Labeless and reversible immunosensor assay based upon an electrochemical current-transient protocol

A novel labeless and reversible immunoassay based upon an electrochemical current-transient protocol is reported which offers many advantages in comparison to classical immuno-biochemical analyses in terms of simplicity, speed of response, reusability and possibility of multiple determinations. Conducting polypyrrole films containing antibodies against 1) Bovine Serum Albumin (BSA) and 2) Digoxin were deposited on the surface of platinum electrodes to produce conductive affinity matrices having clearly defined binding characteristics. The deposition process has been investigated using 125I labelled anti-digoxin to determine optimal fabrication protocols. Antibody integrity and activity, together with non-specific binding of antigen on the conducting matrix have also been investigated using tritiated digoxin to probe polypyrrole/anti-digoxin films. Amperometric responses to digoxin were recorded in flow conditions using these films, but the technique was limited in use mainly due to baseline instability. Anti-BSA - polypyrrole matrices were investigated in more detail in both flow and quiescent conditions. No observable response was found in flow conditions, however under quiescent conditions (in non-stirred batch cell), anti-BSA – polypyrrole films have been demonstrated to function as novel quantitative chronoamperometric immuno-biosensors when interrogated using a pulsed potential waveform. The behaviour of the electrodes showed that the antibody/antigen binding and/or interaction process underlying the response observed was reversible in nature, indicating that the electrodes could be used for multiple sensing protocols. Calibration profiles for BSA demonstrated linearity for a concentration range of 0-50 ppm but tended towards a plateau at higher concentrations. Factors relating to replicate sensor production, sample measurement and reproducibility are discuss

International variation in childhood cancer mortality rates from 2001 to 2015: Comparison of trends in the International Cancer Benchmarking Partnership countries

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (-2.9; 95% confidence interval = -4.0 to -1.7) compared to AYAs (-1.8; -2.1 to -1.5) and adults aged >40 years (-1.5; -1.6 to -1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children -4.6 (-6.1 to -3.1) vs AYAs -3.2 (-4.2 to -2.1) and over 40s -1.1 (-1.3 to -0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients.</p

A global database of soil microbial phospholipid fatty acids and enzyme activities

Soil microbes drive ecosystem function and play a critical role in how ecosystems respond to global change. Research surrounding soil microbial communities has rapidly increased in recent decades, and substantial data relating to phospholipid fatty acids (PLFAs) and potential enzyme activity have been collected and analysed. However, studies have mostly been restricted to local and regional scales, and their accuracy and usefulness are limited by the extent of accessible data. Here we aim to improve data availability by collating a global database of soil PLFA and potential enzyme activity measurements from 12,258 georeferenced samples located across all continents, 5.1% of which have not previously been published. The database contains data relating to 113 PLFAs and 26 enzyme activities, and includes metadata such as sampling date, sample depth, and soil pH, total carbon, and total nitrogen. This database will help researchers in conducting both global- and local-scale studies to better understand soil microbial biomass and function

A global database of soil microbial phospholipid fatty acids and enzyme activities

Soil microbes drive ecosystem function and play a critical role in how ecosystems respond to global change. Research surrounding soil microbial communities has rapidly increased in recent decades, and substantial data relating to phospholipid fatty acids (PLFAs) and potential enzyme activity have been collected and analysed. However, studies have mostly been restricted to local and regional scales, and their accuracy and usefulness are limited by the extent of accessible data. Here we aim to improve data availability by collating a global database of soil PLFA and potential enzyme activity measurements from 12,258 georeferenced samples located across all continents, 5.1% of which have not previously been published. The database contains data relating to 113 PLFAs and 26 enzyme activities, and includes metadata such as sampling date, sample depth, and soil pH, total carbon, and total nitrogen. This database will help researchers in conducting both global- and local-scale studies to better understand soil microbial biomass and function

Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project – international benchmarking of childhood cancer survival by stage

IntroductionVariation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers.MethodsPBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created.Results67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)].ConclusionDifferences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans

International benchmarking of stage at diagnosis for six childhood solid tumours (the BENCHISTA project): a population-based, retrospective cohort study

Background: International variation in childhood cancer survival might be explained by differences in stage at diagnosis, among other factors. As part of the BENCHISTA project, we aimed to assess geographical variation in tumour stage at diagnosis through the application, by population-based cancer registries working with clinicians, of the international consensus Toronto Childhood Cancer Stage Guidelines. Methods: This population-based, retrospective cohort study involved 73 cancer registries from 23 European countries, Australia, Brazil, Japan, and Canada. Participating cancer registries applied the Toronto Guidelines to stage all incident cases of six childhood solid tumours—neuroblastoma, medulloblastoma, and Wilms tumour (age 0–14 years) and Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma (age ≤19 years)—diagnosed between Jan 1, 2014, and Dec 31, 2017. Eligible cancer registries were those able to assign stage according to the Toronto Guidelines; information on the staging investigations conducted was collected where available. European countries were grouped by geographical area and non-European countries were considered individually. We used χ2 tests to compare stage distribution across these geographical areas and multivariable logistic models to estimate odds ratios (ORs) for metastatic stage at diagnosis, using central Europe (Austria, Belgium, France, Germany, the Netherlands, and Switzerland) as the comparison. Sensitivity analyses were conducted to overcome potential bias from non-random missing stage information for some geographical areas and cancer types. Findings: Data from 10 937 patients with cancer (6031 [55·1%] male and 4906 [44·9%] female) were analysed. Tumour staging was complete for 93·1% (10 180 of 10 937) of patients, ranging from 88·7% (1347 of 1518 patients) with medulloblastoma to 96·5% (1083 of 1122 patients) with Ewing sarcoma. Stage distribution differed statistically by geographical area for neuroblastoma, Wilms tumour, osteosarcoma, and rhabdomyosarcoma, but not for Ewing sarcoma or medulloblastoma. After excluding patients with missing stage information and, for the sarcomas, patients aged 18–19 years, the proportions of patients with metastases detected at diagnosis were 50·3% with neuroblastoma (1435 of 2852 patients; including 1159 [40·6%] stage M and 276 [9·7%] stage MS), 35·1% with medulloblastoma (473 of 1347 patients; stages M1–M4), 32·6% with Ewing sarcoma (335 of 1028 patients), 29·0% with rhabdomyosarcoma (368 of 1267 patients), 25·5% with osteosarcoma (345 of 1353 patients), and 18·2% with Wilms tumour (384 of 2114 patients). After adjusting by age group, significant differences in the proportions of patients with metastases detected at diagnosis were found between geographical areas for neuroblastoma, Wilms tumour, osteosarcoma, and rhabdomyosarcoma. Interpretation: Assessed at a population level, the stage at diagnosis shows significant variation between geographical areas for several childhood tumours. This finding highlights the need for earlier diagnosis and standardisation of investigations for distant metastases. To enable ongoing comparisons, further cooperation efforts are required between cancer registries and clinicians regarding the sustainable and standardised use of the Toronto Guidelines at diagnosis. Funding: Children with Cancer UK and Associazione Italiana per la Ricerca sul Cancro

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Sonochemically fabricated microelectrode arrays for biosensors offering widespread applicability. Part I

A novel and patented procedure is described for the sonochemical fabrication of a new class of microelectrode array based sensor with electrode element populations of up to 2 x 105 cm-2. For some years it has been accepted that microelectrode arrays offer an attractive route for lowering minimum limits of detection and imparting stir (convectional mass transport) independence to sensor responses; despite this no commercial biosensors, to date, have employed microelectrode arrays, largely due to the cost of conventional fabrication routes that have not proved commercially viable for disposable devices. Biosensors formed by our sonochemical approach offer unrivalled sensitivity and impart stir independence to sensor responses. This format lends itself for mass fabrication due to the simplicity and inexpensiveness of the approach; in the first instance impedimetric and amperometric sensors are reported for glucose as model systems. Sensors already developed for ethanol, oxalate and a number of pesticide determinations will be reported in subsequent publications

International variation in childhood cancer mortality rates from 2001 to 2015:Comparison of trends in the International Cancer Benchmarking Partnership countries

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends overtime in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Join point regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (2.9; 95% confidence interval=4.0 to1.7) com-pared to AYAs (1.8;2.1 to1.5) and adults aged &gt;40 years (1.5;1.6 to1.4).This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children4.6(6.1 to3.1) vs AYAs3.2 (4.2 to2.1) and over 40s1.1 (1.3 to0.8).AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients