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We present the first results from a reverberation-mapping campaign undertaken during the first half of 2012, with additional data on one active galactic nucleus (AGN) (NGC 3227) from a 2014 campaign. Our main goals are (1) to determine the black hole masses from continuum-Hβ reverberation signatures, and (2) to look for velocity-dependent time delays that might be indicators of the gross kinematics of the broad-line region. We successfully measure Hβ time delays and black hole masses for five AGNs, four of which have previous reverberation mass measurements. The values measured here are in agreement with earlier estimates, though there is some intrinsic scatter beyond the formal measurement errors. We observe velocity-dependent Hβ lags in each case, and find that the patterns have changed in the intervening five years for three AGNs that were also observed in 2007.

The Astropy Project supports and fosters the development of open-source and openly developed Python packages that provide commonly needed functionality to the astronomical community. A key element of the Astropy Project is the core package astropy, which serves as the foundation for more specialized projects and packages. In this article, we provide an overview of the organization of the Astropy project and summarize key features in the core package, as of the recent major release, version 2.0. We then describe the project infrastructure designed to facilitate and support development for a broader ecosystem of interoperable packages. We conclude with a future outlook of planned new features and directions for the broader Astropy Project.

The Seyfert 1 galaxy Arp 151 was monitored as part of three reverberation mapping campaigns spanning 2008-2015. We present modeling of these velocity-resolved reverberation mapping data sets using a geometric and dynamical model for the broad-line region (BLR). By modeling each of the three data sets independently, we infer the evolution of the BLR structure in Arp 151 over a total of 7 yr and constrain the systematic uncertainties in nonvarying parameters such as the black hole mass. We find that the BLR geometry of a thick disk viewed close to face-on is stable over this time, although the size of the BLR grows by a factor of ∼2. The dynamics of the BLR are dominated by inflow, and the inferred black hole mass is consistent for the three data sets, despite the increase in BLR size. Combining the inference for the three data sets yields a black hole mass and statistical uncertainty of log10(/) = with a standard deviation in individual measurements of 0.13 dex.

We present optical continuum lags for two Seyfert 1 galaxies, MCG+08-11-011 and NGC 2617, using monitoring data from a reverberation mapping campaign carried out in 2014. Our light curves span the ugriz filters over four months, with median cadences of 1.0 and 0.6 days for MCG+08-11-011 and NGC 2617, respectively, combined with roughly daily X-ray and near-UV data from Swift for NGC 2617. We find lags consistent with geometrically thin accretion-disk models that predict a lag-wavelength relation of τ ∝ λ 4/3. However, the observed lags are larger than predictions based on standard thin-disk theory by factors of 3.3 for MCG+08-11-011 and 2.3 for NGC 2617. These differences can be explained if the mass accretion rates are larger than inferred from the optical luminosity by a factor of 4.3 in MCG+08-11-011 and a factor of 1.3 in NGC 2617, although uncertainty in the SMBH masses determines the significance of this result. While the X-ray variability in NGC 2617 precedes the UV/optical variability, the long (2.6 day) lag is problematic for coronal reprocessing models.

We present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our targets have diverse and interesting observational properties, including a "changing look" AGN and a broad-line radio galaxy. Based on continuum-Hβ lags, we measure black hole masses for all five targets. We also obtain Hγ and He ii λ4686 lags for all objects except 3C 382. The He ii λ4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines are in general agreement. The relative responsivities of these lines are also in qualitative agreement with photoionization models. These spectra have extremely high signal-to-noise ratios (100-300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.

Swift monitoring of NGC 4151 with an ∼6 hr sampling over a total of 69 days in early 2016 is used to construct light curves covering five bands in the X-rays (0.3-50 keV) and six in the ultraviolet (UV)/optical (1900-5500 Å). The three hardest X-ray bands (>2.5 keV) are all strongly correlated with no measurable interband lag, while the two softer bands show lower variability and weaker correlations. The UV/optical bands are significantly correlated with the X-rays, lagging ∼3-4 days behind the hard X-rays. The variability within the UV/optical bands is also strongly correlated, with the UV appearing to lead the optical by ∼0.5-1 days. This combination of ≳3 day lags between the X-rays and UV and ≲1 day lags within the UV/optical appears to rule out the "lamp-post" reprocessing model in which a hot, X-ray emitting corona directly illuminates the accretion disk, which then reprocesses the energy in the UV/optical. Instead, these results appear consistent with the Gardner & Done picture in which two separate reprocessings occur: first, emission from the corona illuminates an extreme-UV-emitting toroidal component that shields the disk from the corona; this then heats the extreme-UV component, which illuminates the disk and drives its variability.

Background: The multidisciplinary diagnostic clinic (MDC) model for 'non-specific' symptoms has been piloted in the UK. We aimed to assess the degree to which the MDC pathway was influenced by socioeconomic factors., Methods: We collected data for all patients referred to the MDC from 01 January 2017 - 28 March 2019. Indices of multiple deprivation (IMD) scores were matched to patients' postcodes and referring general practitioner (GP) location. Socioeconomic data for MDC patients was compared with all other cancer patients diagnosed in the MDC's base hospital, Airedale General Hospital (AGH), in 2018. Statistical significance was tested using the Mann-Whitney U test and Spearman's rank correlation., Results: No significant difference was found between MDC pathway and the rest of AGH when comparing social deprivation of patients.There was a moderate negative correlation between the IMD associated with the location of GP premises and the number of referrals; practices in more deprived locations referred fewer patients (p≤0.025)., Conclusion: The MDC pathway referral rate seems to be affected by social deprivation in a similar manner to other cancer diagnosis pathways. Our work highlights the importance of engaging GP practices with socially deprived populations as the MDC programme is rolled out across the UK., (© Royal College of Physicians 2022. All rights reserved.)

During the first 3 months of 2020, as the COVID-19 pandemic developed, it was noticed that requests from primary care for investigations were decreasing, including those that form part of the diagnostic process for cancers. We therefore obtained data on the requests from primary care for chest X-rays (CXRs) and CA125 measurement our hospital received in the first half of 2020 and compared them with 2019. The number of CXRs declined by 93% in April 2020 compared with 2019, with the decline being greater for patient living in outlying areas. Requests from the emergency department also declined. Requests for CA125 measurement similarly fell by 77% from all areas. The requests increased in June, CA125 more than CXR. If this phenomenon is widespread it may have an impact on diagnosis of major conditions, particularly cancers and tuberculosis., (© Royal College of Physicians 2021. All rights reserved.)

A mechanistic model of the immune response was evaluated for its ability to predict anti-drug antibody (ADA) and their impact on pharmacokinetics (PK) and pharmacodynamics (PD) for a biotherapeutic in a phase 1 clinical trial. Observed ADA incidence ranged from 33 to 67% after single doses and 27-50% after multiple doses. The model captured the single dose incidence well; however, there was overprediction after multiple dosing. The model was updated to include a T-regulatory (Treg) cell mediated tolerance, which reduced the overprediction (relative decrease in predicted incidence rate of 21.5-59.3% across multidose panels) without compromising the single dose predictions (relative decrease in predicted incidence rate of 0.6-13%). The Treg-adjusted model predicted no ADA impact on PK or PD, consistent with the observed data. A prospective phase 2 trial was simulated, including co-medication effects in the form of corticosteroid-induced immunosuppression. Predicted ADA incidences were 0-10%, depending on co-medication dosage. This work demonstrates the utility in applying an integrated, iterative modeling approach to predict ADA during different stages of clinical development.

Background: Poor geographical access to health services and routes to a cancer diagnosis such as emergency presentations have previously been associated with worse cancer outcomes. However, the extent to which access to GPs determines the route that patients take to obtain a cancer diagnosis is unknown., Methods: We used a linked dataset of cancer registry and hospital records of patients with a cancer diagnosis between 2006 and 2010 across eight different cancer sites. Primary outcomes were defined as 'desirable routes to diagnosis' [screen-detected and 2-week wait (TWW) referrals] and 'less desirable routes' [emergency presentations and death certificate only (DCO)]. All other routes (GP referral, inpatient elective and other outpatient) were specified as the reference category. Geographical access was measured as travel time in minutes from patients to their GP, and multinomial logistic regression was used to estimate relative risk ratios (RRR)., Results: Longer travel was associated with increased risk of diagnosis via emergency and DCO, but decreased risk of diagnosis via screening and TWW. Patients travelling over 30 minutes had the highest risk of a DCO diagnosis, which was statistically significant for breast, colorectal, lung, prostate, stomach and ovarian cancers (compared with patients with travel times ≤10 minutes: RRR 5.89, 7.02, 2.30, 4.75, 10.41; P < 0.01 and 3.51, P < 0.05)., Discussion: Poor access to GPs may discourage early engagement with health services, decreasing the likelihood of screening uptake and increasing the likelihood of emergency presentations. Extra effort is needed to promote early diagnosis in more distant patients., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study investigated the awareness of non-oncology specialist medical staff about commonly used oral anticancer medicines (OAMs)., Methods: Interviews conducted with a range of non-oncology specialist doctors., Results: The recognition of OAMs was poor by all grades of doctors, with capecitabine being the only drug recognised by more than half the doctors (26 of 40; 65%). Consultant medical staff scored significantly better than most junior grades of staff., Conclusions: A barrier to safe patient care appears to be the initial identification of OAMs on acute admission. Once a drug had been identified as an OAM, doctors are aware that they should not prescribe it and should contact the acute oncology service for advice. A range of measures has been introduced to improve the identification of OAMs by doctors., Competing Interests: Competing interests: None declared.

Background: Ovarian cancer presents later in the UK compared to economically similar countries. National guidance suggests measuring CA125 in primary care as a means of bringing patients to specialist attention., Aim: To investigate the outcome of CA125 values measured in accordance with this policy., Setting and Design: Examination of the laboratory records of female patients from the usual catchment population of one general hospital in whom CA125 was measured from primary care in a calendar year., Methods: Those with values >35 u/ml were identified. Electronic records within the hospital were interrogated to identify what further evaluation had been undertaken whether ovarian or primary peritoneal cancer had been diagnosed or what other pathology was identified. We also reviewed the CA125 measurement history of patients diagnosed over 3 years by any route., Results: One hundred and sixty-four new cases of CA125 ≥35 u/ml were found. Further information was available for 152 of them. Sixteen had ovarian or primary peritoneal cancer and 16 had other cancers. In 50 no cause for the abnormality was found. The remainder had various non-malignant conditions. The specificity for carcinoma of ovary/primary peritoneal carcinoma was 95.4% [95% confidence interval: 94.8-96.0). In a 3-year period, 65 patients were diagnosed with ovarian or primary peritoneal cancer, 5 had values of CA125 between 20 and 35 u/ml shortly before diagnosis., Conclusions: The CA125 level is a useful diagnostic test for ovarian cancer which has been embraced by primary care but higher sensitivity for earlier disease will require strategies to improve the specificity.

We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and pH also affect drug-specific signal differentially in individual samples. The results presented here represent the most extensive analyses to date on acid treatment of a wide range of ADA affinities to explore sensitivity and drug tolerance issues. They have led to a refinement of our current best practices for ADA method development and provide a depth of data to interrogate low pH mediated immune complex dissociation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: A potential impact of the centralisation of cancer services in the UK is difficulty in gaining access for members of the population living far from them. This could lead to delayed presentation of cancer with more advanced disease and clinical deterioration at diagnosis. A patient may be recorded in the cancer registry as having cancer of unknown primary (CUP) if the clinical state at presentation precludes investigation. Other patients may be so recorded if investigation identifies sites of metastatic tumour but the primary is not found. We hypothesised that the first group would include more patients who experienced difficulties in gaining access to health services through residing in deprived areas or through poorer geographical access to healthcare facilities., Materials and Methods: We compared the diagnosis of CUP with a comparator tumour, carcinoma of the rectum, where diagnosis is facilitated by an alarm symptom and where variations in access are lower. Records from the Northern and Yorkshire Cancer Registry from 1994 to 2002 with ICD 10 C77-C80 (CUP, including categories where investigations may have been incomplete or no primary cancer was found) and C20 (malignant neoplasm of rectum) were combined with travel time to services (primary care, secondary and tertiary services) and the Index of Multiple Deprivation. Logistic regression modelled predictors of CUP were compared with C20 and, within CUP, the odds of a histological basis of diagnosis., Results: The registry classified 7428 patients as C80, 8849 as C77-C79, and 10 804 as C20. Compared with C20, the number of cases of C80 showed a statistically significant increasing trend with increasing travel time to primary care. Risk also increased strongly with age and deprivation. The results for C77-C79 were similar to those for C80, except that the travel time to primary care showed no effect. Considering all CUP alone, histological diagnosis significantly declined with travel time to the nearest hospital. There was no association with gender and the likelihood of histological diagnosis, but a marked decline with age, a downward trend with deprivation, and an increase when the nearest hospital was a cancer centre., Conclusions: These findings facilitate the understanding of factors associated with the group of patients that includes those with the least effective access to cancer services., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)