609 Combining bintrafusp alfa with abituzumab enhances suppression of the TGF-β signaling pathway

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor fused to a human IgG1 antibody blocking PD-L1. The TGF-βRII moiety of bintrafusp alfa functions as a "trap" to sequester active TGF-β but does not block TGF-β release from its latent form. Multiple mechanisms lead to the release of active TGF-β. Integrins control local activation of latent TGF-β stored in the extracellular matrix and cell-surface reservoirs in the tumor microenvironment (TME). Alpha v integrin mRNA expression is correlated with multiple TGF-β gene signatures. It has been shown that αvβ8 integrin mediates TGF-β activation without releasing it from the latent TGF-β complex, suggesting that the TGF-βRII moiety of bintrafusp alfa may be unable to sequester TGF-β activated by αvβ8 integrin. Therefore, we hypothesize that combining abituzumab, a pan–αv integrin antibody, with bintrafusp alfa may lead to enhanced suppression of TGF-β signaling.MethodsThe expression of αv and β6 integrin mRNA was determined by RNA sequencing of triple-negative breast cancer (TNBC) tumor samples from a phase 1 clinical trial of bintrafusp alfa and correlated with patient response to bintrafusp alfa. The combination of bintrafusp alfa and abituzumab was investigated in vitro and in vivo in a TGF-β–dependent human tumor model, Detroit 562. In this study, CellTiter-Glo 2.0 Assay measured cell proliferation in vitro and enzyme-linked immunosorbent assay measured the level of latency-associated protein (LAP). A TGF-β reporter cell line MDA-MB-231 measured the level of active TGF-β. Antitumor activity in vivo was evaluated via tumor growth of Detroit 562 xenograft model in SCID mice.ResultsIn TNBC, increased expression of αv and β6 integrin mRNA was associated with poor response to bintrafusp alfa, suggesting that TGF-β activated by αv integrin may not be blocked by bintrafusp alfa. In Detroit 562 cells, abituzumab increased LAP levels in the cell culture medium, confirming modulation of the TGF-β pathway. As a result, the amount of active TGF-β released into culture medium was reduced by abituzumab. In vitro, both abituzumab and bintrafusp alfa suppressed Detroit 562 cell proliferation, and the combination suppressed cell proliferation further. In vivo, the combination led to increased tumor growth inhibition of Detroit 562 xenograft tumors relative to either monotherapy, further supporting the potential of this combination.ConclusionsCollectively, these preclinical findings support clinical development of bintrafusp alfa and abituzumab combination therapy to maximally suppress TGF-β signaling in the TME.AcknowledgementsWe thank George Locke for his analysis of the RNAseq data.Ethics ApprovalThis study was approved by the Institutional Animal Care and Use Committee at EMD Serono, Inc.; approval number [17–008]

Adaptive risk prediction system with incremental and transfer learning

Currently, popular methods for prenatal risk assessment of fetal aneuploidies are based on multivariate proba-bilistic modelling, that are built on decades of scientific research and large-scale multi-center clinical studies. These static models that are deployed to screening labs are rarely updated or adapted to local population characteristics. In this article, we propose an adaptive risk prediction system or ARPS, which considers these changing characteristics and automatically deploys updated risk models. 8 years of real-life Down syndrome screening data was used to firstly develop a distribution shift detection method that captures significant changes in the patient population and secondly a probabilistic risk modelling system that adapts to new data when these changes are detected. Various candidate systems that utilize transfer-and incremental learning that implement different levels of plasticity were tested. Distribution shift detection using a windowed approach provides a computationally less expensive alternative to fitting models at every data block step while not sacrificing performance. This was possible when utilizing transfer learning. Deploying an ARPS to a lab requires careful consideration of the parameters regarding the distribution shift detection and model updating, as they are affected by lab throughput and the incidence of the screened rare disorder. When this is done, ARPS could be also utilized for other population screening problems. We demonstrate with a large real-life dataset that our best performing novel Incremental-Learning-Population-to-Population-Transfer-Learning design can achieve on par prediction performance without human intervention, when compared to a deployed risk screening algorithm that has been manually updated over several years.</p

Five‐year effectiveness of bariatric surgery on disease remission, weight loss, and changes of metabolic parameters in obese patients with type 2 diabetes: A population‐based propensity score‐matched cohort study

Aims: To compare disease remission rates, weight loss, and changes of metabolic parameters of patients after bariatric surgery with nonsurgical patients. Methods: Based on the 2006‐2017 Hospital Authority database, a population‐based retrospective cohort of obese type 2 diabetes mellitus (T2DM) patients with and without bariatric surgery were identified. Surgical patients were matched with nonsurgical patients on 1‐to‐5 propensity score. Remission rates of diabetes, hypertension, and dyslipidaemia were reported annually up to 60 months. Changes in weight loss measurements (Body Mass Index [BMI], percentage of total weight loss [%TWL], percentage of excess weight loss [%EWL], and percentage of rebound in excess weight loss [%REWL]) and metabolic parameters (haemoglobin A1c [HbA1c], systolic blood pressure [SBP], diastolic blood pressure [DBP], and low‐density lipoprotein cholesterol [LDL‐C]) were measured for both groups. Results: Four hundred one surgical patients (310 restrictive surgeries; 91 bypass surgeries) and 1894 nonsurgical patients were included. Surgical patients had higher remission rates in diabetes and dyslipidaemia and better glycaemic control at 12 to 60 months (all Ps &lt; .01). SBP and DBP were significantly lower for surgical group up to 12 months and similar between two groups after 12 months. Surgical patients had significantly lower BMI during follow‐up period. %TWL and %EWL were higher in the surgery group (15.7% vs 3.7%; 48.8% vs 12.0%) at 60 months (P &lt; .001); differences in %REWL between two groups were insignificant. The effectiveness of restrictive and bypass surgeries was similar at 60 months, although restrictive surgeries were slightly more effective in T2DM remission. Conclusions: Bariatric surgery was effective in weight loss, remission of diabetes, and dyslipidaemia in 5‐year post‐surgery

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Market Expectation of Appreciation of the Renminbi

This paper proposes a path-dependent approach for estimating maximum appreciations of the renminbi expected by the market based on first-passage-time distributions. Using market data of the renminbi spot exchange rates, non-deliverable forward rates and currency option prices from 21 July 2005 (the reform of the exchange rate regime) to 28 February 2008 for model parameters, the maximum appreciations of the renminbi estimated under the proposed approach show that the market expected another large movement of the exchange rate during the 14 months after the reform. Subsequently, the few occasions of appreciations beyond the expected maximums coincided with trade-related issues and speculation that greater momentum of appreciation would be allowed by the authorities. The PBoC¡¦s measures were however largely incorporated into the derivatives¡¦ prices. The proposed approach can be used to gauge the range of appreciations of the renminbi anticipated in the market and to identify any exchange rate movements beyond market expectations.renminbi exchange rate, first-passage-time distributions, currency options