bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular clarity: a logistic regression approach to identify root epidermal regulators of iron deficiency response
Authors: Schmittling Selene R. , Muhammad DurreShahwar , Haque Samiul , Long Terri A. , Williams Cranos M.
Published: October 2023

Background

Plants respond to stress through highly tuned regulatory networks. While prior works identified master regulators of iron deficiency responses in A. thaliana from whole-root data, identifying regulators that act at the cellular level is critical to a more comprehensive understanding of iron homeostasis. Within the root epidermis complex molecular mechanisms that facilitate iron reduction and uptake from the rhizosphere are known to be regulated by bHLH transcriptional regulators. However, many questions remain about the regulatory mechanisms that control these responses, and how they may integrate with developmental processes within the epidermis. Here, we use transcriptional profiling to gain insight into root epidermis-specific regulatory processes.

Results

Set comparisons of differentially expressed genes (DEGs) between whole root and epidermis transcript measurements identified differences in magnitude and timing of organ-level vs. epidermis-specific responses. Utilizing a unique sampling method combined with a mutual information metric across time-lagged and non-time-lagged windows, we identified relationships between clusters of functionally relevant differentially expressed genes suggesting that developmental regulatory processes may act upstream of well-known Fe-specific responses. By integrating static data (DNA motif information) with time-series transcriptomic data and employing machine learning approaches, specifically logistic regression models with LASSO, we also identified putative motifs that served as crucial features for predicting differentially expressed genes. Twenty-eight transcription factors (TFs) known to bind to these motifs were not differentially expressed, indicating that these TFs may be regulated post-transcriptionally or post-translationally. Notably, many of these TFs also play a role in root development and general stress response.

Conclusions

This work uncovered key differences in -Fe response identified using whole root data vs. cell-specific root epidermal data. Machine learning approaches combined with additional static data identified putative regulators of -Fe response that would not have been identified solely through transcriptomic profiles and reveal how developmental and general stress responses within the epidermis may act upstream of more specialized -Fe responses for Fe uptake.
Comparative age-period-cohort analysis
Authors: Rosenberg Philip S. , Miranda-Filho Adalberto , Whiteman David C.
Published: October 2023

Background

Cancer surveillance researchers analyze incidence or mortality rates jointly indexed by age group and calendar period using age-period-cohort models. Many studies consider age- and period-specific rates in two or more strata defined by sex, race/ethnicity, etc. A comprehensive characterization of trends and patterns within each stratum can be obtained using age-period-cohort (APC) estimable functions (EF). However, currently available approaches for joint analysis and synthesis of EF are limited.

Methods

We develop a new method called Comparative Age-Period-Cohort Analysis to quantify similarities and differences of EF across strata. Comparative Analysis identifies whether the stratum-specific hazard rates are proportional by age, period, or cohort.

Results

Proportionality imposes natural constraints on the EF that can be exploited to gain efficiency and simplify the interpretation of the data. Comparative Analysis can also identify differences or diversity in proportional relationships between subsets of strata (“pattern heterogeneity”). We present three examples using cancer incidence from the United States Surveillance, Epidemiology, and End Results Program: non-malignant meningioma by sex; multiple myeloma among men stratified by race/ethnicity; and in situ melanoma by anatomic site among white women.

Conclusions

For studies of cancer rates with from two through to around 10 strata, which covers many outstanding questions in cancer surveillance research, our new method provides a comprehensive, coherent, and reproducible approach for joint analysis and synthesis of age-period-cohort estimable functions.
Adaptive designs in critical care trials: a simulation study
Authors: Li W. , Cornelius V. , Finfer S. , Venkatesh B. , Billot L.
Published: October 2023

Background

Adaptive clinical trials are growing in popularity as they are more flexible, efficient and ethical than traditional fixed designs. However, notwithstanding their increased use in assessing treatments for COVID-19, their use in critical care trials remains limited. A better understanding of the relative benefits of various adaptive designs may increase their use and interpretation.

Methods

Using two large critical care trials (ADRENAL. ClinicalTrials.gov number, NCT01448109. Updated 12-12-2017; NICE-SUGAR. ClinicalTrials.gov number, NCT00220987. Updated 01-29-2009), we assessed the performance of three frequentist and two bayesian adaptive approaches. We retrospectively re-analysed the trials with one, two, four, and nine equally spaced interims. Using the original hypotheses, we conducted 10,000 simulations to derive error rates, probabilities of making an early correct and incorrect decision, expected sample size and treatment effect estimates under the null scenario (no treatment effect) and alternative scenario (a positive treatment effect). We used a logistic regression model with 90-day mortality as the outcome and the treatment arm as the covariate. The null hypothesis was tested using a two-sided significance level (α) at 0.05.

Results

Across all approaches, increasing the number of interims led to a decreased expected sample size. Under the null scenario, group sequential approaches provided good control of the type-I error rate; however, the type I error rate inflation was an issue for the Bayesian approaches. The Bayesian Predictive Probability and O’Brien-Fleming approaches showed the highest probability of correctly stopping the trials (around 95%). Under the alternative scenario, the Bayesian approaches showed the highest overall probability of correctly stopping the ADRENAL trial for efficacy (around 91%), whereas the Haybittle-Peto approach achieved the greatest power for the NICE-SUGAR trial. Treatment effect estimates became increasingly underestimated as the number of interims increased.

Conclusions

This study confirms the right adaptive design can reach the same conclusion as a fixed design with a much-reduced sample size. The efficiency gain associated with an increased number of interims is highly relevant to late-phase critical care trials with large sample sizes and short follow-up times. Systematically exploring adaptive methods at the trial design stage will aid the choice of the most appropriate method.
FEEDBACK trial - A randomised control trial to investigate the effect of personalised feedback and financial incentives on reducing the incidence of road crashes
Authors: Stevenson Mark , Mortimer Duncan , Meuleners Lynn , Harris Anthony , Senserrick Teresa , Thompson Jason , De Silva Anurika , Barrera-Jimenez Humberto , Streatfield Avita , Perera Maneesha
Published: October 2023

Background

Road crashes continue to pose a significant threat to global health. Young drivers aged between 18 and 25 are over-represented in road injury and fatality statistics, especially the first six months after obtaining their license. This study is the first multi-centre two-arm parallel-group individually randomised controlled trial (the FEEDBACK Trial) that will examine whether the delivery of personalised driver feedback plus financial incentives is superior to no feedback and no financial incentives in reducing motor vehicle crashes among young drivers (18 to 20 years) during the first year of provisional licensing.

Methods

A total of 3,610 young drivers on their provisional licence (P1, the first-year provisional licensing) will participate in the trial over 28 weeks, including a 4-week baseline, 20-week intervention and 4-week post-intervention period. The primary outcome of the study will be police-reported crashes over the 20-week intervention period and the 4-week post-intervention period. Secondary outcomes include driving behaviours such as speeding and harsh braking that contribute to road crashes, which will be attained weekly from mobile telematics delivered to a smartphone app.

Discussion

Assuming a positive finding associated with personalised driver feedback and financial incentives in reducing road crashes among young drivers, the study will provide important evidence to support policymakers in introducing the intervention(s) as a key strategy to mitigate the risks associated with the burden of road injury among this vulnerable population.

Trial registration

Registered under the Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12623000387628p on April 17, 2023.
Comparison of the physical activity levels between shift workers and non-shift workers in a large-scale cross-sectional study in Iran
Authors: Najafi Anahita , Safari-Faramani Roya , Selk-Ghaffari Maryam , Najafi Farid , Ghafouri Mohammad , Darbandi Mitra , Mahdaviani Behnaz , Nakhostin-Ansari Amin
Published: October 2023

Background

Shift work has been related to adverse health outcomes that can partially be attributed to physical inactivity. However, our knowledge of the influence of shift work on physical activity and sedentary behavior is inconclusive. Therefore, this study aimed to assess physical activity levels among shift and non-shift workers among a sample of Iranian adults.

Methods

Baseline data of the Ravansar Non-Communicable Disease (RaNCD) cohort study were used. All participants of RaNCD except those excluded due to unemployment or considerable disability were included in the study. We evaluated participants’ physical activity levels using the PERSIAN cohort questionnaire and examined its associations with being a shift worker.

Results

A total of 4695 participants with a mean age of 46.1 (SD = 7.74) were included in the study. In total, 1108 (23.6%) participants were shift workers, 1420 (30.2%) had insufficient physical activity levels, and 4283 (91.2%) were male. The prevalence of physical inactivity was significantly lower among shift workers compared to non-shift workers (21% vs. 33.1%, p < 0.001). Multiple backward stepwise binary logistic regression tests indicated that being a shift worker was significantly associated with a lower chance of having insufficient physical activity levels (OR = 0.77, 95% CI = 0.65–0.92, p = 0.003).

Conclusions

The prevalence of insufficient physical activity was higher among non-shift workers than shift workers in our study. By providing the factors associated with insufficient physical activity among the workers in a region of Iran, the current study findings might help policymakers target groups at higher risk of physical activity in Iran and design interventions to improve physical activity, especially among non-shift workers.
Long-term effects of air pollutants on respiratory and cardiovascular mortality in a port city along the Adriatic sea
Authors: Mei Federico , Renzi Matteo , Bonifazi Martina , Bonifazi Floriano , Pepe Nicola , D’Allura Alessio , Brusasca Giuseppe , Viegi Giovanni , Forastiere Francesco
Published: October 2023

Background

Shipping and port-related air pollution has a significant health impact on a global scale. The present study aimed to assess the mortality burden attributable to long-term exposure to ambient particulate matter (PM2.5, PM10) and nitrogen dioxide (NO2) in the city of Ancona (Italy), with one of the leading national commercial harbours.

Methods

Exposure to air pollutants was derived by dispersion models. The relationship between the long-term exposure of air pollution exposure and cause-specific mortality was evaluated by Poisson regression models, after adjustment for gender, age and socioeconomic status. Results are expressed as percent change of risk (and relative 95% confidence intervals) per 5 unit increases in the exposures. The health impact on the annual number of premature cause-specific deaths was also assessed.

Results

PM2.5 and NO2 annual concentrations were higher in the area close to the harbour than in the rest of the city. Positive associations between each pollutant and most of the mortality outcomes were observed, with estimates of up to 7.6% (95%CI 0.1, 15.6%) for 10 µg/m3 increase in NO2 and cardiovascular mortality and 15.3% (95%CI-1.1, 37.2%) for 10 µg/m3 increase PM2.5 and lung cancer. In the subpopulation living close to the harbour, there were excess risks of up to 13.5%, 24.1% and 37.9% for natural, cardiovascular and respiratory mortality. The number of annual premature deaths due to the excess of PM2.5 and NO2 exposure (having as a reference the 2021 World Health Organization Air Quality Guidelines) was 82 and 25, respectively.

Conclusions

Our study confirms the long-term health effects of PM and NO2 on mortality and reveals a higher mortality burden in areas close to shipping and port-related emissions. Estimating the source-specific health burdens is key to achieve a deeper understanding of the role of different emission sources, as well as to support effective and targeted mitigation strategies.
Receiver operating characteristic (ROC) to determine cut-off points of clinical and biomolecular markers to discriminate mortality in severe COVID-19 living at high altitude
Authors: Vélez-Páez Jorge Luis , Baldeón-Rojas Lucy , Cañadas Herrera Cristina , Montalvo Mario Patricio , Jara Fernando Esteban , Aguayo-Moscoso Santiago , Tercero-Martínez Wendy , Saltos Lenin , Jiménez-Alulima Glenda , Guerrero Verónica , Pérez-Galarza Jorge
Published: October 2023

Background

In 2020, Ecuador had one of the highest death rates because of COVID-19. The role of clinical and biomolecular markers in COVID disease prognosis, is still not well supported by available data. In order for these markers to have practical application in clinical decision-making regarding patient treatment and prognosis, it is necessary to know an optimal cut-off point, taking into consideration ethnic differences and geographic conditions.

Aim

To determine the value of clinical and biomolecular markers, to predict mortality of patients with severe COVID-19 living at high altitude.

Methods

In this study, receiver operating characteristic (ROC) curves, area under the curve (AUC) of ROC, sensitivity, specificity and likelihood ratios were calculated to determine levels of clinical and biomolecular markers that best differentiate survivors versus non-survivors in severe COVID subjects that live at a high altitude setting.

Results

Selected cut-off values for ferritin (≥ 1225 ng/dl, p = 0.026), IL-6 (≥ 11 pg/ml, p = 0.005) and NLR (≥ 22, p = 0.008) at 24 h, as well as PaFiO2 (≤ 164 mmHg, p = 0.015), NLR (≥ 16, p = p = 0.013) and SOFA (≥ 6, p = 0.031) at 72 h, appear to have good discriminating power to differentiate survivors versus non-survivors. Additionally, odds ratios for ferritin (OR = 3.38); IL-6 (OR = 17.07); PaFiO2 (OR = 4.61); NLR 24 h (OR = 4.95); NLR 72 h (OR = 4.46), and SOFA (OR = 3.77) indicate increased risk of mortality when cut-off points were taken into consideration.

Conclusions

We proposed a straightforward and understandable method to identify dichotomized levels of clinical and biomolecular markers that can discriminate between survivors and non-survivors patients with severe COVID-19 living at high altitudes.
The effect of generation change on the accuracy of full arch digital impressions
Authors: Schmalzl Judit , Róth Ivett , Borbély Judit , Hermann Péter , Vecsei Bálint
Published: October 2023

Purpose

This study is aimed to evaluate the effect of generation change on accuracy of IOSs on full-arch scans and the inter-operator reliability.

Methods

In this study, 6 different IOS were tested: 3Shape Trios 3 (20.1.2.), 3Shape Trios 4 (20.1.1.), Medit i500 (2.3.6.), Medit i700 (2.4.6.), Planmeca Emerald (6.0.1.) and Planmeca Emerald S (6.0.1.). Eighteen dental students, inexperienced in scanning, took part in this study as operators. Each operator made 10 digital impressions; altogether, 30 impressions were made by each scanner. The 30 STL files were imported to the Geomagic Control X program, where they were compared to a reference STL file; the surface point’s deviation of the full arch and the distance between the second molars’ distobuccal cusps were measured, the inter-operator reliability was also investigated.

Results

A significant increase in accuracy was found between Trios 3 and 4 in the case of both parameters and between Medit i500 and i700 in the case of full arch. There was no significant difference between Planmeca generations. In case of the inter-operator reliability no significant difference was detected.

Conclusion

Within this current study’s limitation, it can be concluded that surface digitalization’s accuracy can be modified with generation changes and that digital technology is less technique sensitive than traditional impression taking.
Improving computerized decision support system interventions: a qualitative study combining the theoretical domains framework with the GUIDES Checklist
Authors: Yamada Janet , Kouri Andrew , Simard Sarah Nicole , Lam Shin Cheung Jeffrey , Segovia Stephanie , Gupta Samir
Published: October 2023

Background

Computerized clinical decision support systems (CDSSs) can improve care by bridging knowledge to practice gaps. However, the real-world uptake of such systems in health care settings has been suboptimal. We sought to: (1) use the Theoretical Domains Framework (TDF) to identify determinants (barriers/enablers) of uptake of the Electronic Asthma Management System (eAMS) CDSS; (2) match identified TDF belief statements to elements in the Guideline Implementation with Decision Support (GUIDES) Checklist; and (3) explore the relationship between the TDF and GUIDES frameworks and the usefulness of this sequential approach for identifying opportunities to improve CDSS uptake.

Methods

In Phase 1, we conducted semistructured interviews with primary care physicians in Toronto, Canada regarding the uptake of the eAMS CDSS. Using content analysis, two coders independently analyzed interview transcripts guided by the TDF to generate themes representing barriers and enablers to CDSS uptake. In Phase 2, the same reviewers independently mapped each belief statement to a GUIDES domain and factor. We calculated the proportion of TDF belief statements that linked to each GUIDES domain and the proportion of TDF domains that linked to GUIDES factors (and vice-versa) and domains.

Results

We interviewed 10 participants before data saturation. In Phase 1, we identified 53 belief statements covering 12 TDF domains; 18 (34.0%) were barriers, and 35 (66.0%) were enablers. In Phase 2, 41 statements (77.4%) linked to at least one GUIDES factor, while 12 (22.6%) did not link to any specific factor. The GUIDES Context Domain was linked to the largest number of belief statements (19/53; 35.8%). Each TDF domain linked to one or more GUIDES factor, with 6 TDF domains linking to more than 1 factor and 8 TDF domains linking to more than 1 GUIDES domain.

Conclusions

The TDF provides unique insights into barriers and enablers to CDSS uptake, which can then be mapped to GUIDES domains and factors to identify required changes to CDSS context, content, and system. This can be followed by conventional mapping of TDF domains to behaviour change techniques to optimize CDSS implementation. This novel step-wise approach combines two established frameworks to optimize CDSS interventions, and requires prospective validation.
Development, implementation, and evaluation of neonatal thermoregulation decision support web application
Authors: Beykmirza Raziyeh , Mehrabani Elahe Rastkar , Hashemi Maryam , Shahri Maryam Mahdizade , Negarandeh Reza , Varzeshnejad Maryam
Published: October 2023

Objectives

Thermoregulation is important for all age groups, and in neonates, it is considered a crucial event to adapt to extrauterine life. Therefore, using systems that provide frequent reminders in different ways in the field of thermoregulation can help thermal stability in neonates. The present study aimed to develop, implement, and evaluate a neonatal thermoregulation decision support system (DSS) as a web application.

Methods

The present research was a multi-method study because it included the three phases of development, implementation, and evaluation of the neonatal thermoregulation decision support web application. In the system designing phase, the waterfall model is used. The second and third phases of the study, implementation, and evaluation, were conducted as a quasi-experimental study.

Results

The results of this study were presented in two parts: the developed web application, and the results of the evaluation of the web application. The results of the statistical tests revealed that the use of the web application had a positive and significant effect on both the adjustment of the temperature of the incubator (maintaining the neutral temperature) and the maintenance of the temperature of the neonate’s body (p = 0.000).

Conclusions

These results indicate that a nurse’s sensitization and guidance with a neonatal thermoregulation decision support system can help to effectively neonate thermoregulation and the nurse has brought the temperature care close to the standard care based on the conditions of each neonate.
Interpreting deep learning models for glioma survival classification using visualization and textual explanations
Authors: Osadebey Michael , Liu Qinghui , Fuster-Garcia Elies , Emblem Kyrre E.
Published: October 2023

Background

Saliency-based algorithms are able to explain the relationship between input image pixels and deep-learning model predictions. However, it may be difficult to assess the clinical value of the most important image features and the model predictions derived from the raw saliency map. This study proposes to enhance the interpretability of saliency-based deep learning model for survival classification of patients with gliomas, by extracting domain knowledge-based information from the raw saliency maps.

Materials and methods

Our study includes presurgical T1-weighted (pre- and post-contrast), T2-weighted and T2-FLAIR MRIs of 147 glioma patients from the BraTs 2020 challenge dataset aligned to the SRI 24 anatomical atlas. Each image exam includes a segmentation mask and the information of overall survival (OS) from time of diagnosis (in days). This dataset was divided into training ($$n=118$$

n
=
118

) and validation ($$n=29$$

n
=
29

) datasets. The extent of surgical resection for all patients was gross total resection. We categorized the data into 42 short (mean $$\mu =157$$

μ
=
157

days), 30 medium ($$\mu =369$$

μ
=
369

days), and 46 long ($$\mu =761$$

μ
=
761

days) survivors. A 3D convolutional neural network (CNN) trained on brain tumour MRI volumes classified all patients based on expected prognosis of either short-term, medium-term, or long-term survival. We extend the popular 2D Gradient-weighted Class Activation Mapping (Grad-CAM), for the generation of saliency map, to 3D and combined it with the anatomical atlas, to extract brain regions, brain volume and probability map that reveal domain knowledge-based information.

Results

For each OS class, a larger tumor volume was associated with a shorter OS. There were 10, 7 and 27 tumor locations in brain regions that uniquely associate with the short-term, medium-term, and long-term survival, respectively. Tumors located in the transverse temporal gyrus, fusiform, and palladium are associated with short, medium and long-term survival, respectively. The visual and textual information displayed during OS prediction highlights tumor location and the contribution of different brain regions to the prediction of OS. This algorithm design feature assists the physician in analyzing and understanding different model prediction stages.

Conclusions

Domain knowledge-based information extracted from the saliency map can enhance the interpretability of deep learning models. Our findings show that tumors overlapping eloquent brain regions are associated with short patient survival.
Effect of patient-centered and family-centered self-care education program on the quality of life of patients with multiple sclerosis: a quasi-experimental study
Authors: Rooddehghan Zahra , Nezhad Mozhgan Moghaddasi , Zakerimoghadam Masoumeh , Karimi Raoofeh
Published: October 2023

Background

Performing self-care behaviors education improves the quality of life of MS patients and reduces their fatigue. This study was conducted with the aim of comparing the effect of patient-centered and family-centered self-care training programs on the quality of life and fatigue of patients with multiple sclerosis.

Methods

This is a quasi-experimental study that was conducted on the MS patients referred to the Iranian MS Association. Sampling was done by convenience method from November 2017 to September 2018. To create a random sequence in the three groups, blocks of nine were used. The control group received no intervention but the intervention groups 1 and 2 received the desired training in the form of workshop with the difference that in the intervention group 2, the patient participated in the training sessions along with one of his/her family members. The phone call follow-up was continued for 8 weeks after the last session. The questionnaire of quality of life in patients with MS (MSQOL-54), fatigue scale (FIS) and demographic information form were used for data collection. The collected data was analyzed by SPSS-16 statistical software, using descriptive (Mean and Standard deviation) and statistical statistics (paired t-test, Analysis of variance and Bonferroni).

Result

A statistically significant difference in the mean scores of quality of life(53/16 ± 15/19 vs 56/03 ± 14/40 vs 52/48 ± 21/20)(P < 0.001) and fatigue(50/08 ± 3/28 vs 46/54 ± 28/69 vs 56/11 ± 27/93) (P < 0.001) was observed between both patient-centered and family-centered groups and the control group.

Conclusions

Considering the importance and role of the family and nurses in the care and education of patients with multiple sclerosis, it is possible to improve the quality of life and reduce their fatigue by providing self-care training packages to patients and their families.
Guideline documents on caesarean section on maternal request in Sweden: varying usability with a restrictive approach
Authors: Mattebo Magdalena , Holmström Inger K , Höglund Anna T , Fredriksson Mio
Published: October 2023

Background

Globally, studies illustrate different approaches among health care professionals to decision making about caesarean section (CS) and that attitudes regarding the extent to which a CS on maternal request (CSMR) can be granted vary significantly, both between professionals and countries. Absence of proper regulatory frameworks is one potential explanation for high CSMR rates in some countries, but overall, it is unclear how recommendations and guidelines on CSMR relate to CSMR rates. In Sweden, CSMR rates are low by international comparison, but statistics show that the extent to which maternity clinics perform CSMR vary among Sweden’s 21 self-governing regions. These regions are responsible for funding and delivery of healthcare, while national guidelines provide guidance for the professions throughout the country; however, they are not mandatory. To further understand considerations for CSMR requests and existing practice variations, the aim was to analyse guideline documents on CSMR at all local maternity clinics in Sweden.

Methods

All 43 maternity clinics in Sweden were contacted and asked for any guideline documents regarding CSMR. All clinics replied, enabling a total investigation. We used a combined deductive and inductive design, using the framework method for the analysis of qualitative data in multi-disciplinary health research.

Results

Overall, 32 maternity clinics reported guideline documents and 11 denied having any. Among those reporting no guideline documents, one referred to using national guideline document. Based on the Framework method, four theme categories were identified: CSMR is treated as a matter of fear of birth (FOB); How important factors are weighted in the decision-making is unclear; Birth contracts are offered in some regions; and The post-partum care is related to FOB rather than CSMR.

Conclusion

In order to offer women who request CS equal and just care, there is a pressing need to either implement current national guideline document at all maternity clinics or rewrite the guideline documents to enable clinics to adopt a structured approach. The emphasis must be placed on exploring the reasons behind the request and providing unbiased information and support. Our results contribute to the ongoing discussion about CSMR and lay a foundation for further research in which professionals, as well as stakeholders and both women planning pregnancy and pregnant women, can give their views on this issue.
A review of three decades of use of the cattle brucellosis rough vaccine Brucella abortus RB51: myths and facts
Authors: Blasco J. M. , Moreno E. , Muñoz P. M. , Conde-Álvarez R. , Moriyón I.
Published: October 2023

Cattle brucellosis is a severe zoonosis of worldwide distribution caused byBrucella abortusandB. melitensis. In some countries with appropriate infrastructure, animal tagging and movement control, eradication was possible through efficient diagnosis and vaccination withB. abortusS19, usually combined with test-and-slaughter (T/S). Although S19 elicits anti-smooth lipopolysaccharide antibodies that may interfere in the differentiation of infected and vaccinated animals (DIVA), this issue is minimized using appropriate S19 vaccination protocols and irrelevant when high-prevalence makes mass vaccination necessary or when eradication requisites are not met. However, S19 has been broadly replaced by vaccine RB51 (a rifampin-resistant rough mutant) as it is widely accepted that is DIVA, safe and as protective as S19. These RB51 properties are critically reviewed here using the evidence accumulated in the last 35 years. Controlled experiments and field evidence shows that RB51 interferes in immunosorbent assays (iELISA, cELISA and others) and in complement fixation, issues accentuated by revaccinating animals previously immunized with RB51 or S19. Moreover, contacts with virulent brucellae elicit anti-smooth lipopolysaccharide antibodies in RB51 vaccinated animals. Thus, accepting that RB51 is truly DIVA results in extended diagnostic confusions and, when combined with T/S, unnecessary over-culling. Studies supporting the safety of RB51 are flawed and, on the contrary, there is solid evidence that RB51 is excreted in milk and abortifacient in pregnant animals, thus being released in abortions and vaginal fluids. These problems are accentuated by the RB51 virulence in humans, lack diagnostic serological tests detecting these infections and RB51 rifampicin resistance. In controlled experiments, protection by RB51 compares unfavorably with S19 and lasts less than four years with no evidence that RB51-revaccination bolsters immunity, and field studies reporting its usefulness are flawed. There is no evidence that RB51 protects cattle againstB. melitensis,infection common when raised together with small ruminants. Finally, data acumulated during cattle brucellosis eradication in Spain shows that S19-T/S is far more efficacious than RB51-T/S, which does not differ from T/S alone. We conclude that the assumption that RB51 is DIVA, safe, and efficaceous results from the uncritical repetition of imperfectly examined evidence, and advise against its use.
Interaction, immune infiltration characteristics and prognostic modeling of efferocytosis-related subtypes in glioblastoma
Authors: Zhao Songyun , Wang Qi , Liu Yuankun , Zhang Pengpeng , Ji Wei , Xie Jiaheng , Cheng Chao
Published: October 2023

Background

Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. This process is initiated by the release of inflammatory mediators from apoptotic cells and plays a crucial role in resolving inflammation. The signals associated with efferocytosis have been found to regulate the inflammatory response and the tumor microenvironment (TME), which promotes the immune escape of tumor cells. However, the role of efferocytosis in glioblastoma multiforme (GBM) is not well understood and requires further investigation.

Methods

In this study, we conducted a comprehensive analysis of 22 efferocytosis-related genes (ERGs) by searching for studies related to efferocytosis. Using bulk RNA-Seq and single-cell sequencing data, we analyzed the expression and mutational characteristics of these ERGs. By using an unsupervised clustering algorithm, we obtained ERG clusters from 549 GBM patients and evaluated the immune infiltration characteristics of each cluster. We then identified differential genes (DEGs) in the two ERG clusters and classified GBM patients into different gene clusters using univariate cox analysis and unsupervised clustering algorithms. Finally, we utilized the Boruta algorithm to screen for prognostic genes and reduce dimensionality, and the PCA algorithm was applied to create a novel efferocytosis-related scoring system.

Results

Differential expression of ERGs in glioma cell lines and normal cells was analyzed by rt-PCR. Cell function experiments, on the other hand, validated TIMD4 as a tumor risk factor in GBM. We found that different ERG clusters and gene clusters have distinct prognostic and immune infiltration profiles. The ERG signature we developed provides insight into the tumor microenvironment of GBM. Patients with lower ERG scores have a better survival rate and a higher likelihood of benefiting from immunotherapy.

Conclusions

Our novel efferocytosis-related signature has the potential to be used in clinical practice for risk stratification of GBM patients and for selecting individuals who are likely to respond to immunotherapy. This can help clinicians design appropriate targeted therapies before initiating clinical treatment.
Causal relationships between blood lipids and major psychiatric disorders: Univariable and multivariable mendelian randomization analysis
Authors: Li Bozhi , Qu Yue , Fan Zhixin , Gong Xiayu , Xu Hanfang , Wu Lili , Yan Can
Published: October 2023

Background

Whether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders.

Methods

Univariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10− 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium.

Results

We observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85–0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71–0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003–1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74–0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD.

Conclusions

Our results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.
Enhanced effect of seasonal malaria chemoprevention when coupled with nutrients supplementation for preventing malaria in children under 5 years old in Burkina Faso: a randomized open label trial
Authors: Sondo Paul , Kaboré Bérenger , Rouamba Toussaint , Compaoré Eulalie , Tibiri Yssimini Nadège Guillène , Kaboré Hyacinthe Abd-El Latif Faïçal , Derra Karim , Tahita Marc Christian , Ilboudo Hamidou , Tougri Gauthier , Bouda Ismaïla , Dakyo Tikanou , Kafando Hyacinthe , Ouédraogo Florence , Rouamba Eli , Hien So-vii Franck , Kazienga Adama , Compaoré Cheick Saïd , Bambara Estelle , Nana Macaire , Dahal Prabin , Garanet Franck , Kaboré William , Léfèvre Thierry , Guerin Philippe , Tinto Halidou
Published: October 2023

Background

In rural African settings, most of the children under the coverage of Seasonal Malaria Chemoprevention (SMC) are also undernourished at the time of SMC delivery, justifying the need for packaging malarial and nutritional interventions. This study aimed at assessing the impact of SMC by coupling the intervention with nutrients supplementation for preventing malaria in children less than 5 years old in Burkina Faso.

Methods

A randomized trial was carried out between July 2020 and June 2021 in the health district of Nanoro, Burkina Faso. Children (n = 1059) under SMC coverage were randomly assigned to one of the three study arms SMC + Vitamin A (SMC-A, n = 353) or SMC + Vitamin A + Zinc (SMC-AZc, n = 353) or SMC + Vitamin A + PlumpyDoz(tm) (SMC-APd, n = 353)-a medium quantity—lipid-based nutrient supplement (MQ-LNS). Children were followed up for one year that included an active follow-up period of 6 months with scheduled monthly home visits followed by 6 months passive follow-up. At each visit, capillary blood sample was collected for malaria diagnosis by rapid diagnosis test (RDT).

Results

Adding nutritional supplements to SMC had an effect on the incidence of malaria. A reduction of 23% (adjusted IRR = 0.77 (95%CI 0.61–0.97) in the odds of having uncomplicated malaria in SMC-APd arm but not with SMC-AZc arm adjusted IRR = 0.82 (95%CI 0.65–1.04) compare to control arm was observed. A reduction of 52%, adjusted IRR = 0.48 (95%CI 0.23–0.98) in the odds of having severe malaria was observed in SMC-APd arm compared to control arm. Besides the effect on malaria, this combined strategy had an effect on all-cause morbidity. More specifically, a reduction of morbidity odds of 24%, adjusted IRR = 0.76 (95%CI 0.60–0.94) in SMC-APd arm compared to control arm was observed. Unlike clinical episodes, no effect of nutrient supplementation on cross sectional asymptomatic infections was observed.

Conclusion

Adding nutritional supplements to SMC significantly increases the impact of this intervention for preventing children from malaria and other childhood infections.

Trial registration: NCT04238845.
Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer
Authors: Zeng Zhen , Fu Minyang , Hu Yuan , Wei Yuquan , Wei Xiawei , Luo Min
Published: October 2023

Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
Persistent dyslipidemia increases the longitudinal changes in telomere length
Authors: Liu Xiaowei , Ma Tao , Yang Chan , Li Juan , Zhang Yuhong , Zhao Yi
Published: October 2023

Background and aims

Leukocyte telomere length (LTL) as a ‘biological clock’ of aging is closely related to human health, its association with an aging-related disease, dyslipidemia, has been less studied and mainly focused on cross-sectional investigations.

Methods

Two rounds of information and blood collections were conducted on a cohort of 1624 individuals residing in rural Ningxia, located in northwest China, with an average time gap of 9.8 years. The relative telomere length (RTL) of peripheral blood leukocytes was assessed using real-time quantitative PCR. To investigate the association between dyslipidemia, blood lipid levels, and alterations in RTL, multiple linear regression and generalized linear models were employed.

Results

After conducting the follow-up analysis, it was observed that 83.3% of the participants in the study exhibited a reduction in telomere length, while 16.7% experienced an increase in telomere length. The results suggested that dyslipidemia at baseline or follow-up may increase longitudinal changes in telomere length, but it was more significant in the healthy group, especially in those aged ≥ 60 years. Furthermore, HDL-C levels in baseline and follow-up were found to be associated with longitudinal changes in telomere length, and lower HDL-C levels may be associated with increased longitudinal changes in telomere length.

Conclusions

The change in telomere length is correlated with dyslipidemia and its lipid indicators especially HDL-C. Persistent dyslipidemia and a reduction in HDL-C levels may be associated with elevated longitudinal fluctuations in telomere length.
Exosomes from umbilical cord-derived mesenchymal stem cells combined with gelatin methacryloyl inhibit vein graft restenosis by enhancing endothelial functions
Authors: Deng Yuhang , Li Yiming , Chu Zhuyang , Dai Chun , Ge Jianjun
Published: October 2023

Background

The prevalence of coronary artery disease is increasing. As a common treatment method, coronary artery bypass transplantation surgery can improve heart problems while also causing corresponding complications. Venous graft restenosis is one of the most critical and intractable complications. Stem cell-derived exosomes could have therapeutic promise and value. However, as exosomes alone are prone to inactivation and easy removal, this therapeutic method has not been widely used in clinical practice. Methacrylated gelatin (GelMA) is a polymer with a loose porous structure that maintains the biological activity of the exosome and can control its slow release in vivo. In this study, we combined human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) and GelMA to explore their effects and underlying mechanisms in inhibiting venous graft restenosis.

Results

Human umbilical cord mesenchymal stem cells (hUCMSCs) were appraised using flow cytometry. hUCMSC-Exos were evaluated via transmission electron microscopy and western blotting. hUCMSC-Exos embedded in a photosensitive GelMA hydrogel (GelMA-Exos) were applied topically around venous grafts in a rat model of cervical arteriovenous transplantation, and their effects on graft reendothelialization and restenosis were evaluated through ultrasonic, histological, and immunofluorescence examinations. Additionally, we analyzed the material properties, cellular reactions, and biocompatibility of the hydrogels. We further demonstrated that the topical application of GelMA-Exos could accelerate reendothelialization after autologous vein transplantation and reduce restenosis in the rat model. Notably, GelMA-Exos caused neither damage to major organs in mice nor excessive immune rejection. The uptake of GelMA-Exos by endothelial cells stimulated cell proliferation and migration in vitro. A bioinformatic analysis of existing databases revealed that various cell proliferation and apoptosis pathways, including the mammalian target of rapamycin (mTOR)–phosphoinositide 3-kinase (PI3K)–AKT signaling pathways, might participate in the underlying regulatory mechanism.

Conclusions

Compared with the tail vein injection of hUCMSC-Exos, the local application of a mixture of hUCMSC-Exos and GelMA was more effective in promoting endothelial repair of the vein graft and inhibiting restenosis. Therefore, the proposed biomaterial-based therapeutic approach is a promising treatment for venous graft restenosis.
NF-κB signaling in neoplastic transition from epithelial to mesenchymal phenotype
Authors: Oh Amy , Pardo Makayla , Rodriguez Anaelena , Yu Connie , Nguyen Lisa , Liang Olin , Chorzalska Anna , Dubielecka Patrycja M.
Published: October 2023

NF-κB transcription factors are critical regulators of innate and adaptive immunity and major mediators of inflammatory signaling. The NF-κB signaling is dysregulated in a significant number of cancers and drives malignant transformation through maintenance of constitutive pro-survival signaling and downregulation of apoptosis. Overactive NF-κB signaling results in overexpression of pro-inflammatory cytokines, chemokines and/or growth factors leading to accumulation of proliferative signals together with activation of innate and select adaptive immune cells. This state of chronic inflammation is now thought to be linked to induction of malignant transformation, angiogenesis, metastasis, subversion of adaptive immunity, and therapy resistance. Moreover, accumulating evidence indicates the involvement of NF-κB signaling in induction and maintenance of invasive phenotypes linked to epithelial to mesenchymal transition (EMT) and metastasis. In this review we summarize reported links of NF-κB signaling to sequential steps of transition from epithelial to mesenchymal phenotypes. Understanding the involvement of NF-κB in EMT regulation may contribute to formulating optimized therapeutic strategies in cancer.