bluuebunny/crossref_metadata_2025 huggingface dataset:
Place of death in Parkinson’s disease and related disorders in England and Wales: post-pandemic trends and implications for care planning
Authors: Wilson Elisabeth , Baker Amy , Stockley Lauren , Allgar Victoria , Richfield Edward
Published: March 2024

Background

With growing emphasis on palliative care for neurodegenerative conditions, understanding trends in place of death helps improve quality of end-of-life care for people with Parkinson’s disease and related disorders (PDRDs), focusing allocation of resources and training and identifying inequalities.

Objectives

Review national and regional place of death trends for people with PDRD including pre- and post-pandemic trends.

Methods

Mortality data for England and Wales (March 2018 and July 2022) were analysed with summary statistics and interrupted time series, exploring place of death for those who died with PDRD, with and without coexisting dementia, with reference to all deaths in England and Wales.

Results

Of 2,415,566 adult deaths, 56,790 included mention of PDRD. Hospital deaths were most common in people with PDRD (39.17%), followed by care homes (38.84%). People with PDRD were half as likely to die in hospice compared with the general population (2.03 vs 4.94%). Proportion of care home deaths fell significantly after March 2020 (40.6–37%, P = 0.035). Regionally, London was an outlier with a lower proportion of deaths occurring in care homes with a higher proportion of hospital deaths.

Conclusion

Place of death for people with PDRD is changing, with more hospice and home deaths. People with PDRD, particularly those with co-existent dementia, are less likely to access inpatient hospice care than the general population. Since the COVID-19 pandemic, the proportion of care home deaths has reduced significantly with an increase in home deaths, with implications for service and resource allocation.
scGIR: deciphering cellular heterogeneity via gene ranking in single-cell weighted gene correlation networks
Authors: Xu Fei , Hu Huan , Lin Hai , Lu Jun , Cheng Feng , Zhang Jiqian , Li Xiang , Shuai Jianwei
Published: March 2024

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for investigating cellular heterogeneity through high-throughput analysis of individual cells. Nevertheless, challenges arise from prevalent sequencing dropout events and noise effects, impacting subsequent analyses. Here, we introduce a novel algorithm, Single-cell Gene Importance Ranking (scGIR), which utilizes a single-cell gene correlation network to evaluate gene importance. The algorithm transforms single-cell sequencing data into a robust gene correlation network through statistical independence, with correlation edges weighted by gene expression levels. We then constructed a random walk model on the resulting weighted gene correlation network to rank the importance of genes. Our analysis of gene importance using PageRank algorithm across nine authentic scRNA-seq datasets indicates that scGIR can effectively surmount technical noise, enabling the identification of cell types and inference of developmental trajectories. We demonstrated that the edges of gene correlation, weighted by expression, play a critical role in enhancing the algorithm’s performance. Our findings emphasize that scGIR outperforms in enhancing the clustering of cell subtypes, reverse identifying differentially expressed marker genes, and uncovering genes with potential differential importance. Overall, we proposed a promising method capable of extracting more information from single-cell RNA sequencing datasets, potentially shedding new lights on cellular processes and disease mechanisms.
Conditional modeling of panel count data with partly interval-censored failure event
Authors: Hu Xiangbin , Su Wen , Ye Zhisheng , Zhao Xingqiu
Published: March 2024

In longitudinal follow-up studies, panel count data arise from discrete observations on recurrent events. We investigate a more general situation where a partly interval-censored failure event is informative to recurrent events. The existing methods for the informative failure event are based on the latent variable model, which provides indirect interpretation for the effect of failure event. To solve this problem, we propose a failure-time-dependent proportional mean model with panel count data through an unspecified link function. For estimation of model parameters, we consider a conditional expectation of least squares function to overcome the challenges from partly interval-censoring, and develop a two-stage estimation procedure by treating the distribution function of the failure time as a functional nuisance parameter and using the B-spline functions to approximate unknown baseline mean and link functions. Furthermore, we derive the overall convergence rate of the proposed estimators and establish the asymptotic normality of finite-dimensional estimator and functionals of infinite-dimensional estimator. The proposed estimation procedure is evaluated by extensive simulation studies, in which the finite-sample performances coincide with the theoretical results. We further illustrate our method with a longitudinal healthy longevity study and draw some insightful conclusions.
Chikungunya fever with a positive tourniquet test: a novel description
Authors: Mansilla-Polo Miguel , Torres-Navarro Ignacio , Martín-Torregrosa Daniel , López-Davia Javier , Botella-Estrada Rafael
Published: March 2024

We report a clinical case of a patient with a relatively rare disease, chikungunya fever, a viral disease characterized by a sudden fever accompanied by skin rashes and joint pain, followed by persistent rheumatic symptoms. The singularity of our clinical case (to our knowledge, not yet reported in the literature) lies in the fact that it presented a positive tourniquet test, a finding traditionally described in severe dengue infections.
BMP9 is a key player in endothelial identity and its loss is sufficient to induce arteriovenous malformations
Authors: Desroches-Castan Agnes , Koca Dzenis , Liu Hequn , Roelants Caroline , Resmini Léa , Ricard Nicolas , Bouvard Claire , Chaumontel Nicolas , Tharaux Pierre-Louis , Tillet Emmanuelle , Battail Christophe , Lenoir Olivia , Bailly Sabine
Published: March 2024

Aims

BMP9 is a high affinity ligand of ALK1 and endoglin receptors that are mutated in the rare genetic vascular disorder hereditary hemorrhagic telangiectasia (HHT). We have previously shown that loss of Bmp9 in the 129/Ola genetic background leads to spontaneous liver fibrosis via capillarization of liver sinusoidal endothelial cells (LSEC) and kidney lesions. We aimed to decipher the molecular mechanisms downstream of BMP9 to better characterize its role in vascular homeostasis in different organs.

Methods and results

For this, we performed an RNA-seq analysis on LSEC from adult WT and Bmp9-KO mice and identified over 2000 differentially expressed genes. Gene ontology analysis showed that Bmp9 deletion led to a decrease in BMP and Notch signalling, but also LSEC capillary identity while increasing their cell cycle. The gene ontology term ‘glomerulus development’ was also negatively enriched in Bmp9-KO mice vs. WT supporting a role for BMP9 in kidney vascularization. Through different imaging approaches (electron microscopy, immunostainings), we found that loss of Bmp9 led to vascular enlargement of the glomeruli capillaries associated with alteration of podocytes. Importantly, we also showed for the first time that the loss of Bmp9 led to spontaneous arteriovenous malformations (AVMs) in the liver, gastrointestinal tract, and uterus.

Conclusion

Altogether, these results demonstrate that BMP9 plays an important role in vascular quiescence both locally in the liver by regulating endothelial capillary differentiation markers and cell cycle but also at distance in many organs via its presence in the circulation. It also reveals that loss of Bmp9 is sufficient to induce spontaneous AVMs, supporting a key role for BMP9 in the pathogenesis of HHT.
Assessing genetic diversity and geographical differentiation in a global collection of wild soybean (Glycine soja Sieb. et Zucc.) and assigning a mini-core collection
Authors: Li Feng , Sayama Takashi , Yokota Yuko , Hiraga Susumu , Hashiguchi Masatsugu , Tanaka Hidenori , Akashi Ryo , Ishimoto Masao
Published: March 2024

Wild soybean (Glycine soja), the ancestor of the cultivated soybean (G. max), is a crucial resource for capturing the genetic diversity of soybean species. In this study, we used a set of 78 genome-wide microsatellite markers to analyse the genetic diversity and geographic differentiation patterns in a global collection of 2,050 G. soja accessions and a mini-core collection of G. max stored in two public seed banks. We observed a notable reduction in the genetic diversity of G. max compared with G. soja and identified a close phylogenetic relationship between G. max and a G. soja subpopulation located in central China. Furthermore, we revealed substantial genetic divergence between northern and southern subpopulations, accompanied by diminished genetic diversity in the northern subpopulations. Two clusters were discovered among the accessions from north-eastern China—one genetically close to those from South Korea and Southern Japan, and another close to those from Amur Oblast, Russia. Finally, 192 accessions were assigned to a mini-core collection of G. soja, retaining 73.8% of the alleles detected in the entire collection. This mini-core collection is accessible to those who need it, facilitating efficient evaluation and utilization of G. soja genetic resources in soybean breeding initiatives.
Yet another fast variant of Newton’s method for nonconvex optimization
Authors: Gratton Serge , Jerad Sadok , Toint Philippe L
Published: March 2024

A class of second-order algorithms is proposed for minimizing smooth nonconvex functions that alternates between regularized Newton and negative curvature steps in an iteration-dependent subspace. In most cases, the Hessian matrix is regularized with the square root of the current gradient and an additional term taking moderate negative curvature into account, a negative curvature step being taken only exceptionally. Practical variants are detailed where the subspaces are chosen to be the full space, or Krylov subspaces. In the first case, the proposed method only requires the solution of a single linear system at nearly all iterations. We establish that at most $\mathcal{O}\big ( |\!\log \epsilon |\,\epsilon ^{-3/2}\big )$ evaluations of the problem’s objective function and derivatives are needed for algorithms in the new class to obtain an $\epsilon $-approximate first-order minimizer, and at most $\mathcal{O}\big (|\!\log \epsilon |\,\epsilon ^{-3}\big )$ to obtain a second-order one. Encouraging initial numerical experiments with two full-space and two Krylov-subspaces variants are finally presented.
Outpatient Visits and Antibiotic Use Due to Higher-Valency Pneumococcal Vaccine Serotypes
Authors: King Laura M , Andrejko Kristin L , Kabbani Sarah , Tartof Sara Y , Hicks Lauri A , Cohen Adam L , Kobayashi Miwako , Lewnard Joseph A
Published: March 2024

Background

In 2022–2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15/PCV20) were recommended for infants. We aimed to estimate the incidence of outpatient visits and antibiotic prescriptions in US children (≤17 years) from 2016–2019 for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional (non-PCV13) serotypes to quantify PCV15/20 potential impacts.

Methods

We estimated the incidence of PCV15/20-additional serotype-attributable visits and antibiotic prescriptions as the product of all-cause incidence rates, derived from national health care surveys and MarketScan databases, and PCV15/20-additional serotype-attributable fractions. We estimated serotype-specific attributable fractions using modified vaccine-probe approaches incorporating incidence changes post-PCV13 and ratios of PCV13 versus PCV15/20 serotype frequencies, estimated through meta-analyses.

Results

Per 1000 children annually, PCV15-additional serotypes accounted for an estimated 2.7 (95% confidence interval, 1.8–3.9) visits and 2.4 (95% CI, 1.6–3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (95% CI, 11.2–20.4) visits and 13.2 (95% CI, 9.9–18.0) antibiotic prescriptions annually per 1000 children. PCV15/20-additional serotypes account for 0.4% (95% CI, 0.2%–0.6%) and 2.1% (95% CI, 1.5%–3.0%) of pediatric outpatient antibiotic use.

Conclusions

Compared with PCV15-additional serotypes, PCV20-additional serotypes account for > 5 times the burden of visits and antibiotic prescriptions. Higher-valency PCVs, especially PCV20, may contribute to preventing pediatric pneumococcal respiratory infections and antibiotic use.
Pharmacodynamic evaluation of ceftriaxone single-dose therapy (0.125–1 g) to eradicate ceftriaxone-susceptible and ceftriaxone-resistant Neisseria gonorrhoeae strains in a hollow fibre infection model for gonorrhoea
Authors: Unemo Magnus , Golparian Daniel , Oxelbark Joakim , Kong Fabian Y S , Brown David , Louie Arnold , Drusano George , Jacobsson Susanne
Published: March 2024

Background

Antimicrobial resistance in Neisseria gonorrhoeae is threatening the gonorrhoea treatment, and optimizations of the current ceftriaxone-treatment regimens are crucial. We evaluated the pharmacodynamics of ceftriaxone single-dose therapy (0.125–1 g) against ceftriaxone-susceptible and ceftriaxone-resistant gonococcal strains, based on EUCAST ceftriaxone-resistance breakpoint (MIC > 0.125 mg/L), in our hollow fibre infection model (HFIM) for gonorrhoea.

Methods

Gonococcal strains examined were WHO F (ceftriaxone-susceptible, MIC < 0.002 mg/L), R (ceftriaxone-resistant, MIC = 0.5 mg/L), Z (ceftriaxone-resistant, MIC = 0.5 mg/L) and X (ceftriaxone-resistant, MIC = 2 mg/L). Dose-range HFIM 7 day experiments simulating ceftriaxone 0.125–1 g single-dose intramuscular regimens were conducted.

Results

Ceftriaxone 0.125–1 g single-dose treatments rapidly eradicated WHO F (wild-type ceftriaxone MIC). Ceftriaxone 0.5 and 1 g treatments, based on ceftriaxone human plasma pharmacokinetic parameters, eradicated most ceftriaxone-resistant gonococcal strains (WHO R and Z), but ceftriaxone 0.5 g failed to eradicate WHO X (high-level ceftriaxone resistance). When simulating oropharyngeal gonorrhoea, ceftriaxone 0.5 g failed to eradicate all the ceftriaxone-resistant strains, while ceftriaxone 1 g eradicated WHO R and Z (low-level ceftriaxone resistance) but failed to eradicate WHO X (high-level ceftriaxone resistance). No ceftriaxone-resistant mutants were selected using any ceftriaxone treatments.

Conclusions

Ceftriaxone 1 g single-dose intramuscularly cure most of the anogenital and oropharyngeal gonorrhoea cases caused by the currently internationally spreading ceftriaxone-resistant gonococcal strains, which should be further confirmed clinically. A ceftriaxone 1 g dose (±azithromycin 2 g) should be recommended for first-line empiric gonorrhoea treatment. This will buy countries some time until novel antimicrobials are licensed. Using ceftriaxone 1 g gonorrhoea treatment, the EUCAST ceftriaxone-resistance breakpoint is too low.
Cost-effectiveness of point-of-care diagnostics for AMR: a systematic review
Authors: Tolley Abraham , Bansal Akhil , Murerwa Rebecca , Howard Dicks James
Published: March 2024

Background

Antimicrobial resistance (AMR) is a major threat to global health. By 2050, it is forecast that AMR will cause 10 million deaths and cost 100 trillion USD annually. Point-of-care tests (POCTs) may represent a cost-effective approach to reduce AMR.

Objectives

We systematically reviewed which POCTs addressing AMR have undergone economic evaluation in primary and secondary healthcare globally, how these POCTs have been economically evaluated, and which are cost-effective in reducing antimicrobial prescribing or the burden of AMR. Clinical cost-effectiveness was additionally addressed.

Methods

This systematic review, accordant with PRISMA guidelines, was pre-registered on PROSPERO (CRD42022315192). MEDLINE, PubMed, Embase, Cochrane Library, and Google Scholar were searched from 2000 to 2023 for relevant publications. Quality assessment was performed using the Consensus of Health Economic Criteria.

Results

The search strategy identified 1421 studies, of which 20 met the inclusion criteria. The most common POCTs assessed were for respiratory infections (n = 10), STIs (n = 3), and febrile patients in low- and middle-income countries (n = 3). All studies assessed costs from a healthcare provider perspective; five additionally considered the societal cost of AMR.

Eighteen studies identified POCT strategies that reduced antimicrobial prescribing. Of these, 10 identified POCTs that would be considered cost-effective at a willingness-to-pay (WTP) threshold of £33.80 per antibiotic prescription avoided. Most POCT strategies improved clinical outcomes (n = 14); the remainder were clinically neutral.

Conclusions

There is evidence that some POCTs are cost-effective in reducing antimicrobial prescribing, with potential concomitant clinical benefits. Such interventions—especially CRP POCTs in both high- and low-income settings—merit further, large-scale clinical evaluation.
Generalizing Parkinson’s disease detection using keystroke dynamics: a self-supervised approach
Authors: Tripathi Shikha , Acien Alejandro , Holmes Ashley A , Arroyo-Gallego Teresa , Giancardo Luca
Published: March 2024

Objective

Passive monitoring of touchscreen interactions generates keystroke dynamic signals that can be used to detect and track neurological conditions such as Parkinson’s disease (PD) and psychomotor impairment with minimal burden on the user. However, this typically requires datasets with clinically confirmed labels collected in standardized environments, which is challenging, especially for a large subject pool. This study validates the efficacy of a self-supervised learning method in reducing the reliance on labels and evaluates its generalizability.

Materials and Methods

We propose a new type of self-supervised loss combining Barlow Twins loss, which attempts to create similar feature representations with reduced feature redundancy for samples coming from the same subject, and a Dissimilarity loss, which promotes uncorrelated features for samples generated by different subjects. An encoder is first pre-trained using this loss on unlabeled data from an uncontrolled setting, then fine-tuned with clinically validated data. Our experiments test the model generalizability with controls and subjects with PD on 2 independent datasets.

Results

Our approach showed better generalization compared to previous methods, including a feature engineering strategy, a deep learning model pre-trained on Parkinsonian signs, and a traditional supervised model.

Discussion

The absence of standardized data acquisition protocols and the limited availability of annotated datasets compromise the generalizability of supervised models. In these contexts, self-supervised models offer the advantage of learning more robust patterns from the data, bypassing the need for ground truth labels.

Conclusion

This approach has the potential to accelerate the clinical validation of touchscreen typing software for neurodegenerative diseases.
Association of lung immune prognostic index with survival outcomes in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab
Authors: Yamashita Shimpei , Hamamoto Shuzo , Furukawa Junya , Fujita Kazutoshi , Takahashi Masayuki , Miyake Makito , Ito Noriyuki , Iwamoto Hideto , Kohjimoto Yasuo , Hara Isao
Published: March 2024

Objective

Lung immune prognostic index is based on derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. Lung immune prognostic index has reported association with survival outcomes in patients with various malignancies undergoing treatment with immune checkpoint inhibitors. However, the prognostic impact of pre-treatment lung immune prognostic index in patients with metastatic renal cell carcinoma receiving nivolumab plus ipilimumab treatment remains unclear. This study examines the association between lung immune prognostic index and outcomes in this setting.

Methods

We retrospectively evaluated 156 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab at eight institutions. We assessed the associations between pre-treatment lung immune prognostic index and survival outcomes including progression-free survival, second progression-free survival (PFS2), cancer-specific survival and overall survival.

Results

Patients were classified into good (n = 84, 54%), intermediate (n = 52, 33%) and poor (n = 20, 13%) lung immune prognostic index groups. Progression-free survival did not significantly differ between lung immune prognostic index groups, but there was significant difference in PFS2, cancer-specific survival and overall survival. In multivariable Cox proportional hazard analyses, high pre-treatment lung immune prognostic index was a significant predictor of poor PFS2 (vs. good group, intermediate group: P = 0.01 and poor group: P = 0.04) and poor overall survival (vs. good group, intermediate group: P = 0.01 and poor group: P < 0.01). Moreover, the patients with poor lung immune prognostic index had significantly poorer cancer-specific survival than those with good LIPI (P < 0.01).

Conclusions

High pre-treatment LIPI is suggested by our results to be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.
NLRP3 inflammasome in sepsis: don’t overlook the small steps—they can make a big difference!
Authors: Belicard Felicie , Tarte Karin , Tadié Jean-Marc
Published: March 2024

Sentence abstract for use in TOC alerts

“In sepsis, persistent activation of NLRP3 is associated with expansion of both monocytic and granulocytic MDSCs, along with high plasma concentration of IL-10.”
Grazing effects on the relationship between plant functional diversity and soil carbon sequestration regulated by livestock species
Authors: Ding Shiwen , van der Plas Fons , Li Jie , Liu Bai , Xu Man , Xu Tongtong , Pan Xiaobin , Chang Qing , Chen Ying , Li Yinong
Published: March 2024

Grazing exerts a profound influence on both the plant diversity and productivity of grasslands, while simultaneously exerting a significant impact on regulating grassland soil carbon sequestration. Moreover, besides altering the taxonomic diversity of plant communities, grazing can also affect their diversity of functional traits. However, we still poorly understand how grazing modifies the relationship between plant functional diversity (FD) and soil carbon sequestration in grassland ecosystems. Here, we conducted a grazing manipulation experiment to investigate the effects of different grazing regimes (no grazing, sheep grazing (SG) and cattle grazing (CG)) on the relationships between plant FD and soil carbon sequestration in meadow and desert steppe. Our findings showed that different livestock species changed the relationships between plant FD and soil organic carbon (SOC) in the meadow steppe. SG decoupled the originally positive relationship between FD and SOC, whereas CG changed the relationship from positive to negative. In the desert steppe, both SG and CG strengthened the positive relationship between FD and SOC. Our study illuminates the considerable impact of livestock species on the intricate mechanisms of soil carbon sequestration, primarily mediated through the modulation of various measures of functional trait diversity. In ungrazed meadows and grazed deserts, maintaining high plant FD is conducive to soil carbon sequestration, whereas in grazed meadows and ungrazed deserts, this relationship may disappear or even reverse. By measuring the traits and controlling the grazing activities, we can accurately predict the carbon sequestration potential in grassland ecosystems.
How Rohingya refugee parents support children’s prosocial development in crisis-affected and resettlement contexts: Findings from India and Canada
Authors: Didkowsky Nora , Corbit John , Gora Vikas , Reddy Harini , Muhammad Saifullah , Callaghan Tara
Published: March 2024

We know little about how parents protect and promote children’s prosocial development during humanitarian crises. This qualitative study examined Rohingya refugee parents’ psychosocial perspectives and the processes they use to socialize prosocial values and behaviours in their children. Interviews (descriptive and in-depth qualitative) were conducted with 100 parents living in a refugee settlement in India (n = 100 descriptive; n = 5 in-depth) and 4 parents resettled in a mid-sized Canadian city (n = 4 descriptive; n = 4 in-depth). An inductive, ‘contextualist’ thematic analysis (TA) was conducted on the in-depth interviews to develop three overarching themes: (1) parents’ prosocial values and beliefs; (2) environmental conditions influencing parents’ available pathways for promoting children’s prosocial development; and (3) parents’ prosocial socialization and protection practices. The findings indicate that parents’ prosocial beliefs and contextual factors inform their parenting decisions and practices. Recommendations are provided for enriching parents’ capacity to promote child prosocial development in contexts of adversity.
Adapting the in vitro micronucleus assay (OECD Test Guideline No. 487) for testing of manufactured nanomaterials: recommendations for best practices
Authors: Burgum Michael J , Ulrich Clarissa , Partosa Natascha , Evans Stephen J , Gomes Caroline , Seiffert Svenja Berit , Landsiedel Robert , Honarvar Naveed , Doak Shareen H
Published: March 2024

The current Organisation for Economic Co-Operation and Development test guideline number 487 (OECD TG No. 487) provides instruction on how to conduct the in vitro micronucleus assay. This assay is one of the gold standard approaches for measuring the mutagenicity of test items; however, it is directed at testing low molecular weight molecules and may not be appropriate for particulate materials (e.g. engineered nanoparticles [ENPs]). This study aimed to adapt the in vitro micronucleus assay for ENP testing and underpins the development of an OECD guidance document. A harmonized, nano-specific protocol was generated and evaluated by two independent laboratories. Cell lines utilized were human lymphoblastoid (TK6) cells, human liver hepatocytes (HepG2) cells, Chinese hamster lung fibroblast (V79) cells, whole blood, and buffy coat cells from healthy human volunteers. These cells were exposed to reference ENPs from the Joint Research Council (JRC): SiO2 (RLS-0102), Au5nm and Au30nm (RLS-03, RLS-010), CeO2 (NM212), and BaSO4 (NM220). Tungsten carbide-cobalt (WC/Co) was used as a trial particulate positive control. The chemical controls were positive in all cell cultures, but WC/Co was only positive in TK6 and buffy coat cells. In TK6 cells, mutagenicity was observed for SiO2- and both Au types. In HepG2 cells, Au5nm and SiO2 showed sub-two-fold increases in micronuclei. In V79 cells, whole blood, and buffy coat cells, no genotoxicity was detected with the test materials. The data confirmed that ENPs could be tested with the harmonized protocol, additionally, concordant data were observed across the two laboratories with V79 cells. WC/Co may be a suitable particulate positive control in the in vitro micronucleus assay when using TK6 and buffy coat cells. Detailed recommendations are therefore provided to adapt OECD TG No. 487 for testing ENP.
Substrate specificity of Mycobacterium tuberculosis tRNA terminal nucleotidyltransferase toxin MenT3
Authors: Liu Jun , Yashiro Yuka , Sakaguchi Yuriko , Suzuki Tsutomu , Tomita Kozo
Published: March 2024

Mycobacterium tuberculosis transfer RNA (tRNA) terminal nucleotidyltransferase toxin, MenT3, incorporates nucleotides at the 3′-CCA end of tRNAs, blocking their aminoacylation and inhibiting protein synthesis. Here, we show that MenT3 most effectively adds CMPs to the 3′-CCA end of tRNA. The crystal structure of MenT3 in complex with CTP reveals a CTP-specific nucleotide-binding pocket. The 4-NH2 and the N3 and O2 atoms of cytosine in CTP form hydrogen bonds with the main-chain carbonyl oxygen of P120 and the side chain of R238, respectively. MenT3 expression in Escherichia coli selectively reduces the levels of seryl-tRNASers, indicating specific inactivation of tRNASers by MenT3. Consistently, MenT3 incorporates CMPs into tRNASer most efficiently, among the tested E. coli tRNA species. The longer variable loop unique to class II tRNASers is crucial for efficient CMP incorporation into tRNASer by MenT3. Replacing the variable loop of E. coli tRNAAla with the longer variable loop of M. tuberculosis tRNASer enables MenT3 to incorporate CMPs into the chimeric tRNAAla. The N-terminal positively charged region of MenT3 is required for CMP incorporation into tRNASer. A docking model of tRNA onto MenT3 suggests that an interaction between the N-terminal region and the longer variable loop of tRNASer facilitates tRNA substrate selection.
GLABRA 2 regulates ETHYLENE OVERPRODUCER 1 accumulation during nutrient deficiency-induced root hair growth
Authors: Cheng Jianing , Wang Jinshu , Bi Shuangtian , Li Mingyang , Wang Lina , Wang Lu , Li Tong , Zhang Xiaolan , Gao Yue , Zhu Lei , Wang Che
Published: March 2024

Root hairs (RHs), extensive structures of root epidermal cells, are important for plant nutrient acquisition, soil anchorage, and environmental interactions. Excessive production of the phytohormone ethylene (ET) leads to substantial root hair growth, manifested as tolerance to plant nutrient deficiencies. However, the molecular basis of ET production during root hair growth in response to nutrient starvation remains unknown. Herein, we found that a critical transcription factor, GLABRA 2 (GL2), inhibits ET production during root hair growth in Arabidopsis (Arabidopsis thaliana). GL2 directly binds to the promoter of the gene encoding ET OVERPRODUCER 1 (ETO1), one of the most important ET-production-regulation factors, in vitro and in vivo, and then regulates the accumulation and function of ETO1 in root hair growth. The GL2-regulated-ETO1 module is required for promoting root hair growth under nitrogen, phosphorus, or potassium deficiency. Genome-wide analysis revealed numerous genes, such as ROOT HAIR DEFECTIVE 6-LIKE 4, ETHYLENE-INSENSITIVE 3-LIKE 2, ROOT HAIR SPECIFIC 13, are involved in the GL2-regulated-ETO1 module. Our work reveals a key transcription mechanism in the control of ET production during root hair growth under three major nutrient deficiencies.
New Frontiers: The Origins and Content of New Work, 1940–2018
Authors: Autor David , Chin Caroline , Salomons Anna , Seegmiller Bryan
Published: March 2024

We answer three core questions about the hypothesized role of newly emerging job categories (“new work”) in counterbalancing the erosive effect of task-displacing automation on labor demand: what is the substantive content of new work, where does it come from, and what effect does it have on labor demand? We construct a novel database spanning eight decades of new job titles linked to U.S. Census microdata and to patent-based measures of occupations’ exposure to labor-augmenting and labor-automating innovations. The majority of current employment is in new job specialties introduced since 1940, but the locus of new-work creation has shifted from middle-paid production and clerical occupations over 1940–1980 to high-paid professional occupations and secondarily to low-paid services since 1980. New work emerges in response to technological innovations that complement the outputs of occupations and demand shocks that raise occupational demand. Innovations that automate tasks or reduce occupational demand slow new-work emergence. Although the flow of augmentation and automation innovations is positively correlated across occupations, the former boosts occupational labor demand while the latter depresses it. The demand-eroding effects of automation innovations have intensified in the past four decades while the demand-increasing effects of augmentation innovations have not.
Effectiveness of a novel digital patient education programme to support self-management of early rheumatoid arthritis: a randomized controlled trial
Authors: Knudsen Line R , Ndosi Mwidimi , Hauge Ellen-Margrethe , Lomborg Kirsten , Dreyer Lene , Aaboe Sidsel , Kjær Marie B , Sørensen Lis , Volsmann Lena , Christensen Heidi M , de Thurah Annette
Published: March 2024

Objectives

To evaluate the effectiveness of a novel digital patient education (PE) programme in improving self-management in patients newly diagnosed with rheumatoid arthritis (RA).

Methods

This was a parallel, open-label, two-armed, randomized controlled trial with superiority design. Patients from five rheumatology clinics were randomized into digital PE (intervention) or face-to-face PE (control). The primary outcome was self-efficacy, measured by average difference in the Rheumatoid Arthritis Self-Efficacy (RASE) score from baseline to month 12. Secondary outcomes were RA knowledge, health literacy, adherence and quality of life. Healthcare utilization data and digital PE programme usage were recorded. Self-efficacy, knowledge and health literacy data were analysed using mixed-effects repeated measures modelling; adherence using logistic regression, and quality of life and healthcare utilization using descriptive statistics with the Wilcoxon rank-sum test.

Results

Of the 180 patients randomized (digital PE, n = 89; face-to-face PE, n = 91), 175 had data available for analysis. Median age was 59.0 years and 61% were women. The average difference in self-efficacy between groups from baseline to month 12 was significant by a −4.34 difference in RASE score, favouring the intervention group (95% CI: −8.17 to −0.51; P = 0.026). RA knowledge, health literacy and quality of life showed minor improvements over time but no difference between groups, except out-patient clinic contacts, which were fewer in the intervention group.

Conclusion

The findings suggest that digital PE is effective in improving self-efficacy and therefore self-management in patients with early RA. This intervention has potential to lower healthcare costs by decreasing out-patient clinic contacts.

Trial registration number

clinicaltrials.gov, NCT04669340.
Assessment of fetal radiation exposure in pregnant women undergoing computed tomography and rotational angiography examinations for pelvic trauma
Authors: Matsunaga Yuta , Haba Tomonobu , Kobayashi Masanao , Suzuki Shoichi , Asada Yasuki , Chida Koichi
Published: March 2024

This study aimed to assess fetal radiation exposure in pregnant women undergoing computed tomography (CT) and rotational angiography (RA) examinations for the diagnosis of pelvic trauma. In addition, this study aimed to compare the dose distributions between the two examinations. Surface and average fetal doses were estimated during CT and RA examinations using a pregnant phantom model and real-time dosemeters. The pregnant model phantom was constructed using an anthropomorphic phantom, and a custom-made abdominal phantom was used to simulate pregnancy. The total average fetal dose received by pregnant women from both CT scans (plain, arterial and equilibrium phases) and a single RA examination was ~60 mGy. Because unnecessary repetition of radiographic examinations, such as CT or conventional 2D angiography can increase the radiation risk, the irradiation range should be limited, if necessary, to reduce overall radiation exposure.
Proteoglycan 4 (PRG4) treatment improves skin wound healing in a porcine model
Authors: Ninkovic Nicoletta , Sparks Holly D. , Ponjevic Dragana , Muench Greg , Biernaskie Jeff A. , Krawetz Roman J.
Published: March 2024

Proteoglycan 4 (PRG4) is a boundary lubricant originally identified in articular cartilage and has been since shown to have immunomodulation and antifibrotic properties. Previously, we have demonstrated that recombinant human (rh)PRG4 treatment accelerates auricular cartilage injury closure through an inhibition of the fibrotic response, and promotion of tissue regeneration in mice. The purpose of the current study was to examine the effects of rhPRG4 treatment (vs. a DMSO carried control) on full‐thickness skin wound healing in a preclinical porcine model. Our findings suggest that while rhPRG4 did not significantly accelerate nor impede full‐thickness skin wound closure, it did improve repair quality by decreasing molecular markers of fibrosis and increasing re‐vascularization. We also demonstrated that rhPRG4 treatment increased dermal adipose tissue during the healing process specifically by retaining adipocytes in the wound area but did not inhibit lipolysis. Overall, the results of the current study have demonstrated that rhPRG4 acts as antifibrotic agent and regulates dermal adipose tissue during the healing processes resulting in a tissue with a trajectory that more resembles the native skin vs. a fibrotic patch. This study provides strong rationale to examine if rhPRG4 can improve regeneration in human wounds.
LncTCONS_00058568 is involved in the pathophysiologic processes mediated by P2X7R in the lower thoracic spinal cord after acute kidney injury
Authors: Wang Yiru , Chen Zhi , Liu Qingquan , Lv Yongman
Published: March 2024

Acute kidney injury (AKI), a prevalent clinical syndrome, involves the participation of the nervous system in neuroimmune regulation. However, the intricate molecular mechanism that governs renal function regulation by the central nervous system (CNS) is complex and remains incompletely understood. In the present study, we found that the upregulated expression of lncTCONS_00058568 in lower thoracic spinal cord significantly ameliorated AKI‐induced renal tissue injury, kidney morphology, inflammation and apoptosis, and suppressed renal sympathetic nerve activity. Mechanistically, the purinergic ionotropic P2X7 receptor (P2X7R) was overexpressed in AKI rats, whereas lncTCONS_00058568 was able to suppress the upregulation of P2X7R. In addition, RNA sequencing data revealed differentially expressed genes associated with nervous system inflammatory responses after lncTCONS_00058568 was overexpressed in AKI rats. Finally, the overexpression of lncTCONS_00058568 inhibited the activation of PI3K/Akt and NF‐κB signaling pathways in spinal cord. Taken together, the results from the present study show that lncTCONS_00058568 overexpression prevented renal injury probably by inhibiting sympathetic nerve activity mediated by P2X7R in the lower spinal cord subsequent to I/R‐AKI.
Sex reporting of cells used in cancer research: A systematic review
Authors: Park Mi‐Na , Kim Sung‐Eun , Choi Sungin , Chang Yoomee , Kim Hyeyoon , Lee Ha‐Eun , Lee Suk Kyeong , Sung Mi‐Kyung , Paik Hee‐Young
Published: March 2024

Sex and gender disparities in biomedical research have been emphasized to improve scientific knowledge applied for the health of both men and women. Despite sex differences in cancer incidence, prognosis, and responses to therapeutic agents, mechanistic explanations at molecular levels are far from enough. Recent studies suggested that cell sex is an important biological variable due to differences in sex chromosome gene expression and differences in events associated with developmental biology. The objective of this study was to analyze the reporting of sex of cells used in cancer research using articles published in Cancer Cell, Molecular Cancer, Journal of Hematology & Oncology, Journal for ImmunoTherapy of Cancer, and Cancer Research in 2020, and to examine whether there exists any sex bias. We found that the percentage of cells with sex notation in the article was 36.5%. Primary cells exhibited higher sex notation compared to cell lines. A higher percentage of female cells were used in cell cultures with sex notation. Also, sex‐common cells omitted sex description more often compared to sex‐specific cells. None of the cells isolated from embryo and esophagus reported the cell sex in the article. Our results indicate cell sex report in cancer research is limited to a small proportion of cells used in the study. These results call for acknowledging the sex of cells to increase the applicability of biomedical research discoveries.
Resolvin D2 limits atherosclerosis progression via myeloid cell‐GPR18
Authors: Lipscomb Masharh , Walis Sean , Marinello Michael , Mena Hebe Agustina , MacNamara Katherine C. , Spite Matthew , Fredman Gabrielle
Published: March 2024

Dysregulated inflammation‐resolution programs are associated with atherosclerosis progression. Resolvins, in part, mediate inflammation‐resolution programs. Indeed, Resolvin D2 (RvD2) activates GPR18, a G‐protein‐coupled receptor, and limits plaque progression, though the cellular targets of RvD2 remain unknown. Here, we developed a humanized GPR18 floxed (“fl/fl”) and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow‐derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. To understand the functions of RvD2‐GPR18 in atherosclerosis, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr−/− recipients. For these experiments, we treated each genotype with either Vehicle/PBS or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis, increased cleaved caspase‐3+ cells and decreased percentage of Arginase‐1+‐Mac2+ cells without a change in overall Mac2+ plaque macrophages, compared with fl/fl➔Ldlr−/− transplanted mice. RvD2 treatment decreased plaque necrosis, the percent of cleaved caspase‐3+ cells and increased the percent of Arginase‐1+‐Mac2+ cells in fl/fl➔Ldlr−/− mice, but not in the mKO➔Ldlr−/− transplanted mice. These results suggest that GPR18 plays a causal role in limiting atherosclerosis progression and that RvD2's ability to limit plaque necrosis is in part dependent on myeloid GRP18.
Alterations in gut microbiota and bile acids by proton‐pump inhibitor use and possible mediating effects on elevated glucose levels and insulin resistance
Authors: He Qiangsheng , Xia Bin , Yang Man , Lu Kuiqing , Fan Die , Li Wenjing , Liu Yuchen , Pan Yihang , Yuan Jinqiu
Published: March 2024

Several observational studies have suggested that proton‐pump inhibitor (PPI) use might increase diabetes risk, but the mechanism remains unclear. This study aimed to investigate the effects of PPI use on gut microbiota and bile acids (BAs) profiles, and to explore whether these changes could mediate the association of PPIs use with fasting blood glucose (FBG) levels and insulin resistance (IR) in Chinese population. A cross‐sectional study was conducted in Shenzhen, China, from April to August 2021, enrolled 200 eligible patients from the local hospital. Participants completed a questionnaire and provided blood and stool samples. Gut microbiome was measured by16S rRNA gene sequencing, and bile acids were quantified by UPLC‐MS/MS. Insulin resistance (IR) was assessed using the Homeostasis Model Assessment 2 (HOMA2‐IR). PPI use was positively associated with higher levels of FBG and HOMA2‐IR after controlling for possible confounders. PPI users exhibited a decreased Firmicutes and an increase in Bacteroidetes phylum, alongside higher levels of glycoursodeoxycholic acid (GUDCA) and taurochenodeoxycholic acid (TCDCA). Higher abundances of Bacteroidetes and Fusobacterium as well as higher levels of TCDCA in PPI users were positively associated with elevated FBG or HOMA2‐IR. Mediation analyses indicated that the elevated levels of FBG and HOMA2‐IR with PPI use were partially mediated by the alterations in gut microbiota and specific BAs (i.e., Fusobacterium genera and TCDCA). Long‐term PPI use may increase FBG and HOMA2‐IR levels, and alterations in gut microbiota and BAs profiles may partially explain this association.
Classification and Treatment of Pediatric Capitellar Fractures
Authors: Yang Daniel , Baghdadi Soroush , Värk Pille-Riin , Buttrick Eliza , Shah Apurva S.
Published: March 2024

Background:

Fractures of the capitellum are rare in children. The purpose of this study was to report fracture characteristics, treatment, and outcomes of pediatric capitellar fractures at a single children’s hospital. We also aimed to update the classification of these fractures based on a large sample size by revising the Murthy (Boston) classification.

Methods:

In a retrospective study at a single tertiary care children’s hospital, fractures of the capitellum in patients below 18 years of age were queried and reviewed for demographics, injury characteristics, imaging, treatment, outcomes, and complications. Three surgeons reviewed all imaging to classify the fractures and assess interobserver and intraobserver reliability.

Results:

Forty-four patients (25 male) with capitellar fractures with a mean age of 11.7±3.7 years were identified. Seven fractures did not belong to an existing type and were grouped into a new type IV capitellar fracture, defined as LCL avulsions with extension to the articular surface of the capitellum. We found good to excellent inter-rater and intrarater reliability for the new classification system. Our raters believed that cross-sectional imaging was essential to classifying fractures in 84% of the cases. Thirty-three of 44 patients underwent early surgical intervention, with favorable outcomes. Five patients presented late with substantial elbow contracture and malunion and were treated surgically with the excision of the fragment.

Conclusions:

The new classification of pediatric capitellar fractures is more comprehensive and offers good to excellent reliability. We found excellent outcomes in the majority of cases with early diagnosis and management, but substantial risk for complications with missed and delayed diagnosis. Malunion and subsequent loss of ROM were the most common presentations of a missed diagnosis, which can be surgically treated with favorable outcomes.

Level of evidence:

Level III—retrospective cohort study.
Alcohol Withdrawal Severity Measures for Identifying Patients Requiring High-Intensity Care
Authors: To Daniel C. , Steel Tessa L. , Carey Kyle A. , Joyce Cara J. , Salisbury-Afshar Elizabeth M. , Edelson Dana P. , Mayampurath Anoop , Churpek Matthew M. , Afshar Majid
Published: March 2024

OBJECTIVES:

Alcohol withdrawal syndrome (AWS) may progress to require high-intensity care. Approaches to identify hospitalized patients with AWS who received higher level of care have not been previously examined. This study aimed to examine the utility of Clinical Institute Withdrawal Assessment Alcohol Revised (CIWA-Ar) for alcohol scale scores and medication doses for alcohol withdrawal management in identifying patients who received high-intensity care.

DESIGN:

A multicenter observational cohort study of hospitalized adults with alcohol withdrawal.

SETTING:

University of Chicago Medical Center and University of Wisconsin Hospital.

PATIENTS:

Inpatient encounters between November 2008 and February 2022 with a CIWA-Ar score greater than 0 and benzodiazepine or barbiturate administered within the first 24 hours. The primary composite outcome was patients who progressed to high-intensity care (intermediate care or ICU).

INTERVENTIONS:

None.

MAIN RESULTS:

Among the 8742 patients included in the study, 37.5% (n = 3280) progressed to high-intensity care. The odds ratio for the composite outcome increased above 1.0 when the CIWA-Ar score was 24. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at this threshold were 0.12 (95% CI, 0.11–0.13), 0.95 (95% CI, 0.94–0.95), 0.58 (95% CI, 0.54–0.61), and 0.64 (95% CI, 0.63–0.65), respectively. The OR increased above 1.0 at a 24-hour lorazepam milligram equivalent dose cutoff of 15 mg. The sensitivity, specificity, PPV, and NPV at this threshold were 0.16 (95% CI, 0.14–0.17), 0.96 (95% CI, 0.95–0.96), 0.68 (95% CI, 0.65–0.72), and 0.65 (95% CI, 0.64–0.66), respectively.

CONCLUSIONS:

Neither CIWA-Ar scores nor medication dose cutoff points were effective measures for identifying patients with alcohol withdrawal who received high-intensity care. Research studies for examining outcomes in patients who deteriorate with AWS will require better methods for cohort identification.