PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Multiple uncontrolled conditions and blood pressure medication intensification: an observational study

Abstract Background Multiple uncontrolled medical conditions may act as competing demands for clinical decision making. We hypothesized that multiple uncontrolled cardiovascular risk factors would decrease blood pressure (BP) medication intensification among uncontrolled hypertensive patients. Methods We observed 946 encounters at two VA primary care clinics from May through August 2006. After each encounter, clinicians recorded BP medication intensification (BP medication was added or titrated). Demographic, clinical, and laboratory information were collected from the medical record. We examined BP medication intensification by presence and control of diabetes and/or hyperlipidemia. 'Uncontrolled' was defined as hemoglobin A1c ≥ for diabetes, BP ≥ 140/90 mmHg (≥ 130/80 mmHg if diabetes present) for hypertension, and low density lipoprotein cholesterol (LDL-c) ≥ 130 mg/dl (≥ 100 mg/dl if diabetes present) for hyperlipidemia. Hierarchical regression models accounted for patient clustering and adjusted medication intensification for age, systolic BP, and number of medications. Results Among 387 patients with uncontrolled hypertension, 51.4% had diabetes (25.3% were uncontrolled) and 73.4% had hyperlipidemia (22.7% were uncontrolled). The BP medication intensification rate was 34.9% overall, but higher in individuals with uncontrolled diabetes and uncontrolled hyperlipidemia: 52.8% overall and 70.6% if systolic BP ≥ 10 mmHg above goal. Intensification rates were lowest if diabetes or hyperlipidemia were controlled, lower than if diabetes or hyperlipidemia were not present. Multivariable adjustment yielded similar results. Conclusions The presence of uncontrolled diabetes and hyperlipidemia was associated with more guideline-concordant hypertension care, particularly if BP was far from goal. Efforts to understand and improve BP medication intensification in patients with controlled diabetes and/or hyperlipidemia are warranted.http://deepblue.lib.umich.edu/bitstream/2027.42/78266/1/1748-5908-5-55.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78266/2/1748-5908-5-55.pdfPeer Reviewe

The addition of fluoxetine to cognitive behavioural therapy for youth depression (YoDA-C): study protocol for a randomised control trial.

The aim of the Youth Depression Alleviation-Combined Treatment (YoDA-C) study is to determine whether antidepressant medication should be started as a first-line treatment for youth depression delivered concurrently with psychotherapy. Doubts about the use of medication have been raised by meta-analyses in which the efficacy and safety of antidepressants in young people have been questioned, and subsequent treatment guidelines for youth depression have provided only qualified support

Clinical applications and limitations of current ovarian stem cell research: a review

The publication of a report in Nature in 2004 by the Tilly group suggesting that mouse ovaries are capable of generating oocytes de novo post-natally, has sparked interest in a problem long thought to have been resolved from classical studies in a variety of mammalian species. Within a nearly two year time period, laboratories around the world have taken up the challenge to dogma raised by this initial report, either to test this concept in an experimental basic science setting or give direction to clinical applications that could result, were the original premises of this work in the mouse valid for extrapolation to humans. This review provides a status report for this promising area of research, (1) to summarize recent findings in the literature with respect to the validity of the original hypothesis proffered by the Tilly group, and, (2) to gauge the potential utility of ovarian stem cells as a treatment for certain forms of human infertility

The semicentennial binary system PSR J2032+4127 at periastron: X-ray photometry, optical spectroscopy, and SPH modelling

X-ray photometry and optical spectra are presented covering the periastron passage of the highly eccentric, ∼50 yr binary system PSR J2032+4127 in 2017 November. This system consists of a 143 ms pulsar in orbit around a massive OB star, MT 91-213. The data show dramatic changes during the encounter as the pulsar wind collided with the stellar wind. The X-ray flux rose on the approach to periastron, then underwent a major dip in the few days around periastron, and then gradually declined over the next few weeks. The optical spectroscopy revealed a steady decline in the H α line strength on the approach to periastron (from an equivalent width of −15 to −7 Å) implying a truncation of the OB star’s circumstellar disc by the approaching neutron star. Smooth particle hydrodynamic modelling is used here to model the system within the context of the observed behaviour and predict the geometrical configuration of the circumstellar disc with respect to the pulsar’s orbit

Interactions among mitochondrial proteins altered in glioblastoma

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change ≥2) and significantly altered in GBM (p ≤ 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein–protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology

A Randomised Controlled Trial of Two Infusion Rates to Decrease Reactions to Antivenom

Background: Snake envenoming is a major clinical problem in Sri Lanka, with an estimated 40,000 bites annually. Antivenom is only available from India and there is a high rate of systemic hypersensitivity reactions. This study aimed to investigate whether the rate of infusion of antivenom reduced the frequency of severe systemic hypersensitivity reactions. Methods and findings: This was a randomized comparison trial of two infusion rates of antivenom for treatment of non-pregnant adult patients (>14 y) with snake envenoming in Sri Lanka. Snake identification was by patient or hospital examination of dead snakes when available and confirmed by enzyme-immunoassay for Russell’s viper envenoming. Patients were blindly allocated in a 11 randomisation schedule to receive antivenom either as a 20 minute infusion (rapid) or a two hour infusion (slow). The primary outcome was the proportion with severe systemic hypersensitivity reactions (grade 3 by Brown grading system) within 4 hours of commencement of antivenom. Secondary outcomes included the proportion with mild/moderate hypersensitivity reactions and repeat antivenom doses. Of 1004 patients with suspected snakebites, 247 patients received antivenom. 49 patients were excluded or not recruited leaving 104 patients allocated to the rapid antivenom infusion and 94 to the slow antivenom infusion. The median actual duration of antivenom infusion in the rapid group was 20 min (Interquartile range[IQR]:20–25 min) versus 120 min (IQR:75–120 min) in the slow group. There was no difference in severe systemic hypersensitivity reactions between those given rapid and slow infusions (32% vs. 35%; difference 3%; 95%CI:−10% to +17%;p = 0.65). The frequency of mild/moderate reactions was also similar. Similar numbers of patients in each arm received further doses of antivenom (30/104 vs. 23/94). Conclusions: A slower infusion rate would not reduce the rate of severe systemic hypersensitivity reactions from current high rates. More effort should be put into developing better quality antivenoms

Does home neighbourhood supportiveness influence the location more than volume of adolescent's physical activity? An observational study using Global Positioning Systems

Background: Environmental characteristics of home neighbourhoods are hypothesised to be associated with residents’ physical activity levels, yet many studies report only weak or equivocal associations. We theorise that this may be because neighbourhood characteristics influence the location of activity more than the volume. Using a sample of UK adolescents, we examine the role of home neighbourhood supportiveness for physical activity, both in terms of volume of activity undertaken and a measure of proximity to home at which activity takes place. Methods: Data were analysed from 967 adolescents living in and around the city of Bristol, UK. Each participant wore an accelerometer and a GPS device for seven days during school term time. These data were integrated into a Geographical Information System containing information on the participants’ home neighbourhoods and measures of environmental supportiveness. We then identified the amount of out-of-school activity of different intensities that adolescents undertook inside their home neighbourhood and examined how this related to home neighbourhood supportiveness. Results: We found that living in a less supportive neighbourhood did not negatively impact the volume of physical activity that adolescents undertook. Indeed these participants recorded similar amounts of activity (e.g. 20.5 mins per day of moderate activity at weekends) as those in more supportive neighbourhoods (18.6 mins per day). However, the amount of activity adolescents undertook inside their home neighbourhood did differ according to supportiveness; those living in less supportive locations had lower odds of recording activity inside their home neighbourhood. This was observed across all intensities of activity including sedentary, light, moderate, and vigorous. Conclusions: Our findings suggest that the supportiveness of the neighbourhood around home may have a greater influence on the location of physical activity than the volume undertaken. This finding is at odds with the premise of the socio-ecological models of physical activity that have driven this research field for the last two decades, and has implications for future research, as by simply measuring volumes of activity we may be underestimating the impact of the environment on physical activity behaviours