bluuebunny/crossref_metadata_2025 huggingface dataset:
Mask R‐CNN‐based building extraction from VHR satellite data in operational humanitarian action: An example related to Covid‐19 response in Khartoum, Sudan
Authors: Tiede Dirk , Schwendemann Gina , Alobaidi Ahmad , Wendt Lorenz , Lang Stefan
Published: May 2021

Within the constraints of operational work supporting humanitarian organizations in their response to the Covid‐19 pandemic, we conducted building extraction for Khartoum, Sudan. We extracted approximately 1.2 million dwellings and buildings, using a Mask R‐CNN deep learning approach from a Pléiades very high‐resolution satellite image with 0.5 m pixel resolution. Starting from an untrained network, we digitized a few hundred samples and iteratively increased the number of samples by validating initial classification results and adding them to the sample collection. We were able to strike a balance between the need for timely information and the accuracy of the result by combining the output from three different models, each aiming at distinctive types of buildings, in a post‐processing workflow. We obtained a recall of 0.78, precision of 0.77 and F1 score of 0.78, and were able to deliver first results in only 10 days after the initial request. The procedure shows the great potential of convolutional neural network frameworks in combination with GIS routines for dwelling extraction even in an operational setting.
Biomechanical effects of a titanium intervertebral cage as a stand‐alone device, and in combination with locking plates in the canine caudal cervical spine
Authors: Beishuizen Rick , Reints Bok Tjarda E. , Teunissen Michelle , van der Veen Albert J. , Emanuel Kaj S. , Tryfonidou Marianna A. , Meij Bjorn P.
Published: May 2021

Objective

To evaluate the change in ex vivo biomechanical properties of the canine cervical spine, due to an intervertebral cage, both as a stand‐alone device and in combination with plates.

Study Design

Experimental ex vivo study.

Animals

Cervical spinal segments (C5‐C7) from eight canine cadavers.

Methods

The range of motion (ROM) and elastic zone stiffness (EZS) of the spines were determined with a four‐point bending device in flexion/extension, lateral bending, and axial rotation for four conditions: native, discectomy, cage (at C6‐C7), and cage with plates (at C6‐C7). The disc height index (DHI) for each condition was determined using radiography.

Results

Discectomy resulted in overall increased ROM (p < .01) and EZS (p < .05) and decreased DHI (p < .005) when compared to the native condition. Placement of the cage increased DHI (p < .001) and restored total ROM during flexion/extension, lateral bending and axial rotation, and EZS during flexion/extension to the level of the native spine. Application of the plates further reduced the total ROM during flexion/extension (p < .001) and lateral bending (p < .001), but restored ROM in extension and EZS during lateral bending. No implant failure, subsidence, or significant cage migration occurred during loading.

Conclusion

An anchorless intervertebral cage used as a stand‐alone device was able to restore the disc height and spinal stability to the level of the native cervical spine, whereas the addition of plates further reduced the spinal unit mobility.

Clinical Significance

This study implies that the intervertebral cage may be used as a stand‐alone device in the spinal unit fixation in the canine cervical spine.
Influence of oxygen partial pressure on properties of monoclinic Ga2O3 deposited on sapphire substrates
Authors: Freitas Jaime A. , Culbertson James C. , Nepal Neeraj , Mock Alyssa L. , Tadjer Marko J. , Feng Zixuan , Zhao Hongping
Published: May 2021

Thin monoclinic Ga2O3 films were deposited on c-plane sapphire substrates by low pressure chemical vapor deposition. The thin films were synthesized using high purity metallic gallium (Ga) and oxygen gas (O2) as precursors. The effect of oxygen volume percentage on the growth rate of thin films was observed at two growth temperatures. Within the investigated growth window, a maximum growth rate of ∼2.9 μm/h was obtained for an oxygen volume percentage of 4.8% with a growth temperature at 800 °C. The film growth rate decreased as growth temperature increased when other growth parameters were kept the same. X-ray diffraction indicates that all films have the β-Ga2O3 structure with (−201) orientation, and those deposited with higher oxygen partial pressure are thicker and have improved crystalline quality. Polarized micro-Raman scattering is consistent with small grains of (−201) β-Ga2O3 having random in-plane orientations. The large variation of the relative intensities of overlapping emission bands contributing to the broad luminescence emission extending between 1.5 and 4.5 eV (∼825 and 275 nm) suggest that deposition conditions strongly affect different defect concentrations. Films deposited at 800 °C with a higher oxygen partial pressure yielded higher resistance, which may result from the incorporation of gallium vacancies, identified as a compensating point defect affecting the electrical conductivity of bulk monoclinic Ga2O3.
Attention to the Principles of Exercise Training in Exercise Studies of Persons With Lung Cancer: A Systematic Review
Authors: Medysky Mary E. , Bland Kelcey A. , Neil-Sztramko Sarah E. , Campbell Kristin L. , Sullivan Donald R. , Winters-Stone Kerri M.
Published: May 2021

The authors systematically reviewed and summarized exercise trials in persons with lung cancer on (a) attention to the principles of exercise training (specificity, progression, overload, initial values, reversibility, and diminishing returns); (b) methodological reporting of FITT (frequency, intensity, time, and type) components; and (c) reporting on participant adherence to prescribed FITT. Randomized controlled trials of exercise that reported on ≥1 physical fitness, physical function, or body composition outcome in persons with lung cancer were included. Of 20 trial arms, none incorporated all principles of exercise training. Specificity was included by 95%, progression by 45%, overload by 75%, and initial values by 80%, while one trial arm applied reversibility and diminishing returns. Fourteen interventions reported all FITT components; however, none reported adherence to each component. Including the principles of training and reporting FITT components will contribute to better understanding of the efficacy of exercise for persons with lung cancer and inform evidence-based exercise prescriptions.
Persistent spectral–based machine learning (PerSpect ML) for protein-ligand binding affinity prediction
Authors: Meng Zhenyu , Xia Kelin
Published: May 2021

PerSpect-based machine learning models can significantly improve prediction accuracy for protein-ligand binding affinity.
Tissue-like skin-device interface for wearable bioelectronics by using ultrasoft, mass-permeable, and low-impedance hydrogels
Authors: Lim Chanhyuk , Hong Yongseok Joseph , Jung Jaebong , Shin Yoonsoo , Sunwoo Sung-Hyuk , Baik Seungmin , Park Ok Kyu , Choi Sueng Hong , Hyeon Taeghwan , Kim Ji Hoon , Lee Sangkyu , Kim Dae-Hyeong
Published: May 2021

A tissue-like skin-device interface was prepared by using ultrathin functionalized hydrogels for wearable bioelectronics.
A distinct parabrachial–to–lateral hypothalamus circuit for motivational suppression of feeding by nociception
Authors: Phua Siew Cheng , Tan Yu Lin , Kok Alison Maun Yeng , Senol Esra , Chiam Christine Jin Hui , Lee Chun-Yao , Peng Yanmin , Lim Auriel Theodora Jacobea , Mohammad Hasan , Lim Jing-Xuan , Fu Yu
Published: May 2021

A specific neural circuit for resolving the motivational conflict between feeding and acute pain.
Combinatorial screen of dynamic mechanical stimuli for predictive control of MSC mechano-responsiveness
Authors: Liu Haijiao , Usprech Jenna F. , Parameshwar Prabu Karthick , Sun Yu , Simmons Craig A.
Published: May 2021

A previously unexplored mechanical loading strategy is found to promote efficient tissue synthesis by mesenchymal stem cells.
XBAT31 regulates thermoresponsive hypocotyl growth through mediating degradation of the thermosensor ELF3 in
Arabidopsis
Authors: Zhang Lin Lin , Shao Yu Jian , Ding Lan , Wang Mei Jing , Davis Seth Jon , Liu Jian Xiang
Published: May 2021

This paper reveals that XBAT31 ubiquitinates and degrades ELF3 to attenuate its inhibitory effects on PIF4.
Fractional Coulomb blockade for quasi-particle tunneling between edge channels
Authors: Röösli Marc P. , Hug Michael , Nicolí Giorgio , Märki Peter , Reichl Christian , Rosenow Bernd , Wegscheider Werner , Ensslin Klaus , Ihn Thomas
Published: May 2021

Magnetic field periodic conductance of a quantum dot in fractional quantum Hall regime indicates fractional charge tunneling.
The AIM2 and NLRP3 inflammasomes trigger IL-1–mediated antitumor effects during radiation
Authors: Han Chuanhui , Godfrey Victoria , Liu Zhida , Han Yanfei , Liu Longchao , Peng Hua , Weichselbaum Ralph R. , Zaki Hasan , Fu Yang-Xin
Published: May 2021

Radiation activates AIM2 and NLRP3 inflammasomes to enhance IL-1 signaling on DCs, leading to antitumor immunity.
A T-rojan horse strategy for cancer immunotherapy
Authors: Rafie Christine , Pillai Asha
Published: May 2021

CDK4/6 inhibitor–treated breast cancer cells recruit T cells via metabolic stress-induced chemokines.
Mutational Activation of Antibiotic-Resistant Mechanisms in the Absence of Major Drug Efflux Systems of Escherichia coli
Authors: Cho Hyunjae , Misra Rajeev
Published: May 2021

Antibiotic resistance among bacterial pathogens is a chronic health concern. Bacteria possess or acquire various mechanisms of antibiotic resistance, and chief among them is the ability to accumulate beneficial mutations that often alter antibiotic targets.
Inhibition of Antiviral Innate Immunity by Foot-and-Mouth Disease Virus L
pro
through Interaction with the N-Terminal Domain of Swine RNase L
Authors: Sui Chao , Jiang Dandan , Wu Xiangju , Liu Sidang , Li Feng , Pan Li , Cong Xiaoyan , Li Juntong , Yoo Dongwan , Rock Daniel L. , Miller Laura C. , Lee Changhee , Du Yijun , Qi Jing
Published: May 2021

FMDV is a picornavirus that causes a significant disease in agricultural animals. FMDV has developed diverse strategies to escape the host interferon response.
A Conserved Machinery Underlies the Synthesis of a Chitosan Layer in the
Candida
Chlamydospore Cell Wall
Authors: Bemena Leo D. , Min Kyunghun , Konopka James B. , Neiman Aaron M.
Published: May 2021

The cell wall is the interface between the fungal cell and its environment and disruption of cell wall assembly is an effective strategy for antifungal therapies. Therefore, a detailed understanding of how cell walls form is critical to identify potential drug targets and develop therapeutic strategies.
Streptococcus pneumoniae, S. mitis, and S. oralis Produce a Phosphatidylglycerol-Dependent,
ltaS
-Independent Glycerophosphate-Linked Glycolipid
Authors: Wei Yahan , Joyce Luke R. , Wall Ashley M. , Guan Ziqiang , Palmer Kelli L.
Published: May 2021

The cell wall is a critical structural component of bacterial cells that confers important physiological functions. For pathogens, it is a site of host-pathogen interactions.
Interface leakage during neonatal CPAP treatment: a randomised, cross-over trial
Authors: Falk Markus , Gunnarsdottir Kolbrun , Baldursdottir Sonja , Donaldsson Snorri , Jonsson Baldvin , Drevhammar Thomas
Published: May 2021

Objective

To determine leakage for two neonatal continuous positive airway pressure (CPAP) interfaces and evaluate leak-corrective manoeuvres.

Design

The ToNIL (Trial of NCPAP Interface Leakage) study was a randomised, clinical, cross-over trial with data collection between August 2018 and October 2019. The primary outcome was blinded to the treating staff.

Setting

One secondary, 8-bed neonatal intensive care unit (NICU) and three larger (>15 beds), academic NICU referral centres.

Patients

Newborn infants with CPAP were screened (n=73), and those with stable spontaneous breathing, low oxygen requirement, postmenstrual age (PMA) over 28 weeks and no comorbidities were eligible. In total, 50 infants were included (median PMA 33 completed weeks).

Interventions

Leakage was measured for both prongs and nasal mask, before and after leak-corrective manoeuvres. Interface application was performed in a randomised order by a nurse, blinded to the measured leakage.

Main outcome measures

30 s average leakage, measured in litres per minute (LPM).

Results

Analyses showed a significantly lower leakage (mean difference 0.86 LPM, 95% CI 0.07 to 1.65) with prongs (median 2.01 LPM, IQR 1.00–2.80) than nasal mask (median 2.45 LPM, IQR 0.99–5.11). Leak-corrective manoeuvres reduced leakage significantly for both prongs (median 1.22 LPM, IQR 0.54–1.87) and nasal mask (median 2.35 LPM, IQR 0.76–4.75).

Conclusions

Large leakages were common for both interfaces, less with prongs. Simple care manoeuvres reduced leakage for both interfaces. This is the first report of absolute leakage for nasal interfaces and should encourage further studies on leakage during CPAP treatment.
Endovascular abdominal aortic stenosis treatment alleviates renal failure after kidney transplantation
Authors: Tsuda Shigeyasu
Published: May 2021

A 79-year-old man developed bilateral intermittent claudication. Peritoneal dialysis had been initiated at 55 years of age to manage chronic renal failure. In addition, he underwent kidney transplantation at 61 years of age. His Ankle-Brachial Index (ABI) was 0.82 and 0.71 for the right leg and left leg, respectively. Furthermore, his serum creatinine level had increased from 0.98 mg/dL to 2.38 mg/dL over the past 2 years. CT angiography revealed focal calcified stenosis in the terminal abdominal aorta. However, ultrasound revealed no significant stenotic lesion in the supplied artery bound to the transplanted kidney from the right external iliac artery. We performed endovascular therapy for abdominal aortic stenosis using the pressure gradient. Following the procedure, the patient’s symptoms disappeared and the ABI increased to 1.25 and 1.14 in the right leg and left leg, respectively. Furthermore, the serum creatinine level improved to 0.96 mg/dL.
Chronic giardiasis: a rare cause of exocrine pancreatic insufficiency
Authors: Pophali Prateek , Veyseh Maedeh , Fraij Omar , Hapangama Sahan
Published: May 2021

Exocrine pancreatic insufficiency (EPI) is a major cause of maldigestion/malabsorption syndromes. It is routinely diagnosed in clinical practice with the use of faecal elastase 1 levels, and pancreatic enzyme replacement therapy continues to be the mainstay of treatment. Numerous primary pancreatic and extrapancreatic causes for EPI have been established. Chronic giardiasis is a common condition with symptoms similar to EPI; however, it has also been described as an infrequent cause of EPI. Much remains to be understood about the pathobiology of this association. Here, we present our experience of an intriguing case of severe pancreatic insufficiency in the setting of chronic giardiasis. The patient showed improvement in symptoms over weeks after completion of treatment for chronic giardiasis.
Natural hazards, disasters and violence against women and girls: a global mixed-methods systematic review
Authors: Thurston Alyssa Mari , Stöckl Heidi , Ranganathan Meghna
Published: May 2021

Introduction

Disasters triggered by climate and other natural hazards are increasing in frequency, severity and duration worldwide. Disasters disproportionately impact women and girls, with some evidence suggesting that violence against women and girls (VAWG) increases in disaster settings. Suggested risk factors for postdisaster VAWG include increased life stressors, failure of law enforcement, exposure to high-risk environments, exacerbation of existing gender inequalities and unequal social norms. We aim to systematically appraise the global literature on the association between disasters from natural hazards and VAWG.

Methods

We conducted a systematic review using the following databases: Embase, Global Health, Medline, PubMed and Social Policy and Practice and searched grey literature. We included quantitative, qualitative or mixed-methods studies published in English language that examined the association between disasters from natural hazards and VAWG. We summarised the findings using a narrative synthesis approach.

Results

Of 555 non-duplicate records, we included a total of 37 quantitative, qualitative and mixed-methods studies. Among the quantitative studies, eight studies found a positive association between disaster exposure and increased VAWG, and four additional studies found positive associations with some violence types but not others. Qualitative findings offered insights into three hypothesised pathways: disaster exposure associated with (1) an increase of stressors that trigger VAWG; (2) an increase of enabling environments for VAWG and (3) an exacerbation of underlying drivers of VAWG.

Conclusion

As the first known global systematic review on the relationship between disasters from natural hazards and VAWG, this review contributes to the evidence base. We were limited by the quality of quantitative studies, specifically study designs, the measurement of variables and geographic scope. The severe health consequences of VAWG and increasing frequency of extreme events means that rigorously designed and better quality studies are needed to inform evidence-based policies and safeguard women and girls during and after disasters.
User testing of a diagnostic decision support system with machine-assisted chart review to facilitate clinical genomic diagnosis
Authors: Kulchak Rahm Alanna , Walton Nephi A , Feldman Lynn K , Jenkins Conner , Jenkins Troy , Person Thomas N , Peterson Joeseph , Reynolds Jonathon C , Robinson Peter N , Woltz Makenzie A , Williams Marc S , Segal Michael M
Published: May 2021

Objectives

There is a need in clinical genomics for systems that assist in clinical diagnosis, analysis of genomic information and periodic reanalysis of results, and can use information from the electronic health record to do so. Such systems should be built using the concepts of human-centred design, fit within clinical workflows and provide solutions to priority problems.

Methods

We adapted a commercially available diagnostic decision support system (DDSS) to use extracted findings from a patient record and combine them with genomic variant information in the DDSS interface. Three representative patient cases were created in a simulated clinical environment for user testing. A semistructured interview guide was created to illuminate factors relevant to human factors in CDS design and organisational implementation.

Results

Six individuals completed the user testing process. Tester responses were positive and noted good fit with real-world clinical genetics workflow. Technical issues related to interface, interaction and design were minor and fixable. Testers suggested solving issues related to terminology and usability through training and infobuttons. Time savings was estimated at 30%–50% and additional uses such as in-house clinical variant analysis were suggested for increase fit with workflow and to further address priority problems.

Conclusion

This study provides preliminary evidence for usability, workflow fit, acceptability and implementation potential of a modified DDSS that includes machine-assisted chart review. Continued development and testing using principles from human-centred design and implementation science are necessary to improve technical functionality and acceptability for multiple stakeholders and organisational implementation potential to improve the genomic diagnosis process.
Reference values and validation of the 1-minute sit-to-stand test in healthy 5–16-year-old youth: a cross-sectional study
Authors: Haile Sarah R , Fühner Thea , Granacher Urs , Stocker Julien , Radtke Thomas , Kriemler Susi
Published: May 2021

Objectives

It is essential to have simple, reliable and valid tests to measure children’s functional capacity in schools or medical practice. The 1-minute sit-to-stand (STS) test is a quick fitness test requiring little equipment or space that is increasingly used in both healthy populations and those with chronic disease. We aimed to provide age-specific and sex-specific reference values of STS test in healthy children and adolescents and to evaluate its short-term reliability and construct validity.

Design setting and participants

Cross-sectional convenience sample from six public schools and one science fair in central Europe. Overall, 587 healthy participants aged 5–16 years were recruited and divided into age groups of 3 years each.

Outcomes

1-minute STS. To evaluate short-term reliability, some children performed the STS test twice. To evaluate construct validity, some children also performed a standing long jump (SLJ) and a maximal incremental exercise test.

Results

Data from 547 youth aged 5–16 years were finally included in the analyses. The median number of repetitions in 1 min in males (females) ranged from 55 [95% CI: 38 to 72] (53 [95% CI: 35 to 76]) in 14–16-year olds to 59 [95% CI: 41 to 77] (60 [95% CI: 38 to 77]) in 8–10-year olds. Children who repeated STS showed a learning effect of on average 4.8 repetitions more than the first test (95% limits of agreement: −6.7 to 16.4). Moderate correlations were observed between the STS and the SLJ (r=0.48) tests and the maximal exercise test (r=0.43).

Conclusions

The reported STS reference values can be used to interpret STS test performance in children and adolescents. The STS appears to have good test–retest reliability, but a learning effect of about 10%. The association of STS with other measures of physical fitness should be further explored in a larger study and technical standards for its conduct are needed.
Exploring the actionability of healthcare performance indicators for quality of care: a qualitative analysis of the literature, expert opinion and user experience
Authors: Barbazza Erica , Klazinga Niek S , Kringos Dionne S
Published: May 2021

Background

This study explores the meaning of actionable healthcare performance indicators for quality of care-related decisions. To do so, we analyse the constructs offitness for purposeandfitness for useacross healthcare systems and in practice based on the literature, expert opinion and user experience.

Methods

A multiphase qualitative study was undertaken. Phases included a literature review, a first round of one-on-one interviews with a panel of academics and thought leaders in the field (n=16), and a second round of interviews with real-world users of performance indicators (n=16). Thematic analysis was conducted between phases in order to triangulate findings in a stepwise process.

Results

Common uses of healthcare performance indicators were differentiated within micro-meso-macro contexts of healthcare systems. Each purpose of use signals different decision-making tasks, and in effect information needs. An indicator’s fitness for use can be appraised by three clusters of considerations: methodological, contextual and managerial. Methodological considerations gauge an indicator’s perceived importance, engagement potential, interpretability, standardisation, feasibility of remedial actions, alignment to care models and sensitivity to change. Information infrastructure, system governance, workforce capacity and learning culture were found as enabling contextual considerations. Managerial considerations influencing an indicator’s use in practice were found to span the selection of indicators, data collection, analysis, display of results and delivery of information to decision-makers.

Conclusion

The actionability of a healthcare performance indicator should be appraised by its alignment with the intended purpose of use beyond aggregate healthcare system levels, in combination with the extent to which methodological, contextual and managerial fitness for use considerations are met. Striking a better balance between the importance weighted to an indicator’s statistical merits and emphasis put to its fitness for purpose and use is needed for indicators that are ultimately actionable for quality of care-related decision-making.
Implantable cardioverter defibrillator devices: when, how and who should discuss deactivation with patients: a systematic literature review
Authors: Freemantle Megan , Murtagh Fliss
Published: May 2021

Background

Implantable cardioverter defibrillators (ICDs) are used to treat life-threatening cardiac arrhythmias and prevent sudden cardiac arrest. As recipients age they may develop greater risk of dying as a result of progressive multimorbidity rather than sudden cardiac death. Defibrillation shocks may prolong an uncomfortable dying process. Deactivation of the defibrillator would prevent this, yet is not always discussed and planned.

Aim

To systematically review published evidence on ICD deactivation discussions and make recommendations on when, how and who should facilitate effective and patient-centred deactivation discussions.

Methods

Using standard systematic review methods, MEDLINE, EMBASE, CINAHL and PsycInfo were searched for studies published in the English language between 2010 and March 2021. Inclusion criteria were studies of adults (≥18 years) and including discussions on ICD deactivation and/or related communication. Included studies were independently reviewed, data extracted, quality assessed and data synthesised using a deductive approach.

Results

Of the 8893 articles identified, 22 papers met the inclusion criteria. Deductive approach led to identification of five main themes: (1) timing of ICD deactivation discussions, (2) initiation of deactivation discussions, (3) advance directives, (4) barriers to discussions and (5) facilitators of discussions.

Conclusions

Despite available guidelines, conversations on device deactivation are not being undertaken consistently. Evidence suggests lack of professional awareness of guidelines and limited training in communication skills. To prevent distress and promote comfortable dying, there needs to be a proactive clinical and policy initiative in the education of both professionals and patients and their relatives about device deactivation.
Lipoprotein(a) is robustly associated with aortic valve calcium
Authors: Kaiser Yannick , Singh Sunny S , Zheng Kang H , Verbeek Rutger , Kavousi Maryam , Pinto Sara-Joan , Vernooij Meike W , Sijbrands Eric J G , Boekholdt S Matthijs , de Rijke Yolanda B , Stroes Erik S G , Bos Daniel
Published: May 2021

Objectives

To investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC.

Methods

We included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC.

Results

The prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (β 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase).

Conclusions

Lp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.
Combination anti-PD1 and ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders
Authors: Brown Lauren J , Weppler Alison , Bhave Prachi , Allayous Clara , Patrinely Jr J. Randall , Ott Patrick , Sandhu Shahneen , Haydon Andrew , Lebbe Celeste , Johnson Douglas B , Long Georgina V , Menzies Alexander A , Carlino Matteo S
Published: May 2021

Background

Clinical trials of immunotherapy have excluded patients with pre-existing autoimmune disease. While the safety and efficacy of single agent ipilimumab and anti-PD1 antibodies in patients with autoimmune disease has been examined in retrospective studies, no data are available for combination therapy which has significantly higher toxicity risk. We sought to establish the safety and efficacy of combination immunotherapy for patients with advanced melanoma and pre-existing autoimmune diseases.

Methods

We performed a retrospective study of patients with advanced melanoma and pre-existing autoimmune disease who received combination ipilimumab and anti-PD1 at 10 international centers from March 2015 to February 2020. Data regarding the autoimmune disease, treatment, toxicity and outcomes were examined in patients.

Results

Of the 55 patients who received ipilimumab and anti-PD1, the median age was 63 years (range 23–83). Forty-six were treated with ipilimumab and nivolumab and nine with ipilimumab and pembrolizumab.

Eighteen patients (33%) had a flare of their autoimmune disease including 4 of 7 with rheumatoid arthritis, 3 of 6 with psoriasis, 5 of 10 with inflammatory bowel disease, 3 of 19 with thyroiditis, 1 of 1 with Sjogren’s syndrome, 1 of 1 with polymyalgia and 1 of 1 with Behcet’s syndrome and psoriasis. Eight (44%) patients ceased combination therapy due to flare. Thirty-seven patients (67%) had an unrelated immune-related adverse event (irAE), and 20 (36%) ceased combination immunotherapy due to irAEs. There were no treatment-related deaths. Patients on immunosuppression (OR 4.59; p=0.03) had a higher risk of flare.

The overall response rate was 55%, with 77% of responses ongoing. Median progression free survival and overall survival were 10 and 24 months, respectively. Patients on baseline immunosuppression had an overall survival of 11 months (95% CI 3.42 to 18.58) compared with 31 months without (95% CI 20.89 to 41.11, p=0.005).

Conclusions

In patients with pre-existing autoimmune disease, not on immunosuppression and advanced melanoma, combination ipilimumab and anti-PD1 has similar efficacy compared with previously reported trials. There is a risk of flare of pre-existing autoimmune disorders, particularly in patients with inflammatory bowel disease and rheumatologic conditions, and patients on baseline immunosuppression.
IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy
Authors: Kohli Karan , Yao Lu , Nowicki Theodore Scott , Zhang Shihong , Black Ralph Graeme , Schroeder Brett A , Farrar Erik A , Cao Jianhong , Sloan Heather , Stief Dawn , Cranmer Lee D , Wagner Michael J , Hawkins Douglas S , Pillarisetty Venu G , Ribas Antoni , Campbell Jean , Pierce Robert H , Kim Edward Y , Jones Robin L , Riddell Stanley R , Yee Cassian , Pollack Seth M
Published: May 2021

Background

Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1–specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression.

Method

We performed a phase I clinical trial evaluating the safety of NY-ESO-1–specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15.

Results

Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1–specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor–based products at other centers.

Conclusions

ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1–specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.
Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis
Authors: Tarhini Ahmad A , Kang Ni , Lee Sandra J , Hodi F Stephen , Cohen Gary I , Hamid Omid , Hutchins Laura F , Sosman Jeffrey A , Kluger Harriet M , Eroglu Zeynep , Koon Henry B , Lawrence Donald P , Kendra Kari L , Minor David R , Lee Carrie B , Albertini Mark R , Flaherty Lawrence E , Petrella Teresa M , Streicher Howard , Sondak Vernon K , Kirkwood John M
Published: May 2021

Background

The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood.

Patients and methods

E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034).

Results

Occurrence of grades 1–2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1–2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1–2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1–2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1–2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3–4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3–4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1–2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found.

Conclusions

Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3–4 irAEs.
Delivering clinical trials at home: protocol, design and implementation of a direct-to-family paediatric lupus trial
Authors: Randell Rachel L , Singler Lindsay , Cunningham Anthony , Schanberg Laura E , Cohen-Wolkowiez Michael , Hornik Christoph P , Balevic Stephen J
Published: May 2021

Introduction

Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.

Methods

Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.

Discussion and dissemination

Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.

Trial registration number

ClinicalTrials.gov Registry (NCT04358302).
MRI: how to understand it
Authors: MacIver Claire Louise , Ebden Sian , Tallantyre Emma C
Published: May 2021

MRI is a staple of the neurologist’s armoury when facing diagnostic challenges. At times, it can reveal or confirm the diagnosis with clarity, at others it brings us no further forwards, or even muddies the water. We rely on the expertise of neuroradiology colleagues to interpret MR images, but the choice of protocol for MR acquisition and its interpretation hinge crucially on the clinical information we provide. Having a degree of understanding about how MRI works, its limitations and pitfalls, can help to optimise what we learn from a scan.
Yachts and marinas as hotspots of coastal risk
Authors: Lazarus Eli D. , Ziros Leonidas A.
Published: May 2021

Despite being exceptional concentrations of valuable economic assets, yachts and marinas are typically overlooked in the geography of coastal risk. Focusing on the Mediterranean, which hosts the majority of the world’s yacht activity, we examine three decades of yacht insurance claims in the context of natural hazards and marina development. We find indications that yachts and marinas manifest the same generic relationships between exposure, hazard, and vulnerability observed in terrestrial coastal-risk systems. Given the fundamental importance of yachts and marinas to nautical tourism and strategies for “Blue Economy” growth, particularly in Europe, the role of yachts and marinas in the dynamics of coastal risk must be better understood—but any such insight will first require standardised, comprehensive datasets of yacht movements and marina infrastructure.
Counting multiplicative groups with prescribed subgroups
Authors: Downey Jenna , Martin Greg
Published: May 2021

We examine two counting problems that seem very group-theoretic on the surface but, on closer examination, turn out to concern integers with restrictions on their prime factors. First, given an odd prime [Formula: see text] and a finite abelian [Formula: see text]-group [Formula: see text], we consider the set of integers [Formula: see text] such that the Sylow [Formula: see text]-subgroup of the multiplicative group [Formula: see text] is isomorphic to [Formula: see text]. We show that the counting function of this set of integers is asymptotic to [Formula: see text] for explicit constants [Formula: see text] and [Formula: see text] depending on [Formula: see text] and [Formula: see text]. Second, we consider the set of integers [Formula: see text] such that the multiplicative group [Formula: see text] is “maximally non-cyclic”, that is, such that all of its prime-power subgroups are elementary groups. We show that the counting function of this set of integers is asymptotic to [Formula: see text] for an explicit constant [Formula: see text], where [Formula: see text] is Artin’s constant. As it turns out, both of these group-theoretic problems can be reduced to problems of counting integers with restrictions on their prime factors, allowing them to be addressed by classical techniques of analytic number theory.
The Realities of Blockchain-Based New Public Governance
Authors: Brinkmann Maik
Published: May 2021

Blockchain technology and New Public Governance (NPG) represent promising concepts for various researchers. As such, both concepts offer the vision of an altered relationship between public administration and its non-public actors by emphasizing a strong position of non-public actors for public service delivery. This research aims to identify the relevance of NPG to leading blockchain implementations in the European public sector. For this purpose, both topics are combined in an explorative analysis. The analysis leverages an adapted analysis framework designed for this research effort to structure the expectations around NPG. Qualitative interviews with multiple key stakeholders of blockchain implementations projects were conducted to understand the actual impact of blockchain on the actor's relationships for public service delivery. This article presents the findings to this question and concludes that the use of blockchain has the changed actor relationships only in parts. Consequently, the author finally draws attention to the importance of blockchain governance and blockchain regulation for further developing the relationships of public administrations and their non-public counterparts.
Functional Transition Metal Perovskite Oxides with 6s2 Lone Pair Activity Stabilized by High-Pressure Synthesis
Authors: Azuma Masaki , Hojo Hajime , Oka Kengo , Yamamoto Hajime , Shimizu Keisuke , Shigematsu Kei , Sakai Yuki
Published: May 2021

Perovskite ABO3 oxides that have Bi and Pb at the A site and transition metals at the B site, when stabilized by high-pressure synthesis at several gigapascals, provide a rich parameter space of fascinating properties. Stereochemical 6 s2 lone pairs of Bi3+ and Pb2+ induce polar or antipolar distortions. 6 s2 and 6 s0 (Bi5+ and Pb4+) charge degree of freedom enable intermetallic charge transfer transitions. The structural distortion and the charge degree of freedom are coupled with magnetism of transition metals, resulting in various functionalities. In particular, we highlight magnetization reversal by electric field and polarization rotation in BiFe1− xCo xO3, negative thermal expansion in modified BiNiO3 and PbVO3, and systematic charge distribution changes in Pb MO3 ( M = 3 d transition metal).
Spontaneous extension wave for in vivo assessment of arterial wall anisotropy
Authors: Ran Dan , Dong Jinping , Li He , Lee Wei-Ning
Published: May 2021

An extension wave formed by longitudinal wall displacements was observed by high-frame-rate ultrasound in the human common carotid artery in vivo. A strong correlation between extension wave velocity and arterial longitudinal stiffness complements the well-established pulse wave, which is linked to circumferential stiffness, to noninvasively assess direction-dependent wall elasticity of the major artery. The proposed anisotropy index, which directly reflects arterial wall microstructure and function, might be a potential risk factor for screening (sub-) clinical cardiovascular diseases.
On Unique and Nonunique Fixed Points in Metric Spaces and Application to Chemical Sciences
Authors: Joshi Meena , Tomar Anita
Published: May 2021

We introduce the notions of a generalized

Θ

-contraction, a generalized

Θ

E

-weak contraction, a

Ψ

E

-weak JS-contraction, an integral-type

Θ

E

-weak contraction, and an integral-type

Ψ

E

-weak JS-contraction to establish the fixed point, fixed ellipse, and fixed elliptic disc theorems. Further, we verify these by illustrative examples with geometric interpretations to demonstrate the authenticity of the postulates. The motivation of this work is the fact that the set of nonunique fixed points may include a geometric figure like a circle, an ellipse, a disc, or an elliptic disc. Towards the end, we provide an application of

Θ

-contraction to chemical sciences.
A Rare Case of Immunotactoid Glomerulopathy Associated with Hodgkin Lymphoma
Authors: Nagaharu Keiki , Sugimoto Yuka , Kawakami Keiki
Published: May 2021

Immunotactoid glomerulopathy (ITG) is characterized by Congo red-negative microtubular deposits, and it has been reported as a rare paraneoplastic syndrome due to hematologic malignancies, viral infections, or autoimmune diseases. In hematologic malignancies, multiple myeloma and other mature B-cell malignancies are the most common hematologic malignancies, and Hodgkin lymphoma (HL) is extremely rare. A 59-year-old woman was admitted to our hospital because of a pulmonary mass and proteinuria. Computed tomography-guided lung biopsy confirmed the presence of HL stage IIA. Immunofixation of peripheral blood was positive for immunoglobulin G (IgG) kappa. Renal biopsy showed mesangial proliferation with deposits in the subendothelial lesion and no invasion of the HL. These deposits were positive for IgG3, C3, and kappa light chain but negative for C1q and lambda light chain. Electron microscopy showed randomly aligned tubular structures with a diameter of approximately 50 nm. We diagnosed the patient with immunotactoid nephropathy and HL. After systemic chemotherapy, the patient achieved a complete response and loss of proteinuria. On the contrary, her serum monoclonal gammopathy was observed after chemotherapy. The existence of a monoclonal antibody itself might not be a sufficient factor for ITG in some cases, and an additive trigger is necessary for development.
Tourism Demand Forecasting Based on Grey Model and BP Neural Network
Authors: Ma Xing
Published: May 2021

This article aims to explore a more suitable prediction method for tourism complex environment, to improve the accuracy of tourism prediction results and to explore the development law of China’s domestic tourism so as to better serve the domestic tourism management and tourism decision‐making. This study uses grey system theory, BP neural network theory, and the combination model method to model and forecast tourism demand. Firstly, the GM (1, 1) model is established based on the introduction of grey theory. The regular data series are obtained through the transformation of irregular data series, and the prediction model is established. Secondly, in the structure algorithm of the BP neural network, the BP neural network model is established using the data series of travel time and the number of people. Then, combining BP neural network with the grey model, the grey neural network combination model is established to forecast the number of tourists. The prediction accuracy of the model is analyzed by the actual time series data of the number of tourists. Finally, the experimental analysis shows that the combination forecasting makes full use of the information provided by each forecasting model and obtains the combination forecasting model and the best forecasting result so as to improve the forecasting accuracy and reliability.