bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient ultrafast all-optical modulation in a nonlinear crystalline gallium phosphide nanodisk at the anapole excitation
Authors: Grinblat Gustavo , Zhang Haizhong , Nielsen Michael P. , Krivitsky Leonid , Berté Rodrigo , Li Yi , Tilmann Benjamin , Cortés Emiliano , Oulton Rupert F. , Kuznetsov Arseniy I. , Maier Stefan A.
Published: August 2020

A crystalline gallium phosphide nanodisk is shown to be the most efficient sub–100-fs nanoscale all-optical switch.
Extracellular matrix compression temporally regulates microvascular angiogenesis
Authors: Ruehle M. A. , Eastburn E. A. , LaBelle S. A. , Krishnan L. , Weiss J. A. , Boerckel J. D. , Wood L. B. , Guldberg R. E. , Willett N. J.
Published: August 2020

Extracellular matrix deformation temporally regulates angiogenesis and upstream angiogenic and mechanosensitive pathways.
Massively parallel single-molecule telomere length measurement with digital real-time PCR
Authors: Luo Yongqiang , Viswanathan Ramya , Hande Manoor Prakash , Loh Amos Hong Pheng , Cheow Lih Feng
Published: August 2020

Digital real-time PCR assay rapidly measures single telomere lengths and uncovers telomere maintenance mechanisms in cancer.
Competition between social cheater viruses is driven by mechanistically different cheating strategies
Authors: Meir Moran , Harel Noam , Miller Danielle , Gelbart Maoz , Eldar Avigdor , Gophna Uri , Stern Adi
Published: August 2020

Conflict between mutant viruses is driven by cheater-of-cheater dynamics, leading to the fall of one cheater and rise of another.
The Many Roles of the Bacterial Second Messenger Cyclic di-AMP in Adapting to Stress Cues
Authors: Zarrella Tiffany M. , Bai Guangchun
Published: August 2020

Bacteria respond to changes in environmental conditions through adaptation to external cues. Frequently, bacteria employ nucleotide signaling molecules to mediate a specific, rapid response. Cyclic di-AMP (c-di-AMP) was recently discovered to be a bacterial second messenger that is essential for viability in many species. In this review, we highlight recent work that has described the roles of c-di-AMP in bacterial responses to various stress conditions. These studies show that depending on the lifestyle and environmental niche of the bacterial species, the c-di-AMP signaling network results in diverse outcomes, such as regulating osmolyte transport, controlling plant attachment, or providing a checkpoint for spore formation.
Cost–utility of sofosbuvir/velpatasvir versus other direct-acting antivirals for chronic hepatitis C genotype 1b infection in China
Authors: Yun Haoya , Zhao Guoqiang , Sun Xiaojie , Shi Lizheng
Published: August 2020

Objective

This study aimed to estimate the cost–utility of sofosbuvir/velpatasvir (SOF/VEL) compared with other direct-acting antivirals (DAAs) in Chinese patients with hepatitis C virus (HCV).

Design

A Markov model was developed to estimate the disease progression of patients with HCV over a lifetime horizon from the healthcare system perspective. Efficacy, clinical inputs and utilities were derived from the published literature. Drug costs were from the market price survey, and health costs for Markov health states were sourced from a Chinese study. Costs and utilities were discounted at an annual rate of 5%. One-way and probabilistic sensitivity analyses were conducted to test the impact of input parameters on the results.

Interventions

SOF/VEL was compared with sofosbuvir+ribavirin (SR), sofosbuvir+dasabuvir (SD), daclatasvir+asunaprevir (DCV/ASV), ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) and elbasvir/grazoprevir (EBR/GZR).

Primary and secondary outcomes

Costs, quality-adjusted life years (QALYs) and incremental cost–utility ratios (ICURs).

Results

SOF/VEL was economically dominant over SR and SD. However, 3D was economically dominant compared with SOF/VEL. Compared with DCV/ASV, SOF/VEL was cost-effective with the ICUR of US$1522 per QALY. Compared with EBR/GZR, it was not cost-effective with the ICUR of US$369 627 per QALY. One-way sensitivity analysis demonstrated that reducing the cost of SOF/VEL to the lower value of CI resulted in dominance over EBR/GZR and 3D. Probabilistic sensitivity analysis demonstrated that 3D was cost-effective in 100% of iterations in patients with genotype (GT) 1b and SOF/VEL was not cost-effective.

Conclusions

Compared with other oral DAA agents, SOF/VEL treatment was not the most cost-effectiveness option for patients with chronic HCV GT1b in China. Lower the price of SOF/VEL will make it cost-effective while simplifying treatment and achieving the goal of HCV elimination.
Risk of preterm birth associated with maternal gingival inflammation and oral hygiene behaviours in rural Nepal: a community-based, prospective cohort study
Authors: Erchick Daniel J , Khatry Subarna K , Agrawal Nitin K , Katz Joanne , LeClerq Steven C , Rai Bhola , Reynolds Mark A , Mullany Luke C
Published: August 2020

Objectives

Observational studies have identified associations between periodontitis and adverse pregnancy outcomes, but randomised controlled trials evaluating the efficacy of periodontal therapy have yielded inconsistent results. Few studies have explored relationships between gingival inflammation and these outcomes or been conducted in rural, low-income communities, where confounding risk factors differ from other settings.

Methods

We conducted a community-based, prospective cohort study with the aim of estimating associations between the extent of gingival inflammation in pregnant women and incidence of preterm birth in rural Nepal. Our primary exposure was gingival inflammation, defined as bleeding on probing (BOP) ≥10%, stratified by BOP <30% and BOP ≥30%. A secondary exposure, mild periodontitis, was defined as ≥2 interproximal sites with probing depth (PD) ≥4 mm (different teeth) or one site with PD ≥5 mm. Our primary outcome was preterm birth (<37 weeks gestation). We used Poisson regression to model this relationship, adjusting for potential confounders.

Results

Of 1394 participants, 554 (39.7%) had gingival inflammation, 54 (3.9%) mild periodontitis and 197 (14.1%) delivered preterm. In the adjusted regression model, increasing extent of gingival inflammation was associated with a non-significant increase in risk of preterm birth (BOP ≥30% vs no BOP: adjusted relative risk (aRR) 1.37, 95% CI: 0.81 to 2.32). A secondary analysis, stratifying participants by when in pregnancy their oral health status was assessed, showed an association between gingival inflammation and preterm birth among women examined in their first trimester (BOP ≥30% vs no BOP: aRR 2.57, 95% CI: 1.11 to 5.95), but not later in pregnancy (BOP ≥30% vs no BOP: aRR 1.05, 95% CI: 0.52 to 2.11).

Conclusions

Gingival inflammation in women examined early in pregnancy and poor oral hygiene behaviours were risk factors for preterm birth. Future studies should evaluate community-based oral health interventions that specifically target gingival inflammation, delivered early in or before pregnancy, on preterm birth.

Trial registration number

Nepal Oil Massage Study, NCT01177111.
What are the implications of using individual and combined sources of routinely collected data to identify and characterise incident site-specific cancers? a concordance and validation study using linked English electronic health records data
Authors: Strongman Helen , Williams Rachael , Bhaskaran Krishnan
Published: August 2020

Objectives

To describe the benefits and limitations of using individual and combinations of linked English electronic health data to identify incident cancers.

Design and setting

Our descriptive study uses linked English Clinical Practice Research Datalink primary care; cancer registration; hospitalisation and death registration data.

Participants and measures

We implemented case definitions to identify first site-specific cancers at the 20 most common sites, based on the first ever cancer diagnosis recorded in each individual or commonly used combination of data sources between 2000 and 2014. We calculated positive predictive values and sensitivities of each definition, compared with a gold standard algorithm that used information from all linked data sets to identify first cancers. We described completeness of grade and stage information in the cancer registration data set.

Results

165 953 gold standard cancers were identified. Positive predictive values of all case definitions were ≥80% and ≥94% for the four most common cancers (breast, lung, colorectal and prostate). Sensitivity for case definitions that used cancer registration alone or in combination was ≥92% for the four most common cancers and ≥80% across all cancer sites except bladder cancer (65% using cancer registration alone). For case definitions using linked primary care, hospitalisation and death registration data, sensitivity was ≥89% for the four most common cancers, and ≥80% for all cancer sites except kidney (69%), oral cavity (76%) and ovarian cancer (78%). When primary care or hospitalisation data were used alone, sensitivities were generally lower and diagnosis dates were delayed. Completeness of staging data in cancer registration data was high from 2012 (minimum 76.0% in 2012 and 86.4% in 2014 for the four most common cancers).

Conclusions

Ascertainment of incident cancers was good when using cancer registration data alone or in combination with other data sets, and for the majority of cancers when using a combination of primary care, hospitalisation and death registration data.
Comparison of strategies for monitoring and treating patients at the early phase of severe traumatic brain injury: the multicentre randomised controlled OXY-TC trial study protocol
Authors: Payen Jean-Francois , Richard Marion , Francony Gilles , Audibert Gérard , Barbier Emmanuel L , Bruder Nicolas , Dahyot-Fizelier Claire , Geeraerts Thomas , Gergele Laurent , Puybasset Louis , Vigue Bernard , Skaare Kristina , Bosson Jean Luc , Bouzat Pierre
Published: August 2020

Introduction

Intracranial hypertension is considered as an independent risk factor of mortality and neurological disabilities after severe traumatic brain injury (TBI). However, clinical studies have demonstrated that episodes of brain ischaemia/hypoxia are common despite normalisation of intracranial pressure (ICP). This study assesses the impact on neurological outcome of guiding therapeutic strategies based on the monitoring of both brain tissue oxygenation pressure (PbtO2) and ICP during the first 5 days following severe TBI.

Methods and analysis

Multicentre, open-labelled, randomised controlled superiority trial with two parallel groups in 300 patients with severe TBI. Intracerebral monitoring must be in place within the first 16 hours post-trauma. Patients are randomly assigned to the ICP group or to the ICP + PbtO2group. The ICP group is managed according to the international guidelines to maintain ICP≤20 mm Hg. The ICP + PbtO2group is managed to maintain PbtO2≥20 mm Hg in addition to the conventional optimisation of ICP. The primary outcome measure is the neurological status at 6 months as assessed using the extended Glasgow Outcome Scale. Secondary outcome measures include quality-of-life assessment, mortality rate, therapeutic intensity and incidence of critical events during the first 5 days. Analysis will be performed according to the intention-to-treat principle and full statistical analysis plan developed prior to database freeze.

Ethics and dissemination

This study has been approved by the Institutional Review Board of Sud-Est V (14-CHUG-48) and from the National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des produits de santé) (141 435B-31). Results will be presented at scientific meetings and published in peer-reviewed publications.The study was registered with ClinTrialsNCT02754063on 28 April 2016 (pre-results).
Protocol for a pilot randomised, double-blind, placebo-controlled trial for assessing the feasibility and efficacy of faecal microbiota transplantation in adolescents with refractory irritable bowel syndrome: FAIS Trial
Authors: Zeevenhooven Judith , de Bruijn Clara Marieke Andrea , Vlieger Arine , Nieuwdorp Max , Benninga Marc Alexander
Published: August 2020

Background

Irritable bowel syndrome (IBS) is a common chronic medical condition, in both children and adults. Despite the availability of effective (non)pharmacological treatments, symptoms persist in a significant amount of patients with IBS. Faecal microbiota transplantation (FMT) may be an effective alternative treatment in adolescents with refractory IBS through manipulation of the intestinal microbiota.

Methods and analysis

This randomised, placebo-controlled single-centre pilot study will assess feasibility and efficacy of FMT in 30 adolescents (16–21 years) with refractory IBS. Patients will be randomly allocated (1:1) to receive two allogeneic (healthy donor) or two autologous (own) faecal infusions at baseline and after 6 weeks. Primary outcomes will assess feasibility, including patient and donor recruitment, adherence and incidence rates of adverse events. To evaluate clinical efficacy, secondary outcomes will include the proportion of patients with at least >50% reduction of their abdominal pain intensity and frequency 12 weeks after the first FMT, and after 6-month and 12-month follow-up. Other outcomes comprise changes in faecal gut microbiota composition, quality of life, depression and anxiety, school or work absenteeism and adequate relief, measured directly after FMTs and after 6 and 12 months of follow-up.

Discussion

This randomised controlled trial will investigate the feasibility and effectiveness of repetitive FMTs in adolescents with refractory IBS.

Ethics and dissemination

The study is approved by the Medical Research Ethics Committees AMC (MEC-AMC) in the Netherlands.

Trial registration number

NCT03074227.
The patient-generated subjective global assessment is a promising screening tool for cancer cachexia
Authors: Cong Minghua , Song Chenxin , Xu Hongxia , Song Chunhua , Wang Chang , Fu Zhenming , Ba Yi , Wu Jing , Xie Conghua , Chen Gongyan , Chen Zihua , Zhou Lan , Li Tao , Deng Li , Xin Lin , Yang Liuqing , Cui Jiuwei , Shi Hanping
Published: August 2020

Background

Cancer cachexia is a complex metabolic syndrome characterised by a loss of muscle with or without loss of fat mass, and is associated with high morbidity and mortality. Despite its clinical importance, there is a lack of simple tools to screen patients for cancer cachexia. The aim of this study was to evaluate and validate the patient-generated subjective global assessment (PG-SGA) as a screening tool for cancer cachexia.

Methods

This is a secondary analysis of a multicentre, cross-sectional, observational study. Cancer cachexia was diagnosed when there was weight loss ≥5% during the past 12 months and at least three of the five following conditions were present: decreased muscle strength, fatigue, anorexia, low Fat-Free Mass Index (FFMI) and abnormal laboratory findings. A quadratic discriminant analysis was conducted for the ability of PG-SGA to predict cachexia.

Results

A total of 4231 patients with cancer were included in this analysis, and 351 patients (8.3%) were diagnosed as having cachexia. The highest incidence of cachexia was found among patients with pancreatic cancer (32.5%), oesophageal cancer (21.5%) and gastric cancer (17.9%). Compared with patients without cachexia, patients with cachexia had a lower body mass index, FFMI, hand grip strength, total protein, prealbumin, albumin, haemoglobin and Karnofsky performance status (p<0.05), while they had a higher C reactive protein level and PG-SGA Score (4.71±3.71 vs 10.87±4.84, p<0.05). The best cut-off value for PG-SGA was 6.5, with 79.8% of sensitivity and 72.3% specificity for cachexia, and the area under the receiver operating characteristic curve was 0.846 (95% CI 0.826 to 0.866, p<0.001).

Conclusions

PG-SGA is a highly specific tool that can be used to screen patients for cancer cachexia.
Volunteers in palliative care: A healthcare system-wide cross-sectional survey
Authors: Vanderstichelen Steven , Cohen Joachim , Van Wesemael Yanna , Deliens Luc , Chambaere Kenneth
Published: August 2020

Objective

Volunteers are an important resource in bridging palliative care (PC) services and communities. However, no studies have systematically mapped volunteers’ actual contributions to PC provision and how well they are supported by healthcare services at the volunteer level. Such insights are important to shape and optimise supportive environments for volunteering in PC. This study aimed to describe organised volunteering practices in PC across dedicated PC services and healthcare services providing generalist PC, in terms of tasks, training, supervision and how volunteers evaluate these.

Methods

A cross-sectional postal survey of 2273 volunteers from healthcare organisations providing care for people with serious illnesses in the Flemish healthcare system (Belgium) was conducted between June and November 2018. A two-step cluster randomised sample was used. Volunteers were recruited through their respective volunteering organisations.

Results

Response was obtained for 801 (35.2%) volunteers. Volunteers were predominantly women (75.5%), retired (70.8%) and aged 60–69 years (43.4%). Almost all volunteers provided psychosocial care (96.3%). Volunteers were found to provide either (1) broad volunteer support, emphasising psychosocial and existential care and signposting tasks or (2) narrow volunteer support, emphasising nursing care tasks. Nursing home volunteers had the lowest prevalence of PC training (7.7% vs 53.7% total, p<0.001).

Conclusions

Multidimensional support was most prevalent among dedicated PC volunteers, while practical support was most prevalent among sitting service volunteers. Results indicate that volunteers can offer complementary support for patients with serious illnesses, although this requires training and consistent supervision. This is currently suboptimal for volunteers in nursing homes and community home care.
Home parenteral nutrition versus artificial hydration in malnourished patients with cancer in palliative care: a prospective, cohort survival study
Authors: Cotogni Paolo , Ossola Marta , Passera Roberto , Monge Taira , Fadda Maurizio , De Francesco Antonella , Bozzetti Federico
Published: August 2020

Objective

The evidence base for home parenteral nutrition (HPN) in patients with advanced cancer is lacking. To compare the survival of malnourished patients with cancer undergoing palliative care who received HPN with a homogeneous group of patients, equally eligible for HPN, who did not receive HPN.

Design

Prospective, cohort study; tertiary university hospital, home care, hospice.

Methods

Patients were assessed for HPN eligibility according to the guidelines. In the eligible population, who received both HPN and chemotherapy was excluded, while who received only HPN was included in the HPN+ group and who received neither HPN nor chemotherapy but artificial hydration (AH) was included in the HPN− group.

Results

301 patients were assessed for HPN eligibility and 86 patients (28.6%) were excluded for having severe organ dysfunction or Karnofsky performance status <50. In outcome analysis, 90 patients (29.9%) were excluded for receiving both HPN and chemotherapy, while 125 (41.5%) were included, 89 in HPN+ group (29.5%) and 36 in HPN− group (12%). The survival of the two groups showed a significant difference favouring patients receiving HPN (median overall survival: 4.3 vs 1.5 months, p<0.001). The multivariate analysis of the risk factors for mortality showed that not receiving HPN accounted for the strongest one (HR 25.72, 95% CI 13·65 to 48.44).

Conclusions

Comparative survival associated with the use of HPN versus AH showed significantly longer survival in malnourished patients with advanced cancer receiving HPN. These data support the guideline recommendation that HPN should be considered when malnutrition represents the overriding threat for the survival of these patients.
Malignant esophagorespiratory fistulas: a comparative effectiveness survival analysis
Authors: Ahmad Irfan , Chufal Kundan Singh , Bajpai Ram , Miller Alexis Andrew , Chowdhary Rahul Lal , Pahuja Anjali Kakria , Chhabra Akanksha , Gairola Munish
Published: August 2020

Objectives

To analyse the survival of patients with malignant esophagorespiratory fistulas (ERF) and perform a comparative effectiveness analysis of ERF-directed interventions.

Methods

Fifty-five patients met our inclusion criteria, and data on ERF-directed interventions (stent placement, surgical repair and best supportive care) and their outcomes, along with clinical and treatment details, were recorded. The primary endpoints were overall survival (OS) and survival after developing ERF (F-OS).

Results

The median OS and F-OS for the entire cohort was 299 days (SE=23.2) and 123 days (SE=11.63), respectively. On univariable analysis, the American Joint Committee on Cancer (AJCC) stage (I–III vs IV) influenced both OS (403 vs 171 days; p=0.006) and F-OS (129 vs 67 days; p=0.034). Proximal location of ERF influenced OS favourably (494 vs 285 days; p=0.021), whereas patients developing ERF late in their disease course experienced inferior F-OS (96 vs 232 days; p=0.03). On multivariable analysis, the AJCC stage (IV vs I–III, HR=3.03 (1.41–6.50)), time to developing ERF from diagnosis (greater than vs within 3 months, HR=5.82 (1.84–18.36)) and location of ERF (distal vs proximal, HR=2.47 (1.14–5.34)) had a significant impact on F-OS. The comparative efficacy (OS and F-OS) of best supportive care was statistically equivalent to any intervention irrespective of AJCC stage and success/failure of initial or subsequent intervention(s).

Conclusions

The survival of patients with ERF is dismal, and our analysis suggests that best supportive care results in equivalent OS and F-OS when compared with any intervention.
Chemotherapy decision-making in advanced lung cancer: a prospective qualitative study
Authors: Nelson Annmarie , Longo Mirella , Byrne Anthony , Sivell Stephanie , Noble Simon , Lester Jason , Radley Lesley , Jones David , Sampson Catherine , Anagnostou Despina
Published: August 2020

Objective

To study how treatment decisions are made alongside the lung cancer clinical pathway.

Methods

A prospective, multicentre, multimethods, five-stage, qualitative study. Mediated discourse, thematic, framework and narrative analysis were used to analyse the transcripts.

Results

51 health professionals, 15 patients with advanced lung cancer, 15 family members and 18 expert stakeholders were recruited from three UK NHS trusts. Multidisciplinary team (MDT) members constructed treatment recommendations around patient performance status, pathology, clinical information and imaging. Information around patients’ social context, needs and preferences were limited. The provisional nature of MDTs treatment recommendations was not always linked to future discussions with the patient along the pathway, that is, patients’ interpretation of their prognosis, treatment discussions occurring prior to seeing the oncologist. This together with the rapid disease trajectory placed additional stress on the oncologist, who had to introduce a different treatment option from that recommended by the MDT or patient’s expectations. Palliative treatment was not referred to explicitly as such, due to its potential for confusion. Patients were unaware of the purpose of each consultation and did not fully understand the non-curative intent of treatment pathways. Patients’ priorities were framed around social and family needs, such as being able to attend a family event.

Conclusion

Missed opportunities for information giving, affect both clinicians and patients; the pathway for patients with non-small cell lung cancer focuses on clinical management at the expense of patient-centred care. Treatment decisions are a complex process and patients draw conclusions from healthcare interactions prior to the oncology clinic, which prioritises aggressive treatment and influences decisions.
Incidence, pattern and severity of abnormal liver blood tests among hospitalised patients with SARS-COV2 (COVID-19) in South Wales
Authors: Yeoman Andrew , Maggs Daniel Raun , Gardezi Syed A A , Haboubi Hasan Nadim , Yahya Muhammad Imran , Yousuf Fidan , Czajkowski Marek Alexander
Published: August 2020

Introduction

SARS-CoV-2 (COVID-19) is a novel coronavirus that emerged in Wuhan, China in late 2019 and since become a global pandemic. As such, its clinical behaviour is a subject of much interest. Initial reports suggested a significant proportion of patients have abnormal liver blood tests. Gwent has experienced one of the highest incidences of COVID-19 infection in the UK, which itself has among the highest COVID-19 impacts worldwide.

Method

We set out to report the incidence, clinical pattern and severity of liver blood test abnormalities in hospitalised patients with confirmed COVID-19 in our institution over a 3-week period. Data on clinical outcomes such as admission to intensive therapy unit (ITU), hospital discharge and mortality were recorded.

Results

318 hospitalised COVID-19 positive had liver blood tests available for analysis. Ninety-seven patients (31%) had one or more abnormal liver blood tests and were abnormal admission in 64%. Liver tests were predominantly cholestatic (72%) in contrast to other studies to date. Male gender and abnormal liver blood tests were associated with ITU admission.

Conclusions

Almost one-third of admissions with COVID-19 have abnormal LBTs which are typically mild and are associated with male gender. Importantly, we have identified that cholestatic patterns dominate but were not clearly associated with ITU admission or death.
Increased risk of cardiac ischaemia in a pan-European cohort of 36 205 childhood cancer survivors: a PanCareSurFup study
Authors: Feijen Elizabeth Arnoldina Maria , van Dalen Elvira C , van der Pal Heleen J H , Reulen Raoul C , Winter David L , Kuehni Claudia E , Morsellino Vera , Alessi Daniela , Allodji Rodrigue S , Byrne Julliana , Bardi Edit , Jakab Zsuzsanna , Grabow Desiree , Garwicz Stanislaw , Haddy Nadia , Jankovic Momcilo , Kaatsch Peter , Levitt Gill A , Ronckers Cecile M , Schindera Christina , Skinner Roderick , Zalatel Lorna , Hjorth Lars , Tissing Wim J E , De Vathaire Florent , Hawkins Mike M , Kremer Leontien C M
Published: August 2020

Objective

In this report, we determine the cumulative incidence of symptomatic cardiac ischaemia and its risk factors among European 5-year childhood cancer survivors (CCS) participating in the PanCareSurFup study.

Methods

Eight data providers (France, Hungary, Italy (two cohorts), the Netherlands, Slovenia, Switzerland and the UK) participating in PanCareSurFup ascertained and validated symptomatic cardiac events among their 36 205 eligible CCS. Data on symptomatic cardiac ischaemia were graded according to the Criteria for Adverse Events V.3.0 (grade 3–5). We calculated cumulative incidences, both overall and for different subgroups based on treatment and malignancy, and used multivariable Cox regression to analyse risk factors.

Results

Overall, 302 out of the 36 205 CCS developed symptomatic cardiac ischaemia during follow-up (median follow-up time after primary cancer diagnosis: 23.0 years). The cumulative incidence by age 60 was 5.4% (95% CI 4.6% to 6.2%). Men (7.1% (95% CI 5.8 to 8.4)) had higher rates than women (3.4% (95% CI 2.4 to 4.4)) (p<0.0001). Of importance is that a significant number of patients (41/302) were affected as teens or young adults (14–30 years). Treatment with radiotherapy/chemotherapy conferred twofold risk (95% CI 1.5 to 3.0) and cases in these patients appeared earlier than in CCS without treatment/surgery only (15% vs 3% prior to age 30 years, respectively (p=0.04)).

Conclusions

In this very large European childhood cancer cohort, we found that by age 60 years, 1 in 18 CCS will develop a severe, life-threatening or fatal cardiac ischaemia, especially in lymphoma survivors and CCS treated with radiotherapy and chemotherapy increases the risk significantly.
Trends in cardiovascular outcomes after acute coronary syndrome in New Zealand 2006–2016
Authors: Wang Tom Kai Ming , Grey Corina , Jiang Yannan , Selak Vanessa , Bullen Chris , Jackson Rodney T , Kerr Andrew J
Published: August 2020

Objectives

Characterisation of trends in acute coronary syndrome (ACS) outcomes are critical to informing clinical practice and quality improvement, but there are few recent population studies for ACS. We reviewed the recent trends in the outcomes of ACS in New Zealand (NZ).

Methods

All patients with ACS admitted to NZ public hospitals in 2006–2016 were identified from hospital discharge records, and their first ACS hospitalisations per year extracted for analysis. Thirty-day and 1-year death, myocardial infarction, stroke, heart failure and bleeding rates were calculated for each calendar year. Trends in outcome rates were assessed using generalised linear mixed models.

Results

Total annual ACS hospitalisations decreased from 685 to 424 per 100 000. Using first patient hospitalisations per year (n=1 55 060), we found significant annual declines in all major outcomes except for non-cardiovascular deaths. All-cause mortality fell from 10.5% to 9.1% at 30 days (adjusted OR 0.985 per year change, p<0.001) and from 21.8% to 18.7% at 1 year (OR=0.994, p=0.016). This was related to significant decreases in cardiovascular death at both time points (OR=0.982 and 0.987, respectively, p<0.001), outweighing a slight increase in non-cardiovascular death at 1 year (OR=1.009, p=0.014). One-year rates of myocardial infarction, heart failure, stroke and bleeding rates all decreased significantly over time.

Conclusion

ACS outcomes including all-cause mortality, cardiovascular death, myocardial infarction, stroke, heart failure and bleeding at 30 days and 1 year improved over the last decade in NZ, reflecting successful implementation and advances in prevention, medical and invasive management in ACS over time.
Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma
Authors: Boutros Celine , Chaput-Gras Nathalie , Lanoy Emilie , Larive Alicia , Mateus Christine , Routier Emilie , Sun Roger , Tao Yun Gan , Massard Christophe , Bahleda Rastilav , Schwob Dominique , Ibrahim Nathalie , Khoury Abboud Rita Maria , Caramella Caroline , Lancia Andrea , Cassard Lydie , Roy Severine , Soria J -C , Robert Caroline , Deutsch Eric
Published: August 2020

Background

A synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.

Patients and methods

A 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.

Results

19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5–2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2–1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.

Conclusion

When combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.

Trial registration number

NCT01557114.
An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy
Authors: Wang Hui , Xu Qian , Zhao Chanyuan , Zhu Ziqi , Zhu Xiaoqing , Zhou Junjie , Zhang Shuming , Yang Tiqun , Zhang Biying , Li Jun , Yan Meiling , Liu Renming , Ma Changchun , Quan Yan , Zhang Yongqu , Zhang Weifeng , Geng Yiqun , Chen Chuangzhen , Chen Shaobin , Liu Ditian , Chen Yuping , Tian Dongping , Su Min , Chen Xueling , Gu Jiang
Published: August 2020

Background

Recent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion.

Methods

The distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo.

Results

In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy.

Conclusion

There appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.
M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
Authors: Hensler Michal , Kasikova Lenka , Fiser Karel , Rakova Jana , Skapa Petr , Laco Jan , Lanickova Tereza , Pecen Ladislav , Truxova Iva , Vosahlikova Sarka , Moserova Irena , Praznovec Ivan , Drochytek Vit , Rehackova Martina , Brtnicky Tomas , Rob Lukas , Benes Vladimir , Pistolic Jelena , Sojka Ludek , Ryska Ales , Sautes-Fridman Catherine , Fridman Wolf Herve , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka
Published: August 2020

Background

The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.

Methods

RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.

Results

1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.

Conclusions

Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.
Republished: Successful treatment of direct carotid–cavernous fistula in a patient with Ehlers–Danlos syndrome type IV without arterial puncture: the transvenous triple-overlay embolization (TAILOREd) technique
Authors: Huynh Thien J , Morton Ryan P , Levitt Michael R. , Ghodke Basavaraj V. , Wink Onno , Hallam Danial K.
Published: August 2020

We report successful transvenous treatment of direct carotid–cavernous fistula in a patient with Ehlers–Danlos syndrome type IV using a novel triple-overlay embolization (TAILOREd) technique without the need for arterial puncture, which is known to be highly risky in this patient group. The TAILOREd technique allowed for successful treatment using preoperative MR angiography as a three-dimensional overlay roadmap combined with cone beam CT and live fluoroscopy, precluding the need for an arterial puncture.
Development and validation of the Canadian retail cut beef yield grades
Authors: Segura J. , Aalhus J.L. , Prieto N. , Larsen I.L. , Dugan M.E.R. , López-Campos Ó
Published: August 2020

The United States Department of Agriculture (USDA) system has five retail cut yield (RCY) classes, whereas the former Canadian system had three total lean yield (TLY) classes. A total of 720 beef carcasses were used to develop a modified grade ruler, harmonizing the Canadian grades into five classes. Beef carcasses (n = 750) from three Canadian federally inspected facilities were graded using both USDA and Canadian (harmonized ruler) systems for external validation. Agreement between the USDA-RCY and the Canadian TLY was high (R2 = 0.80). The validation between the harmonized ruler and the USDA-RCY showed a standard deviation of the difference of 1.32 and a coefficient of concordance of 0.83.
Temperature induced phase transition in fluorescence active zein nanoparticles
Authors: Croxford Charlie Joe , Kaur Rajpreet , Singh Kultar , Bakshi Mandeep Singh
Published: August 2020

Stable colloidal zein nanoparticles (NPs) were synthesized by using controlled precipitation method. They were made fluorescence active by incorporating a small amount of fluorescence quinolinium surfactant. The incorporation of fluorescence surfactant provided both the colloidal stability and the fluorescence ability to determine the phase transition in zein NPs under the effect of temperature variation. Maintaining colloidal stability under the effect of temperature variation is an essential aspect of zein NPs applicability as a source of vegetarian protein supplement in different food suspensions. Different techniques such as fluorescence, DLS size, zeta potential, and FTIR measurements were applied to determine the influence of temperature on the colloidal stability of zein NPs. Zein NPs undergo phase transition well above room temperature while maintaining their size in nanometer range, and the phase transition temperature decreased with the amount of zein used in the synthesis of zein NPs. The results highlighted the potential use of zein NPs as a vegetarian supplement protein in different food products.
Early avian functional assemblages after fire, clearcutting, and post-fire salvage logging in North American forests
Authors: Bognounou F. , Venier L.A. , Van Wilgenburg S.L. , Aubin I. , Candau J.-N. , Arsenault A. , Hebert C. , Ibarzabal J. , Song S.J. , De Grandpré L.
Published: August 2020

Increased demand for timber, the reduction in the available timber resources, and more frequent and severe forest fires under a changing climate have increased the use of salvage logging in North American forests despite concerns regarding impacts on biodiversity and long-term forest productivity. We aimed to complement previous approaches that used bird species richness or individual abundance in salvage-logged habitats to assess the sustainability of this practice. We looked for commonalities in the taxonomic, functional, and phylogenetic components of bird assemblages among these three post-disturbance habitats across a broad geographic range. We compiled six North American datasets selected from primary and grey literature that documented species composition of avian assemblages in habitats after recent fire, post-fire salvage logging, and traditional logging. Our results revealed contrasting patterns of bird trait assemblage among burned, post-fire salvage, and traditionally logged habitats. In salvage-logged habitats, taxonomic diversity, functional diversity, and functional and phylogenetic redundancy were significantly lower than in both burned and traditionally logged habitats. The frequency of insectivores was significantly lower after salvage logging than after both fire and traditional logging. These findings suggest that cumulative disturbances have a negative effect on early assembly of bird communities. The outcomes of this study encourage further assessments, at landscape level, of salvage logging intensity, burn size, and fire severity on bird functional structure to better plan for their conservation.
Nicorandil prevents the nephrotoxic effect of cyclosporine-A in albino rats through modulation of HIF-1α/VEGF/eNOS signaling
Authors: Harb Inas A. , Ashour Hend , Sabry Dina , El-Yasergy Dina Fawzy , Hamza Wael Mostafa , Mostafa Abeer
Published: August 2020

Despite that cyclosporine-A (CsA) is a widely used immunosuppressive drug, its nephrotoxic effect limits its long-term administration. Herein we tried to investigate its renal effect on endothelial dysfunction targeting the hypoxia-inducible factor (HIF-1α) / vascular endothelial growth factor (VEGF) / endothelial nitric oxide synthase (eNOS) pathway and the possible modulation by nicorandil. Eight groups of adult male Wistar rats were included: (1) control; (2) vehicle group (received oil); (3) glibenclamide 5 mg·kg–1·day–1 administered orally; (4) nicorandil 10 mg·kg–1·day–1 administered orally; (5) CsA 25 mg·kg–1·day–1 administered orally; (6) combined administration of CsA and nicorandil; (7) glibenclamide was added to CsA; and (8) both CsA and nicorandil were combined with glibenclamide. The treatment continued for six weeks. Combined nicorandil with CsA improved renal function deterioration initiated by CsA. CsA decreased the renal expression levels (P < 0.001) of HIF-1α, eNOS, and VEGF, inducing endothelial dysfunction and triggering inflammation, and upregulated the profibrotic marker transforming growth factor (TGF-β). Nicorandil fixed the disturbed HIF-1α/VEGF/eNOS signaling. Nicorandil corrected the renal functions, confirmed by the improved histological glomerular tuft retraction that was obvious in the CsA group, without significant influence by glibenclamide. Proper protection from CsA-induced nephrotoxicity was achieved by nicorandil. Nicorandil reversed the disturbed HIF-1α/VEGF/eNOS pathway created by CsA.
A validation of eddy covariance technique for measuring crop evapotranspiration on different time scales in the North China Plain
Authors: Wang Fangfang , Ma Donghao , Zhao Wenju , Lu Yunxuan , Zhou Ding , Zhang Jiabao , Chen Lin , Huang Ping
Published: August 2020

Accurate determination of evapotranspiration (ET) has tremendous potential in guiding irrigation and improving the efficiency of water resources utilization in the North China Plain. Eddy covariance (EC) method is currently a popular method for determining field-scale ET. However, due to varying foot print and unclosed energy balance, the applicability of EC in different regions needs to be tested and corrected. In present work, we compared the ET of the winter wheat – summer maize rotation cropland measured by the EC method with the ET measured by large-scale lysimeters on different time scales. The degree of energy balance closure of EC measurements in this region is 78%. After adjusted by using Bowen ratio forced closure method, the ET monitored by EC is comparable with those monitored by large-scale lysimeters. The results also indicated that the consistency of the observed ET by the EC and lysimeters got better with an increasing time scale, especially for the multi-year average ET values with a relative deviation of less than 1%. The short-time events such as irrigation and precipitation and the mismatch of the varying footprint area of the EC and the small fixed source area of the lysimeter should be responsible for the discrepancy of ET in two methods on daily scale. However, the factors of crop biomass, total available water, and local climate condition exert more effects on the observed ET on large time scale. Overall, the EC technique is responsible for ET measurement of winter wheat – summer maize rotation cropland of the North China Plain.
Supplement of biochar and vermicompost amendments in coir and peat growing media improves N management and yields of leafy vegetables
Authors: Messiga Aimé J. , Hao Xiuming , Dorais Martine , Bineng Carine S. , Ziadi Noura
Published: August 2020

A greenhouse trial assessed the effects of biochar and vermicompost as partial substitutes of conventional growing media on leafy vegetables’ yields and changes of NH4+-N and NO3−-N in growing medium and leachates. Six growing media mixtures [(a) coir, (b) coir + biochar, (c) coir + vermicompost, (d) peat, (e) peat +vermicompost, (f) peat + biochar] combined with three nitrogen (N) rates [0% (0 g N·pot−1), 50% (0.5 g N·pot−1), and 100% (1.0 g N·pot−1) commercial recommendation] were arranged in a split-plot design with three replicates. On average, the yield gap between 100% N and 50% N was improved when biochar and vermicompost were used as substitutes of coir (32% and 28% vs. 49%) and peat (14% and 18% vs. 27%). The concentrations of NH4+-N in the leachates for peat + biochar varied between 17.20 and 1.00 mg·L−1. The concentrations of NO3−-N in the leachates varied between 130.0 and 1.0 mg·L−1for coir + vermicompost, and 60 and 1.0 mg·L−1for peat + vermicompost. The residual NO3−-N in peat + biochar growing media and the leachates did not match the changes observed for NH4+-N, and the much lower residual NH4+-N indicates possible NH4+-N retention by biochar and loss through volatilization in the early growth stages. Our results show that partial substitution of peat with biochar and coir with vermicompost maintained acceptable crop yield at 50% N due probably to N supply by vermicompost and decreased residual mineral N and loss by biochar in the leachates which could be beneficial for the environment.