bluuebunny/crossref_metadata_2025 huggingface dataset:
Gestational trophoblastic disease and associated factors among women experiencing first trimester pregnancy loss at a regional referral hospital in central Tanzania: a cross-sectional study
Authors: Mdoe Mwajuma B , Mwakigonja Amos R , Mwampagatwa Ipyana
Published: March 2022

Background

Gestational trophoblastic diseases (GTDs) may follow any form of pregnancy or a pregnancy loss. Early detection of GTDs is important, as some benign forms of the disease may progress into a chemoresistant and metastatic disease. This study aimed at determining the frequency of GTDs among women experiencing first trimester pregnancy loss and the associated patients’ characteristics.

Methods

This was a cross-sectional study that included 200 conveniently sampled women who experienced first trimester pregnancy loss from January to December 2019 at a Regional Referral Hospital in central Tanzania. The specimen obtained from products of conception were collected, formalin-fixed and paraffin-embedded and submitted for histopathological evaluation, for which haematoxylin and eosin stain was used. Data were analysed using SPSS version 23.0. The χ2 test was used to determine the association between categorical variables. p-Values ˂0.05 were considered statistically significant.

Results

Among 200 study participants, the overall frequency of GTDs was 42 (21%). Among those with GTDs, the most common histopathological diagnosis was partial hydatidiform mole (18 [42.9%]), followed by complete hydatidiform mole (17 [40.5%]) and choriocarcinoma (7 [16.5%]). In the studied participants, only increased human chorionic gonadotropin hormone levels were found to be statistically significantly associated with GTDs (p=0.000).

Conclusions

Results from this study suggest that routine histopathological evaluation of the products of conception is recommended in order to allow early detection of GTDs, including choriocarcinoma, which usually carries a poor prognosis. The histopathological reporting of choriocarcinoma among first trimester products of conception from Tanzania is novel.
Rapid determination of ceftazidime/avibactam susceptibility of carbapenemase-producing Enterobacterales directly from blood cultures: a comparative evaluation of EUCAST disc diffusion RAST and direct Etest® RAST
Authors: Bianco Gabriele , Boattini Matteo , Comini Sara , Iannaccone Marco , Cavallo Rossana , Costa Cristina
Published: March 2022

Objectives

To evaluate the performance of two rapid antimicrobial susceptibility testing (RAST) methods to determine ceftazidime/avibactam susceptibility directly from blood cultures (BCs).

Methods

A total of 246 Escherichia coli or Klebsiella pneumoniae isolates were tested for ceftazidime/avibactam susceptibility directly from BC bottles using EUCAST RAST and Etest® RAST. Results obtained after 4, 6 and 8 h of incubation were compared with those obtained by reference broth microdilution on pure overnight subcultures.

Results

In total, the proportion of readable zones after 4 h of incubation was 96.7% and reached 100% after 6 and 8 h of incubation. EUCAST RAST yielded >98% of categorical agreement (CA) with all reading times. Major error (ME) and very major error (VME) rates were inferior to 3%, for each of the reading times. The proportion of results in the area of technical uncertainty (ATU) was almost similar (3.8%–4.1%) at the different reading times. DET-RAST yielded 97.5%, 98% and 99.6% of CA with readings at 4, 6 and 8 h, respectively. One (0.6%) ME was observed at each reading time, whereas five (5.9%) and four (4.5%) VMEs were observed analysing readings at 4 and 6 h, respectively. No VME was observed with readings at 8 h.

Conclusions

EUCAST RAST was accurate to determine ceftazidime/avibactam susceptibility of carbapenemase-producing K. pneumoniae and E. coli directly from BC bottles. DET-RAST has the advantage of determining MIC values and avoiding ATU results but showed to be an accurate method only with reading at 8 h.
The Future of Burn Care From a Complexity Science Perspective
Authors: van Zuijlen Paul P M , Korkmaz Halil Ibrahim , Sheraton Vivek M , Haanstra Tsjitske M , Pijpe Anouk , de Vries Annebeth , van der Vlies Cornelis H , Bosma Eelke , de Jong Evelien , Middelkoop Esther , Vermolen Fred J , Sloot Peter M A
Published: March 2022

Health care is undergoing a profound technological and digital transformation and has become increasingly complex. It is important for burns professionals and researchers to adapt to these developments which may require new ways of thinking and subsequent new strategies. As Einstein has put it: “We must learn to see the world anew.” The relatively new scientific discipline “Complexity science” can give more direction to this and is the metaphorical open door that should not go unnoticed in view of the burn care of the future. Complexity science studies “why the whole is more than the sum of the parts.” It studies how multiple separate components interact with each other and their environment and how these interactions lead to “behavior of the system.” Biological systems are always part of smaller and larger systems and exhibit the behavior of adaptivity, hence the name complex adaptive systems. From the perspective of complexity science, a severe burn injury is an extreme disruption of the “human body system.” But this disruption also applies to the systems at the organ and cellular levels. All these systems follow the principles of complex systems. Awareness of the scaling process at multilevel helps to understand and manage the complex situation when dealing with severe burn cases. This paper aims to create awareness of the concept of complexity and to demonstrate the value and possibilities of complexity science methods and tools for the future of burn care through examples from preclinical, clinical, and organizational perspectives in burn care.
Learning About One’s Self
Authors: Le Yaouanq Yves , Schwardmann Peter
Published: March 2022

To understand why naiveté about present-biased behavior is so prevalent and persistent, our experiment investigates how well participants learn from their past behavior in a real-effort task. While participants display naive present-biased behavior initially, our novel methodology allows us to establish that their updating is unbiased and would eliminate naiveté in the long run. Moreover, learning is unencumbered by a change in the environment. Our results suggest that persistent naiveté does not result from a fundamental inferential bias. However, participants underestimate their future learning—a bias that may lead to underinvestment in experimentation and a failure to activate self-regulation mechanisms.
High expression of HHLA2 predicts poor prognosis in medullary thyroid carcinoma
Authors: Niu Yongzhi , Wang Wei , Jiang Xiaodan , Huang Yichuan , Yan Shu , Jiang Yan
Published: March 2022

Background

Human endogenous retrovirus-H long terminal repeat-associating protein 2 is a newly identified immune checkpoint molecule that was aberrantly expressed in many malignant tumors. However, its expression in medullary thyroid carcinoma is still unclear. This study aimed to investigate the human endogenous retrovirus-H long terminal repeat-associating protein 2 expression in medullary thyroid carcinoma tissues and to evaluate the relationships between its expression and clinicopathologic together with prognostic relevance.

Methods

Using 51 surgical specimens obtained from medullary thyroid carcinoma patients, the expression levels of the human endogenous retrovirus-H long terminal repeat-associating protein 2 protein in medullary thyroid carcinoma tumor tissues and adjacent noncancerous tissues were measured by immunohistochemistry, and its correlations with clinicopathologic and prognostic features were analyzed. Status of CD8+ tumor infiltrating lymphocytes was also investigated.

Results

The results showed that human endogenous retrovirus-H long terminal repeat-associating protein 2 was only detected in tumor tissues, and 31.4% of the medullary thyroid carcinoma patients had high expression of human endogenous retrovirus-H long terminal repeat-associating protein 2. High human endogenous retrovirus-H long terminal repeat-associating protein 2 expression was significantly associated with lymph node metastasis and advanced American Joint Committee on Cancer stages (P = 0.005). There existed an inverse trend between human endogenous retrovirus-H long terminal repeat-associating protein 2 expression and CD8+ tumor infiltrating lymphocytes infiltration in medullary thyroid carcinoma tumor samples (P = 0.042). The log-rank test showed a shorter disease-free survival in patients with high human endogenous retrovirus-H long terminal repeat-associating protein 2 expression (P = 0.002). The disease-free survival rates were also significantly low in cases of medullary thyroid carcinoma with lymph node metastasis, American Joint Committee on Cancer stages III–IV and multifocality. Multivariate Cox analysis confirmed that human endogenous retrovirus-H long terminal repeat-associating protein 2 acted as an independent predictive factor in the disease-free survival of medullary thyroid carcinoma patients (hazard ratio = 4.138, 95% confidence interval: 1.027–16.667, P = 0.046).

Conclusions

Taken together, human endogenous retrovirus-H long terminal repeat-associating protein 2 is highly expressed in medullary thyroid carcinoma patients and is a poor prognostic biomarker of disease-free survival of medullary thyroid carcinoma patients.
Lower Exome Sequencing Coverage of Ancestrally African Patients in The Cancer Genome Atlas
Authors: Wickland Daniel P , Sherman Mark E , Radisky Derek C , Mansfield Aaron S , Asmann Yan W
Published: March 2022

Background

In the United States, cancer disproportionately impacts Black and African American individuals. Identifying genetic factors underlying cancer disparities has been an important research focus and requires data that are equitable in both quantity and quality across racial groups. It is widely recognized that DNA databases quantitatively underrepresent minorities. However, the differences in data quality between racial groups have not been well studied.

Methods

We compared the qualities of germline and tumor exomes between ancestrally African and European patients in The Cancer Genome Atlas of 7 cancers with at least 50 self-reported Black patients in the context of sequencing depth, tumor purity, and qualities of germline variants and somatic mutations.

Results

Germline and tumor exomes from ancestrally African patients were sequenced at statistically significantly lower depth in 6 out of the 7 cancers. For 3 cancers, most ancestrally European exomes were sequenced in early sample batches at higher depth, whereas ancestrally African exomes were concentrated in later batches and sequenced at much lower depth. For the other 3 cancers, the reasons of lower sequencing coverage of ancestrally African exomes remain unknown. Furthermore, even when the sequencing depths were comparable, African exomes had disproportionally higher percentages of positions with insufficient coverage, likely because of the known European bias in the human reference genome that impacted exome capture kit design.

Conclusions

Overall and positional lower sequencing depths of ancestrally African exomes in The Cancer Genome Atlas led to underdetection and lower quality of variants, highlighting the need to consider epidemiological factors for future genomics studies.
Health Economics Research in Cancer Screening: Research Opportunities, Challenges, and Future Directions
Authors: Shih Ya-Chen Tina , Sabik Lindsay M , Stout Natasha K , Halpern Michael T , Lipscomb Joseph , Ramsey Scott , Ritzwoller Debra P
Published: March 2022

Cancer screening has long been considered a worthy public health investment. Health economics offers the theoretical foundation and research methodology to understand the demand- and supply-side factors associated with screening and evaluate screening-related policies and interventions. This article provides an overview of health economic theories and methods related to cancer screening and discusses opportunities for future research. We review 2 academic disciplines most relevant to health economics research in cancer screening: applied microeconomics and decision science. We consider 3 emerging topics: cancer screening policies in national as well as local contexts, “choosing wisely” screening practices, and targeted screening efforts for vulnerable subpopulations. We also discuss the strengths and weaknesses of available data sources and opportunities for methodological research and training. Recommendations to strengthen research infrastructure include developing novel data linkage strategies, increasing access to electronic health records, establishing curriculum and training programs, promoting multidisciplinary collaborations, and enhancing research funding opportunities.
Cefazolin sodium pentahydrate cause urolithiasis: a case report and literature review
Authors: Wang Fujun , Nie Wen , Wang Zongjun , Tian Sujian , Dong Junqiang
Published: March 2022

We report a rare case of urolithiasis induced by cefazolin sodium pentahydrate and review the relevant literature. A 12-year-old girl with right kidney injury was admitted to our hospital, a computed tomography scan revealed that no signs of disease in her left kidney but her right kidney was traumatized severely. After receiving cefazolin sodium pentahydrate, 2.0 g by intravenous infusion daily for 10 days, urolithiasis was found in the left urinary tract by computed tomography scan. Later, the patient complained of left back pain, nausea and vomiting, and a further computed tomography scan showed calculi persisted in the left urinary tract, and some of which had caused left hydronephrosis. A double-J catheter was placed in the left ureter, but no calculi were seen to drain with urine in the next 2 weeks, those calculi were removed by a flexible ureteroscope.
Kernel weight contribution to yield genetic gain of maize: a global review and US case studies
Authors: Fernández Javier A , Messina Carlos D , Salinas Andrea , Prasad P V Vara , Nippert Jesse B , Ciampitti Ignacio A
Published: March 2022

Over the past century of maize (Zea mays L.) breeding, grain yield progress has been the result of improvements in several other intrinsic physiological and morphological traits. In this study, we describe (i) the contribution of kernel weight (KW) to yield genetic gain across multiple agronomic settings and breeding programs, and (ii) the physiological bases for improvements in KW for US hybrids. A global-scale literature review concludes that rates of KW improvement in US hybrids were similar to those of other commercial breeding programs but extended over a longer period of time. There is room for a continued increase of kernel size in maize for most of the genetic materials analysed, but the trade-off between kernel number and KW poses a challenge for future yield progress. Through phenotypic characterization of Pioneer Hi-Bred ERA hybrids in the USA, we determine that improvements in KW have been predominantly related to an extended kernel-filling duration. Likewise, crop improvement has conferred on modern hybrids greater KW plasticity, expressed as a better ability to respond to changes in assimilate availability. Our analysis of past trends and current state of development helps to identify candidate targets for future improvements in maize.
Consistent equivalence principle tests with fast radio bursts
Authors: Reischke Robert , Hagstotz Steffen , Lilow Robert
Published: March 2022

Fast radio bursts (FRBs) are astrophysical transients of still debated origin. So far several hundred events have been detected, mostly at extragalactic distances, and this number is expected to grow significantly over the next years. The radio signals from the burst experience dispersion as they travel through the free electrons along the line-of-sight characterised by the dispersion measure (DM) of the radio pulse. In addition, each photon also experiences a gravitational Shapiro time delay while travelling through the potentials generated by the large-scale structure. If the weak equivalence principle (WEP) holds, the Shapiro delay is the same for photons of all frequencies. In case the WEP is broken, one would expect an additional dispersion to occur which could be either positive or negative for individual sources. Here, we suggest to use angular statistics of the DM fluctuations to put constraints on the WEP parametrized by the post-Newtonian parameter γ. Previous studies suffer from the problem that the gravitational potential responsible for the delay diverges in a cosmological setting, which our approach avoids. We carry out a forecast for a population of FRBs observable within the next years and show that any significant detection of the DM angular power spectrum will place the tightest constraints on the WEP to date, Δγ < 10−15.
One year of AU Mic with HARPS – I. Measuring the masses of the two transiting planets
Authors: Zicher Norbert , Barragán Oscar , Klein Baptiste , Aigrain Suzanne , Owen James E , Gandolfi Davide , Lagrange Anne-Marie , Serrano Luisa Maria , Kaye Laurel , Nielsen Louise Dyregaard , Rajpaul Vinesh Maguire , Grandjean Antoine , Goffo Elisa , Nicholson Belinda
Published: March 2022

The system of two transiting Neptune-sized planets around the bright, young M-dwarf AU Mic provides a unique opportunity to test models of planet formation, early evolution, and star–planet interaction. However, the intense magnetic activity of the host star makes measuring the masses of the planets via the radial velocity (RV) method very challenging. We report on a 1-yr, intensive monitoring campaign of the system using 91 observations with the HARPS spectrograph, allowing for detailed modelling of the ∼600 ${\rm m\, s^{-1}}$ peak-to-peak activity-induced RV variations. We used a multidimensional Gaussian Process framework to model these and the planetary signals simultaneously. We detect the latter with semi-amplitudes of Kb = 5.8 ± 2.5 ${\rm m\, s^{-1}}$ and Kc = 8.5 ± 2.5 ${\rm m\, s^{-1}}$, respectively. The resulting mass estimates, Mb = 11.7 ± 5.0 M⊕ and Mc = 22.2 ± 6.7 M⊕, suggest that planet b might be less dense, and planet c considerably denser than previously thought. These results are in tension with the current standard models of core-accretion. They suggest that both planets accreted a H/He envelope that is smaller than expected, and the trend between the two planets’ envelope fractions is the opposite of what is predicted by theory.
The TESS Triple-9 Catalog: 999 uniformly vetted exoplanet candidates
Authors: Cacciapuoti Luca , Kostov Veselin B , Kuchner Marc , Quintana Elisa V , Colón Knicole D , Brande Jonathan , Mullally Susan E , Chance Quadry , Christiansen Jessie L , Ahlers John P , Di Fraia Marco Z , Durantini Luca Hugo A , Ienco Riccardo M , Gallo Francesco , de Lima Lucas T , Hyogo Michiharu , Andrés-Carcasona Marc , Fornear Aline U , de Lambilly Julien S , Salik Ryan , Yablonsky John M , Wallace Shaun , Acharya Sovan
Published: March 2022

The Transiting Exoplanet Survey Satellite (TESS) has detected thousands of exoplanet candidates since 2018, most of which have yet to be confirmed. A key step in the confirmation process of these candidates is ruling out false positives through vetting. Vetting also eases the burden on follow-up observations, provides input for demographics studies, and facilitates training machine learning algorithms. Here, we present the TESS Triple-9 (TT9) catalog – a uniformly vetted catalog containing dispositions for 999 exoplanet candidates listed on ExoFOP-TESS, known as TESS Objects of Interest (TOIs). The TT9 was produced using the Discovery And Vetting of Exoplanets pipeline, dave, and utilizing the power of citizen science as a part of the Planet Patrol project. More than 70 per cent of the TOIs listed in the TT9 pass our diagnostic tests, and are thus marked as true planet candidates. We flagged 144 candidates as false positives, and identified 146 as potential false positives. At the time of writing, the TT9 catalog contains $\sim 20{{\ \rm per\ cent}}$ of the entire ExoFOP-TESS TOIs list, demonstrates the synergy between automated tools and citizen science, and represents the first stage of our efforts to vet all TOIs. Our final dispositions and comments are collected in a supplementary table and the dave-generated files are publicly available on ExoFOP TESS.
Applications of a Gaussian process framework for modelling of high-resolution exoplanet spectra
Authors: Meech Annabella , Aigrain Suzanne , Brogi Matteo , Birkby Jayne L
Published: March 2022

Observations of exoplanet atmospheres in high resolution have the potential to resolve individual planetary absorption lines, despite the issues associated with ground-based observations. The removal of contaminating stellar and telluric absorption features is one of the most sensitive steps required to reveal the planetary spectrum and, while many different detrending methods exist, it remains difficult to directly compare the performance and efficacy of these methods. Additionally, though the standard cross-correlation method enables robust detection of specific atmospheric species, it only probes for features that are expected a priori. Here, we present a novel methodology using Gaussian process (GP) regression to directly model the components of high-resolution spectra, which partially addresses these issues. We use two archival CRyogenic Infra-Red Echelle Spectrograph (CRIRES)/Very Large Telescope (VLT) data sets as test cases, observations of the hot Jupiters HD 189733 b and 51 Pegasi b, recovering injected signals with average line contrast ratios of ∼4.37 × 10−3 and ∼1.39 × 10−3, and planet radial velocities ΔKp = 1.45 ± 1.53 $\mathrm{km\, s^{-1}}$ and ΔKp = 0.12 ± 0.12 $\mathrm{km\, s^{-1}}$ from the injection velocities, respectively. In addition, we demonstrate an application of the GP method to assess the impact of the detrending process on the planetary spectrum, by implementing injection-recovery tests. We show that standard detrending methods used in the literature negatively affect the amplitudes of absorption features in particular, which has the potential to render retrieval analyses inaccurate. Finally, we discuss possible limiting factors for the non-detections using this method, likely to be remedied by higher signal-to-noise data.
Asteroid Lightcurves from the MOA-II Survey: a pilot study
Authors: Cordwell A J , Rattenbury N J , Bannister M T , Cowan P ,   The MOA Collaboration:, Abe Fumio , Barry Richard , Bennett David P , Bhattacharya Aparna , Bond Ian A , Fujii Hirosane , Fukui Akihiko , Itow Yoshitaka , Silva Stela Ishitani , Hirao Yuki , Kirikawa Rintaro , Kondo Iona , Koshimoto Naoki , Matsubara Yutaka , Matsumoto Sho , Muraki Yasushi , Miyazaki Shota , Okamura Arisa , Ranc Clément , Satoh Yuki , Sumi Takahiro , Suzuki Daisuke , Tristram Paul J , Toda Taiga , Yama Hibiki , Yonehara Atsunori
Published: March 2022

The Microlensing Observations in Astrophysics (MOA-II) survey has performed high cadence, wide field observations of the Galactic Bulge from New Zealand since 2005. The hourly cadence of the survey during eight months of the year, across nearly 50 deg2 of sky, provides an opportunity to sample asteroid lightcurves in the broad MOA-R filter. We perform photometry of a subset of bright asteroids numbered observed by the survey. We obtain 26 asteroid rotation periods, including for two asteroids where no prior data exist, and present evidence for the possible non-principal axis rotation of (2011) Veteraniya. This archival search could be extended to several thousands of asteroids brighter than 22nd magnitude.
The eccentricity distribution of wide binaries and their individual measurements
Authors: Hwang Hsiang-Chih , Ting Yuan-Sen , Zakamska Nadia L
Published: March 2022

Eccentricity of wide binaries is difficult to measure due to their long orbital periods. With Gaia’s high-precision astrometric measurements, eccentricity of a wide binary can be constrained by the angle between the separation vector and the relative velocity vector (the v-r angle). In this paper, by using the v-r angles of wide binaries in Gaia Early Data Release 3, we develop a Bayesian approach to measure the eccentricity distribution as a function of binary separations. Furthermore, we infer the eccentricities of individual wide binaries and make them publicly available. Our results show that the eccentricity distribution of wide binaries at 102 AU is close to uniform and becomes superthermal at >103 AU, suggesting two formation mechanisms dominating at different separation regimes. The close binary formation, most likely disc fragmentation, results in a uniform eccentricity distribution at <102 AU. The wide binary formation that leads to highly eccentric wide binaries at >103 AU may be turbulent fragmentation and/or the dynamical unfolding of compact triples. With Gaia, measuring eccentricities is now possible for a large number of wide binaries, opening a new window to understanding binary formation and evolution.
Multiply charged naphthalene and its C10H8 isomers: bonding, spectroscopy, and implications in AGN environments
Authors: Santos Julia C , Fantuzzi Felipe , Quitián-Lara Heidy M , Martins-Franco Yanna , Menéndez-Delmestre Karín , Boechat-Roberty Heloisa M , Oliveira Ricardo R
Published: March 2022

Naphthalene (C10H8) is the simplest polycyclic aromatic hydrocarbon (PAH) and an important component in a series of astrochemical reactions involving hydrocarbons. Its molecular charge state affects the stability of its isomeric structures, which is specially relevant in ionized astrophysical environments. We thus perform an extensive computational search for low-energy molecular structures of neutral, singly, and multiply charged naphthalene and its isomers with charge states +q = 0–4 and investigate their geometric properties and bonding situations. We find that isomerization reactions should be frequent for higher charged states and that open chains dominate their low-energy structures. We compute both the scaled-harmonic and anharmonic infrared (IR) spectra of selected low-energy species and provide the calculated scaling factors for the naphthalene neutral, cation, and dication global minima. All simulated spectra reproduce satisfactorily the experimental data and, thus, are adequate for aiding observations. Moreover, the potential presence of these species in the emission spectra of the circumnuclear regions of active galactic nuclei (AGNs), with high energetic X-ray photon fluxes, is explored using the experimental value of the naphthalene photodissociation cross-section, σph − d, to determine its half-life, t1/2, at a photon energy of 2.5 keV in a set of relevant sources. Finally, we show that the computed IR bands of the triply and quadruply charged species are able to reproduce some features of the selected AGN sources.
Reconstruction of the dark sectors’ interaction: A model-independent inference and forecast from GW standard sirens
Authors: Bonilla Alexander , Kumar Suresh , Nunes Rafael C , Pan Supriya
Published: March 2022

Interacting dark matter (DM) – dark energy (DE) models have been intensively investigated in the literature for their ability to fit various data sets as well as to explain some observational tensions persisting within the ΛCDM cosmology. In this work, we employ the Gaussian processes (GP) algorithm to perform a joint analysis by using the geometrical cosmological probes such as Cosmic chronometers, Supernova Type Ia, Baryon Acoustic Oscillations, and the H0LiCOW lenses sample to infer a reconstruction of the coupling function between the dark components in a general framework, where the DE can assume a dynamical character via its equation of state. In addition to the joint analysis with these data, we simulate a catalogue with standard siren events from binary neutron star mergers, within the sensitivity predicted by the Einstein Telescope, to reconstruct the dark sector coupling with more accuracy in a robust way. We find that the particular case, where w = −1 is fixed on the DE nature, has a statistical preference for an interaction in the dark sector at late times. In the general case, where w(z) is analysed, we find no evidence for such dark coupling, and the predictions are compatible with the ΛCDM paradigm. When the mock events of the standard sirens are considered to improve the kernel in GP predictions, we find a preference for an interaction in the dark sector at late times.
XMM–Newton discovery of very high obscuration in the candidate supergiant fast X-ray transient AX J1714.1−3912
Authors: Sidoli L , Sguera V , Esposito P , Oskinova L , Polletta M
Published: March 2022

We have analysed an archival XMM–Newton EPIC observation that serendipitously covered the sky position of a variable X-ray source AX J1714.1−3912, previously suggested to be a supergiant fast X-ray transient (SFXT). During the XMM–Newton observation the source is variable on a time-scale of hundred seconds and shows two luminosity states, with a flaring activity followed by unflared emission, with a variability amplitude of a factor of about 50. We have discovered an intense iron emission line with a centroid energy of 6.4 keV in the power law-like spectrum, modified by a large absorption (NH∼1024 cm−2), never observed before from this source. This X-ray spectrum is unusual for an SFXT, but resembles the so-called ‘highly obscured sources’, high mass X-ray binaries (HMXBs) hosting an evolved B[e] supergiant companion (sgB[e]). This might suggest that AX J1714.1−3912 is a new member of this rare type of HMXBs, which includes IGR J16318-4848 and CI Camelopardalis. Increasing this small population of sources would be remarkable, as they represent an interesting short transition evolutionary stage in the evolution of massive binaries. Nevertheless, AX J1714.1−3912 appears to share X-ray properties of both kinds of HMXBs (SFXT versus sgB[e] HMXB). Therefore, further investigations of the companion star are needed to disentangle the two hypothesis.
Post hoc analysis of clinical characteristics of patients with radiographic progression in a Japanese phase 3 trial of peficitinib and methotrexate treatment (RAJ4)
Authors: Tanaka Yoshiya , Takeuchi Tsutomu , Kato Daisuke , Kaneko Yuichiro , Fukuda Musashi , Izutsu Hiroyuki , Rokuda Mitsuhiro , van der Heijde Désirée
Published: March 2022

Objective

To determine the efficacy of peficitinib in reducing joint damage and predictive factors affecting treatment response in Japanese patients with rheumatoid arthritis.

Methods

This post hoc analysis used data from a placebo-controlled, phase 3 trial (RAJ4) of peficitinib in patients with rheumatoid arthritis and inadequate response to methotrexate. Erosion and joint space narrowing (JSN) were assessed at baseline and at Week 28/early termination of treatment using the van der Heijde-modified Sharp method. A univariate logistic regression analysis of change from baseline in a modified total Sharp score identified predictive factors with significant treatment interaction; the effects of these factors on treatment response were further evaluated using a multivariate model.

Results

The analyses included 481 patients. For most joint groups, peficitinib demonstrated a reduced change from baseline at Week 28/early termination in erosion and JSN scores versus placebo; a numerically greater effect was observed with peficitinib 150 mg versus 100 mg. Baseline C-reactive protein (CRP) and prednisolone dose were identified as clinically significant negative predictive factors: the treatment effect decreased as CRP or prednisolone dose increased for both peficitinib doses.

Conclusions

Peficitinib 100 mg and 150 mg reduced joint damage versus placebo, across almost all joint groups. Higher baseline CRP and/or prednisolone dose were associated with reduced peficitinib efficacy.

ClinicalTrials.gov identifier

NCT02305849
Targeting DNA polymerase to DNA double-strand breaks reduces DNA deletion size and increases templated insertions generated by CRISPR/Cas9
Authors: Yoo Kyung W , Yadav Manish Kumar , Song Qianqian , Atala Anthony , Lu Baisong
Published: March 2022

Most insertions or deletions generated by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) endonucleases are short (<25 bp), but unpredictable on-target long DNA deletions (>500 bp) can be observed. The possibility of generating long on-target DNA deletions poses safety risks to somatic genome editing and makes the outcomes of genome editing less predictable. Methods for generating refined mutations are desirable but currently unavailable. Here, we show that fusing Escherichia coli DNA polymerase I or the Klenow fragment to Cas9 greatly increases the frequencies of 1-bp deletions and decreases >1-bp deletions or insertions. Importantly, doing so also greatly decreases the generation of long deletions, including those >2 kb. In addition, templated insertions (the insertion of the nucleotide 4 nt upstream of the protospacer adjacent motif) were increased relative to other insertions. Counteracting DNA resection was one of the mechanisms perturbing deletion sizes. Targeting DNA polymerase to double-strand breaks did not increase off-targets or base substitution rates around the cleavage sites, yet increased editing efficiency in primary cells. Our strategy makes it possible to generate refined DNA mutations for improved safety without sacrificing efficiency of genome editing.
Bone density, microarchitecture and estimated strength in stone formers: a cross-sectional HR-pQCT study
Authors: Esper Priscila Ligeiro Gonçalves , Rodrigues Fernanda Guedes , Melo Thalita Lima , Ormanji Milene Subtil , Campos Carlos M , Alvarenga Jackeline Couto , Caparbo Valeria de Falco , Carvalho Aluizio Barbosa , Pereira Rosa Maria Rodrigues , Heilberg Ita Pfeferman
Published: March 2022

Background

Low areal bone mineral density (BMD), increased fracture risk and altered bone remodeling have been described among stone formers (SFs), but the magnitude of these findings differs by age, sex, menopausal status and urinary calcium (uCa). This study aimed to investigate volumetric BMD (vBMD), bone microarchitecture and biomechanical properties by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA) in young SFs, irrespective of calciuria, further distinguishing trabecular from cortical compartments.

Methods

HR-pQCT/FEA was performed at the distal tibia (DT) and distal radius (DR) in 106 SFs (57 males and 49 premenopausal females; median age 37 years) and compared with 106 non-SFs (NSFs) retrieved from an existing database, matched for age, sex and body mass index (BMI). Biochemical/hormonal serum and urinary parameters were obtained from SFs.

Results

SFs exhibited significantly lower trabecular number (TbN) and higher trabecular separation (TbSp) than NSFs at both anatomical sites and lower cortical porosity in the DR. In a subgroup analysis separated by sex, female SFs presented significantly lower TbvBMD, relative bone volume fraction (BV/TV) and TbN and higher TbSp than NSFs at both sites, while male SFs showed significantly lower stiffness and failure load. Multivariate analysis showed TbN to be independently associated with sex and BMI at both sites and with uCa at the DR.

Conclusions

The present findings suggest that bone disease represents an early event among SFs, associated at least in part with calcium excretion and mainly characterized by trabecular bone microarchitecture impairment, especially among women, but with reduced bone strength parameters in men.
Cell-Type-Dependent but CME-Independent Polar Localization of Silicon Transporters in Rice
Authors: Konishi Noriyuki , Huang Sheng , Yamaji Naoki , Ma Jian Feng
Published: March 2022

Silicon (Si) is an important nutrient required for sustainable and high production of rice and its uptake is mediated by a pair of influx (OsLsi1)–efflux (OsLsi2) transporters showing polar localization. However, the mechanisms underlying their polarity are unknown. Here, we revealed that the polarity of the Si transporters depends on cell types. The polar localization of both OsLsi1 and OsLsi2 was not altered by Si supply, but their protein abundance was reduced. Double immunostaining showed that localization of OsLsi1 and OsLsi2 was separated at the edge of the lateral polar domain by Casparian strips in the endodermis, whereas they were slightly overlapped at the transversal side of the exodermis. When OsLsi1 was ectopically expressed in the shoots, it showed polar localization at the xylem parenchyma cells of the basal node and leaf sheath, but not at the phloem companion cells. Ectopic expression of non-polar Si transporters, barley HvLsi2 and maize ZmLsi2 in rice, resulted in their polar localization at the proximal side. The polar localization of OsLsi1 and OsLsi2 was not altered by inhibition of clathrin-mediated endocytosis (CME) by dominant-negative induction of dynamin-related protein1A and knockout of mu subunit of adaptor protein 2 complex, although the knockout mutants of OsAP2M gene showed dwarf phenotype. These results indicate that CME is not required for the polar localization of Si transporters. Taken together, our results indicate that CME-independent machinery controls the polar localization of Si transporters in exodermis, endodermis of root cells and xylem parenchyma cells.
Co-Occurrence of HIMU and EM1 Components in a Single Magellan Seamount: Implications for the Formation of West Pacific Seamount Province
Authors: Wei Xun , Zhang Yan , Shi Xue-Fa , Castillo Paterno R , Xu Yi-Gang , Yan Quan-Shu , Liu Ji-Hua
Published: March 2022

Our general understanding of mantle composition and dynamics mainly comes from the composition of lavas from oceanic intraplate volcanoes. They are generally accepted to originate from deep, relatively stationary mantle plumes. Many groups of seamounts comprising the West Pacific Seamount Province (WPSP), however, do not form long-lived, narrow and continuous chains of volcanoes with clear age progression; thus, their origin does not seem to fit this general model. Here we show a wide compositional spectrum of lavas from the Pako guyot within the Magellan seamount trail (MST), an age-progressive but short-lived volcanic chain in the WPSP. For the first time, both extreme high μ = 238U/204Pb mantle (HIMU)- and enriched mantle 1 (EM1)-like mantle plume components occur in a single seamount in the Pacific Ocean. Based on alteration resistant trace element and Sr–Nd–Pb–Hf isotopic compositions, the Pako lavas fall into three distinct groups. Group 1 has a distinctive HIMU composition with high (206Pb/204Pb)i ratios (20.41–20.94) similar to the Arago (also known as ‘Young Rurutu’ or ‘Atiu’) hotspot composition, suggesting derivation from a HIMU mantle source. Groups 2 and 3 EM1-like lavas comprise the dominant rock type and display the largest Sr–Nd–Pb–Hf isotopic variations that can be best explained by mixing between melts of focal zone (FOZO) and EM1-like mantle components. Additionally, olivine phenocrysts from Group 3 EM1-like lavas have high Ni contents, Fe/Mn and Mn/Zn ratios and low Zn/Fe*10 000 ratios, which can be explained through fractional crystallization of high-pressure partial melts from fertile peridotite. The EM1-like Groups 2 and 3 lavas are compositionally similar to the Rarotonga hotspot composition, suggesting that the MST is possibly an old trace of the Rarotonga hotspot, which is most likely a long-lived hotspot generated above a deep mantle plume. Combined with existing geochemical and tectonic data, we propose that the Magellan seamounts were likely derived from partial melting of a heterogeneous mantle plume containing HIMU, FOZO and EM1-like components. Alternatively, they could have been derived from the Arago and Rarotonga mantle plumes, each having its distinct compositional signature. The occurrence of HIMU- and EM1-like mantle plume components in a single volcano suggests that the superposition of compositionally different hotspot volcanic trails in the South Pacific could have played an important role in the generation of the WPSP.
The regulatory role of CARBON STARVED ANTHER-mediated photoperiod-dependent male fertility in rice
Authors: Li Jingbin , Wang Duoxiang , Sun Shiyu , Sun Linlin , Zong Jie , Lei Yaqi , Yu Jing , Liang Wanqi , Zhang Dabing
Published: March 2022

Environmental signals, especially daylength, play important roles in determining fertility in photoperiod-sensitive genic male sterile (PGMS) lines that are critical to sustain production of high-yielding hybrid rice (Oryza sativa) varieties. However, the mechanisms by which PGMS lines perceive changes in photoperiod and transmit those signals to elicit downstream effects are not well understood. In this study, we compared the transcriptomes from the leaves and anthers of carbon starved anther (csa), a PGMS line, to wild-type (WT) tissues under different photoperiods. Components of circadian clock in the leaves, including Circadian Clock-Associated 1 and Pseudo-Response Regulator (PRR95), played vital roles in sensing the photoperiod signals. Photoperiod signals were weakly transduced to anthers, where gene expression was mainly controlled by the CSA allele. CSA played a critical role in regulating sugar metabolism and cell wall synthesis in anthers under short-day conditions, and transcription of key genes inducing csa-directed sterility was upregulated under long-day (LD) conditions though not to WT levels, revealing a mechanism to explain the partial restoration of fertility in rice under LD conditions. Eight direct targets of CSA regulation were identified, all of which were genes involved in sugar metabolism and transport (cell wall invertases, SWEETs, and monosaccharide transporters) expressed only in reproductive tissues. Several hub genes coordinating the effects of CSA regulation were identified as critical elements determining WT male fertility and further analysis of these and related genes will reveal insights into how CSA coordinates sugar metabolism, cell wall biosynthesis, and photoperiod sensing in rice anther development.
Causal cascade of direct and indirect effects of anifrolumab on patient-reported outcomes: structural equation modelling of two Phase 3 trials
Authors: Stull Donald , O’Quinn Sean , Williams Betsy , Bean Stephanie , Schwetje Erik , Abreu Gabriel , Tummala Raj
Published: March 2022

Objectives

SLE significantly impairs health-related quality of life (HRQoL). In this post hoc analysis, structural equation modelling was used to examine the ‘causal cascade’ of interaction between anifrolumab, disease activity and patient-reported outcomes (PROs) in pooled data from the phase 3 TULIP-1 and TULIP-2 trials.

Methods

Data were pooled from the TULIP-1 (n = 364) and TULIP-2 (n = 362) randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). We evaluated changes from baseline to week 24 and week 52 in four clinical (BICLA, BILAG-2004, SLEDAI-2K and changes in glucocorticoid dosage) and six PRO measures (SF-36, FACIT-F, EQ-5D, LupusQoL, PHQ-8 and pain NRS) in our hypothesized model of interactions.

Results

Our hypothesized model had an acceptable fit to the pooled TULIP trial data. At week 24, significant paths revealed that when compared with placebo, anifrolumab treatment improved disease activity as measured by BICLA, BILAG-2004, SLEDAI-2K and changes to glucocorticoid dosage. In turn, these clinical measures reduced pain, which improved fatigue, physical functioning, mood/emotions and HRQoL. When the model incorporated number of glucocorticoid tapers as the measure of change in glucocorticoid dosage, treatment effects of anifrolumab on glucocorticoid tapers were not retained at week 52. However, at week 52 treatment indirectly improved HRQoL through its direct effects on BICLA.

Conclusions

Anifrolumab is associated with significant patient-reported improvements in aspects of HRQoL including pain, fatigue, mood and physical function. These benefits are from the direct effect of anifrolumab treatment on disease activity and reduction in glucocorticoid dosage.
Investigating characteristics of idiopathic inflammatory myopathy flares using daily symptom data collected via a smartphone app
Authors: Oldroyd Alexander G S , Krogh Niels Steen , Dixon William G , Chinoy Hector
Published: March 2022

Objective

The objective of this study was to use daily data collected via a smartphone app for characterization of patient-reported and symptom-based (using an a priori definition) flares in an adult idiopathic inflammatory myopathy (IIM) cohort.

Methods

UK adults with an IIM answered patient-reported outcome measurements (PROMs) daily via a smartphone app during a 91-day study. Daily symptom PROMs addressed global activity, overall pain, myalgia, fatigue, and weakness (on a 0–100 visual analogue scale). Patient-reported flares were recorded via a weekly app question. Symptom-based flares were defined via an a priori definition related to increase in daily symptom data from the previous 4-day mean.

Results

Twenty participants (65% female) participated. Patient-reported flares occurred on a median of 5 weeks (IQR 3, 7) per participant, out of a possible 13. The mean of each symptom score was significantly higher in flare weeks, compared with non-flare weeks (e.g. mean flare week myalgia score 34/100, vs 21/100 during non-flare week, t test P-value <0.01). Fatigue accounted for the most symptom-based flares [incidence-rate 23/100 person-days (95% CI 19, 27)], and myalgia the fewest [incidence rate 13/100 person-days (95% CI 11, 16)]. Symptom-based flares typically resolved after 3 days, although fatigue-predominant flares lasted 2 days. The majority (69%) of patient-reported flare weeks coincided with at least one symptom-based flare.

Conclusions

IIM flares are frequent and associated with increased symptom scores. This study has demonstrated the ability to identify and characterize patient-reported and symptom-based flares (based on an a priori definition), using daily app-collected data.
Sleep architecture based on sleep depth and propensity: patterns in different demographics and sleep disorders and association with health outcomes
Authors: Younes Magdy , Gerardy Bethany , Pack Allan I , Kuna Samuel T , Castro-Diehl Cecilia , Redline Susan
Published: March 2022

Study Objectives

Conventional metrics of sleep quantity/depth have serious shortcomings. Odds-Ratio-Product (ORP) is a continuous metric of sleep depth ranging from 0 (very deep sleep) to 2.5 (full-wakefulness). We describe an ORP-based approach that provides information on sleep disorders not apparent from traditional metrics.

Methods

We analyzed records from the Sleep-Heart-Health-Study and a study of performance deficit following sleep deprivation. ORP of all 30-second epochs in each PSG and percent of epochs in each decile of ORPs range were calculated. Percentage of epochs in deep sleep (ORP < 0.50) and in full-wakefulness (ORP > 2.25) were each assigned a rank, 1–3, representing first and second digits, respectively, of nine distinct types (“1,1”, “1,2” … ”3,3”). Prevalence of each type in clinical groups and their associations with demographics, sleepiness (Epworth-Sleepiness-Scale, ESS) and quality of life (QOL; Short-Form-Health-Survey-36) were determined.

Results

Three types (“1,1”, “1,2”, “1,3”) were prevalent in OSA and were associated with reduced QOL. Two (“1,3” and “2,3”) were prevalent in insomnia with short-sleep-duration (insomnia-SSD), but only “1,3” was associated with poor sleep depth and reduced QOL, suggesting two phenotypes in insomnia-SSD. ESS was high in types “1,1” and “1,2”, and low in “1,3” and “2,3”. Prevalence of some types increased with age while in others it decreased. Other types were either rare (“1,1” and “3,3”) or high (“2,2”) at all ages.

Conclusions

The proposed ORP histogram offers specific and unique information on the underlying neurophysiological characteristics of sleep disorders not captured by routine metrics, with potential of advancing diagnosis and management of these disorders.