score was 21.2/27 (standard deviation: 2.9, 78.5% compliance), and the mean AMSTAR 2 score was 11.7/16 (standard deviation: 1.9, 73%). SRs that had a prospectively registered protocol had a higher PRISMA score (22.9 vs 20.6, P < .001) as did those that were published in higher impact factor journals (23.3 vs 21.0, P = .017). There was a large positive correlation between an SR's PRISMA and AMSTAR 2 scores (Pearson r = 0.655, 95% confidence interval: 0.55-0.74). There were no associations between the PRISMA score and publication year (P = .067) or funding status (P = .076). CONCLUSIONS: Overall, the reporting of SRs and meta-analyses in vascular surgery is less than ideal, with several key items being consistently under-reported. Prospective registration and methodological quality as measured by AMSTAR 2 scores are positively associated with improved reporting. Authors, reviewers, and journal editors should consider these findings moving forward to encourage completeness of SR reporting. Raising awareness surrounding the value of complete reporting of SRs can aid in enhancing the quality of evidence, and journals should consider these findings in methods used to promote SR reporting.

Assessing the robustness of negative vascular surgery randomized controlled trials using their reverse fragility index.

OBJECTIVE: The reverse fragility index (RFI) describes the number of event conversions needed to convert a statistically nonsignificant dichotomous outcome to a significant one. The objective of the present study was to assess the RFI of vascular surgery randomized controlled trials (RCTs) comparing endovascular vs open surgery for the treatment of abdominal aortic aneurysms (AAAs), carotid artery stenosis (CAS), and peripheral artery disease (PAD). METHODS: MEDLINE and Embase were searched for RCTs that had investigated AAAs, CAS, or PAD with statistically nonsignificant binary primary outcomes. The primary outcome for the present study was the median RFI. Calculation of the RFI was performed by creating two-by-two contingency tables and subtracting events from the group with fewer events and adding nonevents to the same group until a two-tailed Fisher exact test had produced a statistically significant result (P ≤ .05). RESULTS: Of 4187 reports, 49 studies reporting 103 different primary end points were included. The overall median RFI was 7 (interquartile range [IQR], 5-13). The specific RFIs for AAA, CAS, and PAD were 10 (IQR, 6-15.5), 6 (IQR, 5-9.5), and 7 (IQR, 5.5-10), respectively. Of the 103 end points, 42 (47%) had had a loss to follow-up greater than the RFI, of which 10 were AAA trials (24%), 23 were CAS trials (55%), and 9 were PAD trials (21%). The Pearson correlation demonstrated a significant positive relationship between a study's RFI and the impact factor of its publishing journal (r = 0.38; 95% confidence interval [CI], 0.20-0.54; P < .01), length of follow-up (r = 0.43; 95% CI, 0.26-0.58; P < .01), and sample size (r = 0.28; 95% CI, 0.09-0.45; P < .01). CONCLUSIONS: A small number of events (median, 7) was required to change the outcome of negative RCTs from statistically nonsignificant to significant, with 47% of the studies having missing data that could have reversed the finding of its primary outcome. Reporting of the RFI relative to the loss to follow-up could be of benefit in future trials and provide confidence regarding the robustness of the P value.

Outcomes After Neuraxial or Regional Anaesthesia Instead of General Anaesthesia for Lower Limb Revascularisation Surgery: A Systematic Review and Meta-Analysis of Randomised and Non-Randomised Studies.

OBJECTIVE: To determine whether receipt of neuraxial or regional anaesthesia instead of general anaesthesia for lower limb revascularisation surgery affects patient outcomes. DATA SOURCES: MEDLINE, EMBASE, Evidence Based Medicine Reviews, and Google Scholar. REVIEW METHODS: After protocol registration, the data sources were searched for randomised and non-randomised studies comparing neuraxial or regional anaesthesia with general anaesthesia for lower limb revascularisation surgery in adults. Two investigators independently selected articles, extracted data, and assessed risks of bias. Data were pooled using random effects models. GRADE was used to assess certainty in cumulative evidence. RESULTS: From 10 755 citations identified, five randomised (n = 970) and 13 non-randomised (n = 96 800) studies were included. Use of neuraxial instead of general anaesthesia for lower limb revascularisation surgery was associated with no statistically significant reduction in short term (in hospital or 30 day) mortality in randomised studies (pooled odds ratio [OR] 0.77; 95% confidence interval [CI] 0.33 - 1.81; low certainty) and a statistically significant reduction in adjusted short term mortality in non-randomised studies (pooled OR 0.67; 95% CI 0.56 - 0.81; low certainty). Adults allocated to neuraxial anaesthesia in randomised studies had fewer pulmonary complications (pooled OR 0.35; 95% CI 0.16 - 0.76; low certainty). In non-randomised studies, neuraxial instead of general anaesthesia was associated with a lower adjusted odds of any morbidity (pooled OR 0.66; 95% CI 0.52 - 0.84), cardiac complications (pooled OR 0.68; 95% CI 0.58 - 0.79), pneumonia (pooled OR 0.81; 95% CI 0.64 - 1.02), prolonged mechanical ventilation (OR 0.09; 95% CI 0.002 - 0.55), and bypass graft thrombosis (OR 0.70; 95% CI 0.59 - 0.85), as well as a shorter operative duration (low certainty for all). Use of a nerve block instead of general anaesthesia was associated with a lower adjusted odds of delirium (OR 0.16; 95% CI 0.06 - 0.42) and a shorter operative duration (low certainty for both). CONCLUSION: Randomised and non-randomised data suggest that neuraxial anaesthesia for lower limb revascularisation surgery reduces morbidity and possibly mortality. Until randomised trials with a low risk of bias become available, this study supports use of neuraxial anaesthesia for these procedures where appropriate.

Engineered RecA Constructs Reveal the Minimal SOS Activation Complex.

The SOS response is a bacterial DNA damage response pathway that has been heavily implicated in bacteria's ability to evolve resistance to antibiotics. Activation of the SOS response is dependent on the interaction between two bacterial proteins, RecA and LexA. RecA acts as a DNA damage sensor by forming lengthy oligomeric filaments (RecA*) along single-stranded DNA (ssDNA) in an ATP-dependent manner. RecA* can then bind to LexA, the repressor of SOS response genes, triggering LexA degradation and leading to induction of the SOS response. Formation of the RecA*-LexA complex therefore serves as the key "SOS activation signal." Given the challenges associated with studying a complex involving multiple macromolecular interactions, the essential constituents of RecA* that allow LexA cleavage are not well defined. Here, we leverage head-to-tail linked and end-capped RecA constructs as tools to define the minimal RecA* filament that can engage LexA. In contrast to previously postulated models, we found that as few as three linked RecA units are capable of ssDNA binding, LexA binding, and LexA cleavage. We further demonstrate that RecA oligomerization alone is insufficient for LexA cleavage, with an obligate requirement for ATP and ssDNA binding to form a competent SOS activation signal with the linked constructs. Our minimal system for RecA* highlights the limitations of prior models for the SOS activation signal and offers a novel tool that can inform efforts to slow acquired antibiotic resistance by targeting the SOS response.

Analysis of spin in vascular surgery randomized controlled trials with nonsignificant outcomes.

OBJECTIVE: Spin is the manipulation of language that distorts the interpretation of objective findings. The purpose of this study is to describe the characteristics of spin found in statistically nonsignificant randomized controlled trials (RCT) comparing carotid endarterectomy with carotid artery stenting for carotid artery stenosis (CS), and endovascular repair with open repair (OR) for abdominal aortic aneurysms (AAA). METHODS: A search of MEDLINE, EMBASE, and the Cochrane Controlled Register of Trials was performed in June 2020 for studies published describing AAA or CS. All phase III RCTs with nonsignificant primary outcomes comparing open repair with endovascular repair or carotid endarterectomy to carotid artery stenting were included. Studies were appraised for the characteristics and severity of spin using a validated tool. Binary logistic regression was performed to assess the association of spin grade to (1) funding source (commercial vs noncommercial) and (2) the publishing journal's impact factor. RESULTS: Thirty-one of 355 articles captured were included for analysis. Spin was identified in 9 abstracts (9/18) and 13 main texts (13/18) of AAA articles and 7 abstracts (7/13) and 10 main texts (10/13) of CS articles. For both AAA and CS articles, spin was most commonly found in the discussion section, with the most commonly used strategy being the interpretation of statistically nonsignificant primary results to show treatment equivalence or rule out adverse treatment effects. Increasing journal impact factor was associated with a statistically significant lower likelihood of spin in the study title or abstract conclusion (ß odds ratio, 0.96; 95% confidence interval, 0.94-0.98; P < .01); no significant association could be found with funding source (ß odds ratio, 1.33; 95% confidence interval, 0.30-5.92; P = .71). CONCLUSIONS: A large proportion of statistically nonsignificant RCTs contain interpretations that are inconsistent with their results. These findings should prompt authors and readers to appraise study findings independently and to limit the use of spin in study interpretations.

Exploration of inhibitors of the bacterial LexA repressor-protease.

Resistant and tolerant bacterial infections lead to billions in healthcare costs and cause hundreds of thousands of deaths each year. The bulk of current antibiotic research efforts focus on molecules which, although novel, are not immune from acquired resistance and seldomly affect tolerant populations. The bacterial SOS response has been implicated in several resistance and tolerance mechanisms, making it an attractive antibiotic target. Using small molecule inhibitors targeting a key step in the deployment of the SOS response, our approach focused on preventing the deployment of mechanisms such as biofilm formation, horizontal gene transfer, and error-prone DNA repair. Herein we report the synthesis and testing of analogs of a triazole-containing tricyclic inhibitor of LexA proteolysis, the key event in the SOS response. Our results hint that our inhibitor's may function by adopting a ß-hairpin conformation, reminiscent of the native cleavage loop of LexA.

A Systematic Review and Bibliometric Analysis of Applications of Artificial Intelligence and Machine Learning in Vascular Surgery.

BACKGROUND: Artificial intelligence (AI) and machine learning (ML) have seen increasingly intimate integration with medicine and healthcare in the last 2 decades. The objective of this study was to summarize all current applications of AI and ML in the vascular surgery literature and to conduct a bibliometric analysis of published studies. METHODS: A comprehensive literature search was conducted through Embase, MEDLINE, and Ovid HealthStar from inception until February 19, 2021. Reporting of this study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Title and abstract screening, full-text screening, and data extraction were conducted in duplicate. Data extracted included study metadata, the clinical area of study within vascular surgery, type of AI/ML method used, dataset, and the application of AI/ML. Publishing journals were classified as having either a clinical scope or technical scope. The author academic background was classified as clinical, nonclinical (e.g., engineering), or both, depending on author affiliation. RESULTS: The initial search identified 7,434 studies, of which 249 were included for a final analysis. The rate of publications is exponentially increasing, with 158 (63%) studies being published in the last 5 years alone. Studies were most commonly related to carotid artery disease (118, 47%), abdominal aortic aneurysms (51, 20%), and peripheral arterial disease (26, 10%). Study authors employed an average of 1.50 (range: 1-6) distinct AI methods in their studies. The application of AI/ML methods broadly related to predictive models (54, 22%), image segmentation (49, 19.4%), diagnostic methods (46, 18%), or multiple combined applications (91, 37%). The most commonly used AI/ML methods were artificial neural networks (155/378 use cases, 41%), support vector machines (64, 17%), k-nearest neighbors algorithm (26, 7%), and random forests (23, 6%). Datasets to which these AI/ML methods were applied frequently involved ultrasound images (87, 35%), computed tomography (CT) images (42, 17%), clinical data (34, 14%), or multiple datasets (36, 14%). Overall, 22 (9%) studies were published in journals specific to vascular surgery, with the majority (147/249, 59%) being published in journals with a scope related to computer science or engineering. Among 1,576 publishing authors, 46% had exclusively a clinical background, 48% a nonclinical background, and 5% had both a clinical and nonclinical background. CONCLUSIONS: There is an exponentially growing body of literature describing the use of AI and ML in vascular surgery. There is a focus on carotid artery disease and abdominal aortic disease, with many other areas of vascular surgery under-represented. Neural networks and support vector machines composed most AI methods in the literature. As AI/ML continue to see expanded applications in the field, it is important that vascular surgeons appreciate its potential and limitations. In addition, as it sees increasing use, there is a need for clinicians with expertise in AI/ML methods who can optimize its transition into daily practice.

Appraisal of systematic reviews on interventions for postpartum depression: systematic review.

BACKGROUND: Postpartum depression (PPD) is a highly prevalent mental health problem that affects parental health with implications for child health in infancy, childhood, adolescence and beyond. The primary aim of this study was to critically appraise available systematic reviews describing interventions for PPD. The secondary aim was to evaluate the methodological quality of the included systematic reviews and their conclusions. METHODS: An electronic database search of MEDLINE, Embase, and the Cochrane Library from 2000 to 2020 was conducted to identify systematic reviews that examined an intervention for PPD. A Measurement Tool to Assess Systematic Reviews was utilized to independently score each included systematic review which was then critically appraised to better define the most effective therapeutic options for PPD. RESULTS: Of the 842 studies identified, 83 met the a priori criteria for inclusion. Based on the systematic reviews with the highest methodological quality, we found that use of antidepressants and telemedicine were the most effective treatments for PPD. Symptoms of PPD were also improved by traditional herbal medicine and aromatherapy. Current evidence for physical exercise and cognitive behavioural therapy in treating PPD remains equivocal. A significant, but weak relationship between AMSTAR score and journal impact factor was observed (p = 0.03, r = 0.24; 95% CI, 0.02 to 0.43) whilst no relationship was found between the number of total citations (p = 0.27, r = 0.12; 95% CI, - 0.09 to 0.34), or source of funding (p = 0.19). CONCLUSION: Overall the systematic reviews on interventions for PPD are of low-moderate quality and are not improving over time. Antidepressants and telemedicine were the most effective therapeutic interventions for PPD treatment.

Quality appraisal of systematic reviews on methods of labour induction: a systematic review.

PURPOSE: Induction of labour has become more common over the last decade, together with an increase in the number of systematic reviews of the subject. However, with multiple systematic reviews it is necessary to evaluate the methodological rigor to ensure the reliability of conclusions and recommendations for clinical practice. Therefore, the aim of this study was to appraise the quality of systematic reviews that examined the efficacy and/or safety of labour induction methods. METHODS: An electronic search of MEDLINE, Embase, and the Cochrane Library from 2000 to 2020 was conducted. Study selection, data extraction and quality assessment were conducted using A Measurement Tool to Assess Systematic Reviews (AMSTAR) by two independent reviewers, in duplicate. RESULTS: The search identified 387 publications, of which 48 studies (13%) met the a priori inclusion criteria. No significant relationships were found between study quality and number of citations, journal impact factor, or publication year. CONCLUSION: Methodological quality for systematic reviews on the induction of labour were ranked as moderate with no significant changes in quality over the past 2 decades. Publication characteristics are not significantly associated with methodological quality, indicating that healthcare professionals should critically appraise studies before applying them to practice.

Clinical trial design: Past, present, and future in the context of big data and precision medicine.

Clinical trials are fundamental for advances in cancer treatment. The traditional framework of phase 1 to 3 trials is designed for incremental advances between regimens. However, our ability to understand and treat cancer has evolved with the increase in drugs targeting an expanding array of therapeutic targets, the development of progressively comprehensive data sets, and emerging computational analytics, all of which are reshaping our treatment strategies. A more robust linkage between drugs and underlying cancer biology is blurring historical lines that define trials on the basis of cancer type. The complexity of the molecular basis of cancer, coupled with manifold variations in clinical status, is driving the individually tailored use of combinations of precision targeted drugs. This approach is spawning a new era of clinical trial types. Although most care is delivered in a community setting, large centers support real-time multi-omic analytics and their integrated interpretation by using machine learning in the context of real-world data sets. Coupling the analytic capabilities of large centers to the tailored delivery of therapy in the community is forging a paradigm that is optimizing service for patients. Understanding the importance of these evolving trends across the health care spectrum will affect our treatment of cancer in the future and is the focus of this review.

Prevalence and intensity of persistent post-surgical pain following breast cancer surgery: a systematic review and meta-analysis of observational studies.

BACKGROUND: The prevalence and intensity of persistent post-surgical pain (PPSP) after breast cancer surgery are uncertain. We conducted a systematic review and meta-analysis to further elucidate this issue. METHODS: We searched MEDLINE, Embase, CINAHL, and PsycINFO, from inception to November 2018, for observational studies reporting persistent pain (≥3 months) after breast cancer surgery. We used random-effects meta-analysis and the Grading of Recommendations, Assessment, Development and Evaluations approach to rate quality of evidence. RESULTS: We included 187 observational studies with 297 612 breast cancer patients. The prevalence of PPSP ranged from 2% to 78%, median 37% (inter-quartile range: 22-48%); the pooled prevalence was 35% (95% confidence interval [CI]: 32-39%). The pooled pain intensity was 3.9 cm on a 10 cm visual analogue scale (95% CI: 3.6-4.2 cm). Moderate-quality evidence supported the subgroup effects of PPSP prevalence for localized pain vs any pain (29% vs 44%), moderate or greater vs any pain (26% vs 44%), clinician-assessed vs patient-reported pain (23% vs 36%), and whether patients underwent sentinel lymph node biopsy vs axillary lymph node dissection (26% vs 43%). The adjusted analysis found that the prevalence of patient-reported PPSP (any severity/location) was 46% (95% CI: 36-56%), and the prevalence of patient-reported moderate-to-severe PPSP at any location was 27% (95% CI: 10-43%). CONCLUSIONS: Moderate-quality evidence suggests that almost half of all women undergoing breast cancer surgery develop persistent post-surgical pain, and about one in four develop moderate-to-severe persistent post-surgical pain; the higher prevalence was associated with axillary lymph node dissection. Future studies should explore whether nerve sparing for axillary procedures reduces persistent post-surgical pain after breast cancer surgery.

A Systematic Review of Economic Evaluations in Vascular Surgery.

BACKGROUND: With increasing healthcare costs and the emergence of new technologies in vascular surgery, economic evaluations play a critical role in informing decision-making that optimizes patient outcomes while minimizing per capita costs. The objective of this systematic review is to describe all English published economic evaluations in vascular surgery and to identify any significant gaps in the literature. METHODS: We conducted a comprehensive English literature review of EMBASE, MEDLINE, The Cochrane Library, Ovid Health Star, and Business Source Complete from inception until December 1, 2018. Two independent reviewers screened articles for eligibility using predetermined inclusion criteria and subsequently extracted data. Articles were included if they compared 2 or more vascular surgery interventions using either a partial economic evaluation (cost analysis) or full economic evaluation (cost-utility, cost-benefit, and/or cost-effectiveness analysis). Data extracted included publishing journal, date of publication, country of origin of authors, type of economic evaluation, and domain of vascular surgery. RESULTS: A total of 234 papers were included in the analysis. The majority of the papers included only a cost analysis (183, 78%), and there were only 51 papers that conducted a full economic analysis (22%). The 51 papers conducted a total of 69 economic analyses. This consisted of 32 cost-effectiveness analyses, 29 cost-utility analyses, and 8 cost-benefit analyses. The most common domains studied were aneurysmal disease (89, 38%) and peripheral vascular disease (50, 21%). Economic evaluations were commonly published in the Journal of Vascular Surgery (83, 35%) and Annals of Vascular Surgery (32, 14%), with most study authors located in the United States (127, 54%). There was a trend of economic evaluations being published more frequently in recent years. CONCLUSIONS: The majority of vascular surgery economic evaluations used only a cost analysis, rather than a full economic evaluation, which may not be ideal in pursuing interventions that simultaneously optimize cost and patient outcomes. The literature is lacking in full economic evaluations-a trend persistent in other surgical specialties-and there is a need for full economic evaluations to be conducted in the field of vascular surgery.

Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency.

We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.