bluuebunny/crossref_metadata_2025 huggingface dataset:
How to design - a database
Authors: Ballard Ron
Published: June 2021

Database design should be agile, iterative and highly disciplined, writes Ron Ballard FBCS.
Health Data Research Innovation Gateway
Authors: Reilly Gerry , Varma Susheel
Published: June 2021

Gerry Reilly FBCS, Technologist in Residence and Susheel Varma, Director of Engineering at HDR UK, share the build process for the new HDR UK Innovation Gateway and explain why open source matters.
How UK digital helped to find a covid vaccine
Authors:   The National Institute for Health Research and NHS Digital
Published: June 2021

The teams from the National Institute for Health Research and NHS Digital explain their work in developing and delivering the NHS COVID-19 Vaccine Research Registry.
Exosomal MicroRNA-21 Promotes Keloid Fibroblast Proliferation and Collagen Production by Inhibiting Smad7
Authors: Li Qijie , Fang Lu , Chen Junjie , Zhou Siqi , Zhou Kai , Cheng Fengrui , Cen Ying , Qing Yong , Wu Junliang
Published: June 2021

In keloid fibroblasts, microRNA-21 (miR-21) enhances activation of the TGF-β–Smad signaling pathway by down-regulating Smad7 expression, thereby promoting keloid fibroblast proliferation and collagen production. However, it is unclear whether miR-21 performs the above-mentioned functions through exosomal transport. Here, we extracted exosomes from the culture supernatants of keloid and normal skin fibroblasts and observed that both types of cells above secrete exosomes; however, keloid fibroblasts secreted significantly more exosomal miR-21 than normal skin fibroblasts (P < .001). Interestingly, we also observed that exosomal miR-21 could enter target keloid fibroblasts. In addition, inhibiting exosomal miR-21 up-regulated Smad7 protein expression and reduced Smad2 and Smad3 protein levels in target keloid fibroblasts. Furthermore, inhibiting exosomal miR-21 down-regulated collagen I and collagen III expression in target keloid fibroblasts, increased the proportion of apoptotic cells, and reduced cell proliferation. Taken together, these results show that exosomal miR-21 promoted proliferation and collagen production in keloid fibroblasts by inhibiting Smad7. Thus, we identified regulatory roles for miR-21 in promoting keloid fibroblast proliferation and participating in keloid formation and development. These findings imply that miR-21 may serve as a novel target for controlling the development of keloids.
Friends of the Earth: ‘Government Policy’, Relevant Considerations and Human Rights
Authors: Martin Stevie
Published: June 2021

Litigation involving climate change is on the increase both domestically and internationally and the Supreme Court's judgment in Friends of the Earth Ltd joins that list. While it was not as directly concerned with the implications of climate change as, perhaps, recent case law from the Netherlands or Australia, the case has significant implications including in terms of future litigation involving human rights challenges based on climate change. Three aspects of the judgment in particular warrant consideration. First, the legitimacy of the Court's purposive interpretation of the meaning of ‘Government policy’. Second, the Supreme Court left unanswered the question of whether the Paris Agreement was so ‘obviously material’ to the exercise of the relevant discretion that a failure to have regard to it would be Wednesbury unreasonable. Finally, the Supreme Court rejected the claim that designating the Airports National Policy Statement would interfere with any rights contained in the European Convention of Human Rights. This case analysis examines each of these aspects of the judgment.
A strongly complete axiomatization of intuitionistic temporal logic
Authors: Chopoghloo Somayeh , Moniri Morteza
Published: June 2021

In this paper, we consider the logic ${\textsf{ITL}}^{e}$, a variant of intuitionistic linear temporal logic that is interpreted over the class of dynamic Kripke frames. These are bi-relational structures of the form $ \langle{W, \preccurlyeq , f}\rangle $ where $\preccurlyeq $ is a partial order on $W$ and $f: W \to W$ is a $\preccurlyeq $-monotone function. Our main result answers a question recently raised by Boudou et al. (2017, A decidable intuitionistic temporal logic. In Computer Science Logic 2017, pp. 14:1–14:17. Vol. 82 of LIPIcs) about axiomatizing this logic. We provide an axiomatization of ${\textsf{ITL}}^{e}$ and prove its strong completeness with respect to the class of all dynamic Kripke frames. The proposed axiomatization is infinitary; it has two derivation rules with countably many premises and one conclusion. It should be mentioned that ${\textsf{ITL}}^{e}$ is semantically non-compact, so no finitary proof system for this logic could be strongly complete.
ASASSN-14lp: two possible solutions for the observed ultraviolet suppression
Authors: Barna Barnabas , Pereira Talytha , Taubenberger Stefan , Magee Mark , Kromer Markus , Kerzendorf Wolfgang , Vogl Christian , Williamson Marc E , Flörs Andreas , Noebauer Ulrich M , Foley Ryan J , Sasdelli Michele , Hillebrandt Wolfgang
Published: June 2021

We test the adequacy of ultraviolet (UV) spectra for characterizing the outer structure of Type Ia supernova (SN) ejecta. For this purpose, we perform spectroscopic analysis for ASASSN-14lp, a normal SN Ia showing low continuum in the mid-UV regime. To explain the strong UV suppression, two possible origins have been investigated by mapping the chemical profiles over a significant part of their ejecta. We fit the spectral time series with mid-UV coverage obtained before and around maximum light by HST, supplemented with ground-based optical observations for the earliest epochs. The synthetic spectra are calculated with the one-dimensional MC radiative transfer code tardis from self-consistent ejecta models. Among several physical parameters, we constrain the abundance profiles of nine chemical elements. We find that a distribution of 56Ni (and other iron-group elements) that extends towards the highest velocities reproduces the observed UV flux well. The presence of radioactive material in the outer layers of the ejecta, if confirmed, implies strong constraints on the possible explosion scenarios. We investigate the impact of the inferred 56Ni distribution on the early light curves with the radiative transfer code turtls, and confront the results with the observed light curves of ASASSN-14lp. The inferred abundances are not in conflict with the observed photometry. We also test whether the UV suppression can be reproduced if the radiation at the photosphere is significantly lower in the UV regime than the pure Planck function. In this case, solar metallicity might be sufficient enough at the highest velocities to reproduce the UV suppression.
An observational testbed for cosmological zoom-in simulations: constraining stellar migration in the solar cylinder using asteroseismology
Authors: Verma Kuldeep , Grand Robert J J , Silva Aguirre Víctor , Stokholm Amalie
Published: June 2021

Large-scale stellar surveys coupled with recent developments in magneto-hydrodynamical simulations of the formation of Milky Way-mass galaxies provide an unparalleled opportunity to unveil the physical processes driving the evolution of the Galaxy. We developed a framework to compare a variety of parameters with their corresponding predictions from simulations in an unbiased manner, taking into account the selection function of a stellar survey. We applied this framework to a sample of over 7000 stars with asteroseismic, spectroscopic, and astrometric data available, together with six simulations from the Auriga project. We found that some simulations are able to produce abundance dichotomies in the [Fe/H]−[α/Fe] plane which look qualitatively similar to observations. The peak of their velocity distributions match the observed data reasonably well; however, they predict hotter kinematics in terms of the tails of the distributions and the vertical velocity dispersion. Assuming our simulation sample is representative of Milky Way-like galaxies, we put upper limits of 2.21 and 3.70 kpc on radial migration for young (<4 Gyr) and old (∈[4, 8] Gyr) stellar populations in the solar cylinder. Comparison between the observed and simulated metallicity dispersion as a function of age further constrains migration to about 1.97 and 2.91 kpc for the young and old populations. These results demonstrate the power of our technique to compare numerical simulations with high-dimensional data sets, and paves the way for using the wider field TESS asteroseismic data together with the future generations of simulations to constrain the sub-grid models for turbulence, star formation, and feedback processes.
Genetic Admixture in the Culturally Unique Peranakan Chinese Population in Southeast Asia
Authors: Wu Degang , Li Peter Yiqing , Pan Bangfen , Tiang Zenia , Dou Jinzhuang , Williantarra Ivanna , Pribowo Amadeus Yeremia , Nurdiansyah Rizky ,   The SG Peranakan Project, Foo Roger S Y , Wang Chaolong
Published: June 2021

The Peranakan Chinese are culturally unique descendants of immigrants from China who settled in the Malay Archipelago ∼300–500 years ago. Today, among large communities in Southeast Asia, the Peranakans have preserved Chinese traditions with strong influence from the local indigenous Malays. Yet, whether or to what extent genetic admixture co-occurred with the cultural mixture has been a topic of ongoing debate. We performed whole-genome sequencing (WGS) on 177 Singapore (SG) Peranakans and analyzed the data jointly with WGS data of Asian and European populations. We estimated that Peranakan Chinese inherited ∼5.62% (95% confidence interval [CI]: 4.76–6.49%) Malay ancestry, much higher than that in SG Chinese (1.08%, 0.65–1.51%), southern Chinese (0.86%, 0.50–1.23%), and northern Chinese (0.25%, 0.18–0.32%). A sex-biased admixture history, in which the Malay ancestry was contributed primarily by females, was supported by X chromosomal variants, and mitochondrial (MT) and Y haplogroups. Finally, we identified an ancient admixture event shared by Peranakan Chinese and SG Chinese ∼1,612 (95% CI: 1,345–1,923) years ago, coinciding with the settlement history of Han Chinese in southern China, apart from the recent admixture event with Malays unique to Peranakan Chinese ∼190 (159–213) years ago. These findings greatly advance our understanding of the dispersal history of Chinese and their interaction with indigenous populations in Southeast Asia.
Dinuclear orthometallated gold(I)-gold(III) anticancer complexes with potent in vivo activity through an ROS-dependent mechanism
Authors: Mirzadeh Nedaossadat , Telukutla Srinivasa Reddy , Luwor Rodney , Privér Steven , Velma Ganga Reddy , Jakku Ranjith Kumar , Andrew N. Stephens , Plebanski Magdalena , Christian Hartinger , Bhargava Suresh
Published: June 2021

Increasingly explored over the last decade, gold complexes have shown great promise in the field of cancer therapeutics. A major obstacle to their clinical progression has been their lack of in vivo stability, particularly for gold(III) complexes, which often undergo a facile reduction in the presence of biomolecules such as glutathione. Herein, we report a new class of promising anticancer gold(I)–gold(III) complexes with the general formula [XAuI(μ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuIIIX] [X = Cl (1), Br (2), NO3 (3)] which feature two gold atoms in different oxidation states (I and III) in a single molecule. Interestingly, gold(I)–gold(III) complexes (1–3) are stable against glutathione reduction under physiological-like conditions. In addition, complexes 1–3 exhibit significant cytotoxicity (276-fold greater than cisplatin) toward the tested cancer cells compared to the noncancerous cells. Moreover, the gold(I)–gold(III) complexes do not interact with DNA-like cisplatin but target cellular thioredoxin reductase, an enzyme linked to the development of cisplatin drug resistance. Complexes 1–3 also showed potential to inhibit cancer and endothelial cell migration, as well as tube formation during angiogenesis. In vivo studies in a murine HeLa xenograft model further showed the gold compounds may inhibit tumor growth on par clinically used cisplatin, supporting the significant potential this new compound class has for further development as cancer therapeutic.
SARS-CoV-2 Nsp3 unique domain SUD interacts with guanine quadruplexes and G4-ligands inhibit this interaction
Authors: Lavigne Marc , Helynck Olivier , Rigolet Pascal , Boudria-Souilah Rofia , Nowakowski Mireille , Baron Bruno , Brülé Sébastien , Hoos Sylviane , Raynal Bertrand , Guittat Lionel , Beauvineau Claire , Petres Stéphane , Granzhan Anton , Guillon Jean , Pratviel Geneviève , Teulade-Fichou Marie-Paule , England Patrick , Mergny Jean-Louis , Munier-Lehmann Hélène
Published: June 2021

The multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Of note, SARS-CoV Nsp3 contains a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. We show herein that the SARS-CoV-2 Nsp3 protein also contains a SUD domain that interacts with G4s. Indeed, interactions between SUD proteins and both DNA and RNA G4s were evidenced by G4 pull-down, Surface Plasmon Resonance and Homogenous Time Resolved Fluorescence. These interactions can be disrupted by mutations that prevent oligonucleotides from folding into G4 structures and, interestingly, by molecules known as specific ligands of these G4s. Structural models for these interactions are proposed and reveal significant differences with the crystallographic and modeled 3D structures of the SARS-CoV SUD-NM/G4 interaction. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARS-CoV-2 replication and the use of inhibitors of these interactions as potential antiviral compounds.
Salvage therapies for radiation-relapsed isocitrate dehydrogenase-mutant astrocytoma and 1p/19q codeleted oligodendroglioma
Authors: Ma Sirui , Rudra Soumon , Campian Jian L , Chheda Milan G , Johanns Tanner M , Ansstas George , Abraham Christopher D , Chicoine Michael R , Leuthardt Eric C , Dowling Joshua L , Dunn Gavin P , Kim Albert H , Huang Jiayi
Published: June 2021

Background

Optimal management for recurrent IDH-mutant glioma after radiation therapy (RT) is not well-defined. This study assesses practice patterns for managing recurrent IDH-mutant astrocytoma (Astro) and 1p/19q codeleted oligodendroglioma (Oligo) after RT and surveys their clinical outcomes after different salvage approaches.

Methods

Ninety-four recurrent Astro or Oligo patients after RT who received salvage systemic therapy (SST) between 2001 and 2019 at a tertiary cancer center were retrospectively analyzed. SST was defined as either alkylating chemotherapy (AC) or nonalkylating therapy (non-AC). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method from the start of SST. Multivariable analysis (MVA) was conducted using Cox regression analysis.

Results

Recurrent Oligo (n = 35) had significantly higher PFS (median: 3.1 vs 0.8 years, respectively, P = .002) and OS (median: 6.3 vs 1.5 years, respectively, P < .001) than Astro (n = 59). Overall, 90% of recurrences were local. Eight-three percent received AC as the first-line SST; 50% received salvage surgery before SST; approximately 50% with local failure >2 years after prior RT received reirradiation. On MVA, non-AC was associated with worse OS for both Oligo and Astro; salvage surgery was associated with improved PFS and OS for Astro; early reirradiation was associated with improved PFS for Astro.

Conclusions

Recurrent radiation-relapsed IDH-mutant gliomas represent a heterogeneous group with variable treatment approaches. Surgery, AC, and reirradiation remain the mainstay of salvage options for retreatment.
Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma
Authors: Ellingson Benjamin M , Patel Kunal , Wang Chencai , Raymond Catalina , Brenner Andrew , de Groot John F , Butowski Nicholas A , Zach Leor , Campian Jian L , Schlossman Jacob , Rizvi Shan , Cohen Yael C , Lowenton-Spier Noa , Minei Tamar Rachmilewitz , Shmueli Shifra Fain , Wen Patrick Y , Cloughesy Timothy F
Published: June 2021

Background

Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial.

Methods

Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low (<1.24 µm2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor.

Results

Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCL had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCL identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADCL phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS.

Conclusion

Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.
Super pathogens from environmental biotechnologies threaten global health
Authors: Xiao Yong , Zhao Feng , Peñuelas Josep , Huang Qiansheng , Zhu Yong-Guan
Published: June 2021

The incubation and release of super pathogens from environmental biotechnologies is an overlooked threat to global health. This perspective calls for collaboration between research community, industry and government to mitigate this growing risk.
Effects of different sources of dietary protein on markers of kidney function in individuals with diabetes: a systematic review and meta-analysis of randomized controlled trials
Authors: Eckert Igor , Koehler Igor C , Bauer Julia , Busnello Fernanda M , Silva Flávia M
Published: June 2021

Context

The type of dietary protein may modulate markers of diabetic kidney disease; however, no attempt to summarize the evidence from randomized controlled trials (RCTs) has been performed to date.

Objective

To assess the effects of different types of dietary protein on urinary albumin excretion and glomerular filtration rate in individuals with diabetes.

Data sources

MEDLINE, EMBASE, and Scopus were searched for all published RCTs, with no language restriction, up to July 2020.

Data Extraction

Study selection and data extraction were performed independently by 3 authors. Risk of bias was assessed independently by 2 authors, and the GRADE approach was used to assess the quality of the evidence.

Results

Twelve RCTs were included, of which 11 (involving 228 participants) were compiled in meta-analyses of random-effects models. Interventions consisted of diets emphasizing plant or white meat protein, with reduced intake of animal or red meat protein. Pooled data from crossover trials (n = 8) favored intervention diets for urinary albumin excretion (ratio of means, 0.86; 95% confidence interval 0.80 to 0.94; I2 = 4%) and glomerular filtration rate (ratio of means, 0.90; 95% confidence interval 0.87 to 0.94; I2 = 45%), compared with control diets. Results from parallel-design studies (n = 3), however, were not statistically significant for any outcome. The quality of the evidence ranged from very low to moderate, and most studies were judged with at least some concerns in terms of risk of bias.

Conclusion

This meta-analysis found weak evidence for small to moderate improvements in markers of kidney function in favor of interventions with lower animal protein (or red meat protein) compared with usual diets in short-term crossover trials. These findings require confirmation in well-designed randomized controlled trials.
The impact of humanoid robot presence in the paediatric emergency department waiting room: A prospective cohort study
Authors: Sivakumar Mithra , Ali Samina , Rajagopal Manasi , Yaskina Maryna , Drury Sharon , Wright Bruce
Published: June 2021

Background

The waiting room represents families’ first point of contact with the emergency department (ED). We wished to study if a humanoid robot technology presence in the waiting room would improve satisfaction and decrease anxiety for caregivers in the paediatric ED.

Methods

This observational cohort study was conducted from September to December 2018 at a Canadian paediatric ED. All caregivers and children >11 years in the ED waiting room were eligible. We compared a robotic intervention (RI) to standard of care (SOC) education in the waiting room. The RI was a 5-minute psychoeducational program describing the ED process and flow. Specific days were designated for RI or SOC. An anonymous survey was administered twice, at the same times, on both SOC and RI days. The primary outcomes were (a) caregiver satisfaction with waiting room experience using a 5-point Likert scale; and (b) caregiver-reported anxiety in the waiting room, as measured by the State Trait Anxiety Inventory – State Scale.

Results

Six hundred and thirty-three caregivers participated, with a median age of 37 years (IQR 32 to 42); 80 children participated, with a median age of 15 years (IQR 13 to 16). Caregivers reported greater overall satisfaction in the RI cohort (174/200, 87.0%) compared to the SOC cohort (144/229, 62.9%; P<0.0001). Caregivers also reported lower anxiety in the RI cohort (39.38±11.38) compared to the SOC cohort (42.04±11.99; P=0.009).

Conclusions

A humanoid robot-based psycho educational intervention in the paediatric ED waiting room has a positive impact on caregiver satisfaction and anxiety.
Reaction Coronas at Olivine–Plagioclase Contacts in Host Rocks from the Nova–Bollinger Ni–Cu–Co Deposit, Albany–Fraser Orogen, Western Australia: Evidence of a Magmatic to Metamorphic Continuum
Authors: Torres-Rodriguez Natalia , Barnes Stephen J , Taranovic Valentina , Pearce Mark A , Verrall Michael , Schoneveld Louise E
Published: June 2021

A prominent feature of the cumulate rocks of the Nova intrusions is the presence of reaction coronas between olivine and plagioclase. A particular spatial arrangement of mineral textures, typical of olivine–plagioclase coronas in high-P troctolites and olivine gabbros worldwide, is almost universally observed: partially resorbed olivine with a cuspate margin, surrounded by orthopyroxene, surrounded by a zone of symplectite comprising hornblende + clinopyroxene, orthopyroxene and Cr-poor Al–(Fe, Mg) spinel, with a cuspate boundary against plagioclase. Where amphibole-free clinopyroxene–spinel symplectite is developed it is typically as an outer layer against plagioclase. The mineralogy and composition of these coronas has been revealed by a combination of scanning electron microscopy and synchrotron X-ray fluorescence microscopy. There is a close spatial association between reaction symplectites and Bowen reaction series sequences developed by reaction between cumulus phases and fractionated trapped interstitial melt, giving rise to local Cr and Ti enrichment within the coronas relative to olivine and plagioclase, accompanying enrichment in water recorded by stabilization of amphibole. These relationships imply that trapped liquid crystallization and corona formation were part of a process continuum, such that the coronas record mineral reactions close to the solidus temperature of the cumulates, initially developing in the presence of evolved hydrous interstitial liquid and continuing to develop in the solid state below the solidus. The symplectites owe their fine microstructure to diffusion-limited growth of the products of solid-state reactions below the solidus. The initial magmatic stage of corona formation records conditions of 0·76 and 0·96 GPa and around 1035 °C based on THERMOCALC pseudosections calculated for the bulk composition of the corona assemblage. Two-pyroxene assemblages within the symplectites record temperatures around 850–900 °C and pressures between 0·7 and 1·1 GPa. These pressure estimates are in good agreement with those obtained from regional metamorphism studies of the country rock paragneisses, confirming independent lines of evidence that the Nova intrusions were syn-metamorphic, emplaced under granulite-facies peak metamorphic conditions at crustal depths of 28–35 km. The unusually extensive development of the symplectites reflects the cooling history of the intrusions, which remained at temperatures close to solidus temperatures on the timescale of regional tectonic uplift and cooling of the deep roots of the orogen.
Looking for a safe haven: tail-anchored proteins and their membrane insertion pathways
Authors: Mehlhorn Dietmar G , Asseck Lisa Y , Grefen Christopher
Published: June 2021

Insertion of membrane proteins into the lipid bilayer is a crucial step during their biosynthesis. Eukaryotic cells face many challenges in directing these proteins to their predestined target membrane. The hydrophobic signal peptide or transmembrane domain (TMD) of the nascent protein must be shielded from the aqueous cytosol and its target membrane identified followed by transport and insertion. Components that evolved to deal with each of these challenging steps range from chaperones to receptors, insertases, and sophisticated translocation complexes. One prominent translocation pathway for most proteins is the signal recognition particle (SRP)-dependent pathway which mediates co-translational translocation of proteins across or into the endoplasmic reticulum (ER) membrane. This textbook example of protein insertion is stretched to its limits when faced with secretory or membrane proteins that lack an amino-terminal signal sequence or TMD. Particularly, a large group of so-called tail-anchored (TA) proteins that harbor a single carboxy-terminal TMD require an alternative, post-translational insertion route into the ER membrane. In this review, we summarize the current research in TA protein insertion with a special focus on plants, address challenges, and highlight future research avenues.
Revisiting characteristics, treatment and outcome of cardiomyopathy in eosinophilic granulomatosis with polyangiitis (formerly Churg–Strauss)
Authors: Sartorelli Silvia , Chassagnon Guillaume , Cohen Pascal , Dunogué Bertrand , Puéchal Xavier , Régent Alexis , Mouthon Luc , Guillevin Loïc , Terrier Benjamin ,   for the French Vasculitis Study Group (FVSG)
Published: June 2021

Objectives

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing eosinophil-rich vasculitis. Specific cardiomyopathy (CM) was described in early studies as the most important predictor of mortality. We aimed to revisit EGPA-related CM and investigate its outcome in recent decades.

Methods

We reviewed all EGPA patients managed from 2000 to 2019 in our vasculitis clinic. Baseline characteristics and outcomes were analysed. EGPA-related CM was defined as clinical or extra-clinical manifestations of patent myocardial involvement, after exclusion of other causes.

Results

We included 176 patients. The median age was 47 years [interquartile range (IQR) 36–58 years]. Specific CM was observed in 70 patients (40%). Cardiac symptoms were observed in 81% of CM+ patients, including mainly typical or atypical chest pain and peripheral oedema. Abnormal ECG, transthoracic echocardiography and cardiac MRI (CMRI) were found in 72%, 72% and 99% of CM+ patients, respectively, contrasting with abnormalities in 32%, 38% and 60% of CM-negative patients, respectively. Late gadolinium enhancement (LGE) was the most frequent abnormality on CMRI (70%). CM+ patients were less frequently ANCA-positive, had less frequent peripheral neuropathy and had higher eosinophil count. Major adverse cardiovascular events (MACEs) occurred in 13% of patients, both in CM+ and CM– patients. Abnormal ECG and LGE on CMRI were associated with the occurrence of MACEs. Four patients died, but none from cardiac causes.

Conclusion

Specific cardiomyopathy is frequent in EGPA, especially in ANCA-negative patients with high eosinophil counts. Long-term outcome was better than previously reported. Abnormal ECG and LGE on CMRI were associated with the occurrence of MACEs.
Complexity in Employment and Coresidential Trajectories Among (Dis)Advantaged Social Groups in Chile
Authors: Madero-Cabib Ignacio , Cabello-Hutt Tania
Published: June 2021

Recent institutional and cultural changes have allowed individuals to gradually (but persistently) follow more complex, less uniform, and less predictable work and family patterns than the patterns often assumed to be the norm in Western settings. However, we identify important gaps in this literature: (i) a persistent focus on high-income countries in Western Europe and North America, (ii) an emphasis on narrowed periods of adulthood, and (iii) a disregard for coresidential histories when analyzing the family domain. In this paper, we aim to address these shortcomings in two ways. First, we identify lifetime employment and coresidential trajectories of individuals living currently in Santiago, Chile, born between 1944 and 1954—a cohort that faced several political, economic, and cultural changes across their lives. Second, we explore how gender and socioeconomic disadvantages are associated with individuals’ life trajectories. We conduct a multichannel sequence analysis of a comprehensive life history dataset and find that about a quarter of the sample (27.2%) follows a modal pattern of continuous formal full-time employment and coresidence with a partner and children. The remaining proportion of individuals follow more complex, unstable, and interrupted patterns, which vary in their levels of work attachment, work informality, solo parenthood, and intergenerational households. Our findings question the idea that socially advantaged individuals opt for more complex life courses and instead confirm the association between socially disadvantaged individuals, particularly women and those lower educated, and complex trajectories. Rather than deliberate individualistic choices, life course instability appears as an additional layer of social disadvantage.
Polysomnographic indicators of restorative sleep and body mass trajectories in the Wisconsin Sleep Cohort Study
Authors: Reither Eric N , Barnet Jodi H , Palta Mari , Liu Yin , Hagen Erika W , Peppard Paul E
Published: June 2021

Study Objectives

Previous research suggests that reductions in restorative, slow-wave (N3), and rapid eye movement (REM) sleep are associated with weight gain and obesity in mid-to-late life. We extend prior work by examining how within-person (WP) changes and between-person (BP) differences in restorative sleep over several years are associated with body mass trajectories among participants in the Wisconsin Sleep Cohort Study (WSCS).

Methods

We used data from 4,862 polysomnographic (PSG) sleep studies and physical exams collected from 1,187 WSCS participants over an average duration of 14.9 years. Primary measures of interest included body mass index (BMI = kg/m2) and the percentages of time spent in N3 and REM sleep. We estimated a series of linear mixed regression models to examine how WP changes and BP differences in N3 and REM sleep affected BMI trajectories, controlling for other sleep measures, demographic characteristics, and health behaviors as potential confounders.

Results

Women in the WSCS experienced more rapid BMI gain than men. With some variation by sex, we found that (1) below-average N3 and REM sleep is associated with above-average BMI, and (2) within-person decreases in N3 and REM sleep over time are associated with gains in BMI. These findings persisted after adjustment for sleep duration and other potential confounders.

Conclusions

Our findings highlight the importance of PSG indices of restorative sleep in mid-to-late life, suggesting that future clinical treatments and public health policies will benefit from heightened attention to sleep quality.
PAX8/PAX8-AS1 DNA methylation levels are associated with objective sleep duration in persons with unexplained hypersomnolence using a deep phenotyping approach
Authors: Plante David T , Papale Ligia A , Madrid Andy , Cook Jesse D , Prairie Michael L , Alisch Reid S
Published: June 2021

Study Objectives

Patients with unexplained hypersomnolence have significant impairment related to daytime sleepiness and excessive sleep duration, the biological bases of which are poorly understood. This investigation sought to examine relationships between objectively measured hypersomnolence phenotypes and epigenetic modification of candidate hypersomnolence genes to advance this line of inquiry.

Methods

Twenty-eight unmedicated clinical patients with unexplained hypersomnolence were evaluated using overnight ad libitum polysomnography, multiple sleep latency testing, infrared pupillometry, and the psychomotor vigilance task. DNA methylation levels on CpG sites annotated to 11 a priori hypersomnolence candidate genes were assessed for statistical association with hypersomnolence measures using independent regression models with adjusted local index of significance (aLIS) P-value threshold of 0.05.

Results

Nine CpG sites exhibited significant associations between DNA methylation levels and total sleep time measured using ad libitum polysomnography (aLIS p-value < .05). All nine differentially methylated CpG sites were annotated to the paired box 8 (PAX8) gene and its related antisense gene (PAX8-AS1). Among these nine differentially methylated positions was a cluster of five CpG sites located in the body of the PAX8 gene and promoter of PAX8-AS1.

Conclusions

This study demonstrates that PAX8/PAX8-AS1 DNA methylation levels are associated with total sleep time in persons with unexplained hypersomnolence. Given prior investigations that have implicated single nucleotide polymorphisms in PAX8/PAX8-AS1 with habitual sleep duration, further research that clarifies the role of DNA methylation levels on these genes in the phenotypic expression of total sleep time is warranted.
Dopaminergic Basis of Spatial Deficits in Early Parkinson’s Disease
Authors: Hanna-Pladdy B , Pahwa R , Lyons K E
Published: June 2021

Dopaminergic mechanisms regulating cognitive and motor control were evaluated comparing visuoperceptual and perceptuomotor functions in Parkinson’s disease (PD). The performance of PD patients (n = 40) was contrasted with healthy controls (n = 42) across two separate visits (on and off dopaminergic medications) on computerized tasks of perception and aiming to a target at variable stimulus lengths (4, 8, 12 cm). Novel visuoperceptual tasks of length equivalence and width interval estimations without motor demands were compared with tasks estimating spatial deviation in movement termination. The findings support the presence of spatial deficits in early PD, more pronounced with increased discrimination difficulty, and with shorter stimulus lengths of 4 cm for both visuoperceptual and perceptumotor functions. Dopaminergic medication had an adverse impact on visuoperceptual accuracy in particular for length equivalence estimations, in contrast with dopaminergic modulation of perceptuomotor functions that reduced angular displacements toward the target. The differential outcomes for spatial accuracy in perception versus movement termination in PD are consistent with involvement of the direct pathway and models of progressive loss of dopamine through corticostriatal loops. Future research should develop validated and sensitive standardized tests of perception and explore dopaminergic selective deficits in PD to optimize medication titration for motor and cognitive symptoms of the disease.
Enrichment and Detection Method for the Prognostic Value of Circulating Tumor Cells in Ovarian Cancer: A Meta-analysis
Authors: Huang Chengying , Lin Xiaoli , He Jinmei , Liu Nan
Published: June 2021

(Abstracted from Gynecol Oncol 2021;161:613–620)

In part due to a lack of early symptoms and robust screening strategies, ovarian cancer is often diagnosed in later stages and has the highest worldwide mortality among gynecologic malignancies. Tumor markers CA125 and HE4 are effective in the diagnosis of ovarian cancer; however, there is a need for prognostic tumor markers for ovarian cancer.
Treatment of Uterine Fibroid Symptoms With Relugolix Combination Therapy
Authors: Al-Hendy Ayman , Lukes Andrea S. , Poindexter Alfred N. , Venturella Roberta , Villarroel Claudio , Critchley Hilary O. D. , Li Yulan , McKain Laura , Arjona Ferreira Juan C. , Langenberg Andria G. M. , Wagman Rachel B. , Stewart Elizabeth A.
Published: June 2021

(Abstracted from N Engl J Med 2021;384:630–642)

Approximately 25% of women with uterine fibroids experience symptoms, most commonly heavy menstrual bleeding (HMB) or fibroid-associated pain. Long-acting gonadotropin-releasing hormone (GnRH) agonists are effective for the medical management of uterine fibroids, but their duration of use is limited by hypoestrogenic sequelae.
Neonatal Abstinence Syndrome and Maternal Opioid-Related Diagnoses in the US, 2010–2017
Authors: Hirai Ashley H. , Ko Jean Y. , Owens Pamela L. , Stocks Carol , Patrick Stephen W.
Published: June 2021

(Abstracted from JAMA 2021;325:146–155)

In the United States, the rates of maternal opioid use disorder (MOD) and neonatal abstinence syndrome (NAS) have seen substantial increases between 2000 and 2014. Although these rates vary across states, they were captured before the 2015 transition to International Classification of Diseases, Tenth Revision (ICD-10).
Bradycardia-to-Delivery Interval and Fetal Outcomes in Umbilical Cord Prolapse
Authors: Wong Lo , Tse Wing T. , Lai Chit Y. , Hui Annie S. Y. , Chaemsaithong Piya , Sahota Daljit S. , Poon Liona C. , Leung Tak Y.
Published: June 2021

(Abstracted from Acta Obstet Gynecol Scand 2021;100:170–177)

Umbilical cord prolapse can lead to significant perinatal complications, including fetal hypoxia and birth asphyxia. In these cases, prompt delivery is required to preserve the life of the fetus and to reduce the risk of brain injury.
Fully Percutaneous Fetoscopic Repair of Myelomeningocele: 30-Month Follow-up Data
Authors: Diehl D. , Belke F. , Kohl T. , Axt-Fliedner R. , Degenhardt J. , Khaleeva A. , Oehmke F. , Faas D. , Ehrhardt H. , Kolodziej M. , Uhl E. , Windhorst A. C. , Neubauer B. A.
Published: June 2021

(Abstracted from Ultrasound Obstet Gynecol 2021;57:113–118)

The 2011 Management of Myelomeningocele Study (MOMS) reported improved postnatal outcomes for fetuses with myelomeningocele (MMC) who underwent intrauterine repair by open surgery, via hysterectomy, compared with those who underwent traditional postnatal surgery. The study found that the need for shunt decreased by 50% in children who underwent intrauterine repair.
The Impact of Chorionicity on Pregnancy Outcome and Neurodevelopment at 2 Years Old Among Twins Born Preterm: The EPIPAGE-2 Cohort Study
Authors: Tosello B. , Garbi A. , Blanc J. , Lorthe E. , Foix-L'Hélias L. , D'Ercole C. , Winer N. , Subtil D. , Goffinet F. , Kayem G. , Resseguier N. , Gire C.
Published: June 2021

(Abstracted from BJOG 2021;128:281–291)

Overall, as many as 60% of twins are born preterm, and are therefore at risk for neonatal and long-term complications. Some evidence has shown that outcomes for preterm twins differ by chorionicity-monochorionic (MC) versus dichorionic (DC).
CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
Authors: Frangoul Haydar , Altshuler David , Cappellini M. Domenica , Chen Yi-Shan , Domm Jennifer , Eustace Brenda K. , Foell Juergen , de la Fuente Josu , Grupp Stephan , Handgretinger Rupert , Ho Tony W. , Kattamis Antonis , Kernytsky Andrew , Lekstrom-Himes Julie , Li Amanda M. , Locatelli Franco , Mapara Markus Y. , de Montalembert Mariane , Rondelli Damiano , Sharma Akshay , Sheth Sujit , Soni Sandeep , Steinberg Martin H. , Wall Donna , Yen Angela , Corbacioglu Selim
Published: June 2021

(Abstracted from N Engl J Med 2021;384:252–260)

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are the most common inherited hematologic disorders, affecting approximately 60,000 and 300,000 patients worldwide, respectively. Current therapies, including red blood cell (RBC) transfusion and iron chelation in TDT and transfusion, pain management, and hydroxyurea in SCD, help to manage the disorders but do not address the underlying cause.
Fertility Treatment and Cancers—The Eternal Conundrum: A Systematic Review and Meta-analysis
Authors: Barcroft Jennifer Frances , Galazis Nicolas , Jones Benjamin P. , Getreu Natalie , Bracewell-Milnes Timothy , Grewal Karen J. , Sorbi Flavia , Yazbek Joseph , Lathouras Kostas , Smith J. Richard , Hardiman Paul , Thum Meen-Yau , Ben-Nagi Jara , Ghaem-Maghami Sadaf , Verbakel Jan , Saso Srdjan
Published: June 2021

(Abstracted from Hum Reprod 2021;36:1093–1107)

Given the increased risk of ovarian, breast, and endometrial cancers associated with nulliparity, there is a higher inherent cancer risk among patients pursuing fertility treatment (FT) than the general population. Endometrial and breast are hormone-sensitive cancers that carry elevated risk associated with estrogen predominant states including ovarian stimulation.
Harnessing the Power of Social Media to Understand the Impact of COVID-19 on People Who Use Drugs During Lockdown and Social Distancing
Authors: El-Bassel Nabila , Hochstatter Karli R. , Slavin Melissa N. , Yang Chenghao , Zhang Yudong , Muresan Smaranda
Published: June 2021

Objectives:

This paper uses a social media platform, Reddit, to identify real-time experiences of people who use drugs during the COVID-19 lock-down.

Methods:

Reddit is a popular and growing social media platform, providing a large, publicly available dataset necessary for high performance of machine learning and topic modeling techniques. We used opioid-related “subreddits,” communities where Reddit users engage in conversations about drug use, to examine COVID-19-related content of posts and comments from March to May 2020. This paper investigates the latent topics of users’ posts/comments using Latent Dirichlet Allocation, an unsupervised machine learning approach that uncovers the thematic structure of a document collection. We also examine how topics changed over time.

Results:

The final dataset consists of 525 posts and 9284 comments, for a total of 9809 posts/comments (3756 posts/comments in r/opiates, 1641 in r/OpiatesRecovery, 1203 in r/suboxone, and 3209 in r/Methadone) among 2342 unique individuals. There were 5256 posts/comments in March; 3185 in April; and 1368 in May (until May 22). Topics that appeared most frequently in COVID-19-related discussions included medication for opioid use disorder experiences and access issues (22.6%), recovery (24.2%), and drug withdrawal (20.2%).

Conclusions:

During the first three months of the COVID-19 pandemic, people who use drugs were impacted in several ways, including forced or intentional withdrawal, confusion between withdrawal and COVID-19 symptoms, take-home medication for opioid use disorder issues, and barriers to recovery. As the pandemic progresses, providers and policymakers should consider these experiences among people who use drugs during the early stage of the pandemic.
Supervised Tablet Injectable Opioid Agonist Therapy (TiOAT): A Strategy to Address Safer Supply for Individuals With an Opioid Use Disorder?
Authors: Weng Jian , Fairbairn Nadia , Sutherland Christy , Johnson Cheyenne , Nolan Seonaid
Published: June 2021

North America is in the midst of an overdose crisis, with up to 130 Americans dying daily from a preventable drug overdose. Opioids account for 70% of overdose deaths. Despite government efforts to improve access to opioid use disorder (OUD) treatment and the implementation of various harm reduction initiatives, overdose mortality remains unacceptably high. Although effective treatments exist for OUD (eg, opioid agonist therapies like buprenorphine/naloxone and methadone), many individuals do not achieve stabilization with these medications. Tablet injectable opioid agonist therapy (TiOAT) is an initiative being piloted in British Columbia to provide witnessed access to a safer opioid supply for individuals with treatment-refractory OUD. The program offers participants a safer opioid supply through physician-prescribed pharmaceutical-grade hydromorphone tablets. TiOAT is suitable for individuals with severe OUD who are actively injecting opioids and are refractory to conventional OUD treatment. As such, a scale-up of the TiOAT program may be a feasible alternative to address persistent opioid-related deaths in North America, while minimizing potential harms associated with unwitnessed safer supply opioid prescribing (eg, diversion and overdose). Although a comprehensive evaluation of TiOAT is of critical importance (including an assessment of the program’s adverse events), completion of the evaluation should not preclude scale-up of the program in the interim as a strategy to reduce opioid-related harms.
Exercise Addiction Stability and Health Effects. A 6-Month Follow-up Postcompetition Study in Amateur Endurance Cyclists
Authors: Bueno-Antequera Javier , Oviedo-Caro Miguel A ´ ngel , Legaz-Arrese Alejandro , Paris-Garcia Federico , Guille´n-Correas Roberto , Munguı´a-Izquierdo Diego , Mayolas-Pi Carmen
Published: June 2021

Objective

To study the longitudinal stability of exercise addiction and its health effects in apparently healthy amateur endurance cyclists from pre- to 6-month post-competition.

Methods

In total, 330 (30 women) adult cyclists were divided into 4 groups based on scores on the Exercise Addiction Inventory at both periods: nonrisk (n=262, 79.1%), transient (n=35, 10.6%), emerging (n=14, 4.2%) and persistent (n=20, 6.1%).

Results

The prevalence of high-risk exercise addiction was reduced postcompetition (16.7% vs 10.3%, P = 0.017). Of the cyclists with a high precompetition risk of exercise addiction, 63.6% (35/55) had a transient addiction associated with favorable effects on mental quality of life (effect size [ES]=0.52, 95% confidence interval: [0.20, 0.86]) and sleep quality (ES=–0.50 [–0.89, –0.12]) and avoided the worsening of depression symptom severity compared to the remaining groups (ES range=0.51–0.65). The 5.1% (14/275) of cyclists with a precompetition low risk of exercise addiction presented emerging exercise addiction that was associated with a worsened mental quality of life compared to the remaining groups (ES ranged 0.59–0.91), sleep quality compared to the nonrisk (ES=–0.56 [–0.02, –1.10]) and transient (ES=–0.72 [–1.36, –0.08]) groups and anxiety symptom severity compared to the persistent group (ES=0.51 [1.20,–0.19]).

Conclusions

Exercise addiction had a marked transitory component at 6-month postcompetition with associated health benefits in amateur endurance cyclists.