Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer.

INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.

Long term field trials demonstrate sustainable nutrient supply and uptake in rehabilitated bauxite residue.

Establishing a sustainable vegetation cover is one of the most important steps in progressive rehabilitation and final closure of ore-processing residues and tailings facilities. Sustainable rehabilitation partly depends on establishing and maintaining a supply of plant-available nutrients, but few long term field studies demonstrating the success or failure of rehabilitation of degraded land such as mineral processing tailings have been reported. Bauxite-processing residues are a highly sodic, highly alkaline, nutrient-poor by-product generated from alumina extraction, and pose many challenges for successful rehabilitation. This study investigated long term performance of rehabilitation established on bauxite-processing residue storage areas (RSAs) by comparing the nutrient content of the vegetation cover with nutrient concentrations in the underlying residue sand. Five plant species having diverse physiology were selected from rehabilitation varying in age from 1 to 10 years old; these being: Hardenbergia comptoniana - a vigorous growing legume ground cover/creeper), Acacia cochlearis and A. rostellifera - legume shrubs tolerant of sandy, alkaline conditions, Grevillea crithmifolia - a drought-tolerant proteaceous shrub tolerant of alkaline soil, and Spyridium globulosum - a robust, fast-growing shrub, commonly found on alkaline coastal soils. Gypsum incorporation reduced the pH and soluble aluminium levels in residue sand, but also acted as a long-term source of nutrients for the vegetation cover. Legume species contained more nitrogen than non-legumes (2.5% N and 1.5% N, respectively), and decomposition of surface litter increased organic carbon and total and mineral nitrogen contents of the residue sand over time. Nutrient cycling maintained a supply of macro- and micro- nutrients for the vegetation cover, and 10-year old rehabilitation exhibited characteristics similar to an analogue site. This study highlighted the importance of organic matter accumulation, developing a functional microbial community, and a diverse plant species mix on transforming the residue sand characteristics and encouraging nutrient cycling as key mechanisms for establishing a sustainable vegetation cover and functional ecosystem on residue sand embankments.

Screening two biodegradable polymers in enhanced efficiency fertiliser formulations reveals the need to prioritise performance goals.

Enhanced efficiency fertilisers (EEF) may reduce nitrogen (N) losses and improve uptake efficiency through synchronising N release with in-season plant requirements. We hypothesised that EEF formed via matrix encapsulation in biodegradable polymers will improve N use efficiency when compared to conventional urea fertiliser. This hypothesis was investigated for two biodegradable polymer matrices: polyhydroxyalkanoate (PHA), containing 11.6% urea (by mass), and polybutylene-adipate-co-terephthalate (PBAT), containing either 19.4 or 32.7% urea; and two contrasting soil types: sand and clay. Nitrogen availability and form was investigated under leaching conditions (water) with a growth accelerator pot experiment involving a horticultural crop and novel non-destructive three-dimensional scanning to measure in-season biomass development. The PBAT 32.7% formulation enabled greater above ground biomass production at both 50 and 100 kg N ha-1 equivalent application rates compared to conventional urea. For the sandy soil, plant scanning indicated that improved uptake performance with PBAT 32.7% was probably the result of greater N availability after 25 days than for conventional urea. Two of the encapsulated formulations (PHA and PBAT 19.4%) tended to decrease nitrogen leaching losses relative to urea (P < 0.05 for the red clay soil). However, decreased N leaching loss was accompanied by poorer N uptake performance, indicative of N being less available in these biopolymer formulations. A snapshot of nitrous oxide emissions collected during peak nitrate concentration (prior to planting and leaching) suggested that the biopolymers promoted N loss via gaseous emission relative to urea in the sandy soil (P < 0.05), and carbon dioxide emissions data suggested that biopolymer-carbon increased microbial activity (P < 0.1). Controlled testing of N release in water was a poor predictor of biomass production and leaching losses. The diverse behaviours of the tested formulations present the potential to optimise biopolymers and their N loadings by taking into account soil and environmental factors that influence the efficient delivery of N to target crops. The greater N uptake efficiency demonstrated for the PBAT 32.7% formulation confirms our hypothesis that matrix encapsulation can enable better synchronisation of N release with crop requirements and decrease leaching losses.

Stereotactic Ablative Body Radiotherapy Versus Radical Radiotherapy: Comparing Real-World Outcomes in Stage I Lung Cancer.

AIMS: Stereotactic ablative body radiotherapy (SABR) is now considered the standard of care for medically inoperable stage I non-small cell lung cancer (NSCLC). The English National Cancer Registration and Analysis Service (NCRAS) collects data on all patients diagnosed with lung cancer, including information on treatment. We wanted to compare outcomes for patients with stage I NSCLC treated with radical radiotherapy with either SABR or fractionated radiotherapy. MATERIALS AND METHODS: All patients diagnosed with stage I NSCLC in 2015 and 2016 were identified from the NCRAS dataset, validated by the National Lung Cancer Audit, and their treatment data were collated. For patients who received radiotherapy, those receiving radical dose fractionations, including SABR, were identified through linkage to the national Radiotherapy Dataset. Clinical outcomes for those receiving SABR or more fractionated radical radiotherapy were compared using univariate and fully adjusted Cox proportional hazards models. RESULTS: In total, 12 384 patients with stage I NSCLC were identified during the study period; 53.5% underwent surgical resection, 24.3% received no documented treatment, 18.6% received radical radiotherapy and 3.5% received other non-curative-intent treatments. For those receiving radical radiotherapy, 69% received SABR and 31% received fractionated treatment. The hazard ratio of death for the 1587 patients who received SABR was 0.69 (95% confidence interval 0.61-0.79) compared with 717 patients who received radical fractionated radiotherapy; this benefit was seen for both stage Ia and stage Ib disease. The median overall survival was also longer for SABR versus radical radiotherapy (715 days versus 648 days). Exploratory travel time analysis shows that compared with stage I NSCLC patients receiving SABR, those receiving fractionated radiotherapy and those receiving no active treatment would have to travel longer and further to reach their nearest radiotherapy SABR centre. CONCLUSION: This study adds to the data that SABR has a survival benefit when compared with fractionated radical radiotherapy. Although the use of SABR increased in England over this study period, it has still not reached levels of use seen in other countries. This study also highlights that one quarter of stage I NSCLC patients overall received no active treatment.

86-GBaud subcarrier multiplexed 16QAM signal generation using an electrical 90 degree hybrid and IQ mixers.

We experimentally demonstrate an aggregate 86-GBaud (over three sub-bands and one polarization) signal generation based on subcarrier multiplexing technique using IQ mixers, an electrical 90 degree hybrid, and diplexers. The electrical hybrid allows transmitter-side digital signal processing to be simplified to pulse shaping and digital pre-emphasis. We verified the configuration by testing the performance of an 86-GBaud Nyquist-shaped 16 quadrature amplitude modulation signal with differential bit encoding. The implementation penalty assuming 7% hard-decision forward error correction is reduced to 2 dB by utilizing a 31-tap decision-directed least mean square based multiple-input multiple-output equalizer for sideband crosstalk mitigation.

The stability of imaging biomarkers in radiomics: a framework for evaluation.

This paper studies the sensitivity of a range of image texture parameters used in radiomics to: (i) the number of intensity levels, (ii) the method of quantisation to select the intensity levels and (iii) the use of an intensity threshold. 43 commonly used texture features were studied for the gross target volume outlined on the CT component of PET/CT scans of 50 patients with non-small cell lung carcinoma (NSCLC). All cases were quantised for all values between 4 and 128 intensity levels using four commonly used quantisation methods. All results were analysed with and without a threshold range of -200 HU to 300 HU. Cases were ranked for each texture feature and for all quantisation methods with the Spearman's rank correlation coefficient determined to evaluate stability. Results showed large fluctuations in ranking, particularly for low numbers of levels, differences between quantisation methods and with the use of a threshold, with values Spearman's Rank Correlation for many parameters below 0.2. Our results demonstrated the sensitivity of radiomics features to the parameters used during analysis and highlight the risk of low reproducibility comparing studies with slightly different parameters. In terms of the lung cancer CT datasets, this study supports the use of 128 intensity levels, the same uniform quantiser applied to all scans and thresholding of the data. It also supports several of the features recommended in the literature for such studies such as skewness and kurtosis. A recommended framework is presented for curation of the data analysis process to ensure stability of results.

Aged biochar alters nitrogen pathways in bauxite-processing residue sand: Environmental impact and biogeochemical mechanisms.

Low nitrogen (N) content and retention in bauxite-processing residue sand (BRS) disposal areas pose a great challenge to the establishment of sustainable vegetation cover in this highly alkaline environment. The budget and fate of applied N in BRS and its potential environmental impacts are largely unknown. We investigated the effect of combined application of biochars [aged acidic (AC) vs alkaline pine (PC)] and di-ammonium phosphate (DAP) fertiliser on ammonia (NH3) volatilisation, nitrous oxide (N2O) emission and N retention in a 116-day glasshouse study. The application of AC to BRS decreased pH (≈0.5 units) in BRS, while PC biochar increased pH (≈0.3 units). The application of AC reduced NH3 volatilisation by ca. 80%, while PC by ca. 25%. On the other hand, the AC treatment increased N2O emission by 5 folds. However, the N loss via N2O emission in the AC treatment only accounted for ca. 0.4% of applied N. The reduction in BRS pH and increased retention of mineral N due to the presence of oxygen-containing (phenolic and carboxylic) functional groups in AC may be responsible for reduced NH3 volatilisation and increased N2O emission. This study has highlighted the potential of biochar (particularly aged biochar) in improving N retention and minimising environmental impacts in highly alkaline environments.

Generalized quantum cumulant dynamics.

A means of unifying some semiclassical models of computational chemistry is presented; these include quantized Hamiltonian dynamics, quantal cumulant dynamics, and semiclassical Moyal dynamics (SMD). A general method for creating the infinite hierarchy of operator dynamics in the Heisenberg picture is derived together with a general method for truncation (or closure) of that series, and in addition, we provide a simple link to the phase space methods of SMD. Operator equations of arbitrary order may be created readily, avoiding the tedious algebra identified previously. Truncation is based on a simple recurrence formula which is related to, but avoids the more complex contractions of, Wick's theorem. This generalized method is validated against a number of trial problems considered using the previous methods. We also touch on some of the limitations involved using such methods, noting, in particular, that any truncation will lead to a state which is in some sense unphysical. Finally, we briefly introduce our quantum algebra package QuantAL which provides an automated method for the generation of the required equation set, the initial conditions for all variables from any start, and all the higher order approximations necessary for truncation of the series, at essentially arbitrary order.

A qualitative exploration of facilitators and barriers to meningitis vaccination uptake among men who have sex with men.

Invasive Meningococcal Disease is a deadly, but preventable disease, with community outbreaks occurring at rate of 9.5 per year. Serogroup C Invasive Meningococcal Disease (IMD) community outbreaks in men who have sex with men (MSM) have been reported with greater frequency in large urban areas since 2010. An effective vaccine exists that can temper and control outbreaks, and is recommended for MSM in outbreak settings; however very little is known about the perceptions, barriers and facilitators to IMD vaccine uptake among MSM. Optimizing awareness and vaccine uptake for MSM is a high priority to reduce and control IMD outbreaks. To that end, we conducted focus groups with MSM during an active IMD outbreak to inform development of a tailored intervention strategy. Participants discussed facilitators (e.g., logistics, relationships, health literacy) and barriers (e.g., fear of disclosure, medical distrust) to vaccination, as well as ideas for intervention strategies (e.g., incentives, use of internet outreach).

Comprehensive geriatric assessment in 326 older women with early breast cancer.

BACKGROUND: One-third of new early breast cancer diagnoses occur in women over 70 years old. However, older women are less likely to receive radical curative treatments. This study prospectively evaluated a cohort of older women using a Comprehensive Geriatric Assessment (CGA) to determine whether fitness explained the apparent under-treatment in this patient group. METHODS: In this multi-centre prospective study, patients aged ⩾70 years with Stages I-III breast cancer underwent a pretreatment baseline CGA consisting of eight assessment tools. Patients were defined as 'fit' if they had normal score in seven out of eight of the assessment tools. 'High risk' patients were defined as those with grade 3, ER negative, HER2 positive, or node positive breast cancer. RESULTS: Data on 326 patients were available for full analysis. The median age was 77 years. In all, 182 (56%) of the total population were defined as high risk, with 49%, 61% and 53% of those in the 70-74, 75-84 and ⩾85 years age groups respectively having high risk tumours. A total of 301 patients had sufficient CGA records of whom 131 (44%) were reported as fit, with 34%, 54% and 12% of them in the 70-74, 75-84 and ⩾85 years age groups respectively. More fit than unfit patients underwent primary breast surgery (100% vs 91%, P=0.0002), axillary surgery (92% vs 84%, P=0.0340), and adjuvant chemotherapy for high-risk disease (51% vs 20%, P=0.0001). Rates of adjuvant radiotherapy after wide local excision were not significantly different (88% vs 90% respectively, P=0.8195). CONCLUSIONS: In this study, all women ⩾70 years deemed fit by CGA underwent primary surgery. Nearly 50% of fit women with high-risk disease did not receive adjuvant chemotherapy suggesting under treatment in this group.

Normal Tissue Complication Probability (NTCP) Modelling of Severe Acute Mucositis using a Novel Oral Mucosal Surface Organ at Risk.

AIMS: A normal tissue complication probability (NTCP) model of severe acute mucositis would be highly useful to guide clinical decision making and inform radiotherapy planning. We aimed to improve upon our previous model by using a novel oral mucosal surface organ at risk (OAR) in place of an oral cavity OAR. MATERIALS AND METHODS: Predictive models of severe acute mucositis were generated using radiotherapy dose to the oral cavity OAR or mucosal surface OAR and clinical data. Penalised logistic regression and random forest classification (RFC) models were generated for both OARs and compared. Internal validation was carried out with 100-iteration stratified shuffle split cross-validation, using multiple metrics to assess different aspects of model performance. Associations between treatment covariates and severe mucositis were explored using RFC feature importance. RESULTS: Penalised logistic regression and RFC models using the oral cavity OAR performed at least as well as the models using mucosal surface OAR. Associations between dose metrics and severe mucositis were similar between the mucosal surface and oral cavity models. The volumes of oral cavity or mucosal surface receiving intermediate and high doses were most strongly associated with severe mucositis. CONCLUSIONS: The simpler oral cavity OAR should be preferred over the mucosal surface OAR for NTCP modelling of severe mucositis. We recommend minimising the volume of mucosa receiving intermediate and high doses, where possible.

QPSK 3R regenerator using a phase sensitive amplifier.

A black box phase sensitive amplifier based 3R regeneration scheme is proposed for non-return to zero quadrature phase shift keyed formatted signals. Performance improvements of more than 2 dB are achieved at the presence of input phase distortion.

Transmission performance improvement using random DFB laser based Raman amplification and bidirectional second-order pumping.

We demonstrate that a distributed Raman amplification scheme based on random distributed feedback (DFB) fiber laser enables bidirectional second-order Raman pumping without increasing relative intensity noise (RIN) of the signal. This extends the reach of 10 × 116 Gb/s DP-QPSK WDM transmission up to 7915 km, compared with conventional Raman amplification schemes. Moreover, this scheme gives the longest maximum transmission distance among all the Raman amplification schemes presented in this paper, whilst maintaining relatively uniform and symmetric signal power distribution, and is also adjustable in order to be highly compatible with different nonlinearity compensation techniques, including mid-link optical phase conjugation (OPC) and nonlinear Fourier transform (NFT).

Improved WDM performance of a fibre optical parametric amplifier using Raman-assisted pumping.

We experimentally demonstrate a Raman-Assisted Fibre Optical Parametric Amplifier (RA-FOPA) with 20dB net gain using wavelength division multiplexed signals. We report amplification of 10x58Gb/s 100GHz-spaced QPSK signals and show that by appropriate tuning of the parametric pump power and frequency, gain improvement of up to 5dB can be achieved for the RA-FOPA compared with combined individual contributions from the parametric and Raman pumps. We compare the RA-FOPA with an equivalent-gain conventional FOPA and find that four-wave mixing crosstalk is substantially reduced by up to 5.8 ± 0.4dB using the RA-FOPA. Worst-case performance penalty of the RA-FOPA is found to be only 1.0 ± 0.2dB over all measured OSNRs, frequencies and input powers, making it an attractive proposal for future communications systems.

1.14 Tb/s DP-QPSK WDM polarization-diverse optical phase conjugation.

Optical phase conjugation (OPC) of a polarization-multiplexed comb of 10x114Gb/s DP-QPSK signals has been demonstrated for the first time, occupying a spectral bandwidth of >1 THz (~9 nm). The nonlinear element employed for the OPC was highly nonlinear fiber (HNLF) optimized for the suppression of stimulated Brillouin scattering (SBS) and configured in a bi-directional loop offering polarization diversity. Pump power (each way about the loop) and input signal power to the OPC subsystem were optimized at 29.7 dBm and + 3 dBm respectively producing a Q(2) penalty of ≤ 0.9 dB over all conjugate wavelengths, polarizations and output OSNR (up to 20 dB).