bluuebunny/crossref_metadata_2025 huggingface dataset:
Modularity optimization for enhancing edge detection in microstructural features using 3D atomic chemical scale imaging
Authors: Mukherjee Arpan , Broderick Scott , Rajan Krishna
Published: March 2020

The definition of microstructural features from an image is a challenge, given the uncertainty of the feature edges and the inherent user bias required in defining what is a feature. This challenge is particularly evident in atom probe tomography (APT), which captures tens of millions of atoms with their three-dimensional (3D) atomic position. Given the data uncertainty, issues with missing data, and dependency of the result on user-defined reconstruction, defining a relationship between the thermodynamic conditions and the resulting microstructure is difficult. Although numerous methods are capable of performing approximate clustering of precipitates, an accurate and fully automatic framework is still unavailable. In this paper, the authors present an advanced unsupervised machine learning framework that uses a graph-theoretic representation of the reconstructed 3D APT data and performs a modularity optimization to estimate an accurate cluster structure. The identified cluster structure can be used to estimate other geometrical properties and also the uncertainty in the precipitates. The authors demonstrate the approach to define and characterize the precipitates of an aluminum-magnesium-scandium sample, free of any user bias. The proposed unsupervised framework has been demonstrated to perform better than two well-known clustering methods. The approach described here was developed for APT data, but is developed in a generalized manner so as to be applicable to any point cloud data.
Fauci's straight talk
Authors: Cohen Jon
Published: March 2020

Science
interviews the director of NIAID about the coronavirus pandemic.
No consistent ENSO response to volcanic forcing over the last millennium
Authors: Dee Sylvia G. , Cobb Kim M. , Emile-Geay Julien , Ault Toby R. , Edwards R. Lawrence , Cheng Hai , Charles Christopher D.
Published: March 2020

Not a big deal after all

Do volcanic eruptions affect El Niño–Southern Oscillation (ENSO) variability? Models indicate that sulfate aerosols resulting from large eruptions can initiate an El Niño–like response in the tropical Pacific, but observations have not shown evidence of such behavior. Dee
et al
. present an oxygen-isotope time series of fossil corals from the central tropical Pacific to investigate ENSO's response to large volcanic eruptions during the past millennium. They found a weak tendency for an El Niño–like response in the year after an eruption, but not one that was statistically significant. These results suggest that large volcanic events have not triggered a detectable response in ENSO over the past thousand years and that their impact is small relative to the degree of natural variability.

Science
, this issue p.
1477
Interglacial instability of North Atlantic Deep Water ventilation
Authors: Galaasen Eirik Vinje , Ninnemann Ulysses S. , Kessler Augustin , Irvalı Nil , Rosenthal Yair , Tjiputra Jerry , Bouttes Nathaëlle , Roche Didier M. , Kleiven Helga (Kikki) F. , Hodell David A.
Published: March 2020

Disrupting deep circulation

Atlantic Meridional Overturning Circulation (AMOC) and the related process of North Atlantic Deep Water (NADW) have been thought to be stable during warm, interglacial periods. Galaasen
et al.
report that episodes of reduced NADW over the past 500,000 years actually have been relatively common and occasionally long-lasting features of interglacials and that they can occur independently of the catastrophic freshwater outburst floods normally thought to be their cause (see the Perspective by Stocker). This discovery implies that large NADW disruptions might be more likely than we have assumed in the warmer climate of the future.

Science
, this issue p.
1485
; see also p.
1425
Observation of dynamical fermionization
Authors: Wilson Joshua M. , Malvania Neel , Le Yuan , Zhang Yicheng , Rigol Marcos , Weiss David S.
Published: March 2020

Capturing the transformation

Quantum statistics dictates the behavior of identical particles in the quantum world: Bosons like to congregate, whereas fermions avoid one another. However, strong interactions can cause a string of bosons to behave like fermions. This so-called fermionization phenomenon has been studied in equilibrium. Wilson
et al.
instead focused on dynamical fermionization in a nonequilibrium system consisting of tubes of strongly interacting bosonic rubidium atoms. After letting the tubes expand in the axial direction, the researchers monitored the momentum distribution of the atoms and found that it evolved from bosonic-like to fermionic-like.

Science
, this issue p.
1461
Ultrahigh-field
67
Zn NMR reveals short-range disorder in zeolitic imidazolate framework glasses
Authors: Madsen Rasmus S. K. , Qiao Ang , Sen Jishnu , Hung Ivan , Chen Kuizhi , Gan Zhehong , Sen Sabyasachi , Yue Yuanzheng
Published: March 2020

Glassy metal-organic frameworks

The node-and-linker structure of metal-organic frameworks could enable detailed structural studies of molecular glasses quenched from melts. Zinc-based zeolitic imidazole frameworks exhibit a high propensity for glass formation at conventional cooling rates. Madsen
et al.
used ultrahigh magnetic fields (19.5 and 35.2 tesla) to perform zinc-67 nuclear magnetic resonance of solid samples with magic-angle spinning on three samples with different ratios of imidazole and benzimidazole linkers. The structural disorder of the tetrahedral ligand environment around zinc nodes was higher in the glassy states than in the parent crystals.

Science
, this issue p.
1473
Reversing the rise in midlife mortality
Deaths of Despair and the Future of Capitalism
Anne Case and Angus Deaton
Princeton University Press, 2020. 324 pp.
Authors: Canning David
Published: March 2020

Stronger safety nets and health care reform could help mitigate “deaths of despair” in America
Efficient, stable silicon tandem cells enabled by anion-engineered wide-bandgap perovskites
Authors: Kim Daehan , Jung Hee Joon , Park Ik Jae , Larson Bryon W. , Dunfield Sean P. , Xiao Chuanxiao , Kim Jekyung , Tong Jinhui , Boonmongkolras Passarut , Ji Su Geun , Zhang Fei , Pae Seong Ryul , Kim Minkyu , Kang Seok Beom , Dravid Vinayak , Berry Joseph J. , Kim Jin Young , Zhu Kai , Kim Dong Hoe , Shin Byungha
Published: March 2020

Engineering perovskites with anions

The bandgap of the perovskite top layer in tandem silicon solar cells must be tuned to ∼1.7 electron volts. Usually, the cation composition is varied because the bromine-rich anion compositions with wide bandgaps are structurally unstable. Kim
et al.
show that by using phenethylammonium as a two-dimensional additive, along with iodine and thiocyanate, bromine-rich perovskite films can be stabilized. A tandem silicon cell delivered >26% certified power conversion efficiency, and a perovskite device maintained 80% of its initial power conversion efficiency of >20% after 1000 hours under illumination.

Science
, this issue p.
155
Frequency-comb spectroscopy on pure quantum states of a single molecular ion
Authors: Chou C. W. , Collopy A. L. , Kurz C. , Lin Y. , Harding M. E. , Plessow P. N. , Fortier T. , Diddams S. , Leibfried D. , Leibrandt D. R.
Published: March 2020

Precision spectroscopy with single ions

Spectroscopy is a powerful tool that can identify chemical species used in a wide range of settings. Usually, the samples are formed of ensembles, and this can limit the resolution with which the different species can be detected or identified. Chou
et al.
demonstrate an optical frequency comb technique with a single pair of trapped ions, Ca
+
and CaH
+
, to obtain the rotational spectrum of a single trapped ion, CaH
+
. With the ions isolated and the ensemble interactions removed, the rotational structure of the trapped molecular ion can then be obtained with high precision. As the trapping and manipulation process is general, this technique could be applied to a number of chemical species for specific purposes.

Science
, this issue p.
1458
Neanderthal surf and turf
Authors: Will Manuel
Published: March 2020

Did our closest relatives adapt to the sea in the same way as early
Homo sapiens
?
Evaluation of the Effect of Contezolid (MRX-I) on the Corrected QT Interval in a Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study in Healthy Chinese Volunteers
Authors: Wu Junzhen , Cao Guoying , Wu Hailan , Chen Yuancheng , Guo Beining , Wu Xiaojie , Yu Jicheng , Ni Kanhong , Qian Jin , Wang Li , Wu Jufang , Wang Yu , Yuan Hong , Zhang Jing , Xi Yuewen
Published: March 2020

Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated.
Progression from ocular hypertension to visual field loss in the English hospital eye service
Authors: Kelly Stephen R , Khawaja Anthony P , Bryan Susan R , Azuara-Blanco Augusto , Sparrow John M , Crabb David P
Published: March 2020

Background

There are more than one million National Health Service visits in England and Wales each year for patients with glaucoma or ocular hypertension (OHT). With the ageing population and an increase in optometric testing, the economic burden of glaucoma-related visits is predicted to increase. We examined the conversion rates of OHT to primary open-angle glaucoma (POAG) in England and assessed factors associated with risk of conversion.

Methods

Electronic medical records of 45 309 patients from five regionally different glaucoma clinics in England were retrospectively examined. Conversion to POAG from OHT was defined by deterioration in visual field (two consecutive tests classified as stage 1 or worse as per the glaucoma staging system 2). Cox proportional hazards models were used to examine factors (age, sex, treatment status and baseline intraocular pressure (IOP)) associated with conversion.

Results

The cumulative risk of conversion to POAG was 17.5% (95% CI 15.4% to 19.6%) at 5 years. Older age (HR 1.35 per decade, 95% CI 1.22 to 1.50, p<0.001) was associated with a higher risk of conversion. IOP-lowering therapy (HR 0.45, 95% CI 0.35 to 0.57, p<0.001) was associated with a lower risk of conversion. Predicted 5-year conversion rates for treated and untreated groups were 14.0% and 26.9%, respectively.

Conclusion

Less than one-fifth of OHT patients managed in glaucoma clinics in the UK converted to POAG over a 5-year period, suggesting many patients may require less intensive follow-up. Our study provides real-world evidence for the efficacy of current management (including IOP-lowering treatment) at reducing risk of conversion.
Binocular superior visual field areas associated with driving self-regulation in patients with primary open-angle glaucoma
Authors: Yamasaki Tomoyo , Yuki Kenya , Awano-Tanabe Sachiko , Ono Takeshi , Murata Hiroshi , Tsubota Kazuo , Asaoka Ryo
Published: March 2020

Background/aims

The aim of our study was to investigate the associations between driving self-regulation and glaucoma severity, and between driving self-regulation and glaucomatous visual field (VF) defect patterns.

Methods

In 247 patients with primary open-angle glaucoma included in this prospective observational study, a battery of ophthalmic examination was performed, including visual acuity (VA) and VF. Integrated binocular VF was constructed and mean of total deviation (mTD) values in four sectors was calculated (mTDsup-peri, mTDsup-centre, mTDinf-peri and mTDinf-centre). In addition, all participants answered seven questions regarding their avoidance in driving. (1) at night, (2) in rain, (3) in fog, (4) on freeways, (5) lane changing, (6) at high speed and (7) close to the car in front. The associations between these driving behaviours and 10 variables (age, gender, best VA, worst VA, the four sectorial average TD values, years holding a driver’s licence and distance driven per week) were analysed using the generalised linear model with binomial distribution, followed by the model section method using the corrected Akaike information criterion.

Results

As a result of the model selection, it was suggested that deterioration of mTDsup-peri was associated with (1) avoiding driving at night and (2) avoiding driving in rain. On the other hand, mTDsup-centre was related to (3) avoiding driving in fog.

Conclusion

Damage in visual function was related with driving behaviours in patients with glaucoma.
Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches
Authors: Berry Vanita , Georgiou Michalis , Fujinami Kaoru , Quinlan Roy , Moore Anthony , Michaelides Michel
Published: March 2020

Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype–phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.
Intraoperative iatrogenic retinal breaks in 23-gauge vitrectomy for stage 3 and stage 4 idiopathic macular holes
Authors: Yu Yanping , Qi Biying , Liang Xida , Wang Zengyi , Wang Jing , Liu Wu
Published: March 2020

Aims

To investigate characteristics of intraoperative iatrogenic retinal breaks in 23-gauge vitrectomy for idiopathic macular hole and classify the breaks based on their causes to analyse the risk factors.

Methods

This retrospective study enrolled patients with stage 3 or 4 idiopathic macular hole who underwent 23-gauge vitrectomy in Beijing Tongren Hospital from July 2015 to August 2018. The intraoperative iatrogenic retinal breaks were classified into three types: by induction of posterior vitreous detachment (type 1), by peripheral vitreous cutting (type 2) and by others (type 3). The types, incidence and distribution of the breaks were analysed, and all clinical features were compared between eyes with and without the breaks.

Results

A total of 364 eyes from 341 patients were recruited. Twenty-five breaks from 24 eyes (6.6%) were encountered, 52% (13/25) of which distributed in the superior region. Type 1 and type 2 breaks contributed 52% (13/25) and 44% (11/25) to all, respectively. Eyes with stage 3 and stage 4 holes showed no significant differences in incidence or distribution in type 2 breaks. No breaks occurred on the surface of lattice degenerations. All clinical features showed no significant differences between eyes with and without the breaks.

Conclusion

Distribution of intraoperative iatrogenic retinal breaks shows no preference for the superior or inferior region. Induction of posterior vitreous detachment and traction from peripheral vitreous cutting are major causes of the breaks, which classify them into two main types. The presence of lattice may not be one of the risk factors if treated properly.
Retinal blood flow reduction in normal-tension glaucoma with single-hemifield damage by Doppler optical coherence tomography
Authors: Yoshioka Takafumi , Song Youngseok , Kawai Motofumi , Tani Tomofumi , Takahashi Kengo , Ishiko Satoshi , Lavinsky Fabio , Wollstein Gadi , Ishikawa Hiroshi , Schuman Joel S , Yoshida Akitoshi
Published: March 2020

Aims

To evaluate the associations between retinal blood flow (RBF) and optical coherence tomography (OCT) structural measurements in normal-tension glaucoma (NTG) eyes with single-hemifield visual field (VF) damage by the Doppler OCT.

Methods

The Doppler OCT was used to measure temporal artery (TA) RBF and temporal vein (TV) RBF. Retinal nerve fibre layer thickness (RNFLT) was measured by spectral-domain OCT.

Results

Forty-three consecutive eyes of 43 patients with NTG with VF defect confined to a single hemifield and 24 eyes of 24 age-matched healthy subjects were studied. TA and TV RBF and RNFLT were reduced in the damaged hemisphere compared with the normal hemisphere (mean (SD), 3.61 (1.68) vs 5.86 (2.59) µL/min, p<0.001; 5.61 (2.51) vs 6.94 (2.83) µL/min, p=0.010; 69.0 (19.7) vs 99.7 (22.8) µm, p<0.001). Those values in the normal hemisphere of NTG eyes also decreased compared with the healthy hemisphere of the healthy eyes (8.40 (3.36) µL/min, p<0.001; 9.28 (4.47) µL/min, p<0.002; 122.8 (20.2) µm, p<0.001). Multivariate model showed that normal and damaged hemispheres and RNFLT were associated with RBF reduction. In addition, the RBF in the normal hemisphere was lower than that in the healthy hemisphere even after adjusting for RNFLT.

Conclusion

In NTG eyes with single-hemifield damage, the RBF was significantly reduced in the damaged hemisphere compared with the normal one. The RBF decreased in the normal and damaged hemispheres of NTG eyes compared with the healthy hemisphere independent from RNFLT.
Retinoblastoma in Finland, 1964–2014: incidence and survival
Authors: Nummi Kalle , Kivelä Tero T
Published: March 2020

Aims

To determine the incidence of retinoblastoma (Rb) and subsequent survival in the Finnish population during five decades.

Methods

This retrospective observational cohort study comprised all patients with Rb born in Finland during 1964–2014 and diagnosed in 2018 (birth cohort analysis) or diagnosed in 1964–2014 (standard annual analysis), identified from the Finnish Cancer Registry and the national referral centre. We report age-adjusted incidences and survival according to cause of death.

Results

Of children born in 1964–2014, 205 developed Rb, whereas 204 Rbs were diagnosed during these years; 196 belonged to both cohorts. Altogether 80 (38%) of the 213 children had heritable Rb and 19 (9%) had familial disease. The sex ratio was 1.34, suggesting male preponderance. Birth cohort analysis showed a median incidence of 6.2 per 100 000 live births (1:16 130) and less variability as compared with standard annual analysis (12.1, 6.5 and 4.4 per million children 0–4, 0–9 and 0–14 years of age, respectively). The incidence of heritable Rb increased with time, reflecting the increase in familial tumours. Five-year mortality rates from Rb were 6.2% and 7.6% for non-heritable and heritable diseases, respectively, and 35-year mortality rates from second malignancies were 0% and 14.3%, respectively. Family history predicted improved survival, whereas the period of diagnosis did not.

Conclusion

The incidence of familial Rb has increased, along with improvement in survival in Finland in 1964–2014, whereas the overall incidence of Rb was stable. Long-term risk of dying of second malignancies after heritable Rb was in line with other countries.
Fracture union rates across a century of war: a systematic review of the literature
Authors: Stewart Sarah K , Tenenbaum O , Higgins C , Masouros S , Ramasamy A
Published: March 2020

Introduction

Fractures have been a common denominator of the injury patterns observed over the past century of warfare. The fractures typified by the blast and ballistic injuries of war lead to high rates of bone loss, soft tissue injury and infection, greatly increasing the likelihood of non-union. Despite this, no reliable treatment strategy for non-union exists. This literature review aims to explore the rates of non-union across a century of conflict, in order to determine whether our ability to heal the fractures of war has improved.

Methods

A systematic review of the literature was conducted, evaluating the rates of union in fractures sustained in a combat environment over a 100-year period. Only those fractures sustained through a ballistic or blast mechanism were included. The review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Quality and bias assessment was also undertaken.

Results

Thirty studies met the inclusion criteria, with a total of 3232 fractures described across 15 different conflicts from the period 1919–2019. Male subjects made up 96% of cases, and tibial fractures predominated (39%). The lowest fracture union rate observed in a series was 50%. Linear regression analysis demonstrated that increasing years had no statistically significant impact on union rate.

Conclusions

Failure to improve fracture union rates is likely a result of numerous factors, including greater use of blast weaponry and better survivability of casualties. Finding novel strategies to promote fracture healing is a key defence research priority in order to improve the rates of fractures sustained in a combat environment.
Physical prognostic factors predicting outcome following anterior cruciate ligament reconstruction: protocol for a systematic review
Authors: Middlebrook Andrew , Bekker Sheree , Middlebrook Nicola , Rushton Alison B
Published: March 2020

Introduction

Injuries of the anterior cruciate ligament (ACL) are a common musculoskeletal complication and can cause significant reduction in patient function and quality of life. Many undergo ACL reconstruction, with high-quality rehabilitation key to successful outcome. Knowledge of physical prognostic factors, such as quadriceps strength, is crucial to inform rehabilitation and has important implications for outcome following ACL reconstruction. However, these factors predicting outcome are poorly defined. Therefore, the aim of this systematic review is to establish physical prognostic factors predictive of outcome in adults following ACL reconstruction. Outcome will be subdivided into two groups of outcome measures, patient-reported and performance-based. Physical prognostic factors of interest will reflect a range of domains and may be modifiable/non-modifiable. Results will help decide most appropriate management and assist in planning and tailoring preoperative and postoperative rehabilitation.

Methods and analysis

This systematic review protocol is reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. MEDLINE, CINAHL and EMBASE databases, key journals and grey literature will be searched from inception to July 2019. Prospective cohort studies including participants aged ≥16 years who have undergone ACL reconstruction will be included, with articles focusing on multi-ligament reconstructions and ACL repair surgery, or not published in English excluded. Two independent reviewers will conduct searches, assess study eligibility, extract data, assess risk of bias (Quality in Prognostic Studies tool) and quantify overall quality of evidence (modified Grading of Recommendations, Assessment, Development and Evaluation guidelines). If possible, a meta-analysis will be conducted, otherwise a narrative synthesis will ensue focusing on prognostic factors, risk of bias of included studies and strength of association with outcomes.

Ethics and dissemination

Findings will be published in a peer-reviewed journal, presented at conferences and locally to physiotherapy departments. Ethical approval is not required for this systematic review.

PROSPERO registration number

CRD42019127732.
Trends in disease incidence and survival and their effect on mortality in Scotland: nationwide cohort study of linked hospital admission and death records 2001–2016
Authors: Timmers Paul R H J , Kerssens Joannes J , Minton Jon , Grant Ian , Wilson James F , Campbell Harry , Fischbacher Colin M , Joshi Peter K
Published: March 2020

Objectives

Identify causes and future trends underpinning Scottish mortality improvements and quantify the relative contributions of disease incidence and survival.

Design

Population-based study.

Setting

Linked secondary care and mortality records across Scotland.

Participants

1 967 130 individuals born between 1905 and 1965 and resident in Scotland from 2001 to 2016.

Main outcome measures

Hospital admission rates and survival within 5 years postadmission for 28 diseases, stratified by sex and socioeconomic status.

Results

‘Influenza and pneumonia’, ‘Symptoms and signs involving circulatory and respiratory systems’ and ‘Malignant neoplasm of respiratory and intrathoracic organs’ were the hospital diagnosis groupings associated with most excess deaths, being both common and linked to high postadmission mortality. Using disease trends, we modelled a mean mortality HR of 0.737 (95% CI 0.730 to 0.745) from one decade of birth to the next, equivalent to a life extension of ~3 years per decade. This improvement was 61% (30%–93%) accounted for by improved disease survival after hospitalisation (principally cancer) with the remainder accounted for by lowered hospitalisation incidence (principally heart disease and cancer). In contrast, deteriorations in infectious disease incidence and survival increased mortality by 9% (~3.3 months per decade). Disease-driven mortality improvements were slightly greater for men than women (due to greater falls in disease incidence), and generally similar across socioeconomic deciles. We project mortality improvements will continue over the next decade but slow by 21% because much progress in disease survival has already been achieved.

Conclusion

Morbidity improvements broadly explain observed mortality improvements, with progress on prevention and treatment of heart disease and cancer contributing the most. The male–female health gaps are closing, but those between socioeconomic groups are not. Slowing improvements in morbidity may explain recent stalling in improvements of UK period life expectancies. However, these could be offset if we accelerate improvements in the diseases accounting for most deaths and counteract recent deteriorations in infectious disease.
Hypoxia is not the primary mechanism contributing to exercise-induced proteinuria
Authors: Joyce Kelsley E , Delamere John , Bradwell Susie , Myers Stephen David , Ashdown Kimberly , Rue Carla , Lucas Samuel JE , Thomas Owen D , Fountain Amy , Edsell Mark , Myers Fiona , Malein Will , Imray Chris , Clarke Alex , Lewis Chrisopher T , Newman Charles , Johnson Brian , Cadigan Patrick , Wright Alexander , Bradwell Arthur
Published: March 2020

Introduction

Proteinuria increases at altitude and with exercise, potentially as a result of hypoxia. Using urinary alpha-1 acid glycoprotein (α1-AGP) levels as a sensitive marker of proteinuria, we examined the impact of relative hypoxia due to high altitude and blood pressure-lowering medication on post-exercise proteinuria.

Methods

Twenty individuals were pair-matched for sex, age and ACE genotype. They completed maximal exercise tests once at sea level and twice at altitude (5035 m). Losartan (100 mg/day; angiotensin-receptor blocker) and placebo were randomly assigned within each pair 21 days before ascent. The first altitude exercise test was completed within 24–48 hours of arrival (each pair within ~1 hour). Acetazolamide (125 mg two times per day) was administrated immediately after this test for 48 hours until the second altitude exercise test.

Results

With placebo, post-exercise α1-AGP levels were similar at sea level and altitude. Odds ratio (OR) for increased resting α1-AGP at altitude versus sea level was greater without losartan (2.16 times greater). At altitude, OR for reduced post-exercise α1-AGP (58% lower) was higher with losartan than placebo (2.25 times greater, p=0.059) despite similar pulse oximetry (SpO2) (p=0.95) between groups. Acetazolamide reduced post-exercise proteinuria by approximately threefold (9.3±9.7 vs 3.6±6.0 μg/min; p=0.025) although changes were not correlated (r=−0.10) with significant improvements in SpO2(69.1%±4.5% vs 75.8%±3.8%; p=0.001).

Discussion

Profound systemic hypoxia imposed by altitude does not result in greater post-exercise proteinuria than sea level. Losartan and acetazolamide may attenuate post-exercise proteinuria, however further research is warranted.
Ethics of providing clinically assisted nutrition and hydration: current issues
Authors: Rochford Andrew
Published: March 2020

The provision of clinically assisted nutrition and hydration (CANH) often presents clinicians with ethical dilemmas. As the population grows there is increasing prevalence of patients with conditions such as stroke, dementia, advanced malignancy, cerebral palsy and eating disorders and a greater demand for CANH. It is important that healthcare professionals are familiar with the ethical and legal position for the provision of CANH. In addition, it is important to be aware of the clinical indications, relative contraindications and alternative means of supporting patients for whom CANH is not appropriate; this includes education and training for staff, patients, carers and relatives. The lack of high-quality evidence around clinical outcomes, particularly in the form of randomised clinical trials, and the challenges of accurate prognostication in patients who are approaching the end of life make decisions around the provision of CANH difficult for healthcare professionals.
Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles
Authors: Yan Helen H N , Siu Hoi Cheong , Ho Siu Lun , Yue Sarah S K , Gao Yang , Tsui Wai Yin , Chan Dessy , Chan April S , Wong Jason W H , Man Alice H Y , Lee Bernard C H , Chan Annie S Y , Chan Anthony K W , Hui Ho Sang , Cheung Arthur K L , Law Wai Lun , Lo Oswens S H , Yuen Siu Tsan , Clevers Hans , Leung Suet Yi
Published: March 2020

Objective

Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.

Design

We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.

Results

We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.

Conclusions

These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.
Transmucosal diverticular myotomy for the treatment of oesophageal diverticula associated with spastic motility disorders
Authors: Sidhu Mayenaaz , Tate David J , Bourke Michael J
Published: March 2020

Thoracic oesophageal diverticula are often associated with spastic motility disorders. Despite correction of the underlying motility disorder, in a subgroup of patients, symptoms persist, primarily regurgitation. Surgical diverticulectomy is then proposed; however, as the approach is thoracoscopic or via thoracotomy, it is associated with significant morbidity and cost. Descriptions of endoscopic techniques for the treatment of symptomatic midoesophageal diverticula are few. We propose the novel technique of diverticular myotomy (DM) to treat this disorder. In this case series, we describe two patients who successfully underwent DM with no adverse outcomes and excellent clinical results at 24-month follow-up.
Multifaceted effects of soluble human CD6 in experimental cancer models
Authors: Simões Inês T , Aranda Fernando , Casadó-Llombart Sergi , Velasco-de Andrés María , Català Cristina , Álvarez Pilar , Consuegra-Fernández Marta , Orta-Mascaró Marc , Merino Ramón , Merino Jesús , Alberola-Ila José , González-Aseguinolaza Gloria , Carreras Esther , Martínez Vanesa , Lozano Francisco
Published: March 2020

Background

CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor.

Methods

High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEμTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins.

Results

Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells.

Conclusions

Evidence is provided for the disruption of CD6 receptor–ligand interactions as a feasible immunomodulatory approach in cancer.
CD244 represents a new therapeutic target in head and neck squamous cell carcinoma
Authors: Agresta Laura , Lehn Maria , Lampe Kristin , Cantrell Rachel , Hennies Cassandra , Szabo Sara , Wise-Draper Trisha , Conforti Laura , Hoebe Kasper , Janssen Edith M
Published: March 2020

Background

Developing novel strategies to overcome the immunosuppressive tumor microenvironment is a critically important area of cancer therapy research. Here, we assess the therapeutic potential of CD244 (2B4/signaling lymphocyte activation molecule family 4), an immunoregulatory receptor found on a variety of immune cells, including exhausted CD8+T cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs).

Methods

Using de-identified human tumor and blood samples from patients with head and neck squamous cell carcinoma (HNSCC) and HNSCC models in WT and CD244-/-mice, we assessed the therapeutic potential of CD244 using flow cytometry, RT-PCR, Luminex immunoassays and histopathological analyses.

Results

Compared with healthy tissues, tumor infiltrating CD8+T cells from HNSCC patients and a HNSCC mouse model showed significant increased expression of CD244 expression that correlated with PD1 expression. Moreover, CD244 was increased on intratumoral DC and MDSC and high CD244 expression correlated with PD-L1 expression and increased spontaneous expression of immune-suppressive mediators. In addition, CD244 activation inhibited production of proinflammatory cytokines in human DC in vitro. Importantly, CD244-/-mice showed significantly impaired tumor growth of HNSCC and interventional treatment of WT mice with anti-CD244 monoclonal antibody significantly impaired the growth of established HNSCC tumors and increased tumor-infiltrating CD8+T cells.

Conclusions

Together these data suggest that CD244 contributes to the overall immune-suppressive environment and therefore has potential as a new immunotherapy target in the treatment of malignancies.
Cellular cytotoxicity is a form of immunogenic cell death
Authors: Minute Luna , Teijeira Alvaro , Sanchez-Paulete Alfonso R , Ochoa Maria C , Alvarez Maite , Otano Itziar , Etxeberrria Iñaki , Bolaños Elixabet , Azpilikueta Arantza , Garasa Saray , Casares Noelia , Luis Perez Gracia Jose , Rodriguez-Ruiz Maria E , Berraondo Pedro , Melero Ignacio
Published: March 2020

Background

The immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown.

Methods

In this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient inBatf3,Ifnar1andSting1were used to study mechanistic requirements.

Results

We observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA+EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient inBatf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8+T lymphocytes.

Conclusion

These results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.
Characterization of human cancer xenografts in humanized mice
Authors: Rios-Doria Jonathan , Stevens Christina , Maddage Christopher , Lasky Kerri , Koblish Holly K
Published: March 2020

Background

Preclinical evaluation of drugs targeting the human immune system has posed challenges for oncology researchers. Since the commercial introduction of humanized mice, antitumor efficacy and pharmacodynamic studies can now be performed with human cancer cells within mice bearing components of a human immune system. However, development and characterization of these models is necessary to understand which model may be best suited for different agents.

Methods

We characterized A375, A549, Caki-1, H1299, H1975, HCC827, HCT116, KU-19–19, MDA-MB-231, and RKO human cancer cell xenografts in CD34+humanized non-obese diabetic-scid gamma mice for tumor growth rate, immune cell profiling, programmed death ligand 1 (PD-L1) expression and response to anti-PD-L1 therapy. Immune cell profiling was performed using flow cytometry and immunohistochemistry. Antitumor response of humanized xenograft models to PD-L1 therapy was performed using atezolizumab.

Results

We found that CD4+and CD8+T-cell composition in both the spleen and tumor varied among models, with A375, Caki-1, MDA-MB-231, and HCC827 containing higher intratumoral frequencies of CD4+and CD8+T cells of CD45+cells compared with other models. We demonstrate that levels of immune cell infiltrate within each model are strongly influenced by the tumor and not the stem cell donor. Many of the tumor models showed an abundance of myeloid cells, B cells and dendritic cells. RKO and MDA-MB-231 tumors contained the highest expression of PD-L1+tumor cells. The antitumor response of the models to atezolizumab was positively associated with the level of CD4+and CD8+tumor-infiltrating lymphocytes (TILs).

Conclusions

These data demonstrate that there are tumor-intrinsic factors that influence the immune cell repertoire within tumors and spleen, and that TIL frequencies are a key factor in determining response to anti-PD-L1 in tumor xenografts in humanized mice. These data may also aid in the selection of tumor models to test antitumor activity of novel immuno-oncology or tumor-directed agents.
Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study
Authors: Martinez Chanza Nieves , Xie Wanling , Issa Majd , Dzimitrowicz Hannah , Tripathi Abhishek , Beuselinck Benoit , Lam Elaine , Zakharia Yousef , Mckay Rana , Shah Sumit , Mortazavi Amir , R. Harrison Michael , Sideris Spyridon , Kaymakcalan Marina D , Abou Alaiwi Sarah , Nassar Amin H , Nuzzo Pier Vitale , Hamid Anis , K Choueiri Toni , C Harshman Lauren
Published: March 2020

Background

There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.

Methods

This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.

Results

Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).

Conclusions

Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.
Migraine and risk of stroke
Authors: Øie Lise R , Kurth Tobias , Gulati Sasha , Dodick David W
Published: March 2020

Migraine and stroke are two common and heterogeneous neurovascular disorders responsible for a significant burden for those affected and a great economic cost for the society. There is growing evidence that migraine increases the overall risk of cerebrovascular diseases. In this review, based on available literature through a PubMed search, we found that ischaemic stroke in people with migraine is strongly associated with migraine with aura, young age, female sex, use of oral contraceptives and smoking habits. The risk of transient ischaemic attack also seems to be increased in people with migraine, although this issue has not been extensively investigated. Although migraine appears to be associated with haemorrhagic stroke, the migraine aura status has a small influence on this relationship. Neuroimaging studies have revealed a higher prevalence of asymptomatic structural brain lesions in people with migraine. They are also more likely to have unfavourable vascular risk factors; however, the increased risk of stroke seems to be more apparent among people with migraine without traditional risk factors. The mechanism behind the migraine-stroke association is unknown. In light of the higher risk of stroke in people with migraine with aura, it is important to identify and modify any vascular risk factor. There is currently no direct evidence to support that a migraine prophylactic treatment can reduce future stroke in people with migraine.
Incorporation of transradial approach in neuroendovascular procedures: defining benchmarks for rates of complications and conversion to femoral access
Authors: Almallouhi Eyad , Al Kasab Sami , Sattur Mithun G , Lena Jonathan , Jabbour Pascal M , Sweid Ahmad , Chalouhi Nohra , Gooch M Reid , Starke Robert M , Peterson Eric C , Yavagal Dileep R , Chen Stephanie H , Li Yangchun , Gross Bradley A , Tonetti Daniel A , Zussman Benjamin M , Stone Jeremy G , Jadhav Ashutosh P , Jankowitz Brian T , Young Christopher C , Lim Do H , Levitt Michael R , Osbun Joshua W , Spiotta Alejandro M
Published: March 2020

Background

The transradial approach (TRA) has gained increasing popularity for neuroendovascular procedures. However, the experience with TRA in neuroangiography is still in early stages in most centers, and the safety and feasibility of this approach have not been well established. The purpose of this study is to report the safety and feasibility of TRA for neuroendovascular procedures.

Methods

We reviewed charts from six institutions in the USA to include consecutive patients who underwent diagnostic or interventional neuroendovascular procedures through TRA from July 2018 to July 2019. Collected data included baseline characteristics, procedural variables, complications, and whether there was a crossover to transfemoral access.

Results

A total of 2203 patients were included in the study (age 56.1±15.2, 60.8% women). Of these, 1697 (77%) patients underwent diagnostic procedures and 506 (23%) underwent interventional procedures. Successfully completed procedures included aneurysm coiling (n=97), flow diversion (n=89), stent-assisted coiling (n=57), balloon-assisted coiling (n=19), and stroke thrombectomy (n=76). Crossover to femoral access was required in 114 (5.2%). There were no major complications related to the radial access site. Minor complications related to access site were seen in 14 (0.6%) patients.

Conclusion

In this early stage of transforming to the ‘radial-first’ approach for neuroendovascular procedures, TRA was safe with low complication rates for both diagnostic and interventional procedures. A wide range of procedures were completed successfully using TRA.