bluuebunny/crossref_metadata_2025 huggingface dataset:
Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Authors: Dampalla Chamandi S. , Zheng Jian , Perera Krishani Dinali , Wong Lok-Yin Roy , Meyerholz David K. , Nguyen Harry Nhat , Kashipathy Maithri M. , Battaile Kevin P. , Lovell Scott , Kim Yunjeong , Perlman Stanley , Groutas William C. , Chang Kyeong-Ok
Published: July 2021

Significance

Protease inhibitors targeting viral 3C-like protease are attractive therapeutic options for COVID-19. Here, we synthesized deuterated variants of a coronavirus protease inhibitor, GC376, and determined the therapeutic efficacy in a lethal mouse model. The transgenic mice infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of COVID-19, develop lung pathology resembling that of severe COVID-19 patients and were used for antiviral drug testing. The deuterated variants of GC376 have improved potency against SARS-CoV-2 in in vitro assays. Furthermore, treatment with a deuterated variant starting at 24 h postinfection resulted in significantly increased survival of mice compared to vehicle-treated mice. The results suggest that deuterated variants have excellent potential as antiviral agents against SARS-CoV-2.
Evaluation of Conflicts of Interest among Systematic Review Authors on Pharmacological Therapies for Alcohol use Disorder: A Cross-Sectional Study
Authors: Crow Matt , Hartwell Micah , Anderson J. Michael , Tritz Daniel , Vassar Matt
Published: July 2021

Introduction and aims: The high prevalence and economic burden of alcohol use disorder (AUD) requires methodologically sound research to guide treatment decisions. Systematic reviews (SR) are fundamental to clinical decision making as they collate results of all studies for a given topic and provide summaries of the clinical evidence. Bias resulting from industry relationships can compromise the validity of SRs. Thus, we investigated financial conflicts of interests (FCOI) within SRs involving the pharmacologic treatment of AUD. Design and Methods: We conducted a systematic search of PubMed, Embase, and the Cochrane Database to retrieve SRs published between September 2016 and December 2019. Screening and data extraction were performed in duplicate, blinded fashion—collecting characteristics of the reviews including the authors’ FCOI statements. The results and discussion sections were rated as favorable or unfavorable toward the treatment drug. A stepwise method was used to identify undisclosed FCOIs for all SR authors. Results: Nineteen (of 51) authors representing 7 (of 12) SRs were found to have FCOI. Among reviews with conflicted authors, 3 of 7 (42.9%) results sections were favorable toward the treatment drug, whereas 6 of 7 (85.7%) conclusions were rated as favorable. Discussion and Conclusions: More than one-third of SR authors and nearly two-thirds of studies were found to have FCOIs. Our investigation shows that financial ties are frequent among SR authors on AUD pharmacotherapies and that discussion sections often favored the drug for which the sponsor provided payments.
Impact of Medicaid Expansion on Mental Health and Substance use Related Emergency Department Visits
Authors: Jayawardhana Jayani
Published: July 2021

Background: Although Medicaid expansion under the Affordable Care Act reduces uninsurance, little evidence exists on its impact on mental health and substance use (MHSU) related healthcare utilization. Therefore, the objectives of this study are to examine the impact of Medicaid expansion on emergency department visits related to mental health and substance use disorders and to examine its effect on the variation in payer mix. Methods: The study utilizes state-level quarterly emergency department (ED) visit data from Healthcare Cost and Utilization Project's Fast Stats Database, along with state socio-demographic and health policy data for the analysis. A difference-in-differences regression analysis approach was utilized in comparing MHSU-related ED visit data between expansion and non-expansion states from 2006 to 2019 for all visits and by payer mix. Results: Medicaid expansion was associated with additional 0.35 non-Medicare adult MHSU-related ED visits per 1,000 population ( p < 0.05) in expansion states compared with non-expansion states. In addition, Medicaid expansion was associated with about 20.4% increase ( p < 0.01) in Medicaid-share of MHSU-related ED visits, about 17.4% reduction ( p < 0.01) in uninsured-share of MHSU-related ED visits, and about 3% reduction ( p < 0.05) in privately-insured share of MHSU-related ED visits in expansion states compared with non-expansion states. Conclusions: The findings indicate that Medicaid expansion was associated with increased MHSU-related ED visits among the Medicaid population and the overall non-Medicare adult population, while it was associated with reductions in MHSU-related ED visits among the uninsured and privately-insured populations in expansion states compared with non-expansion states.
Bufferless Epitaxial Growth of GaAs on Step-Free Ge (001) Mesa
Authors: Huang Ding-Ming , Zhang Jie-Yin , Wang Jian-Huan , Wei Wen-Qi , Wang Zi-Hao , Wang Ting , Zhang Jian-Jun
Published: July 2021

GaAs/Ge heterostructures have been employed in various semiconductor devices such as solar cells, high-performance CMOS transistors, and III–V/IV heterogeneous optoelectronic devices. The performance of these devices is directly dependent on the material quality of the GaAs/Ge heterostructure, while the material quality of the epitaxial GaAs layer on the Ge is limited by issues such as the antiphase domain (APD), and stacking-fault pyramids (SFP). We investigate the epitaxial growth of high-quality GaAs on a Ge (001) mesa array, via molecular beam epitaxy. Following a systematic study of the Ge terrace via an in situ scanning tunneling microscope, an atomically step-free terrace on the Ge mesa measuring up to 5 × 5 μm2 is obtained, under optimized growth conditions. The step-free terrace has a single-phase c (4 × 2) surface reconstruction. The deposition of a high-quality GaAs layer with no APD and SFP is then achieved on this step-free Ge terrace. High-resolution transmission electron microscopy and electron channel contrast image characterizations reveal the defect-free growth of the GaAs layer on the step-free Ge mesa. Furthermore, InAs quantum dots on this GaAs/Ge mesa reveal photoluminescent intensity comparable to that achieved on a GaAs substrate, which further confirms the high quality of the GaAs layer on Ge.
FeSO4 as a Novel Li-Ion Battery Cathode
Authors: Yang Jiachao , Zou Jian , Luo Chun , Ran Qiwen , Wang Xin , Chen Pengyu , Hu Chuan , Niu Xiaobin , Ji Haining , Wang Liping
Published: July 2021

FeSO4 has the characteristics of low cost and theoretical high energy density (799 W⋅h⋅kg−1 with a two-electron reaction), which can meet the demand for next-generation lithium-ion batteries. Herein, FeSO4 as a novel high-performance conversion-reaction type cathode is investigated. We use dopamine as a carbon coating source to increase its electronic conductivity. FeSO4@C demonstrates a high reversible specific capacity (512 mA⋅h⋅g−1) and a superior cycling performance (482 mA⋅h⋅g−1 after 250 cycles). In addition, we further study its reaction mechanism. The FeSO4 is converted to Fe and Li2SO4 during lithium ion insertion and the Fe|Li2SO4 grain boundaries further store additional lithium ions. Our findings are valuable in exploring other new conversion-type lithium ion battery cathodes.
Rabi Spectroscopy and Sensitivity of a Floquet Engineered Optical Lattice Clock
Authors: Yin Mo-Juan , Wang Tao , Lu Xiao-Tong , Li Ting , Wang Ye-Bing , Zhang Xue-Feng , Li Wei-Dong , Smerzi Augusto , Chang Hong
Published: July 2021

We periodically modulate the lattice trapping potential of a 87Sr optical clock to Floquet engineer the clock transition. In the context of atomic gases in lattices, Floquet engineering has been used to shape the dispersion and topology of Bloch quasi-energy bands. Differently from these previous works manipulating the external (spatial) quasi-energies, we target the internal atomic degrees of freedom. We shape Floquet spin quasi-energies and measure their resonance profiles with Rabi spectroscopy. We provide the spectroscopic sensitivity of each band by measuring the Fisher information and show that this is not depleted by the Floquet dynamical modulation. The demonstration that the internal degrees of freedom can be selectively engineered by manipulating the external degrees of freedom inaugurates a novel device with potential applications in metrology, sensing and quantum simulations.
Random statistics of OPE coefficients and Euclidean wormholes
Authors: Belin Alexandre , de Boer Jan
Published: July 2021

We propose an ansatz for OPE coefficients in chaotic conformal field theories which generalizes the eigenstate thermalization hypothesis and describes any OPE coefficient involving heavy operators as a random variable with a Gaussian distribution. In two dimensions this ansatz enables us to compute higher moments of the OPE coefficients and analyse two and four-point functions of OPE coefficients, which we relate to genus-2 partition functions and their squares. We compare the results of our ansatz to solutions of Einstein gravity in AdS3, including a Euclidean wormhole that connects two genus-2 surfaces. Our ansatz reproduces the non-perturbative correction of the wormhole, giving it a physical interpretation in terms of OPE statistics. We propose that calculations performed within the semi-classical low-energy gravitational theory are only sensitive to the random nature of OPE coefficients, which explains the apparent lack of factorization in products of partition functions.
Nonlinear gravitational-wave memory from cusps and kinks on cosmic strings
Authors: Jenkins Alexander C , Sakellariadou Mairi
Published: July 2021

The nonlinear memory effect is a fascinating prediction of general relativity (GR), in which oscillatory gravitational-wave (GW) signals are generically accompanied by a monotonically-increasing strain which persists in the detector long after the signal has passed. This effect is directly accessible to GW observatories, and presents a unique opportunity to test GR in the dynamical and nonlinear regime. In this article we calculate, for the first time, the nonlinear memory signal associated with GW bursts from cusps and kinks on cosmic string loops, which are an important target for current and future GW observatories. We obtain analytical waveforms for the GW memory from cusps and kinks, and use these to calculate the ‘memory of the memory’ and other higher-order memory effects. These are among the first memory observables computed for a cosmological source of GWs, with previous literature having focused almost entirely on astrophysical sources. Surprisingly, we find that the cusp GW signal diverges for sufficiently large loops, and argue that the most plausible explanation for this divergence is a breakdown in the weak-field treatment of GW emission from the cusp. This shows that previously-neglected strong gravity effects must play an important rôle near cusps, although the exact mechanism by which they cure the divergence is not currently understood. We show that one possible resolution is for these cusps to collapse to form primordial black holes (PBHs); the kink memory signal does not diverge, in agreement with the fact that kinks are not predicted to form PBHs. Finally, we investigate the prospects for detecting memory from cusps and kinks with current and future GW observatories, considering both individual memory bursts and the contribution of many such bursts to the stochastic GW background. We find that in the scenario where the cusp memory divergence is cured by PBH formation, the memory signal is strongly suppressed and is not likely to be detected. However, alternative resolutions of the cusp divergence may in principle lead to much more favourable observational prospects.
Stability and optimal decay for a system of 3D anisotropic Boussinesq equations
Authors: Wu Jiahong , Zhang Qian
Published: July 2021

This paper focuses on a system of three-dimensional (3D) Boussinesq equations modeling anisotropic buoyancy-driven fluids. The goal here is to solve the stability and large-time behavior problem on perturbations near the hydrostatic balance, a prominent equilibrium in fluid dynamics, atmospherics and astrophysics. Due to the lack of the vertical kinematic dissipation and the horizontal thermal diffusion, this stability problem is difficult. When the spatial domain is

Ω
=

R

2

×
T

with

T
=

[

−
1
/
2
,
1
/
2

]

being a 1D periodic box, this paper establishes the desired stability for fluids with certain symmetries. The approach here is to distinguish the vertical averages of the velocity and temperature from their corresponding oscillation parts. In addition, the oscillation parts are shown to decay exponentially to zero in time.
Corrigendum: Influence of metal matrix powder size on the tensile strength of a SiCp/AlSi7Mg0,6 composite produced by field assisted sintering technique (2021 IOP Conf. Ser.: Mater Sci Eng. 1147 012020)
Authors: Pippig R , Hirsch S J , Grund T , Lampke T
Published: July 2021

In the section Results and Discussion of our published paper the units for the heating energy and the toughness contain a mistake.
Gallium-effect in a lead-free solder for silver-sheathed superconducting tape
Authors: Shamoto Shin-Ichi , Lee Min Kai , Fujimura Yuki , Kondo Keietsu , Ito Takashi U , Ikeuchi Kazuhiko , Yasuda Satoshi , Chang Lieh-Jeng
Published: July 2021

Solder joints of silver-sheathed superconducting tapes are promising for various commercial applications. In this research, Pb, Ga, and Ga-doped lead-free Sn–Ag–Cu solders are used to study the gallium effect for the low joint resistivity with silver-sheathed DI-BISCCO type H tapes. In Ga-doped Sn–Ag–Cu solder, a smooth interfacial Ag2Ga layer is uniformly formed on the Ag-sheath surface. As a result, the solder joint achieved a very low joint resistivity of 16 nΩcm2 at 40 K. The present gallium-doped lead-free solder can also be applied to general soldering use with Ag materials.
Achieving Expert-Level Interpretation of Serum Protein Electrophoresis through Deep Learning Driven by Human Reasoning
Authors: Chabrun Floris , Dieu Xavier , Ferre Marc , Gaillard Olivier , Mery Anthony , Chao de la Barca Juan Manuel , Taisne Audrey , Urbanski Geoffrey , Reynier Pascal , Mirebeau-Prunier Delphine
Published: July 2021

Background

Serum protein electrophoresis (SPE) is a common clinical laboratory test, mainly indicated for the diagnosis and follow-up of monoclonal gammopathies. A time-consuming and potentially subjective human expertise is required for SPE analysis to detect possible pitfalls and to provide a clinically relevant interpretation.

Methods

An expert-annotated SPE dataset of 159 969 entries was used to develop SPECTR (serum protein electrophoresis computer-assisted recognition), a deep learning-based artificial intelligence, which analyzes and interprets raw SPE curves produced by an analytical system into text comments that can be used by practitioners. It was designed following academic recommendations for SPE interpretation, using a transparent architecture avoiding the “black box” effect. SPECTR was validated on an external, independent cohort of 70 362 SPEs and challenged by a panel of 9 independent experts from other hospital centers.

Results

SPECTR was able to identify accurately both quantitative abnormalities (r ≥ 0.98 for fractions quantification) and qualitative abnormalities [receiver operating characteristic–area under curve (ROC–AUC) ≥ 0.90 for M-spikes, restricted heterogeneity of immunoglobulins, and beta-gamma bridging]. Furthermore, it showed highly accurate at both detecting (ROC–AUC ≥ 0.99) and quantifying (r = 0.99) M-spikes. It proved highly reproducible and resilient to minor variations and its agreement with human experts was higher (κ = 0.632) than experts between each other (κ = 0.624).

Conclusions

SPECTR is an algorithm based on artificial intelligence suitable to high-throughput SPEs analyses and interpretation. It aims at improving SPE reproducibility and reliability. It is freely available in open access through an online tool providing fully editable validation assistance for SPE.
Digital Quantification of Chemical Oligonucleotide Synthesis Errors
Authors: Filges Stefan , Mouhanna Pia , Ståhlberg Anders
Published: July 2021

Background

Chemically synthesized oligonucleotides are vital to most nucleic acids-based technologies and several applications are sensitive to oligonucleotide sequence errors. However, it is challenging to identify and quantify the types and amount of errors in synthetic oligonucleotides.

Methods

We applied a digital sequencing approach using unique molecular identifiers to quantify errors in chemically synthesized oligonucleotides from multiple manufacturers with different synthesis strategies, purity grades, batches, and sequence context.

Results

We detected both deletions and substitutions in chemical oligonucleotide synthesis, but deletions were 7 times more common. We found that 97.2% of all analyzed oligonucleotide molecules were intact across all manufacturers and purity grades, although the number of oligonucleotide molecules with deletions ranged between 0.2% and 11.7% for different types. Different batches of otherwise identical oligonucleotide types also varied significantly, and batch effect can impact oligonucleotide quality more than purification. We observed a bias of increased deletion rates in chemically synthesized oligonucleotides toward the 5’-end for 1 out of 2 sequence configurations. We also demonstrated that the performance of sequencing assays depends on oligonucleotide quality.

Conclusions

Our data demonstrate that manufacturer, synthesis strategy, purity, batch, and sequence context all contribute to errors in chemically synthesized oligonucleotides and need to be considered when choosing and evaluating oligonucleotides. High-performance oligonucleotides are essential in numerous molecular applications, including clinical diagnostics.
Level of Decoy Receptor 3 for Monitoring Clinical Progression of Severe Burn Patients
Authors: Min Dong , Wu Bing , Chen Long , Chen Ruiqin , Wang Jiling , Zhang Hailong , Chen Jinrong , Kim Sunghee , Zhang Lurong , Xia Zhaofan , Lin Jianhua
Published: July 2021

The clinical value of Decoy receptor 3 (DcR3) in severe burn is investigated. Ten patients with severe burns were monitored for DcR3, PCT, CRP, IL6, SOFA score, white blood cell (WBC), and platelet. The correlations were analyzed. DcR3 increased on day 1. The nonsurvivors had a steady high level of DcR3 while the survivors had a relatively low level of DcR3. The peak magnitude of DcR3 was high in five nonsurvivors and low in five survivors without overlap. Three patients had a continuously increasing DcR3 level and then died. In the other two nonsurvivors, DcR3 reached the peak and then decreased before death. DcR3 correlated well with PCT (ρ = 0.4469, P < .0001), less with CRP, platelet, IL6, SOFA score and WBC (ρ = 0.4369, 0.4078, 0.3995, 0.2631, 0.1504, respectively, all P < .001). To explore the mechanisms, the HaCaT or THP-1 cells were stimulated by the plasma of burn patients, 45°C, LPS or stimulators of TLRs or NOD2 (PGN, CL264, MDP, iE-DAP, Gardiquimod), and their DcR3 was increased, which could be reduced by GDC-0941 or BEZ235 (inhibitors of PI3K and mTOR). The levels of DcR3 appeared to be a useful biomarker for monitoring the clinical severity and a predictor of mortality of severe burns.
The Under-representation of Canadian Women in Gastroenterology from Residency to Leadership
Authors: Jawaid Noor , LoMonaco Jordan , Bollegala Natasha
Published: July 2021

Background

To determine representation of women in gastroenterology (GI) at residency and leadership levels in Canada.

Methods

The Canadian Resident Matching Service provided data for internal medicine (IM), general surgery (GS), GI and cardiology applicant cycles 2014 to 2018. Z-tests were used to compare proportion of women entering each residency program. An internet search was conducted to calculate percentages of women as GI association presidents, residency program directors, division heads and oral speakers at conferences.

Results

IM residency had on average of 1789 applicants with 487 matched (49.4% versus 49.5% women). GS residency had on average 357 applicants with 90 matched (41% versus 54.4% women). GI residency had on average 46 applicants with 34 matched (37% versus 35.3% women). Cardiology residency had on average 76 applicants with 54 matched (29% versus 27.8% women).

The Canadian Association of Gastroenterology (CAG) has had two out of 47 (4.2%) women presidents. The Ontario Association of Gastroenterology (OAG) has had no women presidents (0/9). The Association des gastro-entérologues du Québec (AGEQ) has had two out of 15 (13%) women presidents. The Alberta Society of Gastroenterology (ASG) has had one out of five (20%) women presidents. From 2018 to 2020, university division heads ranged from 0% to 13.3% women (0 to 2/15). University GI training program directors ranged from 28.6% to 35.7% (4 to 5/14). Women speakers at CAG’s annual conference varied 27% to 42% from 2016 to 2020, averaging 32.7%. Women speakers at OAG’s, AGEQ’s and ASG’s annual conferences averaged 23.3%, 24.1% and 35%, respectively.

Conclusion

Women gastroenterologists display low representation at multiple levels along the GI career pathway.
Judge Shopping
Authors: Kahan Marcel , McKenzie Troy A
Published: July 2021

We examine related case rules, which are local rules adopted by federal district courts to determine whether a newly filed civil action will be assigned to a judge presiding over a previously filed similar case or a randomly chosen judge. Districts have adopted divergent approaches to the definition of “relatedness” as well as to the process for determining whether a case satisfies the definition. We analyze how these design choices affect the ability of parties to strategically manipulate case assignments to gain an advantage in litigation. We also propose suggestions for the optimal design of the assignment rules for related cases.
Accountability and Affective Styles in Administrative Reporting: The Case of UNRWA, 1951–2020
Authors: Patz Ronny , Thorvaldsdottir Svanhildur , Goetz Klaus H
Published: July 2021

This contribution theorizes on the emergence of affective styles in the accountability reporting of public agencies. Under conditions of multiple accountability towards heterogeneous stakeholders, public agencies are expected to make increased use of sentiment in their reporting. Agencies’ differentiated modulation of positive and negative sentiment results in four ideal-typical affective styles: technocratic, political, alarming, and self-praising. The plausibility of this framework is demonstrated for the case of a major international public agency, the United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA), which serves several million Palestine refugees. We conduct a dictionary-based sentiment analysis of UNRWA annual reports published between 1951 and 2020, a corpus of 1.47 million words. Additional evidence from interviews with UNRWA officials and diplomats is also considered. Over time, the agency’s use of sentiment has increased in response to diversifying stakeholders and its affective style of reporting has changed repeatedly. Contrary to established theoretical expectations, multiple accountability not only increases positive reporting and self-praise. Rather, with increasing levels of negativity, the alarming and political styles of communication have played a much stronger role. These findings demonstrate that agencies’ chief goal in accountability reporting is not simply to elicit positive assessments from their respective accountability forums through self-praising language. Agencies may also aim to achieve “negativity congruence” with accountability forums by increasing negative sentiment, thus compelling stakeholders to acknowledge the operational challenges agencies face.
sofia 2 – an automated, parallel H i source finding pipeline for the WALLABY survey
Authors: Westmeier T , Kitaeff S , Pallot D , Serra P , van der Hulst J M , Jurek R J , Elagali A , For B-Q , Kleiner D , Koribalski B S , Lee-Waddell K , Mould J R , Reynolds T N , Rhee J , Staveley-Smith L
Published: July 2021

We present sofia 2, the fully automated 3D source finding pipeline for the WALLABY extragalactic H i survey with the Australian SKA Pathfinder (ASKAP). sofia 2 is a reimplementation of parts of the original sofia pipeline in the c programming language and makes use of OpenMP for multithreading of the most time-critical algorithms. In addition, we have developed a parallel framework called sofia-X that allows the processing of large data cubes to be split across multiple computing nodes. As a result of these efforts, sofia 2 is substantially faster and comes with a much reduced memory footprint compared to its predecessor, thus allowing the large WALLABY data volumes of hundreds of gigabytes of imaging data per epoch to be processed in real time. The source code has been made publicly available to the entire community under an open-source licence. Performance tests using mock galaxies injected into genuine ASKAP data suggest that in the absence of significant imaging artefacts sofia 2 is capable of achieving near-100 per cent completeness and reliability above an integrated signal-to-noise ratio (SNR) of about 5–6. We also demonstrate that sofia 2 generally recovers the location, integrated flux, and w20 line width of galaxies with high accuracy. Other parameters, including the peak flux density and w50 line width, are more strongly biased due to the influence of the noise on the measurement. In addition, very faint galaxies below an integrated SNR of about 10 may get broken up into multiple components, thus requiring a strategy to identify fragmented sources and ensure that they do not affect the integrity of any scientific analysis based on the sofia 2 output.
Exploring the inner-disc region of the atoll source 4U 1705-44 using AstroSat’s SXT and LAXPC observations
Authors: Malu S , Sriram K , Harikrishna S , Agrawal Vivek K
Published: July 2021

For the first time, simultaneous broad-band spectral and timing study of the atoll source 4U 1705-44 was performed using AstroSat Soft X-ray Telescope (SXT) and Large Area X-ray Proportional Counter (LAXPC) data (0.8–70 keV). Based on the HID, the source was in the soft banana state during these observations. Spectral modelling was performed using the full reflection framework and an inner disc radii of 14 Rg was obtained. A hard power-law tail was noticed in the soft state and hot component fluxes and varying power-law indices point towards a varying corona/sub-Keplerian flow. Based on the spectral fits, the boundary layer radius and magnetospheric radius were constrained to be ∼14–18 and ∼9–19 km, respectively. Cross-correlation function studies were performed between the 0.8–3 keV soft SXT light curve and 10–20 keV hard LAXPC light curve and correlated and anticorrelated lags were found, which was used to constrain the coronal height to 0.6–20 km (β = 0.1). Since the inner disc radius is not varying during the observations, we conclude that the detected lags are possibly caused by a varying structure of corona/boundary layer in the inner region of the accretion disc. Based on the observations, a geometrical model is proposed for explaining the detected lags in the atoll source 4U 1705-44.
Integrase Strand Transfer Inhibitors and Weight Gain in Children and Youth With Perinatal Human Immunodeficiency Virus in the DC Cohort
Authors: Koay Wei Li A , Dirajlal-Fargo Sahera , Levy Matthew E , Kulie Paige , Monroe Anne , Castel Amanda D , Rakhmanina Natella Y ,   DC Cohort Executive Committee, D’Angelo Lawrence , Rakhmanina Natella , Kharfen Michael , Serlin Michael , Kumar Princy , Bamdad Aria , Bezabeh Tsedenia , Burrows Pamela Katzen , Reamer Susan , Sapozhnikova Alla , Temprosa Marinella , Younes Naji , Byrne Morgan , Castel Amanda , Greenberg Alan , Jaurretche Maria , Levy Matthew , Monroe Anne , Peterson James , Happ Lindsey Powers , Wilbourn Brittany , Ma Yan , Akselrod Hana , Wilcox Ronald , Rana Sohail , Horberg Michael , Fernandez Ricardo , Hebou Annick , Dieffenbach Carl , Masur Henry , Bordon Jose , Teferi Gebeyehu , Benator Debra , Ruiz Maria Elena , Abbott Stephen
Published: July 2021

We conducted a retrospective analysis of 38 children and youth with human immunodeficiency virus (aged 0–19 years) in the United States and report an increased rate of change of BMI-for-age z score after initiating integrase strand transfer inhibitors (+0.19 z score units/year [95% confidence interval, .01–.37]; P = .036) for a median follow-up of 527.5 days.
Updated Experience of Mycobacterium chimaera Infection: Diagnosis and Management in a Tertiary Care Center
Authors: Tan Nicholas Y , Tarabochia Alex D , DeSimone Daniel C , DeSimone Christopher V , Wilson John W , Bagameri Gabor , Bennett Courtney E , Abu Saleh Omar M
Published: July 2021

Background

Despite safety communications from the Food and Drug Administration (FDA) regarding the outbreak of Mycobacterium chimaera infections (MCIs) from contaminated heater-cooler devices, new cases continue to be identified.

Methods

We retrospectively reviewed confirmed cases of MCI that were managed at Mayo Clinic sites (Arizona, Florida, and Minnesota) from 09/2015 to 01/2021. Clinical histories including prior cardiovascular surgery were recorded. Diagnostic workup including ophthalmologic examination, imaging, and laboratory testing was reviewed. Treatment and survival outcomes on follow-up were obtained.

Results

Twelve patients with MCI were included. All patients had aortic valve or graft replacement. Five patients had their surgical procedures following the 10/15/2015 FDA safety communication. The mean time from surgery to symptom onset (range) was 32 (13–73) months. Ten of 11 patients who underwent ophthalmologic examination had chorioretinal abnormalities. Three patients who underwent microbial cell-free deoxyribonucleic acid sequencing tested positive for M. chimaera, which was subsequently confirmed with blood culture growth. Echocardiography and positron emission tomography/computed tomography (PET/CT) revealed evidence of prosthetic valve/graft infection in 7/12 (58.3%) and 6/10 (60.0%) of cases, respectively. Seven patients (58.3%) underwent redo cardiovascular surgery. Of these, 1 patient died 2 days postdischarge, 1 experienced spinal osteomyelitis relapse, and another had interval prosthetic valve fluorodeoxyglucose (FDG) uptake on PET/CT suspicious for recurrent infection. Among 4 patients on medical therapy only, 3 expired or transitioned to hospice during follow-up.

Conclusions

MCI continues to occur despite the FDA communications. Incorporation of ophthalmologic examination and use of advanced tools may improve MCI diagnosis. The mortality in these patients is high even with aggressive surgical/medical management.
Quality of life among older Chinese people living with HIV/AIDS: a cross-sectional study in Hunan
Authors: Chen Dan , Wang Min , Duan Luxi , Chen Xi , Zhang Qiang , Li Xingli
Published: July 2021

Background

There is little research to date in the area of quality of life (QoL) among older Chinese people living with HIV/AIDS (PLWHA). This study aims to explore the QoL and its influential factors among older PLWHA in China.

Methods

Cross-sectional data of 242 adults with HIV/AIDS aged 50–84 y from Hunan were analyzed to evaluate the associations of demographic characteristics, illness-related factors, HIV-related stigma and social support with QoL. The WHO QOL-HIV BREF questionnaire was used to measure QoL on six domains (physical, psychological, independence, social relationships, environment and spirituality).

Results

A total of 242 older PLWHA completed the survey, of whom 150 (62.0%) were males. Multivariate linear regression analyses identified that females, side effects of highly active antiretroviral therapy, chronic non-communicable diseases and higher levels of perceived negative self-image were negatively associated with QoL, especially in the physical, independence and spirituality domains; whereas higher education or annual income, retired and elevated levels of subjective social support or support availability were positively associated with QoL, especially in the psychological, independence, social relationships and environment domains.

Conclusions

The study findings suggest that interventions to improve QoL should focus on reducing HIV-related stigma and side effects and on enhancing economic situations and social support.
Contribution ofSchistosoma mansonito systemic inflammation and microbial translocation among people with HIV in Zambia
Authors: Furch Briana D , Mwakamui Simutanyi , Sianongo Sandie , Zyambo Kanekwa , Heimburger Douglas C , Koethe John R , Kelly Paul
Published: July 2021

Background

Schistosoma mansoni is hyperendemic in many rural areas of Zambia where up to 77% of people are positive for infection via serologic evaluation. Zambia also has a high prevalence of HIV infection. Individually, S. mansoni and HIV infection impair gastrointestinal barrier integrity and induce inflammation, but the effects of coinfection are not well understood. We set out to test the hypothesis that HIV would exacerbate intestinal barrier failure in patients with S. mansoni infection.

Methods

Adults attending medical outpatient clinics in Kaoma, Western Province, Zambia, were enrolled in a case-control study to determine the relative contributions of schistosomiasis and HIV to microbial translocation (measured as soluble CD14 [sCD14] and lipopolysaccharide binding protein [LBP]) and inflammation (measured as CRP).

Results

Among 152 adults evaluated, 74 (49%) were HIV-seropositive, 45 (29%) were shedding schistosome ova (Kato-Katz), 120 (81%) were seropositive for schistosome antibodies (i.e. prior or current infection, with or without egg shedding) and 16 (11%) were HIV/schistosome coinfected (defined by Kato-Katz). HIV infection was associated with higher circulating sCD14 concentrations (p=0.003 by Kruskal–Wallis test), but schistosomiasis was not. HIV infection was associated with greater exposure to schistosomes assessed serologically (OR=2.48, 95% CI 1.05 to 5.86; p=0.03), but reduced likelihood of egg shedding (OR 0.47, 95% CI 0.21 to 1.01; p=0.03).

Conclusions

There was no evidence for a compounding or synergistic effect of coinfection on microbial translocation that appeared to be correlated with HIV infection. Further studies are needed to understand how the increase in LBP secondary to HIV infection may decrease schistosome egg excretion in coinfected individuals.
Knockdown of enhancer of rudimentary homolog expression attenuates proliferation, cell cycle and apoptosis of melanoma cells
Authors: Xiao Muzhang , Tang Ningning , Yan Yu , Li Zhelin , Shi Shupeng , He Siqi , Chen Zizi , Cao Ke , Chen Jia , Zhou Jianda , Chen Xiang
Published: July 2021

Early stage or localized melanoma can be surgically resected with satisfactory outcome, whereas advanced malignant melanoma responds to treatment poorly and has a negative prognosis even after surgery, radiotherapy and other comprehensive treatments. Gene therapy targeting various biological signaling pathways has become an increasingly popular area in melanoma research. However, for gene therapy success, it is important to reveal the molecular mechanisms of melanoma tumorigenesis and development. The present study examined the effects of downregulating enhancer of rudimentary homolog (ERH) expression on the proliferation, metastasis and cell cycle of melanoma cells. ERH expression levels in melanoma tissues and cells were determined. Then, ERH gene expression in melanoma cell lines was downregulated or overexpressed by the lentiviral RNA interference technique. Furthermore, we performed cell counting kit-8, clone formation, scratch, transwell migration, subcutaneous tumorigenesis and venous metastasis assays as well as carried out flow cytometry analysis to explore the effects of ERH expression on cell proliferation, cell cycle, apoptosis and metastasis. We found that ERH expression in melanoma tissues and cells was markedly higher than in normal melanin nevus. Suppressing ERH expression by RNA interference in melanoma A375, WM35 and SK28 cell lines inhibited their proliferation and induced cell apoptosis. The cell cycle was also found to be blocked in the G1 phase. However, the metastatic properties of melanoma cells in vitro and in vivo remained largely unaltered by ERH knockdown. Our results show that ERH expression is increased in melanoma. Meanwhile, the proliferation and cell cycle transformation abilities are impaired potentially by downregulating the ERH expression in melanoma cells. Therefore, targeting ERH might serve as a novel therapeutic approach for malignant melanoma.
Autozygosity Mapping by Genome-wide Single Nucleotide Polymorphism Array Identifies a Novel Homozygous HR Mutation in a Consanguineous Family with Universal Hereditary Hair Loss
Authors: Zeinali Sirous , Youssefian Leila , Vahidnezhad Hassan , Saeidian Amir Hossein , Sotoudeh Soheila , Bagherian Hamideh , Uitto Jouni
Published: July 2021

Objective:

Isolated hereditary hypotrichosis is caused by mutations in as many as 11 different genes. The conventional mutation detection strategy consists of sequencing of individual candidate genes separately, a time consuming and costly approach. In this study, we perform genome-wide single nucleotide polymorphism (SNP) array to identify candidate genes of hereditary hypotrichosis.

Methods:

A consanguineous family with two patients with hereditary hypotrichosis was enrolled, and autozygosity mapping by genome-wide SNP array was utilized to identify candidate genes.

Results:

Autozygosity mapping delineated runs of homozygosity, and alignment of the 11 genes identified the hairless (HR) gene as the candidate gene. Nucleotide sequencing revealed a novel homozygous mutation c.381delT, p.Ser127ArgfsTer40.

Conclusion:

This study illustrates how autozygosity mapping by a high-density SNP array streamlines mutation detection in heritable skin diseases.
Regulatory involvement of the PerR and SloR metalloregulators in theStreptococcus mutansoxidative stress response
Authors: Ruxin Talia R. , Schwartzman Julia A. , Davidowitz Cleo R. , Haney Robet A. , Spatafora Grace A.
Published: July 2021

Streptococcus mutansis a commensal of the human oral microbiome that can instigate dental caries under conditions of dysbiosis. This study investigatesS. mutansmetalloregulators and their involvement in mediating a response to oxidative stress. Oxidative stress in the oral cavity can derive from temporal increases in reactive oxygen species (ROS) after meal consumption, and from endogenous bacterial ROS-producers that colonize the dentition as constituents of dental plaque. We hypothesize that the PerR (SMU.593) and SloR (SMU.186) metalloregulatory proteins inS. mutanscontribute to oxidative stress tolerance by regulating the expression of genes responsive to H2O2challenge. The results of qRT-PCR experiments withS. mutanscultures exposed to 0.5mM H2O2revealperRtranscription that is responsive to the peroxide stressor, andsloRtranscription that is subject to PerR repression. The results of gel shift assays support direct binding of a PerR homolog to theS. mutans sloRpromoter at Fur and PerR consensus sequences on the UA159 chromosome. In addition, transcription of theS. mutans tpxanddprantioxidant genes is upregulated in aperR/sloRdouble knockout mutant, consistent with heightened resistance of theS. mutansGMS802perR-deficient strain when challenged with H2O2. Cumulatively, these results reveal a relationship of reciprocity between the PerR and SloR metalloregulators during theS. mutansresponse to oxidative stress and begin to elucidate the fitness strategies that evolved to fosterS. mutanssurvival and persistence in the transient environments of the human oral cavity.

IMPORTANCE

In 2020, untreated dental caries, especially in the permanent dentition, ranked among the most prevalent infectious diseases worldwide. Moreover, caries disproportionately affects children and individuals of low socioeconomic status. Untreated caries can lead to systemic health problems and has been associated with extended school and work absences, inappropriate use of emergency departments, and an inability for military forces to deploy. In combination with public health policy, research aimed at alleviatingS. mutans-inducedtooth decay is important because it can improve oral health, as well as overall health, especially for underserved populations. This research is focused on theS. mutansSloR and PerR metalloregulatory proteins that can help inform the development of therapeutics aimed at alleviating and potentially preventing dental caries.
Transcranial direct current stimulation combined with alcohol cue inhibitory control training reduces the risk of early alcohol relapse: a randomized placebo-controlled clinical trial
Authors: Dubuson Macha , Kornreich Charles , Vanderhasselt Anne , Baeken Chris , Wyckmans Florent , Dousset Clémence , Hanak Catherine , Veeser Johannes , Campanella Salvatore , Chatard Armand , Jaafari Nemat , Noël Xavier
Published: July 2021

Background

Approximately half the people with alcohol use disorder (AUD) relapse into alcohol reuse in the few weeks following withdrawal treatment. Brain stimulation and cognitive training represent recent forms of complementary interventions in the context of AUD.

Objective

To evaluate the clinical efficacy of transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) combined with alcohol cue inhibitory control training (ICT) as part of rehabilitation.

Methods

A randomized clinical trial was conducted on patients (n=125) withsevere AUD at a withdrawal treatment unit. Each patient was randomly assigned to one of four conditions, in a 2 [verum vs. sham tDCS] x 2 [alcohol cue vs. neutral ICT] factorial design. The primary outcome of the treatment was the measured abstinence rate after two weeks or more (up to one year).

Results

Verum tDCS improved the abstinence rate at the 2-week follow-up compared to the sham condition, independently of the training condition (79.7% [95% CI = 69.8-89.6] vs. 60.7% [95% CI = 48.3-73.1]; p = 0.02). A priori contrasts analyses revealed higher abstinence rates for the verum tDCS associated with alcohol cue ICT (86.1% [31/36; 95% CI= 74.6-97.6]) than for the other three conditions (64% [57/89; 95% CI = 54-74]). These positive clinical effects on abstinence did not persist beyond two weeks after the intervention.

Conclusions

AUD patients who received tDCS applied to DLPFC showed a significantly higher abstinence rate during the weeks following rehabilitation. When combined with alcohol-specific ICT, brain stimulation may provide better clinical outcomes.

Trial Registration

ClinicalTrials.gov number NCT03447054
DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression
Authors: Kong Tim , Laranjeira Angelo Brunelli Albertoni , Yang Kangning , Fisher Daniel A. C. , Yu LaYow , Wang Anthony Z , Ruzinova Marianna , Fowles Jared S. , Allen Maggie J. , Celik Hamza , Challen Grant A. , Huang Sidong , Oh Stephen T.
Published: July 2021

Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, and identified aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Lastly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, and sAML patient-derived xenografts. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.
Polygenic risk for psychiatric disorder reveals distinct association profiles across social behaviour in the general population
Authors: Schlag Fenja , Allegrini Andrea , Buitelaar Jan , Verhoef Ellen , van Donkelaar Marjolein , Plomin Robert , Rimfeld Kaili , Fisher Simon Edward , Pourcain Beate St
Published: July 2021

Many complex psychiatric disorders are characterised by a spectrum of social difficulties. These symptoms lie on a behavioural dimension that is shared with social behaviour in the general population, with substantial contributions of genetic factors. However, shared genetic links may vary across psychiatric disorders and social symptoms. Here, we systematically investigate heterogeneity in shared genetic liabilities with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BP), major depression (MD) and schizophrenia, across a spectrum of different social symptoms. Specifically, longitudinally assessed low-prosociality and peer-problem scores in two UK population-based/community-based cohorts (ALSPAC, N ≤ 6174, 4-17 years; TEDS, N ≤ 7112, 4-16 years; parent- and teacher-reports) were regressed on polygenic risk scores for ADHD, ASD, BP, MD, and schizophrenia, as informed by genome-wide summary statistics from large consortia, using negative binomial regression models. Across ALSPAC and TEDS, we replicated univariate polygenic associations between social behaviour and risk for ADHD, MD, and schizophrenia. Modelling univariate genetic effects across both cohorts with random-effect meta-regression revealed evidence for polygenic links between social behaviour and ADHD, ASD, MD, and schizophrenia risk, but not BP, where differences in age, reporter and social trait captured 45-88% in univariate effect variation. For ADHD, MD, and ASD polygenic risk, we identified stronger association with peer problems than low prosociality, while schizophrenia polygenic risk was solely associated with low prosociality. The identified association profiles suggest marked differences in the social genetic architecture underlying different psychiatric disorders when investigating population-based social symptoms across 13 years of child and adolescent development.