bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploration of a European-centered strawberry diversity panel provides markers and candidate genes for the control of fruit quality traits
Authors: Prohaska Alexandre , Rey-Serra Pol , Petit Johann , Petit Aurélie , Perrotte Justine , Rothan Christophe , Denoyes Béatrice
Published: May 2024

Fruit quality traits are major breeding targets in cultivated strawberry (Fragaria × ananassa). Taking into account the requirements of both growers and consumers when selecting high quality cultivars is a real challenge. Here, we used a diversity panel enriched with unique European accessions and the 50K FanaSNP array to highlight the evolution of strawberry diversity over the past 160 years, investigate the molecular basis of 12 major fruit quality traits by Genome-Wide Association Studies (GWAS), and provide genetic markers for breeding. Results show that considerable improvements of key breeding targets including fruit weight, firmness, composition and appearance occurred simultaneously in European and American cultivars. Despite the high genetic diversity of our panel, we observed a drop in nucleotide diversity in certain chromosomal regions, revealing the impact of selection. GWAS identified 71 associations with 11 quality traits and, while validating known associations (firmness, sugar), highlighted the predominance of new QTL, demonstrating the value of using untapped genetic resources. Three of the six selective sweeps detected are related to glossiness or skin resistance, two little-studied traits important for fruit attractiveness and, potentially, postharvest shelf-life. Moreover, major QTL for firmness, glossiness, skin resistance and susceptibility to bruising are found within a low diversity region of chromosome 3D. Stringent search for candidate genes underlying QTL uncovered strong candidates for fruit color, firmness, sugar and acid composition, glossiness and skin resistance. Overall, our study provides a potential avenue for extending shelf-life without compromising flavor and color as well as the genetic markers needed to achieve this goal.
Antibiotic Resistance of Urinary Tract Infection Recurrences in a Large Integrated US Healthcare System
Authors: Ku Jennifer H , Tartof Sara Y , Contreras Richard , Ackerson Bradley K , Chen Lie H , Reyes Iris A C , Pellegrini Michele , Schmidt Johannes E , Bruxvoort Katia J
Published: May 2024

Background

Data on antibiotic resistance of uropathogens for urinary tract infection (UTI) recurrences are lacking.

Methods

In a retrospective cohort of adults at Kaiser Permanente Southern California with culture-confirmed index uncomplicated UTI (uUTI) between January 2016 and December 2020, we examined the number and characteristics of subsequent culture-confirmed UTIs through 2021.

Results

We identified 148 994 individuals with a culture-confirmed index uUTI (88% female, 44% Hispanic; mean age, 51 years [standard deviation, 19 years]), of whom 19% developed a subsequent culture-confirmed UTI after a median 300 days (interquartile range, 126–627 days). The proportion of UTI due to Escherichia coli was highest for index uUTI (79%) and decreased to 73% for sixth UTI (UTI 6) (P for trend < .001), while the proportion due to Klebsiella spp increased from index UTI (7%) to UTI 6 (11%) (P for trend < .001). Nonsusceptibility to ≥1 and ≥3 antibiotic classes was observed in 57% and 13% of index uUTIs, respectively, and was higher for subsequent UTIs (65% and 20%, respectively, for UTI 6). Most commonly observed antibiotic nonsusceptibility patterns included penicillins alone (12%), and penicillins and trimethoprim-sulfamethoxazole plus ≥1 additional antibiotic class (9%).

Conclusions

Antibiotic nonsusceptibility is common in UTIs and increases with subsequent UTIs. Continuous monitoring of UTI recurrences and susceptibility patterns is needed to guide treatment decisions.
Extended-Spectrum β-Lactamase Shigella sonnei Cluster Among Men Who Have Sex With Men in Chicago, Illinois, July–October 2022
Authors: Faherty Emily A G , Kling Kendall , Barbian Hannah J , Qi Chao , Altman Shana , Dhiman Vineet K , Teran Richard , Anderson Kendall , Yuce Deniz , Smith Shamika , Richardson Morgan , Vogelzang Kara , Ghinai Isaac , Ruestow Peter , Heimler Ira , Menon Adil , Francois Watkins Louise K , Logan Naeemah , Kim Do Young , Pacilli Massimo , Kerins Janna , Black Stephanie
Published: May 2024

Drug-resistant shigellosis is increasing, particularly among men who have sex with men (MSM). During July–October 2022, an extended-spectrum β-lactamase–producing Shigella sonnei cluster of 9 patients was identified in Chicago, of whom 8 were MSM and 6 were festival attendees. The cluster also included 4 domestic travelers to Chicago. Sexual health care for MSM should include shigellosis diagnosis and prevention.
Distinct Gut Microbiota Signatures Associated With Progression of Atherosclerosis in People Living With Human Immunodeficiency Virus
Authors: Masiá Mar , García José A , García-Abellán Javier , Padilla Sergio , Fernández-González Marta , Agulló Vanesa , Gosalbes Maria José , Ruíz-Pérez Sonia , Mascarell Paula , Botella Angela , Gutiérrez Félix
Published: May 2024

Background

The relationship of microbiota composition dynamics and the progression of subclinical atherosclerosis in people with human immunodeficiency virus (PWH) remains unknown.

Methods

A 96-week, prospective, longitudinal study was performed in virologically suppressed PWH. Carotid intima-media thickness (cIMT) measurements and stool samples were obtained at baseline and at 48- and 96-week visits. cIMT progression was defined as an increase of >10% and/or detection of new carotid plaque. To profile the gut microbiome, amplification and sequencing of 16S ribosomal RNA (V3–V4 variable regions) were carried out, following the Illumina protocol. Sequencing was performed using the MiSeq platform.

Results

At the baseline, 48-week, and 96-week visits, 191, 190, and 167 patients, respectively, had fecal samples available for microbiome analysis. Eighty-seven participants (43%) showed atherosclerosis progression, and 54 (26.7%) presented with new carotid plaque. No significant differences were observed in adjusted α-diversity indices between groups, defined by cIMT progression. β-Diversity, determined through principal coordinate analysis, showed that the groups exhibited distinct microbial profiles (P = .03; permutational multivariate analysis of variance). Longitudinal analysis with Analysis of Compositions of Microbiomes with Bias Correction 2, adjusted for traditional cardiovascular risk factors, status as men who have sex with men, and nadir CD4 count, revealed that cIMT progression was consistently associated with Agathobacter and Ruminococcus 2, while nonprogression was consistently associated with Prevotella 7.

Conclusions

Progression of atherosclerosis in PWH might be associated with distinctive signatures in the gut microbiota.
Metabolic pathways and antimicrobial peptide resistance in bacteria
Authors: Elbediwi Mohammed , Rolff Jens
Published: May 2024

Antimicrobial resistance is a pressing concern that poses a significant threat to global public health, necessitating the exploration of alternative strategies to combat drug-resistant microbial infections. Recently, antimicrobial peptides (AMPs) have gained substantial attention as possible replacements for conventional antibiotics. Because of their pharmacodynamics and killing mechanisms, AMPs display a lower risk of bacterial resistance evolution compared with most conventional antibiotics. However, bacteria display different mechanisms to resist AMPs, and the role of metabolic pathways in the resistance mechanism is not fully understood. This review examines the intricate relationship between metabolic genes and AMP resistance, focusing on the impact of metabolic pathways on various aspects of resistance. Metabolic pathways related to guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) [collectively (p)ppGpp], the tricarboxylic acid (TCA) cycle, haem biosynthesis, purine and pyrimidine biosynthesis, and amino acid and lipid metabolism influence in different ways metabolic adjustments, biofilm formation and energy production that could be involved in AMP resistance. By targeting metabolic pathways and their associated genes, it could be possible to enhance the efficacy of existing antimicrobial therapies and overcome the challenges exhibited by phenotypic (recalcitrance) and genetic resistance toward AMPs. Further research in this area is needed to provide valuable insights into specific mechanisms, uncover novel therapeutic targets, and aid in the fight against antimicrobial resistance.
Distribution and expression of the aac(6′)-Im (aacA16) aminoglycoside resistance gene
Authors: Harmer Christopher J , Nelson Messiah J , Lebreton Francois , Lertsethtakarn Paphavee , McGann Patrick T , Hall Ruth M
Published: May 2024

Background

The aac(6′)-Im (aacA16) amikacin, netilmicin and tobramycin resistance gene cassette had been circulating globally undetected for many years in a sublineage of Acinetobacter baumannii global clone 2.

Objectives

To identify sources for the aac(6′)-Im fragment found in A. baumannii.

Methods

MinION long-read sequencing and Unicycler hybrid assemblies were used to determine the genetic context of the aac(6′)-Im gene. Quantitative reverse transcriptase PCR was used to measure expression.

Results

Among >60 000 non-Acinetobacter draft genomes in the MRSN collection, the aac(6′)-Im gene was detected in Pseudomonas putida and Enterobacter hormaechei isolates recovered from patients in Thailand between 2016 and 2019. Genomes of multiply resistant P. putida MRSN365855 and E. hormaechei MRSN791417 were completed. The class 1 integron containing the aac(6′)-Im cassette was in the chromosome in MRSN365855, and in an HI2 plasmid in MRSN791417. However, MRSN791417 was amikacin susceptible and the gene was not expressed due to loss of the Pc promoter of the integron. Further examples of aac(6′)-Im in plasmids from or the chromosome of various Gram-negative species were found in the GenBank nucleotide database. The aac(6′)-Im context in integrons in pMRSN791417-8 and a Klebsiella plasmid pAMR200031 shared similarities with the aac(6′)-Im region of AbGRI2-Im islands in A. baumannii. In other cases, the cassette array including the aac(6′)-Im cassette was different.

Conclusions

The aac(6′)-Im gene is widespread, being found so far in several different species and in several different gene cassette arrays. The lack of amikacin resistance in E. hormaechei highlights the importance of correlating resistance gene content and antibiotic resistance phenotype.
Influence of fumarate on interspecies electron transfer and the metabolic shift induced in Clostridium pasteurianum by Geobacter sulfurreducens
Authors: Pérez-Bernal María Fernanda , Berthomieu Roland , Quéméner Elie Desmond-Le , Bernet Nicolas , Trably Eric
Published: May 2024

Aims

In previous studies, it was demonstrated that co-culturing Clostridium pasteurianum and Geobacter sulfurreducens triggers a metabolic shift in the former during glycerol fermentation. This shift, attributed to interspecies electron transfer and the exchange of other molecules, enhances the production of 1,3-propanediol at the expense of the butanol pathway. The aim of this investigation is to examine the impact of fumarate, a soluble compound usually used as an electron acceptor for G. sulfurreducens, in the metabolic shift previously described in C. pasteurianum.

Methods and Results

Experiments were conducted by adding along with glycerol, acetate, and different quantities of fumarate in co-cultures of G. sulfurreducens and C. pasteurianum. A metabolic shift was exhibited in all the co-culture conditions. This shift was more pronounced at higher fumarate concentrations. Additionally, we observed G. sulfurreducens growing even in the absence of fumarate and utilizing small amounts of this compound as an electron donor rather than an electron acceptor in the co-cultures with high fumarate addition.

Conclusions

This study provided evidence that interspecies electron transfer continues to occur in the presence of a soluble electron acceptor, and the metabolic shift can be enhanced by promoting the growth of G. sulfurreducens.
To weight or not to weight? The effect of selection bias in 3 large electronic health record-linked biobanks and recommendations for practice
Authors: Salvatore Maxwell , Kundu Ritoban , Shi Xu , Friese Christopher R , Lee Seunggeun , Fritsche Lars G , Mondul Alison M , Hanauer David , Pearce Celeste Leigh , Mukherjee Bhramar
Published: May 2024

Objectives

To develop recommendations regarding the use of weights to reduce selection bias for commonly performed analyses using electronic health record (EHR)-linked biobank data.

Materials and methods

We mapped diagnosis (ICD code) data to standardized phecodes from 3 EHR-linked biobanks with varying recruitment strategies: All of Us (AOU; n = 244 071), Michigan Genomics Initiative (MGI; n = 81 243), and UK Biobank (UKB; n = 401 167). Using 2019 National Health Interview Survey data, we constructed selection weights for AOU and MGI to represent the US adult population more. We used weights previously developed for UKB to represent the UKB-eligible population. We conducted 4 common analyses comparing unweighted and weighted results.

Results

For AOU and MGI, estimated phecode prevalences decreased after weighting (weighted-unweighted median phecode prevalence ratio [MPR]: 0.82 and 0.61), while UKB estimates increased (MPR: 1.06). Weighting minimally impacted latent phenome dimensionality estimation. Comparing weighted versus unweighted phenome-wide association study for colorectal cancer, the strongest associations remained unaltered, with considerable overlap in significant hits. Weighting affected the estimated log-odds ratio for sex and colorectal cancer to align more closely with national registry-based estimates.

Discussion

Weighting had a limited impact on dimensionality estimation and large-scale hypothesis testing but impacted prevalence and association estimation. When interested in estimating effect size, specific signals from untargeted association analyses should be followed up by weighted analysis.

Conclusion

EHR-linked biobanks should report recruitment and selection mechanisms and provide selection weights with defined target populations. Researchers should consider their intended estimands, specify source and target populations, and weight EHR-linked biobank analyses accordingly.
Becoming Nature: Classifying Encounters in Interspecies Contact Zones
Authors: Grant Annetta , Canniford Robin , Shankar Avi
Published: May 2024

Nature affords transformations to consumers’ social, embodied, and temporal experiences. Yet, consumer research has yet to consider how wild species contribute to and are affected by experiential consumption in nature. With data from an ethnography of fly fishing, we theorize human–fish interactions as encounters in interspecies contact zones. Our findings explain how these encounters are established, engendering processes of interspecies becoming that transform both species. We discuss how these transformations are ordered by power relationships that classify roles for entities enrolled in consumption assemblages. Often, humans exert power over other living entities by classifying them as resources for consumption. Yet, we also discover more reciprocal expressions of power between humans and other species. With consumption as a major contributor to the decline of wild species populations, we discuss theoretical and practical implications of our work that are intended to stimulate further research.
Introducing two improved methods for approximating radiative cooling in hydrodynamical simulations of accretion discs
Authors: Young Alison K , Celeste Maggie , Booth Richard A , Rice Ken , Koval Adam , Carter Ethan , Stamatellos Dimitris
Published: May 2024

The evolution of many astrophysical systems depends strongly on the balance between heating and cooling, in particular star formation in giant molecular clouds and the evolution of young protostellar systems. Protostellar discs are susceptible to the gravitational instability, which can play a key role in their evolution and in planet formation. The strength of the instability depends on the rate at which the system loses thermal energy. To study the evolution of these systems, we require radiative cooling approximations because full radiative transfer is generally too expensive to be coupled to hydrodynamical models. Here, we present two new approximate methods for computing radiative cooling that make use of the polytropic cooling approximation. This approach invokes the assumption that each parcel of gas is located within a spherical pseudo-cloud, which can then be used to approximate the optical depth. The first method combines the methods introduced by Stamatellos et al. and Lombardi et al. to overcome the limitations of each method at low and high optical depths, respectively. The second method, the ‘modified Lombardi’ method, is specifically tailored for self-gravitating discs. This modifies the scale height estimate from the method of Lombardi et al. using the analytical scale height for a self-gravitating disc. We show that the modified Lombardi method provides an excellent approximation for the column density in a fragmenting disc, a regime in which the existing methods fail to recover the clumps and spiral structures. We therefore recommend this improved radiative cooling method for more realistic simulations of self-gravitating discs.
Evolution of Chromosomal Inversions across an Avian Radiation
Authors: Knief Ulrich , Müller Ingo A , Stryjewski Katherine F , Metzler Dirk , Sorenson Michael D , Wolf Jochen B W
Published: May 2024

Chromosomal inversions are structural mutations that can play a prominent role in adaptation and speciation. Inversions segregating across species boundaries (trans-species inversions) are often taken as evidence for ancient balancing selection or adaptive introgression, but can also be due to incomplete lineage sorting. Using whole-genome resequencing data from 18 populations of 11 recognized munia species in the genus Lonchura (N = 176 individuals), we identify four large para- and pericentric inversions ranging in size from 4 to 20 Mb. All four inversions cosegregate across multiple species and predate the numerous speciation events associated with the rapid radiation of this clade across the prehistoric Sahul (Australia, New Guinea) and Bismarck Archipelago. Using coalescent theory, we infer that trans-specificity is improbable for neutrally segregating variation despite substantial incomplete lineage sorting characterizing this young radiation. Instead, the maintenance of all three autosomal inversions (chr1, chr5, and chr6) is best explained by selection acting along ecogeographic clines not observed for the collinear parts of the genome. In addition, the sex chromosome inversion largely aligns with species boundaries and shows signatures of repeated positive selection for both alleles. This study provides evidence for trans-species inversion polymorphisms involved in both adaptation and speciation. It further highlights the importance of informing selection inference using a null model of neutral evolution derived from the collinear part of the genome.
Riboswitch and small RNAs modulate btuB translation initiation in Escherichia coli and trigger distinct mRNA regulatory mechanisms
Authors: Bastet Laurène , Korepanov Alexey P , Jagodnik Jonathan , Grondin Jonathan P , Lamontagne Anne-Marie , Guillier Maude , Lafontaine Daniel A
Published: May 2024

Small RNAs (sRNAs) and riboswitches represent distinct classes of RNA regulators that control gene expression upon sensing metabolic or environmental variations. While sRNAs and riboswitches regulate gene expression by affecting mRNA and protein levels, existing studies have been limited to the characterization of each regulatory system in isolation, suggesting that sRNAs and riboswitches target distinct mRNA populations. We report that the expression of btuB in Escherichia coli, which is regulated by an adenosylcobalamin (AdoCbl) riboswitch, is also controlled by the small RNAs OmrA and, to a lesser extent, OmrB. Strikingly, we find that the riboswitch and sRNAs reduce mRNA levels through distinct pathways. Our data show that while the riboswitch triggers Rho-dependent transcription termination, sRNAs rely on the degradosome to modulate mRNA levels. Importantly, OmrA pairs with the btuB mRNA through its central region, which is not conserved in OmrB, indicating that these two sRNAs may have specific targets in addition to their common regulon. In contrast to canonical sRNA regulation, we find that OmrA repression of btuB is lost using an mRNA binding-deficient Hfq variant. Together, our study demonstrates that riboswitch and sRNAs modulate btuB expression, providing an example of cis- and trans-acting RNA-based regulatory systems maintaining cellular homeostasis.
Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates
Authors: Yu Mikyung , Qin June , Liu Xiumin , Ramsden Diane , Williams Brian , Zlatev Ivan , Guenther Dale , Matsuda Shigeo , Tymon Roxanne , Darcy Justin , Wong Catrina , Tsung Jamie , Zawaneh Peter , Chong Saeho , Theile Christopher S , Taneja Nathan , Rogers Arlin , Liu Ju , Castellanos-Rizaldos Elena , Bond Sarah , So Kawai , Denoncourt Jason , Castoreno Adam , Manoharan Muthiah , Wu Jing-Tao , Fitzgerald Kevin , Maier Martin A , Jadhav Vasant , Nair Jayaprakash K
Published: May 2024

Oral delivery is the most widely used and convenient route of administration of medicine. However, oral administration of hydrophilic macromolecules is commonly limited by low intestinal permeability and pre-systemic degradation in the gastrointestinal (GI) tract. Overcoming some of these challenges allowed emergence of oral dosage forms of peptide-based drugs in clinical settings. Antisense oligonucleotides (ASOs) have also been investigated for oral administration but despite the recent progress, the bioavailability remains low. Given the advancement with highly potent and durable trivalent N-acetylgalactosamine (GalNAc)-conjugated small interfering RNAs (siRNAs) via subcutaneous (s.c.) injection, we explored their activities after oral administration. We report robust RNA interference (RNAi) activity of orally administrated GalNAc–siRNAs co-formulated with permeation enhancers (PEs) in rodents and non-human primates (NHPs). The relative bioavailability calculated from NHP liver exposure was <2.0% despite minimal enzymatic degradation in the GI. To investigate the impact of oligonucleotide size on oral delivery, highly specific GalNAc-conjugated single-stranded oligonucleotides known as REVERSIRs with different lengths were employed and their activities for reversal of RNAi effect were monitored. Our data suggests that intestinal permeability is highly influenced by the size of oligonucleotides. Further improvements in the potency of siRNA and PE could make oral delivery of GalNAc–siRNAs as a practical solution.
Phased telomere-to-telomere reference genome and pangenome reveal an expansion of resistance genes during apple domestication
Authors: Su Ying , Yang Xuanwen , Wang Yuwei , Li Jialei , Long Qiming , Cao Shuo , Wang Xu , Liu Zhenya , Huang Siyang , Chen Zhuyifu , Peng Yanling , Zhang Fan , Xue Hui , Cao Xuejing , Zhang Mengyan , Yisilam Gulbar , Chu Zhenzhou , Gao Yuan , Zhou Yongfeng , Liu Zhongjie , Xiao Hua , Tian Xinmin
Published: May 2024

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Earlier versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the apple's highly heterozygous genome, which impeded advances in genetic studies and breeding programs. In this study, we assembled a haplotype-resolved telomere-to-telomere (T2T) reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on 12 assemblies from wild and cultivated species to investigate the dynamic changes of functional genes. Our results revealed the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Our analyses also demonstrated a higher prevalence of different types of resistance gene analogs (RGAs) in cultivars than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR, NB-ARC-LRR, and CC-NB-ARC-LRR genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding.
News and Asset Pricing: A High-Frequency Anatomy of the SDF
Authors: Aleti Saketh , Bollerslev Tim
Published: May 2024

Utilizing real-time newswire data, together with a robustly estimated intraday stochastic discount factor (SDF), we identify and quantify the economic news that is priced. News related to monetary policy and finance on average accounts for most of the variation in the SDF, followed by news about international affairs and macroeconomic data. We also document nontrivial temporal variation in the relative importance of the news, along with marked differences in the estimated news risk premiums in the “factor zoo.” To further highlight the economic mechanisms at work, we associate the different news effects with interest rate, growth, and risk premium shocks.
Can the dose of belimumab be reduced in patients with systemic lupus erythematosus?
Authors: Rua-Figueroa Iñigo , Altabás-González Irene , Mouriño Coral , Roberts Karen , Hernández-Martín Andrea , Casafont-Solé Ivette , Font-Urgelles Judit , Román-Ivorra Jose A , de la Rubia Navarro Marta , Galindo-Izquierdo Maria , Salman-Monte Tarek C , Narváez Javier , Vidal-Montal Paola , García-Villanueva Maria Jesús , Garrote-Corral Sandra , Blazquez-Canamero Maria Angeles , Fernandez-Cid Carlos Marras , Piqueras-García Maria , Martínez-Barrio Julia , Sánchez-Lucas Marina , Cortés-Hernández Josefina , Penzo Eleonora , Calvo-Alén Jaime , de Dios Juan Ramón , Alvarez-Rodríguez Belén , Vasques-Rocha Margarida , Tomero Eva , Menor-Almagro Raul , Gandía Myriam , Gómez-Puerta José A , Frade-Sosa Beatriz , Ramos-Giráldez Consuelo , Trapero-Pérez Carmen , Diez Elvira , Moriano Clara , Muñoz-Jiménez Alejandro , Pego-Reigosa José María
Published: May 2024

Objectives

The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyse treatment modalities, and determine impact on control of disease activity.

Methods

Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6–12 months), and they were compared.

Results

A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in nine patients receiving subcutaneous BEL and in six patients receiving intravenous BEL. The dose per administration was reduced in 16 patients. Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively [not statistically significant (NS)]. As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62–8.75] vs 2.5 [0–5] at baseline).

Conclusion

Doses of BEL can be reduced with no relevant changes in disease activity—at least in the short term—in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.
Biosensor capability of the endometrium is mediated in part, by altered miRNA cargo from conceptus‐derived extracellular vesicles
Authors: De Bem Tiago H. C. , Bridi Alessandra , Tinning Haidee , Sampaio Rafael Vilar , Malo‐Estepa Irene , Wang Dapeng , Vasconcelos Elton J. R. , Nociti Ricardo Perecin , de Ávila Ana C. F. C. M. , Rodrigues Sangalli Juliano , Motta Igor Garcia , Arantes Ataíde Jr Gilmar , da Silva Júlio C. B. , Fumie Watanabe Yeda , Gonella‐Diaza Angela , da Silveira Juliano C. , Pugliesi Guilherme , Vieira Meirelles Flávio , Forde Niamh
Published: May 2024

We tested the hypothesis that the biosensor capability of the endometrium is mediated in part, by the effect of different cargo contained in the extracellular vesicles secreted by the conceptus during the peri‐implantation period of pregnancy. We transferred Bos taurus taurus embryos of different origin, in vivo (high developmental potential (IV)), in vitro (intermediate developmental potential (IVF)), or cloned (low developmental potential (NT)), into Bos taurus indicus recipients. Extracellular vesicles (EVs) recovered from Day 16 conceptus‐conditioned medium were characterized and their microRNA (miRNA) cargo sequenced alongside RNA sequencing of their respective endometria. There were substantial differences in the endometrial response to in vivo versus in vitro and in vivo versus cloned conceptuses (1153 and 334DEGs respectively) with limited differences between in vitro Vs cloned conceptuses (36 DEGs). The miRNA cargo contained in conceptus‐derived EVs was similar between all three groups (426 miRNA in common). Only 8 miRNAs were different between in vivo and cloned conceptuses, while only 6 miRNAs were different between in vivo and in vitro‐derived conceptuses. Treatment of endometrial epithelial cells with mimic or inhibitors for miR‐128 and miR‐1298 changed the proteomic content of target cells (96 and 85, respectively) of which mRNAs are altered in the endometrium in vivo (PLXDC2, COPG1, HSPA12A, MCM5, TBL1XR1, and TTF). In conclusion, we have determined that the biosensor capability of the endometrium is mediated in part, by its response to different EVs miRNA cargo produced by the conceptus during the peri‐implantation period of pregnancy.
Application of the Estimand Framework to Anesthesia Trials
Authors: De Silva Anurika P. , Leslie Kate , Braat Sabine , Grobler Anneke C.
Published: May 2024

Events occurring after randomization, such as use of rescue medication, treatment discontinuation, or death, are common in randomized trials. These events can change either the existence or interpretation of the outcome of interest. However, appropriate handling of these intercurrent events is often unclear. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9(R1) addendum introduced the estimand framework, which aligns trial objectives with the design, conduct, statistical analysis, and interpretation of results. This article describes how the estimand framework can be used in anesthesia trials to precisely define the treatment effect to be estimated, key attributes of an estimand, common intercurrent events in anesthesia trials with strategies for handling them, and use of the estimand framework in a hypothetical anesthesia trial on postoperative delirium. When planning anesthesia trials, clearly defining the estimand is vital to ensure that what is being estimated is clearly understood, is clinically relevant, and helps answer the clinical questions of interest.
Lithium Exposure and Risk of Major Neurocognitive Disorders
Authors: Huang Qing , Ma Xue-qin , Chen Hui-fang
Published: May 2024

Background

Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association.

Methods

A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models.

Results

Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77–1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31–1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71–1.15).

Conclusion

The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.
Prevalence and Risk Factors of Constipation in Trauma Patients: A Prospective Cohort Study
Authors: Liersch Kellie M. , Gumm Kellie M. , Read David J.
Published: May 2024

BACKGROUND:

Hospitalized patients are well described as having a high prevalence of constipation. While the risks associated with constipation in trauma patients are well known, the prevalence rate is not.

OBJECTIVE:

This study aims to measure the prevalence of constipation and associated risk factors in trauma patients.

METHODS:

This study is a single-center analytic cross-sectional study on constipation in hospitalized trauma patients aged 18–65 years, admitted from January 2021 to July 2021 to the trauma service at The Royal Melbourne Hospital, a Level I major trauma and teaching hospital servicing the state of Victoria, Australia. Exclusion criteria include patients with traumatic brain injury, blunt or penetrating abdominal or spinal injuries, pregnancy, and gastrointestinal comorbidities.

RESULTS:

A total of N = 99 patients were studied, of which n = 78 (78.8%) were male with a median (interquartile range) age of 46 years (33–58). The overall prevalence of constipation was 76%. The univariate analysis demonstrated higher constipation rates in males and patients with multisystem injuries. However, in the multivariate analysis, mode of toileting and mobility were not associated with constipation after adjusting for confounding factors.

CONCLUSION:

This study demonstrated a high prevalence of constipation in all trauma patients. There is a strong association between the development of constipation in patients with multisystem injuries when compared to those with single system.
Totally Implantable Venous Access Device Care Practices and Experiences of Pediatric and Adult Oncology Nurses
Authors: Gündogdu Fatma , Semerci Remziye , Bay Figen
Published: May 2024

This study aimed to determine the practices of nurses working in pediatric and adult oncology clinics regarding totally implantable venous access device (TIVAD) care. The descriptive study was conducted with 227 oncology nurse members of the Oncology Nursing Association. The data were collected online with a survey form, which included questions about the participants’ sociodemographic characteristics, professional experience, and TIVAD implementation practices. Descriptive statistics and ꭓ2 tests were used for the analysis of the data. It was determined that 44.1% of the nurses used 0.9% NaCl for active TIVAD flushing; 15.9% of them used a positive-pressure 0.9% NaCl-filled syringe; 12.3% used antireflux connectors; 85.5% used manual positive pressure technique; and 53.7% used the pulsatile technique. A statistical difference was found between nurses’ training on TIVAD care and TIVAD occlusion rate in the clinic, TIVAD infection rate, following the guidelines, and using the pulsatile technique (P < .05). This study revealed that there are differences in the practices for TIVAD care and that the recommendations in the literature/guidelines are not implemented at the desired level to ensure continuity and prevent complications.
Training Opportunities for Managers in Home Health, Hospice, and Community-Based Care Settings
Authors: Nguyen Ann M. , Tallia Alfred F. , Videon Tami M. , Rosati Robert J.
Published: May 2024

OBJECTIVE

The aim of this study was to identify areas for developing management skills-focused continuing education for managers working in home health, hospice, and community-based settings.

BACKGROUND

Healthcare managers play a vital role in organizations, yet they have a range of management training.

METHODS

Researchers conducted a cross-sectional survey of managers at a large Visiting Nurse Association. Descriptive and bivariate analyses were performed to examine confidence in management skills by respondent characteristic. Factor and cluster analyses were used to examine differences by role.

RESULTS

For all 33 management tasks, managers with 6+ years of experience reported greater confidence than managers with 0 to 5 years of experience. Tasks with the lowest confidence were budgeting, interpreting annual reports, strategic planning, measuring organizational performance, and project planning. Managers were clustered into 5 “profiles.”

CONCLUSION

Management training is not 1-size-fits-all. Healthcare organizations should consider investing in training specific to the identified low-confidence areas and manager roles to better support and develop a robust management workforce.
Correlation of Serum High-Sensitivity C-Reactive Protein, Homocysteine, and Macrophage Migration Inhibitory Factor Levels With Symptom Severity and Cognitive Function in Patients With Schizophrenia
Authors: Weng Saizheng , Zheng Rongyan , Lin Ruiqian
Published: May 2024

Objective

This trial analyzed high-sensitivity C-reactive protein (hs-CRP), homocysteine (Hcy), and macrophage migration inhibitory factor (MIF) level in serum and their correlation with symptom severity and cognitive function in patients with schizophrenia (SP).

Methods

Sixty-eight SP patients were enrolled in the SP group, and 68 healthy volunteers were in the control (CN) group. Serum hs-CRP, Hcy, and MIF were measured, and symptom severity was assessed with the Positive and Negative Symptom Scale (PANSS). Cognitive function was determined with the MATRICS Consensus Cognitive Battery (MCCB). The SP group was divided into high PANSS score (PANSS ≥70 points) and low PANSS score (PANSS <70 points), or the mild cognitive dysfunction group and severe cognitive dysfunction group according to the median MCCB score. The correlation between serum hs-CRP, Hcy, and MIF levels and PANSS and MCCB scores in SP patients was examined by Pearson correlation analysis.

Results

SP patients had higher serum hs-CRP, Hcy, and MIF levels and showed higher PANSS scores and lower MCCB total score. Serum hs-CRP, Hcy, and MIF levels in the high PANSS group were higher than those in the low PANSS group and in the severe cognitive dysfunction group than in the mild cognitive dysfunction group. Serum hs-CRP, Hcy, and MIF levels in SP patients were positively correlated with PANSS total score and negatively correlated with MCCB total score.

Conclusion

High serum hs-CRP, Hcy, and MIF levels in SP patients are correlated with symptom severity and cognitive dysfunction.
Microbacterium horticulturae sp. nov., a novel actinobacterium isolated from flowerpot soil
Authors: Choi Hyorim , Choi Yunhee , Kim Seunghwan , Kim Yiseul , Naito Hanako , Yamada Tomomi , Hamada Moriyuki , Kim NamJung , Lee Yonghoon , Heo Jun
Published: May 2024

Strain CJN36-1NT, a Gram-stain-positive, non-flagellated, strictly aerobic and short rod-shaped bacterium, was isolated from flowerpot soil sampled in the Jeonju region of the Republic of Korea. Based on 16S rRNA gene sequences and the resulting phylogenetic tree, the strain belonged to the genus Microbacterium. Strain CJN36-1NT contained a chromosome of 3.6 Mbp with a G+C content of 68.5 mol%. The strain grew at 10–37 °C (optimally at 28 °C), at pH 5.0–8.0 (optimally at pH 8.0), and in the presence of 0–7 % NaCl (w/v; optimally with 0 % NaCl). Digital DNA–DNA hybridization, average nucleotide identity and average amino acid identity values between strain CJN36-1NT and its closest related species, Microbacterium protaetiae DFW100M-13T, were 82.0, 81.2, and 23.2 %, respectively. We propose naming this novel species Microbacterium horticulturae sp. nov., with CJN36-1NT (=KACC 23027T=NBRC 116065T) as the type strain.
Deletion of codY impairs Staphylococcus epidermidis biofilm formation, generation of viable but non-culturable cells and stimulates cytokine production in human macrophages
Authors: Lopes Nathalie , Pereira Renato B. , Correia Alexandra , Vilanova Manuel , Cerca Nuno , França Angela
Published: May 2024

Introduction.
Staphylococcus epidermidis biofilms are one of the major causes of bloodstream infections related to the use of medical devices. The diagnosis of these infections is challenging, delaying their treatment and resulting in increased morbidity and mortality rates. As such, it is urgent to characterize the mechanisms employed by this bacterium to endure antibiotic treatments and the response of the host immune system, to develop more effective therapeutic strategies. In several bacterial species, the gene codY was shown to encode a protein that regulates the expression of genes involved in biofilm formation and immune evasion. Additionally, in a previous study, our group generated evidence indicating that codY is involved in the emergence of viable but non-culturable (VBNC) cells in S. epidermidis.

Gap statement/Hypothesis. As such, we hypothesized that the gene codY has have an important role in this bacterium virulence.

Aim. This study aimed to assess, for the first time, the impact of the deletion of the gene codY in S. epidermidis virulence, namely, in antibiotic susceptibility, biofilm formation, VBNC state emergence and in vitro host immune system response.

Methodology. Using an allelic replacement strategy, we constructed and then characterized an S. epidermidis strain lacking codY, in regards to biofilm and VBNC cell formation, susceptibility to antibiotics as well as their role in the interaction with human blood and plasma. Additionally, we investigate whether the codY gene can impact the activation of innate immune cells by evaluating the production of both pro- and anti-inflammatory cytokines by THP-1 macrophages.

Results. We demonstrated that the deletion of the gene codY resulted in biofilms with less c.f.u. counts and fewer VBNC cells. Furthermore, we show that although WT and mutant cells were similarly internalized in vitro by human macrophages, a stronger cytokine response was elicited by the mutant in a toll-like receptor 4-dependent manner.

Conclusion. Our results indicate that codY contributes to S. epidermidis virulence, which in turn may have an impact on our ability to manage the biofilm-associated infections caused by this bacterium.
Specialized Pericyte Subtypes in the Pulmonary Capillary
Authors: Klouda Timothy , Kim Yunhye , Baek Seung-Han , Bhaumik Mantu , Liu Yu , Liu Tiffany , Que Jianwen , Wu Joseph C , Raby Benjamin A , de Jesus Perez Vinicio , Yuan Ke
Published: May 2024

Pericytes (PCs) play crucial roles in capillary maturation, stability, and homeostasis. Impaired PC coverage and function are implicated in various diseases, including pulmonary arterial hypertension (PAH). Challenges investigating PC biology are largely due to the lack of a concise marker, resulting in difficulty distinguishing PCs from other mural cell populations, including smooth muscle cells (SMCs) and fibroblasts (FBs). Utilizing bioinformatic analysis and RNAscope, we identified HIG hypoxia-inducible domain family member 1B (Higd1b) as a unique and conserved gene marker for PCs and generated a novel knockin mouse line,Higd1b-CreERT2, which precisely labels PCs in the lung and heart. Human lung single-cell RNAseq suggested the presence of twoHIGD1B+ PC subtypes with different functions. By lineage tracing pulmonaryHigd1b+cells exposed to hypoxiain vivo, we identified Type 1 PCs remained in the capillary network, while Type 2 PCs accumulated in the arterioles and coexpressed SMC markers and increased levels of Vimentin, associated with focal adhesion pathways. These results suggest that Type 1 PCs are specialized for supporting capillary EC homeostasis and quiescent, while Type 2 PCs are lineage active and located close to the border zone of the arterioles and capillaries, which may be motile and transition to SMC-like cells in hypoxia-induced pulmonary hypertension. The discovery of PC-type specialization in capillaries transforms our understanding of the structure, function and regulation of pulmonary capillary circulation and their contribution to vascular remodeling.
Possible regulation of the immune modulator tetraspanin CD81 by alpha-synuclein in melanoma
Authors: Aloy Nirjhar M. , Coughlan Christina , Graner Michael W , Witt Stephan N.
Published: May 2024

We probed the mechanism by which the Parkinsons disease-associated protein α–synuclein (α–syn)/SNCApromotes the pathogenesis and progression of melanoma. We found that the human melanoma cell line SK–MEL–28 in whichSNCAis knocked out (SNCA-KO) has low levels of tetraspanin CD81, which is a cell-surface protein that promotes invasion, migration, and immune suppression. Analyzing data from the Cancer Genome Atlas, we show thatSNCAandCD81mRNA levels are positively correlated in melanoma; melanoma survival is inversely related to the levels ofSNCAandCD81; andSNCA/CD81are inversely related to the expression of key cytokine genes (IL12A,IL12B,IFN,IFNG,PRF1andGZMB) for immune activation and immune cell-mediated killing of melanoma cells. We propose that high levels of α–syn and CD81 in melanoma and in immune cells drive invasion and migration and in parallel cause an immunosuppressive microenvironment; these contributing factors lead to aggressive melanomas.
BCG immunization induced KLRG1+ NK cells show memory-like responses to mycobacterial and HIV antigens
Authors: Gunasena Manuja , Alles Mario , Demberg Thorsten , Mulhern Will , Liyanage Namal P.M.
Published: May 2024

The live-attenuated Bacille-Calmette-Guérin (BCG) vaccine is the only approved vaccine againstMycobacterium tuberculosis(MTB), offering broad protection against tuberculosis (TB) and other infectious diseases. ‘Trained immunity’, a process where innate immune cells develop memory-like features, is considered one of the BCG vaccine’s protective mechanisms. In this study, we investigated the effect of BCG vaccination on Natural Killer (NK) cells, a key subset of the innate immune system, and their ability to give rise to heterologous memory-like responses to HIV antigens. Here we found that BCG vaccine-induced KLRG1+ NK cells exhibit memory-like responses to both MTB and HIV antigens, as evidenced by their increased production of IFNγ upon exposure to MTB and HIV-gag antigens. This finding is of great importance, as co-infection with HIV and TB is highly relevant in Asia and Africa where BCG is administered. Understanding these responses is crucial for the development of more effective vaccines and therapeutics for both TB and HIV.