bluuebunny/crossref_metadata_2025 huggingface dataset:
Familial hyperaldosteronism: an European Reference Network on Rare Endocrine Conditions clinical practice guideline
Authors: Mulatero Paolo , Scholl Ute I , Fardella Carlos E , Charmandari Evangelia , Januszewicz Andrzej , Reincke Martin , Gomez-Sanchez Celso E , Stowasser Michael , Dekkers Olaf M
Published: April 2024

We describe herein the European Reference Network on Rare Endocrine Conditions clinical practice guideline on diagnosis and management of familial forms of hyperaldosteronism. The guideline panel consisted of 10 experts in primary aldosteronism, endocrine hypertension, paediatric endocrinology, and cardiology as well as a methodologist. A systematic literature search was conducted, and because of the rarity of the condition, most recommendations were based on expert opinion and small patient series. The guideline includes a brief description of the genetics and molecular pathophysiology associated with each condition, the patients to be screened, and how to screen. Diagnostic and treatment approaches for patients with genetically determined diagnosis are presented. The recommendations apply to patients with genetically proven familial hyperaldosteronism and not to families with more than one case of primary aldosteronism without demonstration of a responsible pathogenic variant.
Analysis of a Large Severe Acute Respiratory Syndrome Coronavirus 2 (Alpha) Outbreak in a Catalan Prison Using Conventional and Genomic Epidemiology
Authors: Bordoy Antoni E , Vallès Xavier , Fernández-Náger Juan , Sánchez-Roig Montserrat , Fernández-Recio Juan , Saludes Verónica , Noguera-Julian Marc , Blanco Ignacio , Martró Elisa ,   for the Quatre Camins COVID-19 Study Group, Balcázar E P , Díaz M R , Encarnación R , Fuentes M , Gallego C , Pale A M , Puig P , Moreno E A , Puertolas A , Chouldry G , Sala I , Jiménez A G , Armenteros B , Alvo J , Gómez S , Guillament M , Martínez D , Martin A , Moruno M A , Parra N , Puig A , Rodríguez F J , Sánchez M , Varoucha A C , Moreno M , Martínez J , Huguet S , Sánchez A , Alonso T , Garcia M , Prat E , Aranda A , Arguelles M J , Azqueta J , Cruz E , Egido R M , Galvany R , Garcia B , González M , González V , Infante J A , Latorre C , Márquez P , Muñoz I , Porras M , Ramos M , Escamilla M , Santalucía J , Riquelme M , Rastrollo L , Pedrerol M , Caraballo V , Fontan J , Verú M , Conill V , Soler L , Panisello Yagüe D , Casañ C , Clarà G , Giménez M , Guerrero-Murillo M , Cardona P J , Marco Andrés
Published: April 2024

Enforcing strict protocols that prevent transmission of airborne infections in prisons is challenging. We examine a large severe acute respiratory syndrome coronavirus 2 outbreak in a Catalan penitentiary center in February–April 2021, prior to vaccination deployment. The aim was to describe the evolution of the outbreak using classical and genomic epidemiology and the containment strategy applied. The outbreak was initially detected in 1 module but spread to 4, infecting 7 staff members and 140 incarcerated individuals, 6 of whom were hospitalized (4.4%). Genomic analysis confirmed a single origin (B.1.1.7). Contact tracing identified transmission vectors between modules and prevented further viral spread. In future similar scenarios, the control strategy described here may help limit transmission of airborne infections in correctional settings.
Tandem amplification of a plasmid-borne tet(A) variant gene confers tigecycline resistance in Escherichia coli
Authors: Zou Chenhui , Xu Chunyan , Yu Runhao , Shan Xinxin , Schwarz Stefan , Li Dexi , Du Xiang-Dang
Published: April 2024

Objectives

To elucidate the mechanism of tigecycline resistance in Escherichia coli that is mediated by the tet(A) variant gene.

Methods

E. coli strain 573 carried a plasmid-borne tet(A) variant gene, tentatively designated tet(A)TIG, that conferred decreased tigecycline susceptibility (MIC 0.5 mg/L). When exposed to increasing concentrations of tigecycline (0.25–8 mg/L), mutants growing at 2, 4 and 8 mg/L were obtained and sequenced. Copies of plasmid and tet(A)TIG relative to the chromosomal DNA in the mutants were determined by WGS and quantitative PCR (qPCR). Expression of tet(A)TIG in the mutants was evaluated by RT–qPCR. The tet(A)TIG-carrying plasmids were visualized by S1-PFGE and Southern blot hybridization. PCR served for the detection of a tet(A)TIG-carrying unconventional circularizable structure (UCS).

Results

Tigecycline resistance with maximum MICs of 16 mg/L was seen in E. coli mutants selected in the presence of tigecycline. Compared with the parental strain, the relative copy number and transcription level of tet(A)TIG in the mutants increased significantly in the presence of 2, 4 and 8 mg/L tigecycline, respectively. With increasing tigecycline selection pressure, the tet(A)TIG-carrying plasmids in the mutants increased in size, correlating with the number of tandem amplificates of a ΔTnAs1-flanked UCS harbouring tet(A)TIG. These tandem amplificates were not stable in the absence of tigecycline.

Conclusions

Tigecycline resistance is due to the tandem amplification of a ΔTnAs1-flanked tet(A)TIG-carrying plasmid-borne segment in E. coli. The gain/loss of the tandem amplificates in the presence/absence of tigecycline represents an economic way for the bacteria to survive in the presence of tigecycline.
Impaired Cholesterol Uptake Capacity in Patients with Hypertriglyceridemia and Diabetes Mellitus
Authors: Seto Yutaro , Nagao Manabu , Iino Takuya , Harada Amane , Murakami Katsuhiro , Miwa Keiko , Shinohara Masakazu , Nishimori Makoto , Yoshikawa Sachiko , Asakura Junko , Fujioka Tomoo , Ishida Tatsuro , Hirata Ken-ichi , Toh Ryuji
Published: April 2024

Background

Although low high-density lipoprotein cholesterol (HDL-C) levels are a common metabolic abnormality associated with insulin resistance, their role in cardiovascular risk stratification remains controversial. Recently, we developed a simple, high-throughput, cell-free assay system to evaluate the “cholesterol uptake capacity (CUC)” as a novel concept for HDL functionality. In this study, we assessed the CUC in patients with hypertriglyceridemia and diabetes mellitus.

Methods

The CUC was measured using cryopreserved serum samples from 285 patients who underwent coronary angiography or percutaneous coronary intervention between December 2014 and May 2019 at Kobe University Hospital.

Results

The CUC was significantly lower in diabetic patients (n = 125) than in nondiabetic patients (93.0 vs 100.7 arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150 mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0 A.U., P = 0.004). Furthermore, the CUC showed a significant inverse correlation with TG, hemoglobin A1c (Hb A1c), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Finally, the HDL-C/Apolipoprotein A1 (ApoA1) ratio, calculated as a surrogate index of HDL particle size, was significantly positively correlated with the CUC (r2 = 0.49, P < 0.001), but inversely correlated with TG levels (r2 = −0.30, P < 0.001).

Conclusions

The CUC decreased in patients with hypertriglyceridemia and diabetes mellitus, and HDL particle size was a factor defining the CUC and inversely correlated with TG levels, suggesting that impaired CUC in insulin-resistant states was partially due to the shift in HDL towards smaller particles. These findings provide a better understanding of the mechanisms underlying impaired HDL functionality.
Implementation of a Self-Audit Tool Improves Regulatory Compliance for Point-of-Care Respiratory Virus Testing in the Emergency Department
Authors: Rackow Ashley R , Mumford Jeanne , Stauffer Jennifer , Colburn Tracy , Bledsoe Lesley , Clarke William A
Published: April 2024

Background

Point-of-care testing in the emergency department decreases wait times and supports evidence-based patient care. However, hurdles to successful implementation include management of interdisciplinary work flows and establishment of an effective quality control program. As COVID-19 testing is now integrated into screening protocols in emergency and urgent care settings, hospital systems must maintain flexible and adaptable respiratory virus testing to adapt to regional trends in transmission. In response to this challenge, our hospital system established a point-of-care respiratory virus laboratory within the emergency department to test for COVID, influenza A/B, and respiratory syncytial virus (RSV). However, maintaining regulatory compliance and standardized protocols within such a dynamic environment became challenging.

Methods

We launched a quality improvement initiative to support improved performance and efficiency in the point-of-care laboratory with a focus on regulatory benchmarks. Following a period of observation and discussion with key stakeholders in the emergency department and pathology, an audit tool was developed and to be deployed in collaboration with ED nursing. Utilizing the new tool, ED nursing would perform audits in parallel to audits performed by point-of-care staff.

Results

Prior to the intervention, the average audit score was approximately 55%; 6 months following the intervention, audit scores have remained stable at approximately 80%, representing a significant improvement in regulatory compliance.

Conclusions

Creation of a regulatory tool enabled real-time cross-departmental monitoring of regulatory compliance. These findings underscore the importance of developing transparent interdisciplinary work flows and effective communication to improve patient care.
Isatuximab-Specific Immunofixation Electrophoresis Assay to Remove Interference in Serum M-Protein Measurement in Patients with Multiple Myeloma
Authors: Thoren Katie , Menad Samia , Nouadje Georges , Macé Sandrine
Published: April 2024

Background

Isatuximab, an IgG-kappa (IgGκ) anti-cluster of differentiation 38 (CD38) monoclonal antibody approved for use in patients with relapsed or refractory multiple myeloma (MM), can potentially interfere with the visualization of endogenous monoclonal protein (M-protein) on standard immunofixation electrophoresis (IFE) and lead to inaccurate classification of a patient’s response to therapy. The Hydrashift 2/4 isatuximab IFE assay (Hydrashift isatuximab assay) removes isatuximab interference from IFE. Using samples from patients enrolled in clinical trials of isatuximab-based therapy for MM, we demonstrate how the Hydrashift isatuximab assay improves the ability to detect residual M-protein and offer recommendations for when the assay is most useful.

Methods

Samples from 141 patients with a variety of known M-protein isotypes were selected and analyzed by standard IFE and the Hydrashift isatuximab assay. A positive control containing isatuximab was run on every standard IFE and Hydrashift gel.

Results

The Hydrashift isatuximab assay reliably shifted the migration of isatuximab in patient samples. Standard IFE was adequate for determining 104 patients’ M-protein status, and the Hydrashift isatuximab assay confirmed these results. In samples from 37 patients with a history of IgGκ MM and a single IgGκ band visible on standard IFE near the isatuximab migration site, the Hydrashift isatuximab assay was able to separate isatuximab from endogenous M-protein, identifying residual M-protein in 17 samples and preventing false-positive interpretations of standard IFE in 20 samples.

Conclusions

The Hydrashift isatuximab assay is most useful in patients with known IgGκ MM when a single IgGκ band appears near the isatuximab migration site on standard IFE during isatuximab-based therapy.

ClinicalTrials.gov Registration Numbers

NCT03275285 and NCT03319667.
Characterizing the target of interest underlying a complex overburden with target-oriented elastic waveform inversion
Authors: Li Yuanyuan , Alkhalifah Tariq , Huang Jianping , Li Zhenchun
Published: April 2024

It remains challenging for elastic full waveform inversion (EFWI) to characterize the elastic properties of a target reservoir deep beneath complex overburden media. This can be attributed to two factors. (1) The complex wavefield distortions arising from the overburden obscure the target reflection properties, resulting in a target zone with limited energy illumination. (2) High-resolution EFWI for the whole inversion domain is computationally expensive. To overcome these challenges, instead of directly inverting for the subsurface model using surface seismic data, we develop a target-oriented elastic waveform inversion scheme. We first retrieve the elastic reflection response to the target zone of interest by projecting seismic data from the surface to the datum level. Then, we can apply high-resolution EFWI on the target zone by using the retrieved elastic reflection data. To better handle the complex overburden, which may include anisotropy and salt bodies, we make full use of the prior estimate of the overburden in the redatuming process to obtain a reliable reflection response to the target zone. In the numerical examples, we use the SEG Advanced Modeling (SEAM) model with an anisotropic overburden and a salt body model to demonstrate the feasibility and effectiveness of the proposed method and analyze the influence of anisotropy and high-contrast salt in the overburden on the redatuming and inversion results, respectively.
Alcohol and colorectal cancer risk, subclassified by mutational signatures of DNA mismatch repair deficiency
Authors: Fang Aiping , Ugai Tomotaka , Gurjao Carino , Zhong Rong , Liu Zhenhua , Zhang Xinyuan , Wang Peilu , Nowak Jonathan , Wang Molin , Giannakis Marios , Ogino Shuji , Zhang Xuehong , Giovannucci Edward
Published: April 2024

Background

We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)–related tumor mutational signatures.

Methods

We used data from 227 916 men and women who participated in the Nurses’ Health Study (1980-2016), the Nurses’ Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair–related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided.

Results

We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (Ptrend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (Ptrend = .41 for heterogeneity).

Conclusions

High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.
NADPH oxidase-mediated sulfenylation of cysteine derivatives regulates plant immunity
Authors: Hino Yuta , Inada Taichi , Yoshioka Miki , Yoshioka Hirofumi
Published: April 2024

Reactive oxygen species (ROS) are rapidly generated during plant immune responses by respiratory burst oxidase homolog (RBOH), which is a plasma membrane-localized NADPH oxidase. Although regulatory mechanisms of RBOH activity have been well documented, the ROS-mediated downstream signaling is unclear. We here demonstrated that ROS sensor proteins play a central role in ROS signaling via oxidative post-translational modification of cysteine residues, sulfenylation. To detect protein sulfenylation, we used dimedone, which specifically and irreversibly binds to sulfenylated proteins. The sulfenylated proteins were labeled by dimedone in Nicotiana benthamiana leaves, and the conjugates were detected by immunoblot analyses. In addition, a reductant dissociated H2O2-induced conjugates, suggesting that cysteine persulfide and/or polysulfides are involved in sulfenylation. These sulfenylated proteins were continuously increased during both pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in a RBOH-dependent manner. Pharmacological inhibition of ROS sensor proteins by dimedone perturbated cell death, ROS accumulation induced by INF1 and MEK2DD, and defense against fungal pathogens. On the other hand, Rpi-blb2-mediated ETI responses were enhanced by dimedone. These results suggest that the sulfenylation of cysteine and its derivatives in various ROS sensor proteins are important events downstream of the RBOH-dependent ROS burst to regulate plant immune responses.
A guide to mycetisms: A toxicological and preventive overview
Authors: Benvenuti Mirko , Zotti Mirca , La Maestra Sebastiano
Published: April 2024

Fungi are often considered a delicacy and are primarily cultivated and harvested, although numerous species are responsible for intoxication due to toxin content. Foodborne diseases are a significant public health concern, causing approximately 420 000 deaths and 600 million morbidities yearly, of which mushroom poisoning is one of the leading causes. Epidemiological data on non-cultivated mushroom poisoning in individual countries are often unrepresentative, as intoxication rarely requires emergency intervention. On the other hand, the lack of specialist knowledge among medical personnel about the toxicological manifestations of mushroom consumption may result in ineffective therapeutic interventions. This work aims to provide an easy-to-consult and wide-ranging tool useful for better understanding the variability of mushroom intoxications, the associated symptoms, and the main treatments for the most severe cases, given the absence of a complete species mapping tool toxic. Moreover, we establish an effective collection network that describes the incidence of mushroom poisonings by reporting the species and associated toxicological manifestations for each case. In conclusion, we highlight the need to establish appropriate primary prevention interventions, such as training the affected population and increasing consultancy relationships between mycological experts and specialised healthcare personnel.
WTP 10aaauow: discovery of a new FU Ori outburst towards the RCW 49 star-forming region in NEOWISE data
Authors: Tran Vinh , De Kishalay , Hillenbrand Lynne
Published: April 2024

Large-amplitude accretion outbursts in young stars are expected to play a central role in protostellar assembly. Outburst identification historically has taken place using optical techniques, but recent, systematic infrared searches are enabling their discovery in heavily dust-obscured regions of the Galactic plane. Here, we present the discovery of Wide-field Infrared Survey Explorer transient pipeline (WTP) 10aaauow, a large-amplitude mid-infrared (MIR) outburst identified in a systematic search of NEOWISE data using new image subtraction techniques. The source is located towards the RCW 49 star-forming region, and estimated to be at a distance of ≈4 kpc via Gaia parallax measurement. Concurrent with the MIR brightening, the source underwent a ≳5 mag outburst in the optical and near-infrared (NIR) bands, reaching a peak luminosity of ≈260 L⊙ in 2014–2015, followed by a slow decline over the next 7 yr. Analysis of the pre- and post-outburst spectral energy distributions reveals a pre-outburst stellar photosphere at a temperature of 3600–4000 K, surrounded by a likely two-component dust structure similar to a flat-spectrum or Class I type young stellar object. We present optical and NIR spectroscopy that shows a GK-type spectrum in the optical bands exhibiting complex line profiles in strong absorption features, and evidence for a wind reaching a terminal velocity of ≈400 km s−1. The NIR bands are characterized by a cooler M-type spectrum exhibiting a forest of atomic and molecular features. Alltogether, the spectra demonstrate that WTP 10aaauow is an FU Ori type outburst. Ongoing systematic infrared searches will continue to reveal the extent of this population in the Galactic disc.
On the tension between the radial acceleration relation and Solar system quadrupole in modified gravity MOND
Authors: Desmond Harry , Hees Aurélien , Famaey Benoit
Published: April 2024

Modified Newtonian dynamics (MOND), postulating a breakdown of Newtonian mechanics at low accelerations, has considerable success at explaining galaxy kinematics. However, the quadrupole of the gravitational field of the Solar system (SS) provides a strong constraint on the way in which Newtonian gravity can be modified. In this paper, we assess the extent to which the AQUAdratic Lagrangian (AQUAL) and QUasilinear MOND (QUMOND) modified gravity formulations of MOND are capable of accounting simultaneously for the radial acceleration relation (RAR), the Cassini measurement of the SS quadrupole and the kinematics of wide binaries in the Solar neighbourhood. We achieve this by inferring the location and sharpness of the MOND transition from the Spitzer Photometry and Accurate Rotation Curves (SPARC) RAR under broad assumptions for the behaviour of the interpolating function and external field effect. We constrain the same quantities from the SS quadrupole, finding that this requires a significantly sharper transition between the deep-MOND and Newtonian regimes than is allowed by the RAR (an 8.7σ tension under fiducial model assumptions). This may be relieved somewhat by allowing additional freedom in galaxies’ mass-to-light ratios – which also improves the RAR fit – and more significantly (to 1.9σ) by removing galaxies with bulges. For the first time, we also apply to the SPARC RAR fit an AQUAL correction for flattened systems, obtaining similar results. Finally, we show that the SS quadrupole constraint implies, to high precision, no deviation from Newtonian gravity in nearby wide binaries, and speculate on possible resolutions of this tension between SS and galaxy data within the MOND paradigm.
Diverse features of dust particles and their aggregates inferred from experimental nanoparticles
Authors: Nakano Yuki , Kimura Yuki , Hashimoto Akihiko
Published: April 2024

Nanometre- to micrometre-sized solid dust particles play a vital role in star and planet formations. Despite of their importance, however, our understanding of physical and chemical properties of dust particles is still provisional. We have conducted a condensation experiment of the vapour generated from a solid starting material having nearly cosmic proportions in elements. A laser flash heating and subsequent cooling has produced a diverse type of nanoparticles simultaneously. Here we introduce four types of nanoparticles as potential dust particles in space: amorphous silicate nanoparticles (type S); core/mantle nanoparticles with iron or hydrogenized iron core and amorphous silicate mantle (type IS); silicon oxycarbide nanoparticles and hydrogenized silicon oxycarbide nanoparticles (type SiOC); and carbon nanoparticles (type C), all produced in a single heating–cooling event. Type IS and SiOC nanoparticles are new for potential astrophysical dust. The nanoparticles are aggregated to a wide variety of structures: compact, fluffy, and networked. A simultaneous formation of these nanoparticles, which are diverse in chemistry, shape, and structure, prompts a re-evaluation of astrophysical dust particles.
Protein G-quadruplex interactions and their effects on phase transitions and protein aggregation
Authors: Sahoo Bikash R , Kocman Vojč , Clark Nathan , Myers Nikhil , Deng Xiexiong , Wong Ee L , Yang Harry J , Kotar Anita , Guzman Bryan B , Dominguez Daniel , Plavec Janez , Bardwell James C A
Published: April 2024

The SERF family of proteins were originally discovered for their ability to accelerate amyloid formation. Znf706 is an uncharacterized protein whose N-terminus is homologous to SERF proteins. We show here that human Znf706 can promote protein aggregation and amyloid formation. Unexpectedly, Znf706 specifically interacts with stable, non-canonical nucleic acid structures known as G-quadruplexes. G-quadruplexes can affect gene regulation and suppress protein aggregation; however, it is unknown if and how these two activities are linked. We find Znf706 binds preferentially to parallel G-quadruplexes with low micromolar affinity, primarily using its N-terminus, and upon interaction, its dynamics are constrained. G-quadruplex binding suppresses Znf706’s ability to promote protein aggregation. Znf706 in conjunction with G-quadruplexes therefore may play a role in regulating protein folding. RNAseq analysis shows that Znf706 depletion specifically impacts the mRNA abundance of genes that are predicted to contain high G-quadruplex density. Our studies give insight into how proteins and G-quadruplexes interact, and how these interactions affect both partners and lead to the modulation of protein aggregation and cellular mRNA levels. These observations suggest that the SERF family of proteins, in conjunction with G-quadruplexes, may have a broader role in regulating protein folding and gene expression than previously appreciated.
PubTator 3.0: an AI-powered literature resource for unlocking biomedical knowledge
Authors: Wei Chih-Hsuan , Allot Alexis , Lai Po-Ting , Leaman Robert , Tian Shubo , Luo Ling , Jin Qiao , Wang Zhizheng , Chen Qingyu , Lu Zhiyong
Published: April 2024

PubTator 3.0 (https://www.ncbi.nlm.nih.gov/research/pubtator3/) is a biomedical literature resource using state-of-the-art AI techniques to offer semantic and relation searches for key concepts like proteins, genetic variants, diseases and chemicals. It currently provides over one billion entity and relation annotations across approximately 36 million PubMed abstracts and 6 million full-text articles from the PMC open access subset, updated weekly. PubTator 3.0's online interface and API utilize these precomputed entity relations and synonyms to provide advanced search capabilities and enable large-scale analyses, streamlining many complex information needs. We showcase the retrieval quality of PubTator 3.0 using a series of entity pair queries, demonstrating that PubTator 3.0 retrieves a greater number of articles than either PubMed or Google Scholar, with higher precision in the top 20 results. We further show that integrating ChatGPT (GPT-4) with PubTator APIs dramatically improves the factuality and verifiability of its responses. In summary, PubTator 3.0 offers a comprehensive set of features and tools that allow researchers to navigate the ever-expanding wealth of biomedical literature, expediting research and unlocking valuable insights for scientific discovery.
The determinants of the rarity of nucleic and peptide short sequences in nature
Authors: Chantzi Nikol , Mareboina Manvita , Konnaris Maxwell A , Montgomery Austin , Patsakis Michail , Mouratidis Ioannis , Georgakopoulos-Soares Ilias
Published: April 2024

The prevalence of nucleic and peptide short sequences across organismal genomes and proteomes has not been thoroughly investigated. We examined 45 785 reference genomes and 21 871 reference proteomes, spanning archaea, bacteria, eukaryotes and viruses to calculate the rarity of short sequences in them. To capture this, we developed a metric of the rarity of each sequence in nature, the rarity index. We find that the frequency of certain dipeptides in rare oligopeptide sequences is hundreds of times lower than expected, which is not the case for any dinucleotides. We also generate predictive regression models that infer the rarity of nucleic and proteomic sequences across nature or within each domain of life and viruses separately. When examining each of the three domains of life and viruses separately, the R² performance of the model predicting rarity for 5-mer peptides from mono- and dipeptides ranged between 0.814 and 0.932. A separate model predicting rarity for 10-mer oligonucleotides from mono- and dinucleotides achieved R² performance between 0.408 and 0.606. Our results indicate that the mono- and dinucleotide composition of nucleic sequences and the mono- and dipeptide composition of peptide sequences can explain a significant proportion of the variance in their frequencies in nature.
Treatment response as surrogate to predict risk for disease progression in pediatric medulloblastoma with persistent magnetic resonance imaging lesions after first-line treatment
Authors: Obrecht-Sturm Denise , Schömig Lena , Mynarek Martin , Bison Brigitte , Schwarz Rudolf , Pietsch Torsten , Pfister Stefan M , Sill Martin , Sturm Dominik , Sahm Felix , Kortmann Rolf-Dieter , Gerber Nicolas U , von Bueren André O , Fleischhack Gudrun , Schüller Ulrich , Nussbaumer Gunther , Benesch Martin , Rutkowski Stefan
Published: April 2024

Background

This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma.

Methods

Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed magnetic resonance imaging (MRI) at the end of first-line therapy were analyzed.

Results

Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥ 25% reduction, minor response [MR]/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5 ± 7.0%[MR/PR] vs. 35.9 ± 12.8%[SD], P = .03; pptOS: 79.7 ± 5.9[MR/PR] vs. 55.5 ± 13.9[SD], P = .04). Furthermore, R+/M + was associated with a higher risk for progression (5-year pptPFS: 22.9 ± 17.9%[R+, M+] vs. 72.4 ± 12.0%[R+, M0]; P = .03). Watch-and-wait was pursued in 58 patients, while n = 26 received additional treatments (chemotherapy only, n = 19; surgery only, n = 2; combined, n = 3; valproic acid, n = 2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5 ± 7.7% vs. 51.6 ± 10.7% P = .71; 5-year pptOS: 76.3 ± 6.9% vs. 69.8 ± 9.7%, P = .74). For the whole cohort, 5-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0 ± 35.4%, group-4, 52.5 ± 10.5, group-3 54.2 ± 13.8%; (P = .08).

Conclusions

Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in the case of solitary persistent medulloblastoma MRI lesions, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information need consideration for indication of additional treatments for persisting lesions.
Fear and Loathing: How Demographic Change Affects Support for Christian Nationalism
Authors: Walker Brooklyn , Haider-Markel Donald P
Published: April 2024

Christian nationalism, the fusion of religious and national identities, has emerged as an important factor shaping public opinion on a range of issues. However, debates in the existing literature on the motivations behind support for Christian nationalism remain unresolved: Is Christian nationalism a response to secularization and/or a cover for discomfort with racial diversity and equality? Is Christian nationalism rooted in fear of social change, disgust about social change, or something else? We use an experiment embedded in a national survey of adults to isolate the effects of knowledge of both religious and racial demographic change among White Christians. Our analysis suggests that exposure to religious demographic change shifts support for Christian nationalism and perceptions of discrimination against Whites and Christians, but exposure to racial demographic change has limited impact. This effect is mediated by emotion—religious demographic change increases fear and disgust, which then influence support for Christian nationalism and perceptions of discrimination against Whites and Christians. Although our treatment suggesting exposure to racial demographic change had null effects, we note that racial attitudes do independently influence support for Christian nationalism and perceptions of discrimination against Whites and Christians.
Responsiveness and sensitivity of PROMs to change in disease activity status in early and established rheumatoid arthritis
Authors: Looijen Agnes E M , van Mulligen Elise , Vonkeman Harald E , van der Helm-van Mil Annette H M , de Jong Pascal H P
Published: April 2024

Objectives

To determine whether patient-reported outcome measures (PROMs) capturing activity limitations, health impact, pain, fatigue and work ability are responsive and sensitive to changes in disease activity status in patients with early and established RA.

Methods

All early RA patients (n = 557) from the tREACH trial and established RA patients (n = 188) from the TARA trial were included. Both studies were multicentre, single-blinded trials with a treat-to-target management approach. The following PROMs were studied: HAQ Disability Index (HAQ-DI), morning stiffness severity, EQ-5D, general health, 36-item short form (SF-36), joint pain, fatigue and productivity loss. Mean changes in PROMs between two consecutive visits were compared with changes in disease activity status (remission, low disease activity and active disease) using linear mixed models and standardized response means. Additionally, the proportion of individual observations that showed an expected PROM response to disease activity status alterations was calculated.

Results

HAQ-DI, morning stiffness severity, general health, EQ-5D and joint pain demonstrated responsiveness to improvement or worsening of disease activity status in both early and established RA. SF-36 physical and mental component scale, fatigue and productivity loss did not show this effect in both groups. Across nearly all PROMs, the magnitude of change and the proportion of individual observations that reflect a shift from and to active disease remained low.

Conclusion

HAQ-DI, morning stiffness severity, EQ-5D, general health and joint pain are responsive to disease activity status alterations on a group level in both early and established RA. For the individual patient the responsiveness of these PROMs is poor.

Clinical trial registration

tREACH trial (www.isrctn.com, ISRCTN26791028) and TARA trial (www.onderzoekmetmensen.nl, NTR2754)
Online feeding behavior monitoring of individual group-housed grow-finish pigs using a low-frequency RFID electronic feeding system
Authors: Funk Taran H , Rohrer Gary A , Brown-Brandl Tami M , Keel Brittney N
Published: April 2024

Early identification of animals in need of management intervention is critical to maximize animal health and welfare and minimize issues with productivity. Feeding behavior, captured by automated feeding systems, can be used to monitor the health and welfare status of individual pigs. Here, we present a framework for monitoring feeding behavior of grow-finish pigs in real time, using a low-frequency radio frequency identification (RFID) system. Using historical data, an autoregressive linear model for predicting daily time at the feeder was developed and utilized to detect anomalous decreases in feeding behavior associated with health status of the pig. A total of 2,826 pigs were individually monitored with our warning system over the entire grow-finish period, and health warnings were compared to caretaker diagnoses. The system detected 55.7% of the caretaker diagnoses, and on average these events were detected 2.8 d earlier than diagnosis by the caretaker. High numbers of potentially spurious health warnings, generated by the system, can be partly explained by the lack of a reliable and repeatable gold standard reference data set. Results from this work provide a solid basis for monitoring individual animals, but further improvements to the system are necessary for practical implementation.
Optimized SMRT-UMI protocol produces highly accurate sequence datasets from diverse populations—Application to HIV-1 quasispecies
Authors: Westfall Dylan H , Deng Wenjie , Pankow Alec , Murrell Hugh , Chen Lennie , Zhao Hong , Williamson Carolyn , Rolland Morgane , Murrell Ben , Mullins James I
Published: April 2024

Pathogen diversity resulting in quasispecies can enable persistence and adaptation to host defenses and therapies. However, accurate quasispecies characterization can be impeded by errors introduced during sample handling and sequencing, which can require extensive optimizations to overcome. We present complete laboratory and bioinformatics workflows to overcome many of these hurdles. The Pacific Biosciences single molecule real-time platform was used to sequence polymerase-chain reaction (PCR) amplicons derived from cDNA templates tagged with unique molecular identifiers (SMRT-UMI). Optimized laboratory protocols were developed through extensive testing of different sample preparation conditions to minimize between-template recombination during PCR. The use of UMI allowed accurate template quantitation as well as removal of point mutations introduced during PCR and sequencing to produce a highly accurate consensus sequence from each template. Production of highly accurate sequences from the large datasets produced from SMRT-UMI sequencing is facilitated by a novel bioinformatic pipeline, Probabilistic Offspring Resolver for Primer IDs (PORPIDpipeline). PORPIDpipeline automatically filters and parses circular consensus reads by sample, identifies and discards reads with UMIs likely created from PCR and sequencing errors, generates consensus sequences, checks for contamination within the dataset, and removes any sequence with evidence of PCR recombination, heteroduplex formation, or early cycle PCR errors. The optimized SMRT-UMI sequencing and PORPIDpipeline methods presented here represent a highly adaptable and established starting point for accurate sequencing of diverse pathogens. These methods are illustrated through characterization of human immunodeficiency virus quasispecies in a virus transmitter-recipient pair of individuals.
Point-of-care ultrasound in pediatric anesthesiology: considerations for training and credentialing
Authors: Lockhart Thomas J. , Lin Elaina E. , Adler Adam C.
Published: April 2024

Purpose of review

To discuss considerations surrounding the use of point-of-care ultrasound (POCUS) in pediatric anesthesiology.

Recent findings

POCUS is an indispensable tool in various medical specialties, including pediatric anesthesiology. Credentialing for POCUS should be considered to ensure that practitioners are able to acquire images, interpret them correctly, and use ultrasound to guide procedures safely and effectively. In the absence of formal guidelines for anesthesiology, current practice and oversight varies by institution. In this review, we will explore the significance of POCUS in pediatric anesthesiology, discuss credentialing, and compare the specific requirements and challenges currently associated with using POCUS in pediatric anesthesia.

Point-of-care ultrasound is being utilized by the pediatric anesthesiologist and has the potential to improve patient assessment, procedure guidance, and decision-making. Guidelines increase standardization and quality assurance procedures help maintain high-quality data. Credentialing standards for POCUS in pediatric anesthesiology are essential to ensure that practitioners have the necessary skills and knowledge to use this technology effectively and safely. Currently, there are no national pediatric POCUS guidelines to base credentialing processes on for pediatric anesthesia practices. Further work directed at establishing pediatric-specific curriculum goals and competency standards are needed to train current and future pediatric anesthesia providers and increase overall acceptance of POCUS use.
Association Between Hypertensive Disorders of Pregnancy and Interval Neurocognitive Decline
Authors: Elfassy Tali , Kulandavelu Shathiyah , Dodds Leah , Mesa Robert A. , Rundek Tatjana , Sharashidze Vera , Paidas Michael , Daviglus Martha L. , Kominiarek Michelle A. , Stickel Ariana M. , Perreira Krista M. , Kobayashi Marissa A. , Garcia Tanya P. , Isasi Carmen R. , Lipton Richard B. , González Hector M.
Published: April 2024

OBJECTIVE:

To evaluate whether hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and eclampsia, are associated with cognitive decline later in life among U.S. Hispanic/Latina individuals.

METHODS:

The HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is a prospective population-based study of Hispanic/Latino individuals aged 18–74 years from four U.S. communities. This analysis included parous individuals aged 45 years or older who participated in the HCHS/SOL clinic study visit 1 (2008–2011) neurocognitive assessment and subsequently completed a repeat neurocognitive assessment as part of the Study of Latinos–Investigation of Neurocognitive Aging ancillary study visit 2 (2015–2018). Hypertensive disorders of pregnancy were assessed retrospectively by self-report of any gestational hypertension, preeclampsia, or eclampsia. Cognitive functioning was measured at both study visits with the Brief Spanish-English Verbal Learning Test, Digit Symbol Substitution, and Word Fluency. A regression-based approach was used to define cognitive decline at visit 2 as a function of cognition at visit 1 after adjustment for age, education, and follow-up time. Linear regression models were used to determine whether hypertensive disorders of pregnancy or their component diagnoses were associated with standardized cognitive decline after adjustment for sociodemographic characteristics, clinical and behavioral risk factors, and follow-up time.

RESULTS:

Among 3,554 individuals included in analysis, the mean age was 56.2 years, and 467 of individuals (13.4%) reported at least one hypertensive disorder of pregnancy. Individuals with hypertensive disorders of pregnancy compared with those without were more likely to have higher mean systolic blood pressure, fasting glucose, and body mass index. After an average of 7 years of follow-up, in fully adjusted models, gestational hypertension was associated with a 0.17-SD relative decline in Digit Symbol Substitution scores (95% CI, −0.31 to −0.04) but not other cognitive domains (Brief Spanish-English Verbal Learning Test or Word Fluency). Neither preeclampsia nor eclampsia was associated with neurocognitive differences.

CONCLUSION:

The presence of preeclampsia or eclampsia was not associated with interval neurocognitive decline. In this cohort of U.S. Hispanic/Latina individuals, gestational hypertension alone was associated with decreased processing speed and executive functioning later in life.
Premature Ovarian Insufficiency After Coronavirus Disease 2019 (COVID-19)
Authors: Stern Rachel , Bibi Moses , Keltz Martin D.
Published: April 2024

BACKGROUND:

Since the onset of the coronavirus disease (COVID-19) pandemic, a variety of long–COVID-19 symptoms and autoimmune complications have been recognized.

CASES:

We report three cases of autoimmune premature poor ovarian response in patients aged 30–37 years after mild to asymptomatic COVID-19 before vaccination, with nucleotide antibody confirmation. Two patients failed to respond to maximum-dose gonadotropins for more than 4 weeks, despite a recent history of response before having COVID-19. After a month of prednisone 30 mg, these two patients had normal follicle-stimulating hormone (FSH) levels, high oocyte yield, and blastocyst formation in successful in vitro fertilization cycles. All three patients have above-average anti-müllerian hormone levels that persisted throughout their clinical ovarian insufficiency. Two patients had elevated FSH levels, perhaps resulting from FSH receptor blockade. One patient, with a history of high response to gonadotropins 75 international units per day and below-normal FSH levels, had no ovarian response to more than a month of gonadotropins (525 international units daily), suggesting autoimmune block of the FSH glycoprotein and possible FSH receptor blockade.

CONCLUSION:

Auto-antibody production in response to COVID-19 before vaccination may be a rare cause of autoimmune poor ovarian response. Although vaccination is likely protective, further study will be required to evaluate the effect of vaccination and duration of autoimmune FSH or FSH receptor blockade.
Highlighting recent progress in the treatment of men with advanced prostate cancer
Authors: Gourdin Theodore
Published: April 2024

Purpose of review

This review is designed to highlight recent research efforts to optimize treatment strategies in men with advanced prostate cancer.

Recent findings

Recent research analyses have suggested an overall survival advantage to treating some men with newly identified metastatic prostate cancer with a “triplet” of androgen deprivation therapy, docetaxel, and an androgen receptor axis-targeted agent (ARAT), but further work remains to refine which men need this aggressive of a treatment approach. Randomized trials have led to the approval of poly(ADP-ribose) polymerase inhibitor/ARAT agent combinations for some men with metastatic castration resistant prostate cancer, but the applicability of this approach to the growing number of men receiving combinations of systemic therapy in the castration-sensitive setting is unclear. Trials to refine use of prostate-specific membrane antigen (PSMA)-directed radiopharmaceuticals are ongoing, while novel treatment approaches targeting mechanisms driving advanced prostate cancer continue to be explored.

Ongoing research focuses on refining the best combination and sequence of treatments for men with advanced prostate cancer. Future questions remain about use of existing therapies, and novel treatment approaches need to be developed.