North Atlantic climate far more predictable than models imply.

Quantifying signals and uncertainties in climate models is essential for the detection, attribution, prediction and projection of climate change1-3. Although inter-model agreement is high for large-scale temperature signals, dynamical changes in atmospheric circulation are very uncertain4. This leads to low confidence in regional projections, especially for precipitation, over the coming decades5,6. The chaotic nature of the climate system7-9 may also mean that signal uncertainties are largely irreducible. However, climate projections are difficult to verify until further observations become available. Here we assess retrospective climate model predictions of the past six decades and show that decadal variations in North Atlantic winter climate are highly predictable, despite a lack of agreement between individual model simulations and the poor predictive ability of raw model outputs. Crucially, current models underestimate the predictable signal (the predictable fraction of the total variability) of the North Atlantic Oscillation (the leading mode of variability in North Atlantic atmospheric circulation) by an order of magnitude. Consequently, compared to perfect models, 100 times as many ensemble members are needed in current models to extract this signal, and its effects on the climate are underestimated relative to other factors. To address these limitations, we implement a two-stage post-processing technique. We first adjust the variance of the ensemble-mean North Atlantic Oscillation forecast to match the observed variance of the predictable signal. We then select and use only the ensemble members with a North Atlantic Oscillation sufficiently close to the variance-adjusted ensemble-mean forecast North Atlantic Oscillation. This approach greatly improves decadal predictions of winter climate for Europe and eastern North America. Predictions of Atlantic multidecadal variability are also improved, suggesting that the North Atlantic Oscillation is not driven solely by Atlantic multidecadal variability. Our results highlight the need to understand why the signal-to-noise ratio is too small in current climate models10, and the extent to which correcting this model error would reduce uncertainties in regional climate change projections on timescales beyond a decade.

Occurrence and removal of drugs and endocrine disruptors in water supply systems in the metropolitan region of Belo Horizonte (Minas Gerais State, Brazil).

This study evaluates both the occurrence and removal of 24 compounds, including drugs and endocrine disruptors, in 8 water treatment plants (WTP) located in the metropolitan region of Belo Horizonte (Minas Gerais State, Brazil). The compounds 4-nonylphenol, 4-octylphenol, 17α-ethinylestradiol, 17ß-estradiol, acyclovir, bisphenol A, bezafibrate, caffeine, dexamethasone, diclofenac sodium, diltiazem, estrone, estriol, gemfibrozil, ibuprofen, linezolid, loratadine, losartan, metformin, naproxen, paracetamol, promethazine, propranolol and sulfamethoxazole were monitored at 3 sampling points (raw water, filtered water, treated water) over 10 or 12 collection campaigns for each WTP. The results showed that bisphenol A occurred at higher concentrations during the dry period with a maximum concentration of 3257.1 ng L-1, while the compounds 4-nonylphenol and losartan exhibited higher concentrations in the rainy period with maximum concentrations of 8577.2 ng L-1 and 705.8 ng L-1, respectively. Regarding the removal of compounds in the monitored WTPs, the clarification step demonstrated better removals for 4-nonylphenol, bisphenol-A, paracetamol, and sulfamethoxazole, whereas the disinfection step mainly removed the compounds 4-octylphenol and estrone. Margin of exposure (ME) assessment results indicated that only dexamethasone, ethinyl estradiol, diclofenac, estradiol, and estrone were classified as imminent risk or alert considering the 95th percentile concentration found in the samples of treated water.

Occurrence and removal of drugs and endocrine disruptors in the Bolonha Water Treatment Plant in Belém/PA (Brazil).

This study aimed to investigate the occurrence of drugs and endocrine disrupters in water supplies and in water for human consumption. Twelve sampling campaigns were carried out during the rainy and dry season at four sampling points in the Bolonha Complex, in the city of Belém, northern region of Brazil: Bolonha reservoir (catchment) and Water Treatment Plant (WTP) Bolonha (filtered water chamber, treated water tank, and washing water from the filters). The determination of the compounds was performed by solid phase extraction followed by gas and liquid chromatography coupled to mass spectrometry. The results confirmed the anthropic influence that the reservoir and WTP-Bolonha have been suffering, as consequence of the discharge of domestic sewage in natura. Among 25 microcontaminants analyzed, 12 were quantified in raw water and 10 in treated water. The antiallergic Loratadine (LRT) was the contaminant that occurred most frequently in all sample points, having been poorly removed (median 12%) in the conventional treatment used. Losartana (LST), 4-octylphenol (4-OP), and Bisphenol A (BPA) also occurred very frequently in raw water with concentrations ranging from 3.7 to 194 ng L-1. Although such contaminants occurred in treated water in concentrations varying from 4.0 to 135 ng L-1, the estimated margin of exposure ranged from 55 to 3333 times which indicates low risk of human exposure to such contaminants through ingestion of treated water.

In vitro and in vivo antitumoral activity of a ternary copper (II) complex.

Recently, a high number of copper derivatives has been evaluated as DNA-targeting metallodrugs, due to the lower toxicity and its potential to cleave DNA. Several strategies have been testing to develop metal compounds effective against tumour cells. In this work, the ternary copper (doxycycline)-(1,10-phenanthroline) complex [Cu(dox)(phen)]2+ was especially designed as an antitumoral drug, previously showing high cytotoxicity and DNA cleavage activity. We aimed to further investigate the in vitro cytotoxic activity in both tumoral and non-tumoral cells, in vitro genotoxic potential, and in vivo antitumor activity using BALB/C mouse injected with sarcoma S180 and Ehrlich cell lines. Our results indicated that this compound exhibits a moderate genotoxic potential, with selective growth inhibition of tumor cells, especially the murine melanoma B16F10. Its main mechanism of action seems to be through ROS generation. We have further shown a significant reduction of the implanted tumor size in the animal model, suggesting that this compound has great antitumoral potential against many tumor types. [Cu(dox)(phen)]2+ is selectively cytotoxic for melanoma B16F10 and showed high chemotherapeutic potential in vivo against implanted sarcoma S180 and Ehrlich ascites tumours.

Oxidative treatments for atenolol removal in water: Elucidation by mass spectrometry and toxicity evaluation of degradation products.

RATIONALE: The presence of pharmaceuticals in water is a worldwide concern due to potential damage to human and environmental health. For example, compounds such as the ß-blocker atenolol (ATE), widely used for the treatment of cardiac disease, are detected in drinking water since conventional water treatment plants are not designed to remove them. Thus, the evaluation of ATE removal at different water oxidative treatment processes, identification of its degradation products and evaluation of their toxicity is necessary. METHODS: Aqueous solutions of ATE (10 mg/L) were submitted to oxidative treatments of chlorination ([NaClO] = 10 mg/L), ozonation ([O3 ] = 8 mg/L), photocatalysis ([TiO2 ] = 120 mg/L and UV-C light) and photolysis (UV-C light). The removal of ATE and formation of degradation products (DPs) were monitored by mass spectrometry. To assess acute cytotoxicity, DPs were submitted to colorimetric MTT assay using HepG2 cells. The Ecological Structure Activity Relationships (ECOSAR) software was applied to estimate the acute and chronic toxicity of identified DPs at different trophic levels. RESULTS: Photocatalysis was the treatment that demonstrated greater efficiency, removing 94% of the initial ATE. For the four tested treatments, 12 DPs were confirmed after 30 min. Moreover, some of the identified DPs were unpublished in the literature. Through high-resolution mass spectrometry (HRMS), it was possible to elucidate the structure of the DPs. Solutions of DPs were not considered to be toxic to HepG2 cells. Only the DP with a molecular formula of C13 H19 NO3 (m/z 238.1438) could be considered detrimental to daphnid and green algae. CONCLUSIONS: Low rates of organic matter removal and high rates of ATE degradation were obtained in the applied treatments after 30 min. Although the treated solutions were not toxic to HepG2 cells, one of the degradation products can be considered an environmental concern since it presents chronic toxicity to daphnid and green algae.

Eosinophil granule major basic protein 1 deposition in eosinophilic esophagitis correlates with symptoms independent of eosinophil counts.

In patients with eosinophilic esophagitis (EoE), symptoms often do not correlate with peak eosinophil counts (PEC) determined on histopathological examination of biopsy specimens. This may be because eosinophils degranulate during active disease and lose their morphological identity as intact cells and, therefore, are not enumerated on microscopic examination. Eosinophil granule proteins that are released into tissues with degranulation, including major basic protein 1 (eMBP1), likely contribute to disease pathogenesis and, therefore, may correlate with symptoms better than PEC. We sought to determine whether symptoms in patients with EoE more closely relate to eosinophil granule protein deposition than to eosinophil enumeration, especially in patients with fewer than 15 eosinophils per high power field (HPF). Esophageal biopsy specimens from 34 patients diagnosed with EoE were obtained for histopathological examination and for evaluation of eMBP1 staining by indirect immunofluorescence. PEC by histopathology were compared to extracellular eMBP1 grades by immunostaining. PEC and eMBP1 grades also were analyzed for their relationship to symptoms and clinical course. Biopsy specimens from 19 of the 34 patients had fewer than 15 PEC on histopathological examination, and the other 15 patients had 15 or greater PEC. Positive eMBP1 immunostaining was found in all symptomatic patients. EoE symptoms were related to eMBP1 immunostaining grades (p = 0.0001), but not PEC (P = 0.14). Eosinophil granule protein deposition, specifically eMBP1, is increased in esophageal biopsy specimens from symptomatic patients with EoE and may be a marker of disease activity, including patients with EoE who have 'resolved' disease.

Ethnic variations in the risk of hypoglycaemia among people with Type 2 diabetes prescribed insulins and/or sulfonylureas: a historical cohort study using general practice-recorded data.

AIM: To identify ethnic differences in hypoglycaemic risk among people with Type 2 diabetes prescribed insulins and/or sulfonylureas in community settings. METHODS: Using routine general practice-recorded data, two cohorts of adults with Type 2 diabetes from east London were studied between January 2013 and December 2015: (1) adults prescribed insulins ± other antidiabetes medications (n=7269) and (2) adults prescribed sulfonylureas ± other antidiabetes medications excluding insulins (n=12 502). Incidence rate ratios of hypoglycaemia by ethnicity, adjusting for age, sex, socio-economic status and clustering within Clinical Commissioning Groups, were estimated using random effects Poisson regression. RESULTS: Compared with white British people prescribed insulins, those of black Caribbean ethnicity were at increased hypoglycaemic risk [adjusted incidence rate ratio 1.56 (95% CI 1.21,2.01)], while Bangladeshi people had a lower risk [adjusted incidence rate ratio 0.49 (95% CI, 0.38,0.64)]. In the sulfonylurea cohort, black Caribbean, black African and Indian people all had increased risks of hypoglycaemia compared with white British people [adjusted incidence rate ratios 1.63 (95% CI 1.15,2.29), 1.90 (95% CI 1.32,2.75) and 1.93 (95% CI 1.39,2.69), respectively]. CONCLUSION: The differences in hypoglycaemic risk among people with Type 2 diabetes prescribed insulin and/or sulfonylureas warrant further investigation of any differing biological responses and/or cultural attitudes to antidiabetes therapy among ethnic groups, and should be considered by clinicians evaluating the treatment goals of people with Type 2 diabetes using insulins or sulfonylureas.

Flexible multistate models for interval-censored data: Specification, estimation, and an application to ageing research.

Continuous-time multistate survival models can be used to describe health-related processes over time. In the presence of interval-censored times for transitions between the living states, the likelihood is constructed using transition probabilities. Models can be specified using parametric or semiparametric shapes for the hazards. Semiparametric hazards can be fitted using P-splines and penalised maximum likelihood estimation. This paper presents a method to estimate flexible multistate models that allow for parametric and semiparametric hazard specifications. The estimation is based on a scoring algorithm. The method is illustrated with data from the English Longitudinal Study of Ageing.

Transitions across cognitive states and death among older adults in relation to education: A multistate survival model using data from six longitudinal studies.

INTRODUCTION: This study examines the role of educational attainment, an indicator of cognitive reserve, on transitions in later life between cognitive states (normal Mini-Mental State Examination (MMSE), mild MMSE impairment, and severe MMSE impairment) and death. METHODS: Analysis of six international longitudinal studies was performed using a coordinated approach. Multistate survival models were used to estimate the transition patterns via different cognitive states. Life expectancies were estimated. RESULTS: Across most studies, a higher level of education was associated with a lower risk of transitioning from normal MMSE to mild MMSE impairment but was not associated with other transitions. Those with higher levels of education and socioeconomic status had longer nonimpaired life expectancies. DISCUSSION: This study highlights the importance of education in later life and that early life experiences can delay later compromised cognitive health. This study also demonstrates the feasibility and benefit in conducting coordinated analysis across multiple studies to validate findings.

Spatialization of Brazilian pig production: relationship between productive, physical, environmental, and socio-economic variables.

Brazilian pig production spans over a large territory encompassing regions of different climatic and socio-economic realities. Production, physical, socio-economic, and environmental data were used to characterize pig production in the country. Multivariate analysis evaluated indices including number productivity, production levels, and income from pigs, together with the average area of pig farm and socio-economic variables such as municipal human development index, technical guidance received from agricultural cooperatives and industrial companies, number of family farms, and offtake; and finally, environmental variables: latitude, longitude, annual temperature range, solar radiation index, as well as temperature and humidity index. The Southern region has the largest herd, number of pigs sold/sow, and offtake rate (p < 0.05), followed by the Midwest and Southeast. No significant correlations were seen between production rates and productivity with the socio-economic and environmental variables in the regions of Brazil. Production indexes, productivity, and offtake rate discriminated Northeast and Midwest and Northeast and Southeast regions. The Northern region, with a large area, has few and far-between farms that rear pigs for subsistence. The Northeast region has large herds, but low productivity. Number of slaughtered pigs has been variable over the past three decades, with few states responsible for maintaining high production in Brazil. However, the activity can be effective in any region of the country with technology and technical assistance adapted to regional characteristics.

Positron Emission Tomography and Magnetic Resonance Imaging of Cellular Inflammation in Patients with Abdominal Aortic Aneurysms.

OBJECTIVES: Inflammation is critical in the pathogenesis of abdominal aortic aneurysm (AAA) disease. Combined (18)F-fludeoxyglucose ((18)F-FDG) positron emission tomography with computed tomography (PET-CT) and ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) are non-invasive methods of assessing tissue inflammation. The aim of this study was to compare these techniques in patients with AAA. MATERIALS AND METHODS: Fifteen patients with asymptomatic AAA with diameter 46 ± 7 mm underwent PET-CT with (18)F-FDG, and T2*-weighted MRI before and 24 hours after administration of USPIO. The PET-CT and MRI data were then co-registered. Standardised uptake values (SUVs) were calculated to measure (18)F-FDG activity, and USPIO uptake was determined using the change in R2*. Comparisons between the techniques were made using a quadrant analysis and a voxel-by-voxel evaluation. RESULTS: When all areas of the aneurysm were evaluated, there was a modest correlation between the SUV on PET-CT and the change in R2* on USPIO-enhanced MRI (n = 70,345 voxels; r = .30; p < .0001). Although regions of increased (18)F-FDG and USPIO uptake co-localised on occasion, this was infrequent (kappa statistic 0.074; 95% CI 0.026-0.122). (18)F-FDG activity was commonly focused in the shoulder region whereas USPIO uptake was more apparent in the main body of the aneurysm. Maximum SUV was lower in patients with mural USPIO uptake. CONCLUSIONS: Both (18)F-FDG PET-CT and USPIO-MRI uptake identify vascular inflammation associated with AAA. Although they demonstrate a modest correlation, there are distinct differences in the pattern and distribution of uptake, suggesting a differential detection of macrophage glycolytic and phagocytic activity respectively.

Trends in the epidemiology of invasive Haemophilus influenzae disease in Queensland, Australia from 2000 to 2013: what is the impact of an increase in invasive non-typable H. influenzae (NTHi)?

Following the introduction of vaccination against Haemophilus influenzae type b (Hib), cases of invasive encapsulated Hib disease have decreased markedly. This study aimed to examine subsequent epidemiological trends in invasive H. influenzae disease in Queensland, Australia and in particular, assess the clinical impact and public health implications of invasive non-typable H. influenzae (NTHi) strains. A multicentre retrospective study was conducted from July 2000 to June 2013. Databases of major laboratories in Queensland including Queensland Forensic and Scientific Services (jurisdictional referral laboratory for isolate typing) were examined to identify cases. Demographic, infection site, Indigenous status, serotype, and mortality data were collected. In total, 737 invasive isolates were identified, of which 586 (79·5%) were serotyped. Hib, NTHi and encapsulated non-b strains, respectively, constituted 12·1%, 69·1% and 18·8% of isolates. The predominant encapsulated non-b strains were f (45·5%) and a (27·3%) serotypes. Of isolates causing meningitis, 48·9% were NTHi, 14·9% Hib, 14·9% Hie, 10·6% Hif, 6·4% Hia and 4·3% were untyped. During the study period, there was an increase in the incidence of invasive NTHi disease (P = 0·007) with seasonal peaks in winter and spring (P 0·001) and Hib (P = 0·039) than non-Indigenous patients. In Queensland, invasive H. influenzae disease is now predominantly encountered in adults and most commonly caused by NTHi strains with demonstrated pathogenicity extending to otherwise young or immunocompetent individuals. Routine public health notification of these strains is recommended and recent available immunization options should be considered.

Behaviour of pharmaceuticals and endocrine disrupting chemicals in simplified sewage treatment systems.

This work assessed the behaviour of nine pharmaceuticals and/or endocrine disrupting chemicals (EDCs) in demo-scale upflow anaerobic sludge blanket reactors (UASB reactors) coupled to distinct simplified post-treatment units (submerged bed, polishing ponds, and trickling filters) fed on raw sewage taken from a municipality in Brazil. The dissolved concentration of the studied micropollutants in the raw and treated sewage was obtained using solid phase extraction (SPE) followed by analysis in a liquid chromatography system coupled to a hybrid high resolution mass spectrometer consisting of an ion-trap and time of flight (LC-MS-IT-TOF). The UASB reactors demonstrated that they were not appropriate for efficiently removing the assessed compounds from the sewage. Furthermore, this study demonstrated that the hydraulic retention time (HRT) was an important parameter for the removal of the hydrophilic and less biodegradable compounds, such as trimethoprim and sulfamethoxazole. The post-treatment units substantially increased the removal of most target micropollutants present in the anaerobic effluents, with a greater removal of micropollutants in simplified systems that require a large construction area, such as the submerged bed and polishing ponds, probably because of the higher HRT employed. Alternatively, compact post-treatment systems, such as trickling filters, tended to be less effective at removing most of the micropollutants studied, and the type of packing proved to be crucial for determining the fate of such compounds using trickling filters.

Non-Positive Experiences Encountered by Pupils During Participation in a Mindfulness-Informed School-Based Intervention.

Mindfulness-informed school-based mental health curricula show much promise in cultivating a positive school climate which supports the well-being and mental health of pupils and staff. However, non-positive pupil outcomes and experiences of school-based mental health interventions are often under-recognised and under-reported. This study sought to capture non-positive pupil experiences of a popular mindfulness-informed curriculum. Some pupils across all schools in the study described non-positive experiences, including having troubling thoughts and emotions, and not finding the programme effective. Contexts surrounding these experiences are explored and linked to existing literature, and subsequent recommendations for improvements are made, including the importance of having clear programme structure, definitions and aims, acknowledging and accommodating fidelity issues as best as possible, and better highlighting the potential for non-positive experiences and how they may be reduced.

Gut bacteria promote proliferation in benign S/RG/C2 colorectal tumour cells, and promote proliferation, migration and invasion in malignant HCT116 cells.

Colorectal cancer (CRC) is a significant global health burden with a rising incidence worldwide. Distinct bacterial populations are associated with CRC development and progression, and it is thought that the relationship between CRC and associated gut bacteria changes during the progression from normal epithelium to benign adenoma and eventually malignant carcinoma and metastasis. This study compared the interaction of CRC-associated species Enterotoxigenic Bacteroides fragilis, Enterococcus faecalis and Fusobacterium nucleatum and one probiotic species, Escherichia coli Nissle 1917 with a colorectal adenoma (S/RG/C2) and a colorectal adenocarcinoma (HCT116) derived cell line. Gentamicin protection assays showed that all species displayed higher attachment to benign tumour monolayers when compared to malignant monolayers. However, invasion of 3/4 species was higher in the HCT116 cells than in the adenoma cells. All species were found to persist within tumour cell monolayers for a minimum of 48 h under standard aerobic cell culture conditions, with persistence significantly higher in HCT116 cells. Downstream assays were performed to analyse the behaviour of S/RG/C2 and HCT116 cells post-infection and revealed that all species increased the tumour cell yield of both cell lines. The migratory and invasive potential of HCT116 cells was increased after infection with F. nucleatum; however, no species significantly altered these characteristics in S/RG/C2 cells. These results add to the growing evidence for the involvement of microorganisms in CRC progression and suggest that these interactions may be dependent on tumour cell-specific characteristics.

Deployment of whole genome next-generation sequencing of SARS-CoV-2 in a military maritime setting.

BACKGROUND: SARS-CoV-2 can spread rapidly on maritime platforms. Several outbreaks of SARS-CoV-2 have been reported on warships at sea, where transmission is facilitated by living and working in close quarters. Core components of infection control measures such as social distancing, patient isolation and quarantine of exposed persons are extremely difficult to implement. Whole genome sequencing (WGS) of SARS-CoV-2 has facilitated epidemiological investigations of outbreaks, impacting on outbreak management in real time by identifying transmission patterns, clusters of infection and guiding control measures. We suggest such a capability could mitigate against the impact of SARS-CoV-2 in maritime settings. METHODS: We set out to establish SARS-CoV-2 WGS using miniaturised nanopore sequencing technology aboard the Royal Fleet Auxiliary ARGUS while at sea. Objectives included designing a simplified protocol requiring minimal reagents and processing steps, the use of miniaturised equipment compatible for use in limited space, and a streamlined and standalone data analysis capability to allow rapid in situ data acquisition and interpretation. RESULTS: Eleven clinical samples with blinded SARS-CoV-2 status were tested at sea. Following viral RNA extraction and ARTIC sequencing library preparation, reverse transcription and ARTIC PCR-tiling were performed. Samples were subsequently barcoded and sequenced using the Oxford Nanopore MinION Mk1B. An offline version of the MinKNOW software was used followed by CLC Genomics Workbench for downstream analysis for variant identification and phylogenetic tree construction. All samples were correctly classified, and relatedness identified. CONCLUSIONS: It is feasible to establish a small footprint sequencing capability to conduct SARS-CoV-2 WGS in a military maritime environment at sea with limited access to reach-back support. This proof-of-concept study has highlighted the potential of deploying such technology in the future to military environments, both maritime and land-based, to provide meaningful clinical data to aid outbreak investigations.

Brucella suis in three dogs: presentation, diagnosis and clinical management.

Brucella suis is an emerging, zoonotic disease predominantly affecting dogs and humans that engage in feral pig hunting in Australia and other countries. Although B. suis infection in dogs shares some clinical similarities to the host-adapted species (B. canis), B. suis remains an incompletely understood pathogen in dogs with limited published data on its pathogenesis and clinical features. This case series describes the presentations, diagnosis, and clinical management of B. suis infection in three dogs: (1) a bitch with dystocia, abortion and mastitis; (2) an entire male dog with septic arthritis and presumptive osteomyelitis; and (3) a castrated male dog with lymphadenitis. Unique features of these cases are reported including the first documented detection of B. suis from milk and isolation from lymph nodes of canine patients, as well as the follow-up of pups born to a B. suis-infected bitch. Consistent with previous reports, all three dogs showed a favourable clinical response to combination antibiotic therapy with rifampicin and doxycycline. Individually tailored drug regimens were required based on the clinical presentation and other factors, including owner expectations and compliance with therapy as well as a zoonotic risk assessment (generally considered low, except around time of whelping). The authors include their recommendations for the clinical management of dogs that are at-risk or seropositive for B. suis with or without clinical signs or laboratory-confirmed infection.

Real-World Progression-Free Survival as an Endpoint in Lung Cancer: Replicating Atezolizumab and Docetaxel Arms of the OAK Trial Using Real-World Data.

Evaluating cancer treatments in real-world data (RWD) requires informative endpoints. This study replicated the atezolizumab and docetaxel arms of the OAK trial using RWD and compared progression-free survival (PFS) outcomes derived from abstracted physician's notes in RWD (rwPFS) against PFS outcomes derived from the clinical trial PFS (ctPFS). Atezolizumab and docetaxel arms of the phase III OAK randomized controlled trial (RCT; NCT02008227) were replicated in a US nationwide real-world database using selected OAK inclusion/exclusion criteria and propensity score-based adjustment for baseline prognostic variables. Concordance of outcomes was assessed using Kaplan-Meier medians and hazard ratios (HRs). The RWD cohorts comprised 133 patients on atezolizumab and 479 patients on docetaxel. After adjustment, prognostic variables were balanced between RCT arms and corresponding RWD cohorts. The rwPFS and ctPFS outcomes showed better concordance for docetaxel (2.99 vs. 3.52 months; HR: 0.99, 95% confidence interval (CI): 0.85-1.15) than for atezolizumab (3.71 vs. 2.76 months; HR: 0.8, 95% CI: 0.61-1.02). Excluding events labeled "pseudo-progression" from both RWD and RCT improved concordance for atezolizumab (4.24 vs. 4.14 months; HR: 0.95, 95% CI: 0.70-1.25). These findings were robust across sensitivity analyses. Replicating RCTs using RWD and comparing outcomes can help characterize RWD endpoints. Similarity of results between rwPFS and ctPFS at the cohort level may depend on drug category, highlighting the need for further studies to verify and understand when the corresponding outcomes can be compared, including within the same patient.

Replication of Overall Survival, Progression-Free Survival, and Overall Response in Chemotherapy Arms of Non-Small Cell Lung Cancer Trials Using Real-World Data.

PURPOSE: The utility of real-world data (RWD) for use as external controls in drug development is informed by studies that replicate trial control arms for different endpoints. The purpose of this study was to replicate control arms from four non-small cell lung cancer (NSCLC) randomized controlled trials (RCT) to analyze overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) using RWD. PATIENTS AND METHODS: This study used RWD from a nationwide de-identified database and a clinico-genomic database to replicate OS, PFS, and ORR endpoints in the chemotherapy control arms of four first-line NSCLC RCTs evaluating atezolizumab [IMpower150-wild-type (WT), IMpower130-WT, IMpower131, and IMpower132]. Additional objectives were to develop a definition of real-world PFS (rwPFS) and to evaluate the real-world response rate (rwRR) endpoint. RESULTS: Baseline demographic and clinical characteristics were balanced after application of propensity score weighting methods. For rwPFS and OS, RWD external controls were generally similar to their RCT control counterparts. Across all four trials, the hazard ratio (HR) point estimates comparing trial controls with external controls were closer to 1.0 for the PFS endpoint than for the OS endpoint. An exploratory assessment of rwRR in RWD revealed a slight but nonsignificant overestimation of RCT ORR, which was unconfounded by baseline characteristics. CONCLUSIONS: RWD can be used to reasonably replicate the OS and PFS of chemotherapy control arms of first-line NSCLC RCTs. Additional studies can provide greater insight into the utility of RWD in drug development.