Search

The current gold standard grafting material is autologous bone due to its osteoinductive and osteoconductive properties. Autograft harvesting results in donors site morbidity. Coral scaffolds offer a natural autograft alternative, sharing the density and porosity of human bone. This study investigated the biocompatibility and osteogenic potential of a novel, sustainably grown Pocillopora scaffold with human bone marrow-derived mesenchymal stromal cells (MSCs). The coral-derived scaffold displays a highly textured topography, with concavities of uniform size and a high calcium carbonate content. Large scaffold samples exhibit compressive and diametral tensile strengths in the range of trabecular bone, with strengths likely increasing for smaller particulate samples. Following the in vitro seeding of MSCs adjacent to the scaffold, the MSCs remained viable, continued proliferating and metabolising, demonstrating biocompatibility. The seeded MSCs densely covered the coral scaffold with organized, aligned cultures with a fibroblastic morphology. In vivo coral scaffolds with MSCs supported earlier bone and blood vessel formation as compared to control constructs containing TCP-HA and MSCs. This work characterized a novel, sustainably grown coral scaffold that was biocompatible with MSCs and supports their in vivo osteogenic differentiation, advancing the current repertoire of biomaterials for bone grafting.

Disinformation - the deliberate spread of false or misleading information poses a significant threat to our society by undermining trust, exacerbating polarization, and manipulating public opinion. With the rapid advancement of artificial intelligence and the growing prominence of large language models (LLMs) such as ChatGPT, new avenues for the dissemination of disinformation are emerging. This review paper explores the potential of LLMs to initiate the generation of multi-media disinformation, encompassing text, images, audio, and video. We begin by examining the capabilities of LLMs, highlighting their potential to create compelling, context-aware content that can be weaponized for malicious purposes. Subsequently, we examine the nature of disinformation and the various mechanisms through which it spreads in the digital landscape. Utilizing these advanced models, malicious actors can automate and scale up disinformation effectively. We describe a theoretical pipeline for creating and disseminating disinformation on social media. Existing interventions to combat disinformation are also reviewed. While these efforts have shown success, we argue that they need to be strengthened to effectively counter the escalating threat posed by LLMs. Digital platforms have, unfortunately, enabled malicious actors to extend the reach of disinformation. The advent of LLMs poses an additional concern as they can be harnessed to significantly amplify the velocity, variety, and volume of disinformation. Thus, this review proposes augmenting current interventions with AI tools like LLMs, capable of assessing information more swiftly and comprehensively than human fact-checkers. This paper illuminates the dark side of LLMs and highlights their potential to be exploited as disinformation dissemination tools.

Mild cognitive impairment (MCI) is the prodromal phase of Alzheimer’s disease (AD) and while it presents as an imperative intervention window, it is difficult to detect which subjects convert to AD (cMCI) and which ones remain stable (sMCI). The objective of this work was to investigate fluid-attenuated inversion recovery (FLAIR) MRI biomarkers and their ability to differentiate between sMCI and cMCI subjects in cross-sectional and longitudinal data. Three types of biomarkers were investigated: volume, intensity and texture. Volume biomarkers included total brain volume, cerebrospinal fluid volume (CSF), lateral ventricular volume, white matter lesion volume, subarachnoid CSF, and grey matter (GM) and white matter (WM), all normalized to intracranial volume. The mean intensity, kurtosis, and skewness of the GM and WM made up the intensity features. Texture features quantified homogeneity and microstructural tissue changes of GM and WM regions. Composite indices were also considered, which are biomarkers that represent an aggregate sum (z-score normalization and summation) of all biomarkers. The FLAIR MRI biomarkers successfully identified high-risk subjects as significant differences (p

Summary: Background: Maternal infections are an important cause of maternal mortality and severe maternal morbidity. We report the main findings of the WHO Global Maternal Sepsis Study, which aimed to assess the frequency of maternal infections in health facilities, according to maternal characteristics and outcomes, and coverage of core practices for early identification and management. Methods: We did a facility-based, prospective, 1-week inception cohort study in 713 health facilities providing obstetric, midwifery, or abortion care, or where women could be admitted because of complications of pregnancy, childbirth, post-partum, or post-abortion, in 52 low-income and middle-income countries (LMICs) and high-income countries (HICs). We obtained data from hospital records for all pregnant or recently pregnant women hospitalised with suspected or confirmed infection. We calculated ratios of infection and infection-related severe maternal outcomes (ie, death or near-miss) per 1000 livebirths and the proportion of intrahospital fatalities across country income groups, as well as the distribution of demographic, obstetric, clinical characteristics and outcomes, and coverage of a set of core practices for identification and management across infection severity groups. Findings: Between Nov 28, 2017, and Dec 4, 2017, of 2965 women assessed for eligibility, 2850 pregnant or recently pregnant women with suspected or confirmed infection were included. 70·4 (95% CI 67·7–73·1) hospitalised women per 1000 livebirths had a maternal infection, and 10·9 (9·8–12·0) women per 1000 livebirths presented with infection-related (underlying or contributing cause) severe maternal outcomes. Highest ratios were observed in LMICs and the lowest in HICs. The proportion of intrahospital fatalities was 6·8% among women with severe maternal outcomes, with the highest proportion in low-income countries. Infection-related maternal deaths represented more than half of the intrahospital deaths. Around two-thirds (63·9%, n=1821) of the women had a complete set of vital signs recorded, or received antimicrobials the day of suspicion or diagnosis of the infection (70·2%, n=1875), without marked differences across severity groups. Interpretation: The frequency of maternal infections requiring management in health facilities is high. Our results suggest that contribution of direct (obstetric) and indirect (non-obstetric) infections to overall maternal deaths is greater than previously thought. Improvement of early identification is urgently needed, as well as prompt management of women with infections in health facilities by implementing effective evidence-based practices. Funding: UNDP–UNFPA–UNICEF–WHO–World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO, Merck for Mothers, and United States Agency for International Development.

New Zealand propolis resin and tinctures are rich in compounds that have in vitro anti-gastrointestinal cancer activity. However, propolis tincture has restricted acceptability for human consumption due to pungency in taste and aroma. We have formulated New Zealand propolis into cyclodextrin complexes (CD) that resolve these acceptability issues, and carried out in vitro bioactivity testing of these complexes using human anti-gastrointestinal cancer, anti-inflammatory and anti-oxidant assays. Demonstration of encapsulation was performed by physical, enzymic and chemical measurements. The New Zealand propolis γCD, αCD, and βCD complexes inhibited the proliferation of 4 human gastro-intestinal cancer cell lines, with the extent of inhibition increasing with increasing exposure time. The complexes were also strongly anti-inflammatory in vitro with respect to the cytokine TNF-α, and showed strong lipid anti-oxidant activity. The bioassay results give a strong first indication of beneficial gastro-intestinal health potential of New Zealand propolis – cyclodextrin complexes.

Summary: Background: Child stunting reduces survival and impairs neurodevelopment. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF) on stunting and anaemia in in Zimbabwe. Methods: We did a cluster-randomised, community-based, 2 × 2 factorial trial in two rural districts in Zimbabwe. Clusters were defined as the catchment area of between one and four village health workers employed by the Zimbabwe Ministry of Health and Child Care. Women were eligible for inclusion if they permanently lived in clusters and were confirmed pregnant. Clusters were randomly assigned (1:1:1:1) to standard of care (52 clusters), IYCF (20 g of a small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counselling; 53 clusters), WASH (construction of a ventilated improved pit latrine, provision of two handwashing stations, liquid soap, chlorine, and play space plus hygiene counselling; 53 clusters), or IYCF plus WASH (53 clusters). A constrained randomisation technique was used to achieve balance across the groups for 14 variables related to geography, demography, water access, and community-level sanitation coverage. Masking of participants and fieldworkers was not possible. The primary outcomes were infant length-for-age Z score and haemoglobin concentrations at 18 months of age among children born to mothers who were HIV negative during pregnancy. These outcomes were analysed in the intention-to-treat population. We estimated the effects of the interventions by comparing the two IYCF groups with the two non-IYCF groups and the two WASH groups with the two non-WASH groups, except for outcomes that had an important statistical interaction between the interventions. This trial is registered with ClinicalTrials.gov, number NCT01824940. Findings: Between Nov 22, 2012, and March 27, 2015, 5280 pregnant women were enrolled from 211 clusters. 3686 children born to HIV-negative mothers were assessed at age 18 months (884 in the standard of care group from 52 clusters, 893 in the IYCF group from 53 clusters, 918 in the WASH group from 53 clusters, and 991 in the IYCF plus WASH group from 51 clusters). In the IYCF intervention groups, the mean length-for-age Z score was 0·16 (95% CI 0·08–0·23) higher and the mean haemoglobin concentration was 2·03 g/L (1·28–2·79) higher than those in the non-IYCF intervention groups. The IYCF intervention reduced the number of stunted children from 620 (35%) of 1792 to 514 (27%) of 1879, and the number of children with anaemia from 245 (13·9%) of 1759 to 193 (10·5%) of 1845. The WASH intervention had no effect on either primary outcome. Neither intervention reduced the prevalence of diarrhoea at 12 or 18 months. No trial-related serious adverse events, and only three trial-related adverse events, were reported. Interpretation: Household-level elementary WASH interventions implemented in rural areas in low-income countries are unlikely to reduce stunting or anaemia and might not reduce diarrhoea. Implementation of these WASH interventions in combination with IYCF interventions is unlikely to reduce stunting or anaemia more than implementation of IYCF alone. Funding: Bill & Melinda Gates Foundation, UK Department for International Development, Wellcome Trust, Swiss Development Cooperation, UNICEF, and US National Institutes of Health.

Abstract Purpose In mitral valve prolapse, determining whether the valve is suitable for surgical repair depends on the location and mechanism of regurgitation. We assessed whether cardiovascular magnetic resonance (CMR) could accurately identify prolapsing or flail mitral valve leaflets and regurgitant jet direction in patients with known moderate or severe mitral regurgitation. Methods CMR of the mitral valve was compared with trans-thoracic echocardiography (TTE) in 27 patients with chronic moderate to severe mitral regurgitation due to mitral valve prolapse. Contiguous long-axis high temporal resolution CMR cines perpendicular to the valve commissures were obtained across the mitral valve from the medial to lateral annulus. This technique allowed systematic valve inspection and mapping of leaflet prolapse using a 6 segment model. CMR mapping was compared with trans-oesophageal echocardiography (TOE) or surgical inspection in 10 patients. Results CMR and TTE agreed on the presence/absence of leaflet abnormality in 53 of 54 (98%) leaflets. Prolapse or flail was seen in 36 of 54 mitral valve leaflets examined on TTE. CMR and TTE agreed on the discrimination of prolapse from flail in 33 of 36 (92%) leaflets and on the predominant regurgitant jet direction in 26 of the 27 (96%) patients. In the 10 patients with TOE or surgical operative findings available, CMR correctly classified presence/absence of segmental abnormality in 49 of 60 (82%) leaflet segments. Conclusion Systematic mitral valve assessment using a simple protocol is feasible and could easily be incorporated into CMR studies in patients with mitral regurgitation due to mitral valve prolapse.

Abstract: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Objective: This study aims to compare trainee self-assessment with supervisor assessment to identify differences in correlations of the demographic data and evaluate whether the instrument can be utilized to identify underperforming trainees., Design: A novel instrument was designed based off the Royal Australasian College of Surgeons original 9 competencies utilizing the JDocs framework and covers 48-items across all surgical competencies. A multiple regression model using age, gender, postgraduate year, IMG status, and level of training as the variables was performed with backwards elimination, and pairwise comparisons made to identify the degree and direction of influence each variable contributed to trainee and supervisor ratings., Setting: Surgical trainees employed in tertiary centers within the Australian Capital Territory and South-East New South Wales health network in Australia., Participants: A total of 36 of 59 (61%) trainees responded. Two grossly incomplete responses were excluded from further analysis resulting in 34 completed self-assessments for analysis. There was a total of 68 supervisor assessments provided by 25 different nominated supervisors. Of these assessments, 67 were fully completed and one was partially complete., Results: We identified that for both self-ratings and supervisor ratings, the most significant correlation is with the postgraduate year of the trainee, with correlation identified in 7 out of 9 competencies, although in different competency domains. International Medical Graduate status is associated in 2 of 9 self-ratings, and in 3 of 9 supervisor ratings. Underperforming trainees were able to be identified through supervisor assessment but not self-assessment., Conclusion: The supervisor assessment form was able to identify underperforming trainees. Our findings resonate with existing literature in other specialty fields, and surgical units that employ assessment forms should feel more confident in the interpretation of the data and provision of feedback to trainees., Competing Interests: DECLARATION OF COMPETING INTEREST None, (Copyright © 2023 Association of Program Directors in Surgery. All rights reserved.)

Background: The Follicular lymphoma international prognostic index (FLIPI) risk score and POD24 have previously been shown to have prognostic value in follicular lymphoma (FL), but the extent to which they can inform prognosis at the time of subsequent relapse is uncertain., Patients and Methods: We conducted a longitudinal cohort study of individuals diagnosed with FL between 2004 and 2010 in Alberta, Canada who received front-line therapy and subsequently relapsed. FLIPI covariates were measured prior to the initiation of front-line therapy. Median overall survival (OS), progression-free survival (PFS2), and time to next treatment (TTNT2) were estimated from the time of relapse., Results: A total of 216 individuals were included. The FLIPI risk score was highly prognostic at the time of relapse for OS (c-statistic = 0.70; HR [High vs. Low]  = 7.38; 95% CI: 3.05-17.88), PFS2 (c-statistic = 0.68; HR [High vs. Low]  = 5.84; 95% CI: 2.93-11.62) and TTNT2 (c-statistic = 0.68; HR [High vs. Low]  = 5.72; 95% CI: 2.87-11.41). POD24 was not prognostic at the time of relapse for either OS, PFS2, or TTNT2 (c-statistic = 0.55)., Conclusion: The FLIPI score measured at diagnosis may help with the risk stratification of individuals with relapsed FL., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Chronic lymphocytic leukemia (CLL) commonly affects older adults. However, few studies have examined the relationship between baseline geriatric domains and clinical outcomes in this population. Here, we aim to evaluate the use of a comprehensive geriatric assessment in older (>65 years) untreated patients with CLL to predict outcomes., Materials and Methods: We conducted a planned analysis of 369 patients with CLL age 65 or older treated in a phase 3 randomized trial of bendamustine plus rituximab versus ibrutinib plus rituximab versus ibrutinib alone (A041202). Patients underwent evaluations of geriatric domains including functional status, psychological status, social activity, cognition, social support, and nutritional status. We examined associations among baseline geriatric domains with grade 3+ adverse events using multivariable logistic regression and overall survival (OS) and progression-free survival (PFS) using multivariable Cox regression models., Results: In this study, the median age was 71 years (range: 65-87). In the combined multivariable model, the following geriatric domains were significantly associated with PFS: Medical Outcomes Study (MOS) - social activities survey score (hazard ratio [HR] [95% confidence interval (CI)] 0.974(0.961, 0.988), p = 0.0002) and nutritional status (≥5% weight loss in the preceding six months: (HR [95% CI] 2.717[1.696, 4.354], p < 0.001). MOS - social activities score [HR (95% CI) 0.978(0.958, 0.999), p = 0.038] was associated with OS. No geriatric domains were significantly associated with toxicity. There were no statistically significant interactions between geriatric domains and treatment., Discussion: Geriatric domains of social activity and nutritional status were associated with OS and/or PFS in older adults with CLL. These findings highlight the importance of assessing geriatric domains to identify high-risk patients with CLL who may benefit from additional support during treatment., Competing Interests: Declaration of Competing Interest PCJ has consulted for AstraZeneca, ADC Therapeutics, and Seagen. JAW has consulted for Abbvie, AstraZeneca, Beigene, Genentech, Janssen, Pharmacyclics, Loxo/Lilly, Merck, and Newave. RAN received equity stock payment from TimeDoc. CO has consulted for Janssen, Beigene, AbbVie, Astrazeneca, Merck and Roche. WD has consulted for Merck, BeiGene, MEI pharama, Alexion and Octapharma. DMS has consulted for Pharmacyclics/Janssen, Karyopharm Therapeutics, Beigene, Innate, AstraZeneca, Abbvie, CSL Behring, Celegene, TG Therapeutics, and Innate Pharma. ASR served on a DSMC for Telios and is an employee of Eli Lilly, although employment began after this work was completed. RS has consulted for GlaxoSmithKline, Hermavant, Takeda, Abbvie, Amgen, AvenCell, BerGenBio, Cellularity, CTI pharma, Jazz, Kura Onc, Rigel, Syros, Novartis, Actinium, Arog, BMS, Boston Pharmaceuticals, and Janssen., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Irritability is a common symptom that may affect children's brain development. This study aims to (1) characterize age-dependent and age-independent neural correlates of irritability in a sample of 4-8 year old children, and (2) examine early irritability as a predictor of change in brain connectivity over time., Methods: Typically developing children, ages 4-8 years, with varying levels of irritability were included. Resting state fMRI and parent-rated irritability (via Child Behavior Checklist; CBCL) were collected at up to three time points, resulting in a cross-sectional sample at baseline (N = 176, M = 6.27, SD = 1.49), and two subsamples consisting of children who were either 4 or 6 years old at baseline that were followed longitudinally for two additional timepoints, one- and two-years post-baseline. That is, a "younger" cohort (age 4 at baseline, n = 34, M age = 4.44, SD = 0.25) and an "older" cohort (age 6 at baseline, n = 29, M age = 6.50, SD = 0.30). Across our exploratory analyses, we examined how irritability related to seed-based intrinsic connectivity via whole-brain connectivity ANCOVAs using the left and right amygdala, and left and right ventral striatum as seed regions., Results: Cross-sectionally, higher levels of irritability were associated with greater amygdala connectivity with the posterior cingulate, controlling for child age. No age-dependent effects were observed in the cross-sectional analyses. Longitudinal analyses in the younger cohort revealed that early higher vs. lower levels of irritability, controlling for later irritability, were associated with decreases in amygdala and ventral striatum connectivity with multiple frontal and parietal regions over time. There were no significant findings in the older cohort., Conclusions: Findings suggest that irritability is related to altered neural connectivity during rest regardless of age in early to middle childhood and that early childhood irritability may be linked to altered changes in neural connectivity over time. Understanding how childhood irritability interacts with neural processes can inform pathophysiological models of pediatric irritability and the development of targeted mechanistic interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Other iatrogenic immunosuppression associated lymphoproliferative disorders (Oii-LPD) is rare subset of lymphoma. There are limited published data on the clinical characteristics and outcomes of this patient population. The primary objective of this study was to describe the clinical characteristics and outcomes of Alberta patients diagnosed with lymphoma following immunosuppressive therapy for autoimmune conditions. Secondary objectives included describing the incidence of Oii-LPD, proportions of subtypes of lymphoma diagnosed and the nature of immunosuppressants used. The outcomes of patients with iatrogenic immunodeficiency-associated diffuse large B cell lymphoma (DLBCL) were compared against a matched control group of patients with de novo DLBCL., Patients and Methods: The study is a descriptive retrospective cohort study with a matched historical control comparison for patients with DLBCL. Alberta lymphoma patients, diagnosed from January 2011 to December 2019, with a history of iatrogenic immunosuppression were identified and described., Results: The incidence of Oii-LPD was 1% of total Alberta lymphoma cases. Majority of this cohort were diagnosed with DLBCL (54.9%) and the most common immunosuppressive agents were methotrexate (62%), hydroxychloroquine (42%), and TNF inhibitors (31%). Survival was not different between Oii-LPD DLBCL and de novo DLBCL with 5-year survival rates of 64.1% and 67%, respectively (HR 1.11 [95% CI, 0.64-1.94])., Conclusion: Oii-LPD are rare with the most frequent subtype being DLBCL occurring in the setting of methotrexate use. In this population-based analysis, the outcomes of iatrogenic immunodeficiency-associated DLBCL were not significantly different from those of de novo DLBCL patients., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The aim of this study was to establish guidelines for the selection of cast and wrought-wire clasps for removable partial dentures (RPDs) that would be appropriate for clinically encountered undercuts and facial curvatures., Methods: Randomly selected discarded casts were collected and 30 premolars and 30 molars were surveyed, sectioned to a line representing the clasp and scanned using a flatbed scanner. The average clasp curvature and length for each group was determined and a three-dimensional model printed, to which wrought wire clasps of 0.9- and 1.0-mm diameter were adapted. Standard wax clasp patterns were adapted and cast in a stellite alloy. Each clasp was deformed beyond its proportional limit; and the forces exerted at that limit and at deflections of 0.25 mm, 0.5 mm, and 0.75 mm were measured, and a safety limit was calculated that would ensure elastic deformation at the required undercuts., Results: A table was produced with guidelines for those clasps that would provide the highest retentive force within the proposed safety limit. The highest forces were provided by cast clasps in a 0.25-mm undercut. Wrought round wire of 1-mm diameter provided the next highest retentive forces, in a 0.25-mm undercut for premolar clasps arms and 0.5-mm for molar clasps., Conclusions: The results provide valid guidelines for the use of combinations of clasp material and undercut that would exert the maximum retentive force without deformation for both short (premolar) as well as long (molar) clasps, for wrought and cast clasps., Competing Interests: Conflict of interest None disclosed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: South Asians, and Indians in particular, are known to have a higher incidence of premature atherosclerosis and acute coronary syndromes (ACS) with worse clinical outcomes, compared to populations with different ethnic backgrounds. However, the underlying pathobiology accounting for these differences has not been fully elucidated., Methods: ACS patients who had culprit lesion optical coherence tomography (OCT) imaging were enrolled. Culprit plaque characteristics were evaluated using OCT., Results: Among 1315 patients, 100 were South Asian, 1009 were East Asian, and 206 were White. South Asian patients were younger (South Asians vs. East Asians vs. Whites: 51.6 ± 13.4 vs. 65.4 ± 11.9 vs. 62.7 ± 11.7; p < 0.001) and more frequently presented with ST-segment elevation myocardial infarction (STEMI) (77.0% vs. 56.4% vs. 35.4%; p < 0.001). On OCT analysis after propensity group matching, plaque erosion was more frequent (57.0% vs. 38.0% vs. 50.0%; p = 0.003), the lipid index was significantly greater (2281.6 [1570.8-3160.6] vs. 1624.3 [940.9-2352.4] vs. 1303.8 [1090.0-1757.7]; p < 0.001), and the prevalence of layered plaque was significantly higher in the South Asian group than in the other two groups (52.0% vs. 30.0% vs. 34.0%; p = 0.003)., Conclusions: Compared to East Asians and Whites, South Asians with ACS were younger and more frequently presented with STEMI. Plaque erosion was the predominant pathology for ACS in South Asians and their culprit lesions had more features of plaque vulnerability., Clinical Trial Registration: http://www.clinicaltrials.gov, NCT03479723., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: The Alliance A041202/CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia. We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies., Methods: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy., Results: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; P < 0.0001) and IR (mean $219,908; P < 0.0001) compared to BR (mean $51,345), driven by higher acquisition costs for ibrutinib. Total mean costs (over 2-years) were $192,615 with ibrutinib, $223,761 with IR, and $55,413 with BR (P < 0.0001 for ibrutinib vs. BR and P < 0.0001 for IR vs. BR). QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR; therefore, a formal cost-utility analysis was not conducted., Conclusions: Direct medical costs are higher for patients receiving ibrutinib-based therapies compared to chemoimmunotherapy in frontline chronic lymphocytic leukemia, with the cost of ibrutinib representing a key driver., Competing Interests: Conflict of interest Dr. Woyach has received honoraria and/or research funding from Pharmacyclics, Abbvie, and Janssen. Dr. Lam has received honoraria from Abbvie and Janssen. Dr. Owen has received honoraria from Janssen., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy., Patients and Methods: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined., Results: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%)., Conclusions: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE., Competing Interests: Disclosure CNO has received non-financial support from Merck Sharp & Dohme. XB receives a merit award supported by BMS. CA has received travel support from Amgen, BMS and Roche. PB has received sponsorship from MSD. WX has served on advisory boards for Merck Serono and Novartis and has received research funding from Merck Serono. BN has received personal financial compensation from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis and AstraZeneca, for public speaking, consultancy and participation in advisory board meetings. His institution (UZ Brussel) received research funding related to research projects conducted by his team from Pfizer, Novartis, Roche and Merck-Serono. CUB has an advisory role for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre and Third Rock Ventures. He has received research funding from BMS, Novartis and NanoString. He has stock ownership in Uniti Cars and is co-founder of Immagene B.V. SJW has received travel support from Ipsen. SS has served on advisory boards for BMS, MSD, Merck, Novartis, Roche, Janssen, AstraZeneca and Amgen and has received research funding from Amgen, Endocyte, MSD and AstraZeneca. JM has intermittent project focused consultant or advisory relationships with Merck/Pfizer, Merck Sharp & Dohme, Amgen, Novartis, Bristol Myers Squibb, Sanofi and Pierre Fabre and has received travel support from Ultrasun, L'oreal, Merck Sharp & Dohme, Bristol Myers Squibb and Pierre Fabre outside of the submitted work. JLM is consultant advisor for BMS, Roche and Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai and Regeneron. He also received research funds from Bristol Myers Squibb, Roche-Genentech and Array, and travel support from MSD. LZ has received honoraria from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis and Pierre Fabre, research funding from Novartis and has served on advisory boards for Bristol Myers Squibb, Novartis, Pierre Fabre, Sun Pharma, Sanofi and Merck Sharp & Dohme. He has received travel support from Bristol Myers Squibb, Pierre Fabre, Sanofi, Amgen, Novartis and Sun Pharma. DBJ has served on advisory boards for Array Biopharma, BMS, Iovance, Jansen, Merck and Novartis, and received research funding from BMS and Incyte. CL has served on advisory boards for BMS, MSD, Novartis, Amgen, Roche, Merck, Serono and Sanofi. She has received honoraria from Roche, BMS, Novartis, Amgen, MSD, Pierre Fabre, Pfizer and Incyte, and speaker's bureau from Roche, BMS, Novartis, Amgen and MSD. She has received research funding from Roche and BMS. She has received travel support from BMS and MSD. She serves on the board of Avantis Medical Systems. MSC has served on advisory boards for Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, Sanofi, Merck, Ideaya, Regeneron, Nektar and Eisai and honoraria from Bristol Myers Squibb, MSD and Novartis. RJS has received research support from Amgen and Merck, as well as served as a paid consultant and/or on a scientific advisory board for Array, AstraZeneca, Asana Biosciences, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Oncosec, Pfizer and Replimune. GVL is consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre Fabre and QBiotics. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

The popularity of laparoscopy to perform radical hysterectomy has massively increased over the last 2 decades. However, oncologic outcomes (overall and disease-free survival) have been found to be better in patients managed by laparotomy compared with laparoscopy, challenging this surgical route. Compared with laparotomy, vaginal access reduces postoperative morbidity, while avoiding potential cancer spread associated with laparoscopy. We describe the procedure of Schauta-Amreich radical vaginal hysterectomy with bilateral salpingo-oophorectomy, assisted laparoscopically, and associated with pelvic sentinel lymph node procedure in a 56-year-old woman with an International Federation of Gynecology and Obstetrics stage IB2 cervical epidermoid carcinoma. A sentinel lymph node procedure was first performed by laparoscopy. Radical hysterectomy was prepared through laparoscopy by dividing the infundibulopelvic, round, and broad ligaments. The procedure was continued by the vaginal route using the Schuchardt incision. We describe each step of the procedure and provide a video. Histology showed a margin-free resection in both the vagina and parametrium with negative sentinel lymph nodes. This description of the Schauta-Amreich radical vaginal hysterectomy technique with a video file could support the teaching of a procedure that may gain in popularity., (Copyright © 2020 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy., Patients and Methods: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately., Results: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors., Conclusions: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1., Competing Interests: Disclosure CNO reports non-financial support from Merck Sharp Dohme (MSD), outside the submitted work. ANS reports grants and personal fees from Bristol-Myers Squibb (BMS), during the conduct of the study; grants and personal fees from Immunocore, grants from Xcovery, grants, personal fees and non-financial support from Castle Biosciences, outside the submitted work. DC reports personal fees from BMS, personal fees from Novartis, outside the submitted work. JM reports other from Merck/Pfizer, other from MSD, other from Pierre Fabre, grants and other from Ultrasun, L'Oreal, Pierre Fabre, MSD, BMS, outside the submitted work. VA reports personal fees and non-financial support from BMS, personal fees from MSD, personal fees from Novartis, personal fees and non-financial support from Pierre Fabre, personal fees from Merck Serono, personal fees from Roche, non-financial support from Onco-sec, outside the submitted work. AY reports grants from National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R38HL143619. CH reports personal fees from Amgen, personal fees from BMS, personal fees from Incyte, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, outside the submitted work. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, MSD, BMS, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome outside the submitted work. MM reports personal fees and non-financial support from MSD, personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Roche, personal fees from Novartis, outside the submitted work. SPP reports personal fees from Merck & Co, Incyte, Castle Biosciences and Cardinal Health, and institutional clinical trial support from Provectus, Ideaya and BMS outside the submitted work. AH reports personal fees from BMS, personal fees from Pierre Fabre, personal fees from Merck, outside the submitted work. DBJ reports other from Array Biopharma, grants and other from BMS, grants and other from Incyte, other from Merck, other from Novartis, other from Genentech, outside the submitted work. CUB reports personal fees from BMS, MSD, GSK, Lilly, Roche, Novartis, Pfizer, GenMab, AZ, Pierre Fabre, grants from BMS, NanoString, Novartis, outside the submitted work; and stockownership Unitit Cars, Neon Therapeutics. SS reports grants and other from MSD, grants and other from BMS, grants from Amgen, grants from Endocyte, grants from Astra Zeneca, other from Roche, outside the submitted work. MSC reports personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Roche, personal fees from Amgen, personal fees from Pierre Fabre, personal fees from Ideaya, outside the submitted work. JMGL reports grants and personal fees from Achilles therapeutics, personal fees from AstraZeneca, personal fees from Boston Biomedical, grants and personal fees from BMS, personal fees from Eisai, personal fees from EUSA Pharma, personal fees from GSK, personal fees from Ipsen, personal fees from Imugene, personal fees from Incyte, personal fees from iOnctura, personal fees from Kymab, personal fees from Merck Sorono, grants and personal fees from MSD, grants and personal fees from Nektar, grants and personal fees from Novartis, personal fees from Pierre Fabre, grants and personal fees from Pfizer, grants and personal fees from Roche/Genetech, personal fees from Secarna, personal fees from Vitaccess, personal fees from Covance, grants and personal fees from Immunocore, grants from Aveo, grants from Pharmacyclics, outside the submitted work. AMM reports personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Roche, personal fees from Pierre Fabre, outside the submitted work. GVL is a Consultant Advisor and reports the following outside of the submitted work; personal fees from Aduro, personal fees from Amgen, personal fees from Array, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Oncosec, personal fees from Roche, personal fees from Sandoz. All other authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

In 2018, around 382,100 new cases of endometrial cancer (EC) were reported worldwide, accounting for about 4.4% of all new cases of cancer in women. In France, in 2018, the EC is the first gynecological cancer in incidence and the fourth cancer in women. The rationale for the therapeutic management of EC is based on the estimation of a theoretical risk of recurrence and lymph node metastasis using MRI and preoperative biopsy criteria. However, lymph node status remains the determining factor of adjuvant treatment. In order to reduce the morbidity of lymphadenectomy, the concept of sentinel lymph node biopsy (SLN) has been developed. The SLN technique has evolved in recent years, thanks to the advent of robotics and the creation of fluorescence detection cameras. It has been shown that detection of SLN with Indocyanine Green (ICG) allows for more frequent bilateral migration of 88 to 100% and better detection of pelvic GS in 97% of cases with a decrease in morbidity. Recently, in view of the absence of a therapeutic role of lymph node staging, the operational risks and the delay of adjuvant treatments, in case of pelvic lymph node metastasis on definitive histological examination, the question of secondarily performing paraaortic lymphadenectomy arises. The SLN procedure, extended to all early-stage endometrial cancers, should lead to a major reduction in the use of secondary staging and better adaptation of adjuvant therapy., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Laparoscopic discoid colorectal resection is a surgical option for bowel endometriosis, 1 of the most severe forms of endometriosis. However, no study has clearly analyzed the feasibility or the complication and recurrence rates of the procedure in a homogeneous population with specific criteria for discoid resection. The aims of this study were to evaluate the rate of conversion to segmental resection, the need for double discoid resection, and the complication and recurrence rates. We conducted a prospective study of 93 consecutive patients who underwent discoid resection in Tenon University Hospital, Paris, France. The median follow-up was 20 months. We included patients with colorectal endometriosis (≤3 cm long and <90° of bowel circumference) experiencing failure of medical treatment or associated infertility. All the patients underwent a discoid colorectal resection using a transanal circular stapler. The primary end point was the rate of conversion to segmental resection (3.2%). The secondary end point was the rate of double discoid resection (6.5%). The overall complication rate was 24%, and the severe complication rate (i.e., Clavien-Dindo IIIB) was 3% (n = 4). Postoperative voiding dysfunction requiring bladder self-catheterization was observed in 16% (n = 15). The mean duration of bladder self-catherization was 30 days (range, 15-90) including 11 cases (74%) lasting less than 30 days and 4 cases lasting more than 30 days. No patients required bladder self-catheterization over 3 months. No difference in the complication rate or in voiding dysfunction was observed between double and single discoid resection. The low rate of conversion to radical resection confirms the satisfactory preoperative evaluation of bowel endometriosis. Few publications report the rate of conversion to radical surgery. This raises the crucial issue of the right indications for discoid resection. The present study confirms that discoid resection is probably the best option for small lesions because of its high feasibility and low complication rate. Further studies are required to evaluate the technique for larger colorectal endometriotic lesions., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

We report the resection of a recurrent epithelioid trophoblastic tumor by laparoscopic laterally extended endopelvic resection (LEER). The LEER technique was developed to resect en bloc multiple visceral compartments involving the lateral pelvic wall with negative margins for local control of advanced and recurrent malignancies. Described by Höckel, this procedure is usually performed by a midline laparotomy. Our patient had undergone prior laparotomic surgery including hysterectomy, partial bladder resection, and a right ureteral reimplantation for an epithelioid trophoblastic tumor without adjuvant treatment. She presented a recurrent tumor infiltrating the bladder, the ureter, and the right pelvic wall as well as the internal and external iliac vessels. A vascular surgeon first performed a femorofemoral bypass by bilateral groin incisions with a subcutaneous tunnel. The surgery was then exclusively performed by laparoscopy using the LEER technique including resection of both external and internal iliac vessels and the pelvic wall through the lateral pelvic muscles and iterative bladder resection associated with a ureteral reimplantation using the psoas hitch bladder technique. The patient experienced Clavien-Dindo classification grade II postoperative complications. Histology showed a margin-free resection (R0)., (Copyright © 2019. Published by Elsevier Inc.)

Background: Little is known about the relationship between bone fragility and respiratory function. We hypothesized that women with osteoporosis or osteopenia, without cardio-pulmonary disease, have perturbations in the pattern of breathing and gas exchange., Methods: In 44 women with bone fragility (BF, T score: < -1), and 20 anthropomorphically-matched control women (T score > -1) we compared pulmonary function tests, central respiratory drive (mouth occlusion pressure or P 0.1), pattern of breathing using optoelectronic plethysmograph and arterial blood gases at rest., Results: Static pulmonary function was similar in BF subjects and controls. However, the arterial blood gas measurements differed significantly. The arterial pH was significantly higher in BF subjects than in controls (P < 0.001). The partial pressure of carbon dioxide (PaCO 2 ) and oxygen (PaO 2 ) in arterial blood were significantly lower in BF subjects than controls (P < 0.001 and P = 0.009, respectively). The BF subjects had a shorter inspiratory fraction compared with controls (P = 0.036). Moreover, T-scores were significantly inversely correlated with the alveolar-arterial gradient of oxygen (r = -0.5; P = 0.0003) and the arterial pH (r = -0.4; P = 0.002), and positively correlated with arterial PaO 2 (r = 0.3; P = 0.01) and PaCO 2 (r = 0.4; P = 0.002) among all subjects., Conclusion: In the absence of known cardio-pulmonary disease, BF is associated with statistically significant perturbations in gas exchange and alterations in the pattern of breathing including shortening of the inspiratory time., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Long-term outcomes following occlusion of spinal dural arteriovenous fistula (SDAVF) are poorly understood and are based on small series reporting predominantly short-term outcomes. The degree and duration of improvement remain unclear. In this study, we analyzed long-term outcomes following occlusion in a cohort of patients with SDAVF., Methods: This was a single-center cohort study of patients with SDAVF identified from a prospective database. Outcomes were assessed using a modified Aminoff and Logue Disability (ALD) Scale, the modified Rankin Scale (mRS), and patient-reported outcomes at presentation and long-term follow-up. Both angiographic recanalization and idiopathic functional recurrence rates were calculated., Results: Of the total of 67 patients with SAVDF identified, 59 were eligible for inclusion in this study. Fifty-seven of these 59 (97%) underwent occlusion. Twenty-two patients underwent initial embolization; 12 were occluded. Two patients recanalized. Eleven patients underwent surgery after attempted embolization; 10 were occluded. Thirty-seven patients treated by surgery only were occluded. The median duration of follow-up was 63 months (range, 12-240 months). After occlusion, the ALD gait and urinary scores improved by a median of 1 point. Although the median mRS score was unchanged, 49% of the patients experienced improvement, most by 1 point. There was no difference between the patients occluded by embolization or surgery, but those requiring both approaches had worse gait and urinary scores (P = 0.005 and 0.03, respectively). The duration of symptoms by itself had no effect on outcomes (P = 0.61). Following occlusion, 5 patients experienced an idiopathic late functional deterioration. Of 16 patients presenting with paraplegia, 13 (81%) improved, with a median mRS improvement of 1 point., Conclusions: Following occlusion, patients with SDAVF experienced a modest improvement in symptoms, most commonly by 1 point on the ALD scale. Idiopathic late deterioration was seen in 9.1% of patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The morphometric characteristics of the retinal vasculature are associated with future risk of many systemic and vascular diseases. However, analysis of data from large population based studies is needed to help resolve uncertainties in some of these associations. This requires automated systems that extract quantitative measures of vessel morphology from large numbers of retinal images. Associations between retinal vessel morphology and disease precursors/outcomes may be similar or opposing for arterioles and venules. Therefore, the accurate detection of the vessel type is an important element in such automated systems. This paper presents a deep learning approach for the automatic classification of arterioles and venules across the entire retinal image, including vessels located at the optic disc. This comprises of a convolutional neural network whose architecture contains six learned layers: three convolutional and three fully-connected. Complex patterns are automatically learnt from the data, which avoids the use of hand crafted features. The method is developed and evaluated using 835,914 centreline pixels derived from 100 retinal images selected from the 135,867 retinal images obtained at the UK Biobank (large population-based cohort study of middle aged and older adults) baseline examination. This is a challenging dataset in respect to image quality and hence arteriole/venule classification is required to be highly robust. The method achieves a significant increase in accuracy of 8.1% when compared to the baseline method, resulting in an arteriole/venule classification accuracy of 86.97% (per pixel basis) over the entire retinal image., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Advances in DNA sequencing and synthesis technologies in the twenty-first century are now making it possible to build large-scale pipelines for engineering plant natural product pathways into heterologous production species using synthetic biology approaches. The ability to decode the chemical potential of plants by sequencing their transcriptomes and/or genomes and to then use this information as an instruction manual to make drugs and other high-value chemicals is opening up new routes to harness the vast chemical diversity of the Plant Kingdom. Here we describe recent progress in methods for pathway discovery, DNA synthesis and assembly, and expression of engineered pathways in heterologous hosts. We also highlight the importance of standardization and the challenges associated with dataset integration in the drive to build a systematic framework for effective harnessing of plant metabolic diversity., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Management of breast cancer is based on national and international guidelines. These are defined on evidence-based medicine. The main purpose of this review is to compare the different guidelines for sentinel lymph node biopsy and completion axillary dissection after positive sentinel lymph node biopsy. This review of breast cancer guidelines led to identify consensus, but in some specific situations, they differ. The guidelines cannot be applied to all clinical cases, mandatoring multidisciplinary meetings are essential., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Morphological changes in the retinal vascular network are associated with future risk of many systemic and vascular diseases. However, uncertainty over the presence and nature of some of these associations exists. Analysis of data from large population based studies will help to resolve these uncertainties. The QUARTZ (QUantitative Analysis of Retinal vessel Topology and siZe) retinal image analysis system allows automated processing of large numbers of retinal images. However, an image quality assessment module is needed to achieve full automation. In this paper, we propose such an algorithm, which uses the segmented vessel map to determine the suitability of retinal images for use in the creation of vessel morphometric data suitable for epidemiological studies. This includes an effective 3-dimensional feature set and support vector machine classification. A random subset of 800 retinal images from UK Biobank (a large prospective study of 500,000 middle aged adults; where 68,151 underwent retinal imaging) was used to examine the performance of the image quality algorithm. The algorithm achieved a sensitivity of 95.33% and a specificity of 91.13% for the detection of inadequate images. The strong performance of this image quality algorithm will make rapid automated analysis of vascular morphometry feasible on the entire UK Biobank dataset (and other large retinal datasets), with minimal operator involvement, and at low cost., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53. Two groups of novel therapeutic agents-anti-CD20 monoclonal antibodies and small molecule inhibitors-are attempting to address these issues, and 5 of these agents have progressed to phase 3 trials: obinutuzumab, idelalisib, ibrutinib, venetoclax (ABT-199), and duvelisib (IPI-145). We present the current evidence for these novel agents in the treatment of CLL, along with the perspectives of 4 Canadian oncology experts., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes., (© 2015 by The American Society of Hematology.)

Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression-free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)