bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical and Thermal Forcing for Upslope Flows and Cumulus Convection over the Sierras de Córdoba
Authors: Lareau Neil P. , Knopp Tracen , Kirshbaum Daniel J.
Published: June 2024

The upslope flow processes affecting the vertical extent of orographic cumulus convection are examined using observations from the Cloud, Aerosol, and Complex Terrain Interactions (CACTI) field campaign. Specifically, clear air returns from the U.S. Department of Energy (DOE) second-generation C-band scanning Atmospheric Radiation Measurement (ARM) precipitation radar (CSAPR2) are used to characterize the structure and variability of the ridge-normal (i.e., up/downslope) flow components, which transport mass to the crest of Argentina’s Sierras de Córdoba and contribute to convective initiation. Data are compiled for the entire CACTI period (October–April), including days with clear skies, shallow cumuli, cumulus congestus, and deep convection. To examine shared variability among >70 000 radar scans, we use (i) a principal component analysis (PCA) to isolate modes of variability in the upslope flow and (ii) composite analysis based on convective outcomes, determined from GOES-16 satellite observations. These data are contextualized with observed surface sensible heat fluxes, thermodynamic profiles, and synoptic-scale analysis. Results indicate distinct thermally and mechanically forced upslope flow modes, modulated by diurnal heating and synoptic-scale variations, respectively. In some instances, there is a superposition of thermal and mechanical forcing, yielding either deeper or shallower upslope flow. The composite analyses based on satellite data show that successively deeper convective outcomes are associated with successively deeper upslope flow layers that more readily transport mass to the ridge crest in conjunction with lower lifting condensation levels, facilitating convective initiation. These results help to isolate the forcing mechanisms for orographic convection and thus provide a foundation for parameterizing orographic convective processes in coarse resolution models.
A specific super-enhancer actuated by berberine regulates EGFR-mediated RAS–RAF1–MEK1/2–ERK1/2 pathway to induce nasopharyngeal carcinoma autophagy
Authors: Wu Yao , Jia Qunying , Tang Qi , Chen Lin , Deng Hongyu , He Yingchun , Tang Faqing
Published: June 2024

Nasopharyngeal carcinoma (NPC), primarily found in the southern region of China, is a malignant tumor known for its highly metastatic characteristics. The high mortality rates caused by the distant metastasis and disease recurrence remain unsolved clinical problems. In clinic, the berberine (BBR) compound has widely been in NPC therapy to decrease metastasis and disease recurrence, and BBR was documented as a main component with multiple anti-NPC effects. However, the mechanism by which BBR inhibits the growth and metastasis of nasopharyngeal carcinoma remains elusive. Herein, we show that BBR effectively inhibits the growth, metastasis, and invasion of NPC via inducing a specific super enhancer (SE). From a mechanistic perspective, the RNA sequencing (RNA-seq) results suggest that the RAS–RAF1–MEK1/2–ERK1/2 signaling pathway, activated by the epidermal growth factor receptor (EGFR), plays a significant role in BBR-induced autophagy in NPC. Blockading of autophagy markedly attenuated the effect of BBR-mediated NPC cell growth and metastasis inhibition. Notably, BBR increased the expression of EGFR by transcription, and knockout of EGFR significantly inhibited BBR-induced microtubule associated protein 1 light chain 3 (LC3)-II increase and p62 inhibition, proposing that EGFR plays a pivotal role in BBR-induced autophagy in NPC. Chromatin immunoprecipitation sequencing (ChIP-seq) results found that a specific SE existed only in NPC cells treated with BBR. This SE knockdown markedly repressed the expression of EGFR and phosphorylated EGFR (EGFR-p) and reversed the inhibition of BBR on NPC proliferation, metastasis, and invasion. Furthermore, BBR-specific SE may trigger autophagy by enhancing EGFR gene transcription, thereby upregulating the RAS–RAF1–MEK1/2–ERK1/2 signaling pathway. In addition, in vivo BBR effectively inhibited NPC cells growth and metastasis, following an increase LC3 and EGFR and a decrease p62. Collectively, this study identifies a novel BBR-special SE and established a new epigenetic paradigm, by which BBR regulates autophagy, inhibits proliferation, metastasis, and invasion. It provides a rationale for BBR application as the treatment regime in NPC therapy in future.
The black honey bee genome: insights on specific structural elements and a first step towards pangenomes
Authors: Eynard Sonia E. , Klopp Christophe , Canale-Tabet Kamila , Marande William , Vandecasteele Céline , Roques Céline , Donnadieu Cécile , Boone Quentin , Servin Bertrand , Vignal Alain
Published: June 2024

Background

The honey bee reference genome, HAv3.1, was produced from a commercial line sample that was thought to have a largely dominant Apis mellifera ligustica genetic background. Apis mellifera mellifera, often referred to as the black bee, has a separate evolutionary history and is the original type in western and northern Europe. Growing interest in this subspecies for conservation and non-professional apicultural practices, together with the necessity of deciphering genome backgrounds in hybrids, triggered the necessity for a specific genome assembly. Moreover, having several high-quality genomes is becoming key for taking structural variations into account in pangenome analyses.

Results

Pacific Bioscience technology long reads were produced from a single haploid black bee drone. Scaffolding contigs into chromosomes was done using a high-density genetic map. This allowed for re-estimation of the recombination rate, which was over-estimated in some previous studies due to mis-assemblies, which resulted in spurious inversions in the older reference genomes. The sequence continuity obtained was very high and the only limit towards continuous chromosome-wide sequences seemed to be due to tandem repeat arrays that were usually longer than 10 kb and that belonged to two main families, the 371 and 91 bp repeats, causing problems in the assembly process due to high internal sequence similarity. Our assembly was used together with the reference genome to genotype two structural variants by a pangenome graph approach with Graphtyper2. Genotypes obtained were either correct or missing, when compared to an approach based on sequencing depth analysis, and genotyping rates were 89 and 76% for the two variants.

Conclusions

Our new assembly for the Apis mellifera mellifera honey bee subspecies demonstrates the utility of multiple high-quality genomes for the genotyping of structural variants, with a test case on two insertions and deletions. It will therefore be an invaluable resource for future studies, for instance by including structural variants in GWAS. Having used a single haploid drone for sequencing allowed a refined analysis of very large tandem repeat arrays, raising the question of their function in the genome. High quality genome assemblies for multiple subspecies such as presented here, are crucial for emerging projects using pangenomes.
Immune-mediated inflammatory diseases and periodontal disease: a bidirectional two-sample mendelian randomization study
Authors: Zhang Rui , Ma Hairong , Wang Dan , Zhang Hualin
Published: June 2024

Background

Previous observational studies have shown a bidirectional association between immune-mediated inflammatory disorders (IMID) and periodontal disease. However, evidence regarding the causal role of IMID and periodontal disease is still lacking. Therefore, we conducted a bidirectional two-sample Mendelian randomization (MR) study to uncover the potential genetic causal effects between IMID and periodontal disease.

Methods

Bidirectional two-sample MR analysis was employed. Data for ten IMIDs were sourced from genome-wide association studies (GWAS) conducted by the FinnGen Consortium (range from 1023 to 36321 cases) and UK Biobank (UKB) (range from 150 to 17574 cases). Furthermore, GWAS data for periodontal disease were obtained from the FinnGen Consortium (87497 cases), UKB (458 cases), and Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 periodontitis cases). Subsequently, the causal relationships were analyzed by random effects inverse variance weighting, weighted median, and MR-Egger. Sensitivity analyses were performed using the Cochrane Q test, funnel plot, and Mr-Egger intercept test to ensure robustness. Eventually, replication analysis and meta-analysis across different databases were carried out.

Results

Systemic lupus erythematosus (SLE) [IVW: OR = 1.079 (95% CI: 1.032–1.128) and P < 0.001], Sjogren syndrome [IVW: OR = 1.082 (95% CI: 1.012–1.157) and P = 0.022] and hypothyroidism [IVW: OR = 1.52 (95% CI: 1.13–2.04) and P = 0.005] may increase the risk of periodontal disease. In addition, periodontal disease may reduce the risk of SLE [IVW: OR = 0.8079 (95% CI: 0.6764–0.9650) and P = 0.019] and hyperthyroidism [IVW: OR = 5.59*10–9 (95% CI: 1.43*10–15-2.18*10–2) and P = 0.014]. Meta-analysis indicated a causal correlation between SLE and an increased risk of periodontal disease: [OR = 1.08 (95% CI: 1.03–1.13), P = 0.0009]. No significant evidence suggests bilateral causal relationships between other IMIDs and periodontal disease. No significant estimation of heterogeneity or pleiotropy is detected.

Conclusions

Our study has confirmed a genetic causal relationship between IMIDs and periodontal disease, thereby unveiling novel potential mechanisms underlying IMIDs and periodontal disease. This discovery is promising in fostering interdisciplinary collaboration between clinicians and stomatologists to facilitate appropriate and precise screening, prevention, and early treatment of IMIDs and periodontal disease.
Metabolomics analysis of the lactobacillus plantarum ATCC 14917 response to antibiotic stress
Authors: Zhong Yilin , Guo Juan , Zheng Yu , Lin Huale , Su Yubin
Published: June 2024

Background

Lactobacillus plantarum has been found to play a significant role in maintaining the balance of intestinal flora in the human gut. However, it is sensitive to commonly used antibiotics and is often incidentally killed during treatment. We attempted to identify a means to protect L. plantarum ATCC14917 from the metabolic changes caused by two commonly used antibiotics, ampicillin, and doxycycline. We examined the metabolic changes under ampicillin and doxycycline treatment and assessed the protective effects of adding key exogenous metabolites.

Results

Using metabolomics, we found that under the stress of ampicillin or doxycycline, L. plantarum ATCC14917 exhibited reduced metabolic activity, with purine metabolism a key metabolic pathway involved in this change. We then screened the key biomarkers in this metabolic pathway, guanine and adenosine diphosphate (ADP). The exogenous addition of each of these two metabolites significantly reduced the lethality of ampicillin and doxycycline on L. plantarum ATCC14917. Because purine metabolism is closely related to the production of reactive oxygen species (ROS), the results showed that the addition of guanine or ADP reduced intracellular ROS levels in L. plantarum ATCC14917. Moreover, the killing effects of ampicillin and doxycycline on L. plantarum ATCC14917 were restored by the addition of a ROS accelerator in the presence of guanine or ADP.

Conclusions

The metabolic changes of L. plantarum ATCC14917 under antibiotic treatments were determined. Moreover, the metabolome information that was elucidated can be used to help L. plantarum cope with adverse stress, which will help probiotics become less vulnerable to antibiotics during clinical treatment.
Living in mangroves: a syntrophic scenario unveiling a resourceful microbiome
Authors: Laux Marcele , Ciapina Luciane Prioli , de Carvalho Fabíola Marques , Gerber Alexandra Lehmkuhl , Guimarães Ana Paula C. , Apolinário Moacir , Paes Jorge Eduardo Santos , Jonck Célio Roberto , de Vasconcelos Ana Tereza R.
Published: June 2024

Background

Mangroves are complex and dynamic coastal ecosystems under frequent fluctuations in physicochemical conditions related to the tidal regime. The frequent variation in organic matter concentration, nutrients, and oxygen availability, among other factors, drives the microbial community composition, favoring syntrophic populations harboring a rich and diverse, stress-driven metabolism. Mangroves are known for their carbon sequestration capability, and their complex and integrated metabolic activity is essential to global biogeochemical cycling. Here, we present a metabolic reconstruction based on the genomic functional capability and flux profile between sympatric MAGs co-assembled from a tropical restored mangrove.

Results

Eleven MAGs were assigned to six Bacteria phyla, all distantly related to the available reference genomes. The metabolic reconstruction showed several potential coupling points and shortcuts between complementary routes and predicted syntrophic interactions. Two metabolic scenarios were drawn: a heterotrophic scenario with plenty of carbon sources and an autotrophic scenario with limited carbon sources or under inhibitory conditions. The sulfur cycle was dominant over methane and the major pathways identified were acetate oxidation coupled to sulfate reduction, heterotrophic acetogenesis coupled to carbohydrate catabolism, ethanol production and carbon fixation. Interestingly, several gene sets and metabolic routes similar to those described for wastewater and organic effluent treatment processes were identified.

Conclusion

The mangrove microbial community metabolic reconstruction reflected the flexibility required to survive in fluctuating environments as the microhabitats created by the tidal regime in mangrove sediments. The metabolic components related to wastewater and organic effluent treatment processes identified strongly suggest that mangrove microbial communities could represent a resourceful microbial model for biotechnological applications that occur naturally in the environment.
Prevalence of Post-COVID conditions among Mexican COVID-19 survivors: a nationwide cross-sectional study
Authors: Ramírez-Toscano Yenisei , Torres-Ibarra Leticia , Carnalla Martha , Basto-Abreu Ana , Vidaña-Perez Dèsirée , Colchero M. Arantxa , Bautista-Arredondo Sergio , Saydah Sharon , Barrientos-Gutiérrez Tonatiuh
Published: June 2024

Background

There are limited population-representative data that describe the potential burden of Post-COVID conditions (PCC) in Mexico. We estimated the prevalence of PCC overall and by sociodemographic characteristics among a representative sample of adults previously diagnosed with COVID-19 in Mexico. We additionally, characterized the PCC symptoms, and estimated the association between diagnosed type-2 diabetes and hypertension with PCC.

Methods

We used data from the 2021 National Health and Nutrition Survey in Mexico, a nationally and regionally representative survey, from August 1st to October 31st, 2021. Using the WHO definition, we estimated the prevalence of PCC by sociodemographics and prevalence of PCC symptoms. We fit multivariable log-binomial regression models to estimate the associations.

Results

The prevalence of PCC was 37.0%. The most common persistent symptoms were fatigue (56.8%), myalgia or arthralgia (47.5%), respiratory distress and dyspnea (42.7%), headache (34.0%), and cough (25.7%). The prevalence was higher in older people, women, and individuals with low socioeconomic status. There was no significant association between hypertension and PCC or diabetes and PCC prevalence.

Conclusions

About one-third of the adult Mexican population who had COVID-19 in 2021 had Post-COVID conditions. Our population-based estimates can help assess potential priorities for PCC-related health services, which is critical in light of our weak health system and limited funding.
The effects of telerehabilitation on physiological function and disease symptom for patients with chronic respiratory disease: a systematic review and meta-analysis
Authors: Dai Yue , Huang Hao , Zhang Yuchen , He Na , Shen Min , Li Hong
Published: June 2024

Objective

To compare the impact of telerehabilitation versus conventional rehabilitation on the recovery outcomes of patients with chronic respiratory disease (CRD).

Methods

The Cochrane Library, MEDLINE, Web of Science and Embase were searched to collect randomized controlled trials (RCTs) on telerehabilitation for the rehabilitation of patients with chronic respiratory system diseases since the establishment of the database to November 14, 2023. Two researchers independently screened the literature and extracted valid data according to the inclusion criteria. The quality assessment of included studies was conducted individually by using the RoB 2(Risk of Bias 2) tool, followed by meta-analysis using RevMan5.3 software.

Results

Based on inclusion and exclusion criteria, 21 RCTs were included, comprising 3030 participants, with 1509 in the telerehabilitation group and 1521 in the conventional rehabilitation group. Meta-analysis results indicated that compared to conventional rehabilitation, video conference-based telerehabilitation demonstrated significant improvements in short-term (≤ 6 months) outcomes, including 6-min walk distance (6MWD) (MD = 7.52, 95% CI: 2.09, 12.94), modified Medical Research Council Dyspnea Scale (mMRC) (MD = -0.29, 95% CI: -0.41, -0.18), COPD assessment test (CAT) (MD = -1.77, 95% CI: -3.52, -0.02), HADS (MD = -0.44, 95% CI: -0.86, -0.03), and St. George’s Respiratory Questionnaire (SGRQ’s) activity, impact, and symptom scores. In the long term (> 6 months), although improvements persisted in 6WMD [MD = 12.89, 95% CI (-0.37, 26.14)], mMRC [MD = -0.38, 95% CI (-0.56, -0.21)], CAT [MD = -1.39, 95% CI (-3.83, 1.05)], Hospital anxiety and depression scale (HADS) [MD = -0.34, 95% CI (-0.66, -0.03)], and SGRQ’s Activity, Impact, and Symptom scores between intervention and control groups, statistically significant differences were observed only for mMRC and HADS. Without considering time factors, the intervention group exhibited some improvement in FEV1% predicted and the forced expiratory volume in the first one second (FEV1)/ forced vital capacity (FVC) (%) without statistical significance compared to the control group.

Conclusion

Telerehabilitation therapy demonstrates short-term benefits in enhancing patients’ daily activity capacity, improving respiratory function, and enhancing mental health status, thereby improving patients’ quality of life. However, further high-quality, large-sample RCTs are required to ascertain its long-term effectiveness conclusively.

Trial registration

This study protocol was approved and registered in PROSPERO: CRD 42024509154.
Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure
Authors: Kasperova Barbora Judita , Mraz Milos , Svoboda Petr , Hlavacek Daniel , Kratochvilova Helena , Modos Istvan , Vrzackova Nikola , Ivak Peter , Janovska Petra , Kobets Tatyana , Mahrik Jakub , Riecan Martin , Steiner Mrazova Lenka , Stranecky Viktor , Netuka Ivan , Cajka Tomas , Kuda Ondrej , Melenovsky Vojtech , Stemberkova Hubackova Sona , Haluzik Martin
Published: June 2024

Background

Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure.

Methods

26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed.

Results

SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects.

Conclusions

Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.
Dual-trajectory of TyG levels and lifestyle scores and their associations with ischemic stroke in a non-diabetic population: a cohort study
Authors: Zhou Hui , Ding Xiong , Lan Yulong , Fang Wei , Yuan Xiaojie , Tian Yan , Chen Shuohua , Wu Shouling , Wu Dan
Published: June 2024

Background

The Triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, has been implicated in the risk of ischemic stroke. However, the interplay between TyG levels, lifestyle factors, and their collective impact on stroke risk in non-diabetic populations remains inadequately explored. This study aims to evaluate the association of ischemic stroke with the joint development of the TyG index and lifestyle in the non-diabetic population.

Methods

In this prospective cohort study, data was collected across three consecutive biennial surveys of the Kailuan Study from 2006 to 2011. The dual-trajectory model was used to determine the temporal development of TyG levels and lifestyle scores. Statistical analysis involved Cox regression models to evaluate the association between TyG-lifestyle trajectories and ischemic stroke risk, adjusting for potential confounders.

Results

A total of 44,403 participants were included, with five distinct TyG levels and lifestyle scores trajectory subtypes identified. In the multivariable-adjusted analyses, significant differences in ischemic stroke risk among the trajectory subtypes. Group 5, characterized by the highest TyG levels and moderate lifestyle scores, exhibited the greatest ischemic stroke risk (HR = 1.81, 95% CI: 1.51–2.18), while group 4, with moderate TyG levels and higher lifestyle scores, demonstrated the lowest risk (HR = 1.19, 95% CI: 1.04–1.37), compared with group 3. Participants with elevated TyG levels were at an increased risk of ischemic stroke in cases of pronounced insulin resistance, even with a healthy lifestyle.

Conclusions

This study reveals the significant associations between the identified TyG and lifestyle trajectories and the stratification of ischemic stroke risk among non-diabetics. The TyG index is a valuable indicator for assessing insulin resistance. However, the potential benefits of lifestyle changes for those with significantly high TyG levels need to be clarified by more research to develop more effective stroke prevention strategies.
Identifying the barriers and facilitators to fruit and vegetable consumption in rural Australian adults: a mixed methods analysis
Authors: Carroll Brooke T. , McNaughton Sarah A. , Parker Kate E. , Marchese Laura E. , Livingstone Katherine M.
Published: June 2024

Background

Low fruit and vegetable consumption is a leading contributor to non-communicable disease risk. However, understanding of barriers and facilitators to fruit and vegetable intake in rural settings is limited. This study used a mixed methods approach to determine the barriers and facilitators to increasing fruit and vegetable intake in rural Australian adults and to identify if these varied by gender.

Methods

Quantitative and qualitative data were used from the 2019 Active Living Census, completed by adults living in north-west Victoria, Australia. Data were collected on fruit and vegetable intakes and barriers and facilitators to meeting fruit and vegetable recommendations. Multivariate logistic regression analyses were used to investigate the association between facilitators, classified using the socio-ecological framework, and meeting recommendations. Machine learning was used to automate content analysis of open ended information on barriers.

Results

A total of 13,464 adults were included in the quantitative analysis (51% female; mean age 48 [SE 0.17] years) with 48% and 19% of participants consuming the recommended two serves of fruit and five serves of vegetables daily, respectively. Strongest facilitators to fruit consumption were at the individual level: never smoked (OR: 2.12 95% CI: 1.83–2.45) and not drinking alcohol (OR: 1.47 95% CI: 1.31–1.64). Strongest facilitators for vegetable consumption were found at all levels; i.e., individual level: used to smoke (OR: 1.48 95% CI: 1.21–1.80), social-environmental level: living with three or more people (OR: 1.41 95% CI: 1.22–1.63), and physical-environmental level: use community gardens (OR: 1.20 95% CI: 1.07–1.34). Qualitative analyses (fruit n = 5,919; vegetable n = 9,601) showed that barriers to fruit consumption included a preference for other snacks and desire to limit sugar content, whilst lack of time and unachievable guidelines were barriers for vegetables. Barriers and facilitators differed by gender; females experienced barriers due to having a more varied diet while males reported a dislike of the taste.

Conclusions

Barriers and facilitators to fruit and vegetable consumption among rural Australian adults were identified across all levels of the socio-ecological framework and varied between fruit and vegetables and by gender. Strategies that address individual, social, and physical-level barriers are required to improve consumption.
Neighbourhood effect and inequality in access to essential health services among mother–child paired samples: a decomposition analysis of data from 58 low- and middle-income countries
Authors: Anjorin Seun , Okolie Elvis Anyaehiechukwu , Onuegbu Chinwe , Ijaiya Mukhtar , Ayorinde Abimbola , Oyebode Oyinlola , Uthman Olalekan
Published: June 2024

Introduction

Neighbourhood effect on health outcomes is well established, but little is known about its effect on access to essential health services (EHS). Therefore, this study aimed to assess the contributing factors to access to EHS in slum versus non-slum settings.

Methodology

The most recent data from 58 Demographic and Health Surveys (DHS) conducted between 2011 and 2018 were used, including a total of 157,000 pairs of currently married women aged 15–49 and their children aged 12–23 months. We used meta-analysis techniques to examine the inequality gaps in suboptimal access to EHS between mother-children pairs living in slums and non-slums. Blinder-Oaxaca decomposition technique was used to identify the factors contributing to the inequality gaps in each low- and middle-income country (LMIC) included.

Result

The percentage of mother–child pairs living in slums ranged from 0.5% in Egypt to 63.7% in Congo. Meta-analysis of proportions for the pooled sample revealed that 31.2% [27.1, 35.5] of slum residents and 20.0% [15.3, 25.2] among non-slum residents had suboptimal access to EHS. We observed significant pro-slum inequalities in suboptimal access to EHS in 28 of the 52 LMICs with sufficient data. Of the 34 African countries included, 16 showed statistically significant pro-slum inequality in suboptimal access to EHS, with the highest in Egypt and Mali (2.64 [0.84–4.44] and 1.76 [1.65, 1.87] respectively). Findings from the decomposition analysis showed that, on average, household wealth, neighbourhood education level, access to media, and neighbourhood-level illiteracy contributed mostly to slum & non-slum inequality gaps in suboptimal access to EHS.

Conclusion

The study showed evidence of inequality in access to EHS due to neighbourhood effects in 26 LMICs. This evidence suggests that increased focus on the urban poor might be a important for increasing access to EHS and achieving the universal health coverage (UHC) goals.
Steering the course of CAR T cell therapy with lipid nanoparticles
Authors: Khawar Muhammad Babar , Afzal Ali , Si Yue , Sun Haibo
Published: June 2024

Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and addressing challenges like immunogenicity, reduced toxicity, and improved safety. Promising preclinical results signal a shift toward safer and more effective CAR T cell treatments. Ongoing research aims to validate these findings in clinical trials, marking a new era guided by LNPs utility in CAR therapy. Herein, we explore the preference for LNPs over traditional methods, highlighting the versatility of LNPs and their effective delivery of nucleic acids. Additionally, we address key challenges in clinical considerations, heralding a new era in CAR T cell therapy.

Graphical Abstract
Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease
Authors: He Qiongyao , He Wu , Dong Hui , Guo Yujin , Yuan Gang , Shi Xiaoli , Wang Dingkun , Lu Fuer
Published: June 2024

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.
Acceptability of an on-demand pericoital oral contraceptive pill: a systematic scoping review
Authors: Bell Stephen , Gibbs Susannah , Winskell Abigail , Villarino Xaviera , Gill Halle , Little Kristen
Published: June 2024

Background

Access to an on-demand pericoital oral contraceptive pill – used to prevent pregnancy within a defined window around sexual intercourse – could offer women more reproductive agency. A contraceptive with this indication is not currently available in any market. This review aims to understand international user appeal for an on-demand pericoital oral contraceptive pill.

Methods

Systematic scoping review, comprising 30 peer-reviewed papers published between 2014–2023.

Results

Data from 30 papers reporting on research from 16 countries across five World Health Organisation regions suggests widespread user appeal for on-demand oral contraceptive pills that can be used peri- or post-coitally, especially among women who are younger, more educated or who have less frequent sex. Women of varying age, wealth, employment or relationship status, and with different prior experience of using modern contraceptives, were also interested. Women identified clear rationale for use and preference of these types of product: close alignment with women’s sexual lives that comprised unplanned, spontaneous or occasional sex; perceived convenience and effectiveness; discreet use of pills to negotiate contextual circumstances that constrained their reproductive agency. Factors inhibiting use included knowledge barriers and attitudes of service providers, a lack of knowledge and misinformation among end-users, women’s dislike of menstrual side effects and myths related to the effects of hormone content on future fertility.

Conclusions

Introduction of an on-demand pericoital oral contraceptive pill could expand contraceptive choice for diverse women experiencing unmet need for modern contraception and constrained sexual and reproductive agency. Priorities for future research include: broadening the geographical scope of evidence to include SE Asia and the Pacific, and international rural and peri-urban settings; documenting the perspectives of adolescents and unmarried young people; identifying opportunities for innovation in the supply channels to enhance appropriate, affordable access to on-demand oral contraceptives; and unpacking how to bring new pericoital contraceptives to the market in a variety of international settings.
Sudden unexpected death after initial infusion of rituximab for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma: an autopsy case
Authors: Ichimata Shojiro , Hata Yukiko , Nomoto Kazuhiro , Sato Tsutomu , Nishida Naoki
Published: June 2024

Background

Waldenström’s macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL.

Case presentation

An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein.

Conclusion

Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.
Transcriptomics-based liquid biopsy panel for early non-invasive identification of peritoneal recurrence and micrometastasis in locally advanced gastric cancer
Authors: Ding Ping’an , Wu Haotian , Wu Jiaxiang , Li Tongkun , Gu Renjun , Zhang Lilong , Yang Peigang , Guo Honghai , Tian Yuan , He Jinchen , Yang Jiaxuan , Meng Ning , Li Xiaolong , Meng Lingjiao , Zhao Qun
Published: June 2024

Background

This study aimed to develop a novel six-gene expression biomarker panel to enhance the early detection and risk stratification of peritoneal recurrence and micrometastasis in locally advanced gastric cancer (LAGC).

Methods

We used genome-wide transcriptome profiling and rigorous bioinformatics to identify a six-gene expression biomarker panel. This panel was validated across multiple clinical cohorts using both tissue and liquid biopsy samples to predict peritoneal recurrence and micrometastasis in patients with LAGC.

Results

Through genome-wide expression profiling, we identified six mRNAs and developed a risk prediction model using 196 samples from a surgical specimen training cohort. This model, incorporating a 6-mRNA panel with clinical features, demonstrated high predictive accuracy for peritoneal recurrence in gastric cancer patients, with an AUC of 0.966 (95% CI: 0.944–0.988). Transitioning from invasive surgical or endoscopic biopsy to noninvasive liquid biopsy, the model retained its predictive efficacy (AUC = 0.963; 95% CI: 0.926–1.000). Additionally, the 6-mRNA panel effectively differentiated patients with or without peritoneal metastasis in 95 peripheral blood specimens (AUC = 0.970; 95% CI: 0.936–1.000) and identified peritoneal micrometastases with a high efficiency (AUC = 0.941; 95% CI: 0.874–1.000).

Conclusions

Our study provides a novel gene expression biomarker panel that significantly enhances early detection of peritoneal recurrence and micrometastasis in patients with LAGC. The RSA model's predictive capability offers a promising tool for tailored treatment strategies, underscoring the importance of integrating molecular biomarkers with clinical parameters in precision oncology.
Gut colonization with multidrug resistant organisms in the intensive care unit: a systematic review and meta-analysis
Authors: Heath Madison R. , Fan Weijia , Leu Cheng-Shiun , Gomez-Simmonds Angela , Lodise Thomas , Freedberg Daniel E.
Published: June 2024

Background

Gut colonization with multidrug-resistant organisms (MDRO) frequently precedes infection among patients in the intensive care unit (ICU), although the dynamics of colonization are not completely understood. We performed a systematic review and meta-analysis of ICU studies which described the cumulative incidence and rates of MDRO gut acquisition.

Methods

We systematically searched PubMed, Embase, and Web of Science for studies published from 2010 to 2023 reporting on gut acquisition of MDRO in the ICU. MDRO were defined as multidrug resistant non-Pseudomonas Gram-negative bacteria (NP-GN), Pseudomonas spp., and vancomycin-resistant Enterococcus (VRE). We included observational studies which obtained perianal or rectal swabs at ICU admission (within 48 h) and at one or more subsequent timepoints. Our primary outcome was the incidence rate of gut acquisition of MDRO, defined as any MDRO newly detected after ICU admission (i.e., not present at baseline) for all patient-time at risk. The study was registered with PROSPERO, CRD42023481569.

Results

Of 482 studies initially identified, 14 studies with 37,305 patients met criteria for inclusion. The pooled incidence of gut acquisition of MDRO during ICU hospitalization was 5% (range: 1–43%) with a pooled incidence rate of 12.2 (95% CI 8.1–18.6) per 1000 patient-days. Median time to acquisition ranged from 4 to 26 days after ICU admission. Results were similar for NP-GN and Pseudomonas spp., with insufficient data to assess VRE. Among six studies which provided sufficient data to perform curve fitting, there was a quasi-linear increase in gut MDRO colonization of 1.41% per day which was stable through 30 days of ICU hospitalization (R2 = 0.50, p < 0.01).

Conclusions

Acquisition of gut MDRO was common in the ICU and increases with days spent in ICU through 30 days of follow-up. These data may guide future interventions seeking to prevent gut acquisition of MDRO in the ICU.
Atypical cell cycle regulation promotes mammary stem cell expansion during mammary development and tumourigenesis
Authors: Fifield Bre-Anne , Vusich John , Haberfellner Erika , Andrechek Eran R. , Porter Lisa A.
Published: June 2024

Background

The cell cycle of mammary stem cells must be tightly regulated to ensure normal homeostasis of the mammary gland to prevent abnormal proliferation and susceptibility to tumorigenesis. The atypical cell cycle regulator, Spy1 can override cell cycle checkpoints, including those activated by the tumour suppressor p53 which mediates mammary stem cell homeostasis. Spy1 has also been shown to promote expansion of select stem cell populations in other developmental systems. Spy1 protein is elevated during proliferative stages of mammary gland development, is found at higher levels in human breast cancers, and promotes susceptibility to mammary tumourigenesis when combined with loss of p53. We hypothesized that Spy1 cooperates with loss of p53 to increase susceptibility to tumour initiation due to changes in susceptible mammary stem cell populations during development and drives the formation of more aggressive stem like tumours.

Methods

Using a transgenic mouse model driving expression of Spy1 within the mammary gland, mammary development and stemness were assessed. These mice were intercrossed with p53 null mice to study the tumourigenic properties of Spy1 driven p53 null tumours, as well as global changes in signaling via RNA sequencing analysis.

Results

We show that elevated levels of Spy1 leads to expansion of mammary stem cells, even in the presence of p53, and an increase in mammary tumour formation. Spy1-driven tumours have an increased cancer stem cell population, decreased checkpoint signaling, and demonstrate an increase in therapy resistance. Loss of Spy1 decreases tumor onset and reduces the cancer stem cell population.

Conclusions

This data demonstrates the potential of Spy1 to expand mammary stem cell populations and contribute to the initiation and progression of aggressive, breast cancers with increased cancer stem cell populations.
Cognitive training and promoting a healthy lifestyle for individuals with isolated REM sleep behavior disorder: study protocol of the delayed-start randomized controlled trial CogTrAiL-RBD
Authors: Ophey Anja , Röttgen Sinah , Pauquet Julia , Weiß Kim-Lara , Scharfenberg Daniel , Doppler Christopher E. J. , Seger Aline , Hansen Clint , Fink Gereon R. , Sommerauer Michael , Kalbe Elke
Published: June 2024

Background

Isolated REM sleep behavior disorder (iRBD) is an early α-synucleinopathy often accompanied by incipient cognitive impairment. As executive dysfunctions predict earlier phenotypic conversion from iRBD to Parkinson’s disease and Lewy body dementia, cognitive training focusing on executive functions could have disease-modifying effects for individuals with iRBD.

Methods

The study CogTrAiL-RBD investigates the short- and long-term effectiveness and the feasibility and underlying neural mechanisms of a cognitive training intervention for individuals with iRBD. The intervention consists of a 5-week digital cognitive training accompanied by a module promoting a healthy, active lifestyle. In this monocentric, single-blinded, delayed-start randomized controlled trial, the intervention’s effectiveness will be evaluated compared to an initially passive control group that receives the intervention in the second, open-label phase of the study. Eighty individuals with iRBD confirmed by polysomnography will be consecutively recruited from the continuously expanding iRBD cohort at the University Hospital Cologne. The evaluation will focus on cognition and additional neuropsychological and motor variables. Furthermore, the study will examine the feasibility of the intervention, effects on physical activity assessed by accelerometry, and interrogate the intervention’s neural effects using magnetic resonance imaging and polysomnography. Besides, a healthy, age-matched control group (HC) will be examined at the first assessment time point, enabling a cross-sectional comparison between individuals with iRBD and HC.

Discussion

This study will provide insights into whether cognitive training and psychoeducation on a healthy, active lifestyle have short- and long-term (neuro-)protective effects for individuals with iRBD.

Trial registration

The study was prospectively registered in the German Clinical Trial Register (DRKS00024898) on 2022–03-11, https://drks.de/search/de/trial/DRKS00024898. Protocol version: V5 2023–04-24.
Anaesthesiologists’ guideline adherence in pre-operative evaluation: a retrospective observational study
Authors: Kagerbauer Simone Maria , Wißler Jennifer , Blobner Manfred , Biegert Ferdinand , Andonov Dimislav Ivanov , Schneider Gerhard , Podtschaske Armin Horst , Ulm Bernhard , Jungwirth Bettina
Published: June 2024

Background

Surveys suggest a low level of implementation of clinical guidelines, although they are intended to improve the quality of treatment and patient safety. Which guideline recommendations are not followed and why has yet to be analysed. In this study, we investigate the proportion of European and national guidelines followed in the area of pre-operative anaesthetic evaluation prior to non-cardiac surgery.

Methods

We conducted this monocentric retrospective observational study at a German university hospital with the help of software that logically links guidelines in such a way that individualised recommendations can be derived from a patient's data. We included routine logs of 2003 patients who visited our pre-anaesthesia outpatient clinic between June 2018 and June 2020 and compared the actual conducted pre-operative examinations with the recommendations issued by the software. We descriptively analysed the data for examinations not performed that would have been recommended by the guidelines and examinations that were performed even though they were not covered by a guideline recommendation. The guidelines examined in this study are the 2018 ESAIC guidelines for pre-operative evaluation of adults undergoing elective non-cardiac surgery, the 2014 ESC/ESA guidelines on non-cardiac surgery and the German recommendations on pre-operative evaluation on non-cardiothoracic surgery from the year 2017.

Results

Performed ECG (78.1%) and cardiac stress imaging tests (86.1%) indicated the highest guideline adherence. Greater adherence rates were associated with a higher ASA score (ASA I: 23.7%, ASA II: 41.1%, ASA III: 51.8%, ASA IV: 65.8%, P < 0.001), lower BMI and age > 65 years. Adherence rates in high-risk surgery (60.5%) were greater than in intermediate (46.5%) or low-risk (44.6%) surgery (P < 0.001). 67.2% of technical and laboratory tests performed preoperatively were not covered by a guideline recommendation.

Conclusions

Guideline adherence in pre-operative evaluation leaves room for improvement. Many performed pre-operative examinations, especially laboratory tests, are not recommended by the guidelines and may cause unnecessary costs. The reasons for guidelines not being followed may be the complexity of guidelines and organisational issues. A software-based decision support tool may be helpful.

Trial registration

ClinicalTrials.gov ID NCT04843202.