bluuebunny/crossref_metadata_2025 huggingface dataset:
From Mentee to Leader—Thoughts From an Immigrant
Authors: Gyamfi-Bannerman Cynthia
Published: April 2024

The editors’ request to reflect on one’s career is a daunting one. There is an inherent implication that some pivotal point has been achieved, and usually, it’s the point of retirement. There is also an assumption that the author can be impartial, though some writers will be laudatory and others excessively critical. I tend to fall in the latter group, and I firmly believe that it stems from my experience as an immigrant. What follows will be my thoughts about my experiences as a mentee and eventual mentor framed in the context of my upbringing.
Long-Term Trends in Decisional Regret Among Men with Localized Prostate Cancer
Authors: Spellman Alexandria Alverdy , Golla Vishnukamal , Lin Li , Katz Aaron , Chen Ronald C. , Zullig Leah L.
Published: April 2024

Purpose:

There are several evidence-based treatment options for localized prostate cancer (PCa). Decisional regret (DR), or regret based on the treatment a patient chooses, is poorly understood in patients with PCa. We describe long-term trends in DR for patients with localized PCa and factors associated with regret.

Materials and Methods:

We surveyed an established prospective cohort of patients with PCa in North Carolina who were diagnosed between 2011 and 2013. DR was assessed by a validated instrument at 12, 24, 36, 48, 60, 72, 84, and 120 months after treatment or active surveillance (AS). We estimated the overall trend of DR and examined how DR was associated with treatment and demographic data using generalized linear mixed-model regressions.

Results:

The sample included 1456 men. At 12 months, 88% (n = 1100) of patients did not regret their treatment. With all time points included, DR increased slightly in early months and the speed of increase slowed over time (P = .003 for time, .02 for time-squared). Divorced men were more likely to have DR compared with married men (odds ratio [OR] = 1.5; 95% confidence interval [CI] 0.9-2.7). African Americans (OR = 1.5; 95% CI 1.0-2.1) and those who underwent surgery had significantly more regret (14.6%; 95% CI 11.3-18.0, P = .01) than patients of other racial groups or who underwent AS, respectively.

Conclusions:

Although DR is low overall in this cohort, being married and AS were associated with lower regret than those who were not married or who underwent surgery, respectively. Understanding factors that affect DR can guide urologists to more effectively direct resources and counseling.
Innovative Percutaneous 3-Stitch Suture Technique for Site Closure in Venoarterial Extracorporeal Membrane Oxygenation Decannulation Without Direct Artery Repair: A Case Series
Authors: Peng Kaiyi , Hu Linhui , Huang Xiangwei , He Yuemei , Wu Xinxin , Li Huihua , Zhang Wentao , Zhu Hengling , Wang Zheng , Chen Chunbo
Published: April 2024

No previous studies have reported the use of a percutaneous suture technique performed by bedside intensivists for site closure during decannulation without direct artery repair in venoarterial extracorporeal membrane oxygenation (VA-ECMO) cases. Thus, the objective of this study was to evaluate the safety and effectiveness of this alternative approach. This retrospective study included 26 consecutive patients who underwent percutaneous VA-ECMO decannulation at Maoming People’s Hospital. Bedside percutaneous suture technique performed by intensivists facilitated cannula site closure. Primary outcome was successful closure without additional interventions. Secondary outcomes included procedural time, surgical conversion rate, complications (bleeding, vascular/wound complications, neuropathy, lymphocele), procedure-related death. Follow-up ultrasound were conducted within 6 months after discharge. All patients achieved successful site hemostasis with a median procedural time of 28 minutes. Procedure-related complications included minor bleeding (7.7%), acute lower limb ischemia (15.4%), venous thrombus (11.5%), minor arterial stenosis (7.7%), wound infection (4.2%), delayed healing (15.4%), and wound secondary suturing (6.3%). No procedure-related deaths occurred. Follow-up vascular ultrasound revealed two cases (7.7%) of minor arterial stenosis. The perivascular suture technique may offer intensivists a safe and effective alternative method for access site closure without direct artery suture during ECMO decannulation.
The interaction between gut microbiome and bone health
Authors: Inchingolo Francesco , Inchingolo Angelo Michele , Piras Fabio , Ferrante Laura , Mancini Antonio , Palermo Andrea , Inchingolo Alessio Danilo , Dipalma Gianna
Published: April 2024

Purpose of review

This review critically examines interconnected health domains like gut microbiome, bone health, interleukins, chronic periodontitis, and coronavirus disease 2019 (COVID-19), offering insights into fundamental mechanisms and clinical implications, contributing significantly to healthcare and biomedical research.

Recent findings

This review explores the relationship between gut microbiome and bone health, a growing area of study. It provides insights into skeletal integrity and potential therapeutic avenues. The review also examines interleukins, chronic periodontitis, and COVID-19, highlighting the complexity of viral susceptibility and immune responses. It highlights the importance of understanding genetic predispositions and immune dynamics in the context of disease outcomes. The review emphasizes experimental evidence and therapeutic strategies, aligning with evidence-based medicine and personalized interventions. This approach offers actionable insights for healthcare practitioners and researchers, paving the way for targeted therapeutic approaches and improved patient outcomes.

The implications of these findings for clinical practice and research underscore the importance of a multidisciplinary approach to healthcare that considers the complex interactions between genetics, immune responses, oral health, and systemic diseases. By leveraging advances in biomedical research, clinicians can optimize patient care and improve health outcomes across diverse patient populations.
Metastasis-directed therapy in testicular cancer
Authors: Pandit Kshitij , Yuen Kit , Puri Dhruv , Yodkhunnatham Nuphat , Millard Frederick , Bagrodia Aditya
Published: April 2024

Purpose of review

This review highlights the importance of addressing testicular cancer metastasizing beyond the retroperitoneum, focusing on multidisciplinary approaches and advances in treatment.

Recent findings

Recent literature emphasizes on the evolving landscape of metastasis-directed therapy, including surgical interventions, chemotherapy regimens, and radiation therapy. The effectiveness of these treatments varies depending on the site of metastasis, with various approaches improving survival rates and quality of life for patients. We divide our review in an organ-specific manner and focus on chemotherapeutic, surgical, and radiation therapy approaches pertaining to each site of metastasis.

Our review suggests the pressing need for continued research to refine and personalize treatment strategies. These efforts are important for enhancing clinical practice, ultimately leading to better outcomes for patients with metastatic testicular cancer.
Associations Between Early-Life Adversity, Ambient Air Pollution, and Telomere Length in Children
Authors: de la Rosa Rosemarie , Le Austin , Holm Stephanie , Ye Morgan , Bush Nicole R. , Hessler Danielle , Koita Kadiatou , Bucci Monica , Long Dayna , Thakur Neeta
Published: April 2024

Objective

Examine the independent associations and interaction between early-life adversity and residential ambient air pollution exposure on relative buccal telomere length (rBTL).

Methods

Experiences of abuse, neglect, household challenges, and related life events were identified in a cross-sectional sample of children aged 1 to 11 years (n = 197) using the 17-item Pediatric ACEs and Related Life Event Screener (PEARLS) tool. The PEARLS tool was analyzed both as a total score and across established domains (Maltreatment, Household Challenges, and Social Context). Ground-level fine particulate matter (PM2.5) concentrations were matched to residential locations for the 1 and 12 months before biospecimen collection. We used multivariable linear regression models to examine for independent associations between continuous PM2.5 exposure and PEARLS score/domains with rBTL. In addition, effect modification by PEARLS scores and domains on associations between PM2.5 exposure and rBTL was examined.

Results

Study participants were 47% girls, with mean (standard deviation) age of 5.9 (3.4) years, median reported PEARLS score of 2 (interquartile range [IQR], 4), median 12-month prior PM2.5 concentrations of 11.8 μg/m3 (IQR, 2.7 μg/m3), median 1-month prior PM2.5 concentrations of 10.9 μg/m3 (IQR, 5.8 μg/m3), and rBTL of 0.1 (IQR, 0.03). Mean 12-month prior PM2.5 exposure was inversely associated with rBTL (β = −0.02, 95% confidence interval = −0.04 to −0.01). Although reported PEARLS scores and domains were not independently associated with rBTL, we observed a greater decrement in rBTL with increment of average annual PM2.5 as reported Social Context domain items increased (p-interaction < .05).

Conclusions

Our results suggest that adverse Social Context factors may accelerate the association between chronic PM2.5 exposure on telomere shortening during childhood.
Normal Brain and Brain Tumor ADC
Authors: Johansson Jens , Lagerstrand Kerstin , Björkman-Burtscher Isabella M. , Laesser Mats , Hebelka Hanna , Maier Stephan E.
Published: April 2024

Objectives

Increasing gradient performance on modern magnetic resonance imaging scanners has profoundly reduced the attainable diffusion and echo times for clinically available pulsed-gradient spin echo (PGSE) sequences. This study investigated how this may impact the measured apparent diffusion coefficient (ADC), which is considered an important diagnostic marker for differentiation between normal and abnormal brain tissue and for therapeutic follow-up.

Materials and Methods

Diffusion time and echo time dependence of the ADC were evaluated on a high-performance 3 T magnetic resonance imaging scanner. Diffusion PGSE brain scans were performed in 10 healthy volunteers and in 10 brain tumor patients using diffusion times of 16, 40, and 70 ms, echo times of 60, 75, and 104 ms at 3 b-values (0, 100, and 1000 s/mm2), and a maximum gradient amplitude of 68 mT/m. A low gradient performance system was also emulated by reducing the diffusion encoding gradient amplitude to 19 mT/m. In healthy subjects, the ADC was measured in 6 deep gray matter regions and in 6 white matter regions. In patients, the ADC was measured in the solid part of the tumor.

Results

With increasing diffusion time, a small but significant ADC increase of up to 2.5% was observed for 6 aggregate deep gray matter structures. With increasing echo time or reduced gradient performance, a small but significant ADC decrease of up to 2.6% was observed for 6 aggregate white matter structures. In tumors, diffusion time–related ADC changes were inconsistent without clear trend. For tumors with diffusivity above 1.0 μm2/ms, with prolonged echo time, there was a pronounced ADC increase of up to 12%. Meanwhile, for tumors with diffusivity at or below 1.0 μm2/ms, no change or a reduction was observed. Similar results were observed for gradient performance reduction, with an increase of up to 21%. The coefficient of variation determined in repeat experiments was 2.4%.

Conclusions

For PGSE and the explored parameter range, normal tissue ADC changes seem negligible. Meanwhile, observed tumor ADC changes can be relevant if ADC is used as a quantitative biomarker and not merely assessed by visual inspection. This highlights the importance of reporting all pertinent timing parameters in ADC studies and of considering these effects when building scan protocols for use in multicenter investigations.
Hypoperfusion in Alzheimer’s Disease–Prone Regions and Dementia Conversion in Parkinson’s Disease
Authors: Chun Min Young , Lee Taein , Kim Su Hong , Lee Hye Sun , Kim Yun Joong , Lee Phil Hyu , Sohn Young H. , Jeong Yong , Chung Seok Jong
Published: April 2024

Purpose of the Report

Although early detection of individuals at risk of dementia conversion is important in patients with Parkinson’s disease (PD), there is still no consensus on neuroimaging biomarkers for predicting future cognitive decline. We aimed to investigate whether cerebral perfusion patterns on early-phase 18F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) PET have the potential to serve as a neuroimaging predictor for early dementia conversion in patients with PD.

Materials and Methods

In this retrospective analysis, we enrolled 187 patients with newly diagnosed PD who underwent dual-phase 18F-FP-CIT PET at initial assessment and serial cognitive assessments during the follow-up period (>5 years). Patients with PD were classified into 2 groups: the PD with dementia (PDD)-high-risk (PDD-H; n = 47) and the PDD-low-risk (PDD-L; n = 140) groups according to dementia conversion within 5 years of PD diagnosis. We explored between-group differences in the regional uptake in the early-phase 18F-FP-CIT PET images. We additionally performed a linear discriminant analysis to develop a prediction model for early PDD conversion.

Results

The PDD-H group exhibited hypoperfusion in Alzheimer’s disease (AD)-prone regions (inferomedial temporal and posterior cingulate cortices, and insula) compared with the PDD-L group. A prediction model using regional uptake in the right entorhinal cortex, left amygdala, and left isthmus cingulate cortex could optimally distinguish the PDD-H group from the PDD-L group.

Conclusions

Regional hypoperfusion in the AD-prone regions on early-phase 18F-FP-CIT PET can be a useful biomarker for predicting early dementia conversion in patients with PD.
How to Safely Use the Perforator-based Keystone Island Flap in the Scalp: Basal Cell Carcinoma of the Scalp With Local Invasion to Calvarium
Authors: Park Tae Hwan , Lee Ju Hyung , Kim Jae Hyung
Published: April 2024

Scalp reconstruction has always been a challenging problem for even the most experienced surgeon to provide good aesthetic and functional results. This is mainly because the scalp is less mobile and tight, requiring a much larger dissection for the size of the original defect. We hypothesized that the omega variant perforator-based keystone island flap at the subgaleal plane provides a versatile and easily reproducible reconstructive option for scalp reconstruction after wide skin cancer excision. We reviewed all patients who underwent reconstruction with the keystone flap or its modification to repair scalp defects following wide resection of skin cancer in the scalp abutting calvarium from May 2021 to July 2023. We designed the flap width 50% wider than original keystone flap design first introduced by Dr. Behan. We reconstructed medium- to large-sized scalp defects ranging from 2×2 to 5×5 cm2 using an omega variant perforator-based keystone island flap. All patients were satisfied with the aesthetic outcomes without complications. Keystone flaps are a versatile option for reconstructing the scalp after cancer resection. This strategy obviates the need for skin grafting, myocutaneous flap or free flap after cancer removal in the scalp.
Intrinsic Factors and Psychological Safety Among Nursing Students During Simulation-Based Learning—A Correlational Design
Authors: Sessions Laura C. , Kim Hee Jun , Brewer Katherine C. , El-Banna Majeda M. , Farina Crystel L.
Published: April 2024

Introduction

Well-designed simulation-based learning (SBL) experiences enhance students' self-confidence, self-efficacy, clinical judgment, and psychomotor skill development. An emerging concept in SBL research is psychological safety. There is currently no research on factors influencing psychological safety specifically related to the SBL environment, nor is there any literature found to determine whether intrinsic student characteristic, such as self-compassion and resilience, contributes to SBL learning outcomes. The aim of this study is to determine whether there is a relationship between nursing students' intrinsic characteristics (self-compassion, resilience, and anxiety sensitivity) and their psychological safety.

Methods

Bivariate correlation was used to examine associations among sociodemographic variables and outcome variables. Multiple regression was used to determine the predictive nature of the sociodemographic variables. Assumptions for variables in multiple regression models were tested (normal distribution, heteroscedasticity, multicollinearity). All data were analyzed in SPSS, Version 28. The P value of significance was set at 0.05 for all analyses.

Results

Most of the 118 participants were non-Hispanic (89%), White (65%), and females (95%). Results of the demographic bivariate analysis revealed no significant differences among this diverse group or semester in the curriculum for psychological safety. The multiple regression found self-compassion (β = 29, P = 0.004), anxiety sensitivity (β = −0.16, P = 0.049), and resilience (β = 0.26, P = 0.004) predict psychological safety.

Conclusions

The importance of creating a psychologically safe learning environment has been recognized as essential to best practices. Our findings suggest that an understanding of student characteristics that impact their perception of psychological safety will allow educators to develop strategies to better support learners in the simulation environment.
Investigation and validation of the TEG6s during rotary wing aeromedical flight
Authors: Bardes James , Grabo Daniel , Shmookler Aaron , Wen Sijin , Wilson Alison
Published: April 2024

INTRODUCTION

To improve rural and austere trauma care, hospital-based testing performed at the point of injury may shorten the time lapsed from injury to intervention. This study aimed to evaluate the use of the TEG6s device (Haemonetics(R), Clinton, PA) in a rotary wing aircraft. Prior attempts suffered from limitation related to lack of vibration mitigation.

METHODS

This was an investigator-initiated, industry-supported study. Haemonetics provided a TEG6s analyzer. The device underwent a standard validation. It was secured in place on the aircraft using shipping foam for vibration mitigation. Donors provided two tubes of sample blood in one sitting. Paired studies were performed on the aircraft during level flight and in the hospital, using the Global Hemostasis with Lysis Cartridge(Haemonetics (R), Clinton, PA). Both normal and presumed pathologic samples were tested in separate phases. Paired t tests were performed.

RESULTS

For normal donors, the mean R for laboratory compared with the aircraft was 6.2 minutes versus 7.2 minutes (p = 0.025). The mean ± SD Citrated Rapid TEG Maximum Amplitude (CRT MA) was 59.3 ± 5.6 mm and 55.9 ± 7.3 mm (p < 0.001) for laboratory and aircraft (p < 0.001). Among normal donors, R was within normal range for 17 of 18 laboratory tests and 18 of 18 aircraft tests (p > 0.99). During the testing of pathologic samples, the mean R time was 14.8 minutes for laboratory samples and 12.6 minutes for aircraft (p = 0.02). Aircraft samples were classified as abnormal in 78% of samples; this was not significantly different than laboratory samples (p = 0.5).

CONCLUSION

The use of the TEG6s for inflight viscoelastic testing appears promising. While statistically significant differences are seen in some results, these values are not considered clinically significant. Classifying samples as normal or abnormal demonstrated a higher correlation. Future studies should focus on longer flight times to evaluate for LY30, takeoff, and landing effects. Overall, this study suggests that TEG6s can be used in a prehospital environment, and further study is warranted.

LEVEL OF EVIDENCE

Diagnostic Tests or Criteria; Level III.
The Dual-specificity Phosphatase 3 (DUSP3): A Potential Target Against Renal Ischemia/Reperfusion Injury
Authors: Khbouz Badr , Musumeci Lucia , Grahammer Florian , Jouret François
Published: April 2024

Renal ischemia/reperfusion (I/R) injury is a common clinical challenge faced by clinicians in kidney transplantation. I/R is the leading cause of acute kidney injury, and it occurs when blood flow to the kidney is interrupted and subsequently restored. I/R impairs renal function in both short and long terms. Renal ischemic preconditioning refers to all maneuvers intended to prevent or attenuate ischemic damage. In this context, the present review focuses on the dual-specificity phosphatase 3 (DUSP3), also known as vaccinia H1-related phosphatase, an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 has different biological functions: (1) it acts as a tumor modulator and (2) it is involved in the regulation of immune response, thrombosis, hemostasis, angiogenesis, and genomic stability. These functions occur either through MAPK-dependent or MAPK-independent mechanisms. DUSP3 genetic deletion dampens kidney damage and inflammation caused by I/R in mice, suggesting DUSP3 as a potential target for preventing renal I/R injury. Here, we discuss the putative role of DUSP3 in ischemic preconditioning and the potential mechanisms of such an attenuated inflammatory response via improved kidney perfusion and adequate innate immune response.
ELISA for leptospiral 3-hydroxyacyl-CoA dehydrogenase in urine is a promising screening tool for acute leptospirosis
Authors: Karunadasa A.K.U.I. , Toma C. , Senaratne P. , Kumara K.G.R.A. , Herath T.M. , Pathirage M.M.K. , Gamage C.D.
Published: April 2024

Introduction: Leptospirosis is a zoonotic disease that is prevalent worldwide. The leptospiral 3-hydroxyacyl-CoA dehydrogenase (3-HADH) is excreted in the urine of infected individuals. However, the potential use of 3-HADH as a biomarker for the diagnosis of leptospirosis using enzyme-linked immunosorbent assay (ELISA) has not been investigated. A technique that identifies Leptospira in a patient in urine sample will be valuable in regular diagnostics and epidemic scenarios, as opposed to existing serological approaches. This study aimed to develop and evaluate an ELISA that can detect 3-HADH in the urine of patients with confirmed acute leptospirosis and to assess its potential as a screening test for leptospirosis.
Methods: Laboratory confirmation of acute leptospirosis was done by flaB-nested polymerase chain reaction (PCR) of plasma samples from suspected patients. ELISA-based determination of the presence of 3-HADH in the urine of PCR-positive patients versus PCR-negative patients matched for fever date was performed by coating ELISA plates with urine supernatants and using rabbit anti-3-HADH as the primary antibody. Receiver operating characteristic curve analysis was used to determine the cutoff values for the ELISA. The diagnostic measures between the PCR-positive and PCR-negative patients were compared using the Mann-Whitney U test.
Results: In total 158 febrile patients were assessed, of whom 121 (76.6%) were male. Of the 15 flaB-nested PCR-positive patients, 12 were in the acute phase of the febrile illness. The best cutoff was an average optical density (ODav) value of 0.2200 for febrile patients. Sensitivity and specificity were 83.33% (95% confidence interval [CI], 51.59–97.91%) and 83.33% (95% CI, 76.05–89.13%), respectively. The ODav values for PCR-positive patients in the acute phase of the disease (≤7 days of fever) were significantly higher than those for PCR-negative patients (p<0.001, U=114.0, z= -4.946).
Conclusion: Detection of 3-HADH in urine by ELISA appears promising for the screening of acute leptospirosis in suspected patients.
Interneuron diversity and normalization specificity in a visual system
Authors: Seung H. Sebastian
Published: April 2024

Normalization is a fundamental operation in image processing. Convolutional nets have evolved to include a large number of normalizations (Ioffe and Szegedy 2015; Ulyanov, Vedaldi, and Lempitsky 2016; Wu and He 2018), and this architectural shift has proved essential for robust computer vision (He et al. 2015; Bjorck et al. 2018; Santurkar, Tsipras, and Ilyas 2018). Studies of biological vision, in contrast, have invoked just one or a few normalizations to model psychophysical (Mach 1868; Furman 1965; Sperling 1970) and physiological (Carandini and Heeger 2011; Shin and Adesnik 2024) observations that have accumulated for over a century. Here connectomic information (Matsliah et al. 2023) is used to argue that interneurons of the fly visual system support a large number of normalizations with unprecedented specificity. Ten interneuron types in the distal medulla (Dm) of the fly optic lobe, for example, appear to support chiefly spatial normalizations, each of which is specific to a single cell type and length scale. Another Dm type supports normalization over features as well as space. Two outlier types do not appear to support normalization at all. Interneuron types likely to be normalizers are identified not only in Dm but also in all other interneuron families of the optic lobe. For fly vision, the diversity of interneurons appears to be an inevitable consequence of the specificity of normalizations.
Morphometrical asymmetries and tractography of speech-relevant cortex in relation to language lateralisation and rapid temporal processing
Authors: Bourke Jesse D , Cooper Gavin , Forstmann Birte U , Schall Ulrich , Todd Juanita
Published: April 2024

Differences in the functional roles of the left and right cortices for speech-related processes have been known since the findings of Broca [1] and Wernicke [2]. Nearly 100 years later anatomical asymmetries of speech-related cortex was emphasised as a potential substrate to such functional lateralisations [3]. Exploration of associations of anatomical asymmetries and functional lateralisations in speech has since continued, with developing technologies and theoretical insights mutually affording increasingly refined understandings. The present study is another such continuance; we outline and report associations of neuroanatomical (morphometrical) and connective (diffusion tractography) measures of speech-related cortex with differences of participant speech lateralisation and rapid temporal acuity (a hypothesised general auditory ability that contributes to superior speech processing). Review and support of developments in methodological approaches to morphometry and tractography to are also provided. Overall, our study affirms complex and selectively overlapping relationships of anatomy and connectivity (especially in the planum temporale) with behavioural language lateralisation and the processing of rapid temporal acoustics. Implications, limitations, and recommendations are discussed.
Spatial heterogeneity of menstrual discriminatory practices against Nepalese women: a population-based study using the 2022 Demographic and Health Survey
Authors: Barini Geoffrey , Amima Sharon , Mulwa Damaris , Mogeni Polycarp
Published: April 2024

Background

Menstrual discrimination hinders progress toward Sustainable Development Goals including gender equality, health, education, and sanitation. Examining spatial heterogeneity of menstrual discriminatory practices presents an opportunity for targeted interventions. Our goal was to evaluate geographical disparities in menstrual restrictions among Nepalese women and assess their association with socio-economic and demographic factors.

Methodology

We utilized data from the 2022 Nepal Demographic and Health Survey, focusing on women aged 15 to 49 who had experienced a menstrual period in the last year. Our analysis explored the spatial patterns of menstrual restriction outcomes related to engagement in religious activities, household level restrictions, and the severe form of menstrual restrictions referred toChhaupadi. The standard Gaussian kernel density estimation was used to create continuous prevalence maps and the spatial scan statistic was used to detect local clusters. The association between the different forms of menstrual restriction and the socio-economic, and demographic factors were examined using the Poisson regression model with robust standard errors.

Findings

Overall, the prevalence of women who reported any form of menstrual restriction was 84.8% and was subject to geographical variations ranging from 79.0% in Bagmati to 95.6% in Sudurpashchim. Religious restrictions were the most prevalent (79.8%) followed by household level restrictions (39.5%) and thenChhaupadi(6.2%). Geographical variations were detected in all forms of menstrual restriction outcomes and were more prominent forChhaupadi. Individual level factors (age, sex, ethnicity/caste), household level factors (household wealth, age and sex of the household head) and regional factors (province) were significantly associated with at least one form of menstrual restriction outcome. Strikingly, women who reside in households led by female household heads were less likely to report experiencing household level restriction during menstruation (Adjusted prevalence ratio (aPR) =0.89 [95%CI: 0.84–0.94], p<0.001) whilst those residing in wealthy households were associated with lower likelihood of experiencingChhaupadi(aPR =0.26 [95%CI: 0.17-0.39] among the richest).

Interpretation

We observed geographical micro-variations in menstrual discriminatory practices in Nepal presenting an opportunity for targeted behavioral interventions. Women empowerment is a promising strategy in the fight against menstrual discrimination within the household. Therefore, community-based targeted interventions should be designed and tested to determine their utility againstChhaupadiin these settings.
Modeling relaxation experiments with a mechanistic model of gene expression
Authors: Estavoyer Maxime , Dufeu Marion , Ranson Grégoire , Lefort Sylvain , Voeltzel Thibault , Maguer-Satta Véronique , Gandrillon Olivier , Lepoutre Thomas
Published: April 2024

Background

In the present work, we aimed at modeling a relaxation experiment which consists in selecting a subfraction of a cell population and observing the speed at which the entire initial distribution for a given marker is reconstituted.

Methods

For this we first proposed a modification of a previously published mechanistic two-state model of gene expression to which we added a state-dependent proliferation term. This results in a system of two partial differential equations. Under the assumption of a linear proliferation rate, we could derive the asymptotic profile of the solutions of this model.

Results

In order to confront our model with experimental data, we generated a relaxation experiment of the CD34 antigen on the surface of TF1-BA cells, starting either from the highest or the lowest CD34 expression levels. We observed in both cases that after approximately 25 days the distribution of CD34 returns to its initial stationary state. Numerical simulations, based on parameter values estimated from the dataset, have shown that the model solutions closely align with the experimental data from the relaxation experiments.

Conclusion

Altogether our results strongly support the notion that cells should be seen and modeled as probabilistic dynamical systems.
PPARG in osteocytes controls cell bioenergetics and systemic energy metabolism independently of sclerostin levels in circulation
Authors: Baroi Sudipta , Czernik Piotr J. , Khan Mohd Parvez , Letson Joshua , Crowe Emily , Chougule Amit , Griffin Patrick R. , Rosen Clifford J. , Lecka-Czernik Beata
Published: April 2024

Objective

The skeleton is one of the largest organs in the body, wherein metabolism is integrated with systemic energy metabolism. However, the bioenergetic programming of osteocytes, the most abundant bone cells coordinating bone metabolism, is not well defined. Here, using a mouse model with partial penetration of an osteocyte-specific PPARG deletion, we demonstrate that PPARG controls osteocyte bioenergetics and their contribution to systemic energy metabolism independently of circulating sclerostin levels.

Methods

In vivoandin vitromodels of osteocyte-specific PPARG deletion, i.e.Dmp1CrePparγflflmale and female mice (γOTKO) and MLO-Y4 osteocyte-like cells with either siRNA-silenced or CRISPR/Cas9-editedPparγ. As applicable, the models were analyzed for levels of energy metabolism, glucose metabolism, and metabolic profile of extramedullary adipose tissue, as well as the osteocyte transcriptome, mitochondrial function, bioenergetics, insulin signaling, and oxidative stress.

Results

Circulating sclerostin levels of γOTKOmale and female mice were not different from control mice. Male γOTKOmice exhibited a high energy phenotype characterized by increased respiration, heat production, locomotion and food intake. This high energy phenotype in males did not correlate with “beiging” of peripheral adipose depots. However, both sexes showed a trend for reduced fat mass and apparent insulin resistance without changes in glucose tolerance, which correlated with decreased osteocytic responsiveness to insulin measured by AKT activation. The transcriptome of osteocytes isolated from γOTKOmales suggested profound changes in cellular metabolism, fuel transport and usage, mitochondria dysfunction, insulin signaling and increased oxidative stress. In MLO-Y4 osteocytes, PPARG deficiency correlated with highly active mitochondria, increased ATP production, shifts in fuel utilization, and accumulation of reactive oxygen species (ROS).

Conclusions

PPARG in male osteocytes acts as a molecular break on mitochondrial function, and protection against oxidative stress and ROS accumulation. It also regulates osteocyte insulin signaling and fuel usage to produce energy. These data provide insight into the connection between osteocyte bioenergetics and their sex-specific contribution to the balance of systemic energy metabolism. These findings support the concept that the skeleton controls systemic energy expenditureviaosteocyte metabolism.

Highlights

Osteocytes function as a body energostat via their bioenergetics

PPARG protein acts as a “molecular break” of osteocyte mitochondrial activity

PPARG deficiency activates TCA cycle, oxidative stress and ROS accumulation

PPARG controls osteocyte insulin signaling and fuel utilization
The fluctuation-dissipation theorem and the discovery of distinctive off-equilibrium signatures of brain states
Authors: Monti Juan Manuel , Perl Yonatan Sanz , Tagliazucchi Enzo , Kringelbach Morten , Deco Gustavo
Published: April 2024

The brain is able to sustain many different states as shown by the daily natural transitions between wakefulness and sleep. Yet, the underlying complex dynamics of these brain states are essentially in non-equilibrium. Here, we develop a thermodynamical formalism based on the off-equilibrium extension of the fluctuation-dissipation theorem (FDT) together with a whole-brain model. This allows us to investigate the non-equilibrium dynamics of different brain states and more specifically to apply this formalism to wakefulness and deep sleep brain states. We show that the off-equilibrium thermodynamical signatures of brain states are significantly different in terms of the overall level of differential and integral violation of FDT. Furthermore, the framework allows for a detailed understanding of how different brain regions and networks are contributing to the off-equilibrium signatures in different brain states. Overall, this framework shows great promise for characterising and differentiating any brain state in health and disease.
Spatial proteomics identifies a novel CRTC-dependent viral sensing pathway that stimulates production of Interleukin-11
Authors: Ravenhill Benjamin J. , Oliveira Marisa , Wood George , Di Ying , Davies Colin T.R. , Lu Yongxu , Antrobus Robin , Elliott Gill , Irigoyen Nerea , Hughes David J. , Lyons Paul , Chung Betty , Borner Georg H.H , Weekes Michael P.
Published: April 2024

Appropriate cellular recognition of viruses is essential for the generation of effective innate and adaptive antiviral immunity. Viral sensors and their signalling components thus provide a crucial first line of host defence. Many exhibit subcellular relocalisation upon activation, triggering expression of interferon and antiviral genes. To identify novel signalling factors we analysed protein relocalisation on a global scale during viral infection. CREB Regulated Transcription Coactivators-2 and 3 (CRTC2/3) exhibited early cytoplasmic-to-nuclear translocation upon a diversity of viral stimuli, in diverse cell types. This movement was depended on Mitochondrial Antiviral Signalling Protein (MAVS), cyclo-oxygenase proteins and protein kinase A. We identify a key effect of transcription stimulated by CRTC2/3 translocation as production of the pro-fibrogenic cytokine interleukin-11. This may be important clinically in viral infections associated with fibrosis, including SARS-CoV-2.
Metadichol® induced expression of the TLR family of receptors in PBMCs
Authors: Raghavan P.R.
Published: April 2024

Toll-like receptors (TLRs) are fundamental components of the innate immune system and function as the primary sensors of invading pathogens by recognizing prevalent microbial compounds. The expression of all ten transcription factors belonging to the TLR family (1–10), with the exception of TLR4, exhibited an inverted U-shaped reaction to metadichol, a nanoemulsion composed of long-chain alcohol, as determined by the Q-RT□PCR assay. The response pattern suggested that low, moderate, and high concentrations directly affect TLR expression. This may indicate a dual-phase or dose-dependent effect on the immune system regarding TLR regulation. Compounds targeting TLRs can stimulate or inhibit these receptors, thereby affecting the immune response. Adjusting immunological activation, crucial for therapeutic purposes in conditions such as inflammation, cancer, infection, allergies, and autoimmune diseases, requires an inverse U-shaped response. Currently, no single-molecule examples can elicit the activation of every Toll-like receptor (TLR). This study examined the expression levels of all ten Toll-like receptors (TLRs), MYD88, and the downstream genes IRAK4, TRAF3, and TRIF. Metadichol expresses all the 15 genes.
The distribution ofApis laboriosarevisited: range extensions and biogeographic affinities
Authors: Otis Gard W. , Huang Man-Juan , Kitnya Nyaton , Sheikh Umer Ayyaz Aslam , Faiz Abu ul Hassan , Phung Chinh H. , Warrit Natapot , Peng Yan-Qiong , Zhou Xin , Oo Hliang Min , Acharya Namoona , Devkota Kedar
Published: April 2024

Apis laboriosa, the Himalayan giant honeybee, inhabits the foothills of the Himalaya and neighboring mountainous regions. Here we revise its distribution in light of recent reports and discoveries. The range now extends from longitude 105.9°E in Cao Bang, Vietnam, in the east to 74.4°E in the Pir Panjal Range of western Himalaya, a linear distance of 3300 km, with the most notable new localities in northeastern Vietnam, central Myanmar, northern Thailand, and AJK-Pakistan. The species generally occurs at lower elevations in the eastern part of its range than in Nepal, northern India, and the border region between India and Pakistan. Most but not all of the new localities are within the range predicted by species distribution modelling. We discuss the new localities that fall outside of the predicted range, the biotic characteristics of the terrestrial ecoregions in which the species occurs, and the remaining regions that may harbor this spectacular honey bee species.
Podocyte exopher-formation as a novel pathomechanism in membranous nephropathy
Authors: Lahme Karen , Sachs Wiebke , Froembling Sarah , Brehler Michael , Loreth Desiree , Surmann Kristin , Gaffling Simone , Wedekind Uta , Böttcher-Dierks Vincent , Adler Marie R. , Sáez Pablo J. , Conze Christian , Thünauer Roland , Skuza Sinah , Neitzel Karen , Zieliniski Stephanie , Brand Johannes , Bonn Stefan , Michalik Stephan , Völker Uwe , Zimmermann Marina , Wiech Thorsten , Meyer Tobias N. , Fester Lars , Meyer-Schwesinger Catherine
Published: April 2024

Background

Membranous nephropathy (MN) is caused by autoantibody binding to podocyte foot process antigens such as THSD7A and PLA2R1. The mechanisms of the glomerular antigen/autoantibody deposition and clearance are unknown.

Methods

We explore the origin and significance of glomerular accumulations in (1) diagnostic and follow-up biospecimens from THSD7A+and PLA2R1+-MN patients compared to nephrotic non-MN patients, and (2) in experimental models of THSD7A+-MN.

Results

We discovered podocyte exophers as correlates of histological antigen/autoantibody aggregates found in the glomerular urinary space of MN patients. Exopher vesicle formation represents a novel form of toxic protein aggregate removal inCaenorhabditis elegansneurons. In MN patients, podocytes released exophers to the urine. Enrichment of exophers from MN patient urines established them as a glomerular exit route for antigens and bound autoantibody. Exophers also carried disease-associated proteins such as complement and provided a molecular imprint of podocyte injury pathways. In experimental THSD7A+-MN, exophers were formed from podocyte processes and cell body. Their formation involved the translocation of antigen/autoantibody from the subepithelial to the urinary side of podocyte plasma membranes. Urinary exopher-release correlated with lower albuminuria and lower glomerular antigen/autoantibody burden. In MN patients the prospective monitoring of urinary exopher abundance and of exopher-bound autoantibodies was additive in the assessment of immunologic MN activity.

Conclusions

Exopher-formation and release is a novel pathomechanism in MN to remove antigen/autoantibody aggregates from the podocyte. Tracking exopher-release will add a non-invasive diagnostic tool with prognostic potential to clinical diagnostics and follow-up of MN patients.
12/15-Lipoxygenases mediate neuropathic-like pain hypersensitivity in female mice
Authors: Brown B , Chen I , Miliano C , Murdaugh LB , Dong Y , Eddinger KA , Yaksh TL , Burton MD , Buczynski MW , Gregus AM
Published: April 2024

It is estimated that chronic neuropathic pain conditions exhibit up to 10% prevalence in the general population, with increased incidence in females. However, nonsteroidal inflammatory drugs (NSAIDs) are ineffective, and currently indicated prescription treatments such as opioids, anticonvulsants, and antidepressants provide only limited therapeutic benefit. In the current work, we extended previous studies in male rats utilizing a paradigm of central Toll-like receptor 4 (TLR4)-dependent, NSAID-unresponsive neuropathic-like pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) LPS. In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and locomotor hyperactivity in response to IT LPS. Congruent with our previous observations in male rats, systemic inhibition of 12/15-Lipoxygenases (12/15-LOX) in female B6N mice with selective inhibitors – ML355 (targeting 12-LOX-p) and ML351 (targeting 15-LOX-1) – completely reversed allodynia and grip force deficits. We demonstrate here that 12/15-LOX enzymes also are expressed in mouse spinal cord and that 12/15-LOX metabolites produce tactile allodynia when administered spinally (IT) or peripherally (intraplantar in the paw, IPLT) in a hyperalgesic priming model, similar to others observations with the cyclooxygenase (COX) metabolite Prostaglandin E2(PGE2). Surprisingly, we did not detect hyperalgesic priming following IT administration of LPS, indicating that this phenomenon likely requires peripheral activation of nociceptors. Collectively, these data suggest that 12/15-LOX enzymes contribute to neuropathic-like pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and non-reflexive outcome measures.
Multiple Dynamic Modes of the Bcd Gradient are Explained by Quantum Mechanics
Authors: Lone Irfan , Trindle Carl O.
Published: April 2024

Extracellular diffusion coupled with degradation is considered as the dominant mechanism behind the establishment of morphogen gradients. However, the fundamental nature of these biophysical processes visa viz the Bicoid (Bcd) morphogen gradient remains unclear. Fluorescence correlation spectroscopy (FCS) has recently revealed multiple modes of Bcd transport at different spatial and temporal locations across the embryo. We here show that these observations, and a few others, are fitted by a model fundamentally based on quantum mechanics. We also indicate that the abstract and auxiliary feature called chirality of the said formalism finds a natural expression in our model of the Bcd gradient formation that might be verified in future experiments on the system.
A “tug-of-war” between the NuRD and SWI/SNF chromatin remodelers regulates the coordinated activation of Epithelial-Mesenchymal Transition and inflammation in oral cancer
Authors: Stabile Roberto , Tucci Francesco A. , Verhagen Mathijs P. , Embregts Carmen , van den Bosch Thierry P.P. , Joosten Rosalie , De Herdt Maria J. , van der Steen Berdine , Nigg Alex L. , Koljenović Senada , Hardillo Jose A. , Verrijzer C. Peter , Biddle Adrian , Baatenburg de Jong Robert J. , Leenen Pieter J.M. , Fodde Riccardo
Published: April 2024

Phenotypic plasticity and inflammation, two well-established hallmarks of cancer, play key roles in local invasion and distant metastasis by enabling rapid adaptation of tumor cells to dynamic micro- environmental changes. Here, we show that in oral squamous carcinoma cell carcinoma (OSCC), the competition between the NuRD and SWI/SNF chromatin remodeling complexes plays a pivotal role in regulating both epithelial-mesenchymal plasticity (EMP) and inflammation. By perturbing these complexes, we demonstrate their opposing downstream effects on inflammatory pathways and EMP regulation. In particular, downregulation of the BRG1-specific SWI/SNF complex deregulates key inflammatory genes such as TNF-α and IL6 in opposite ways when compared with loss of CDK2AP1, a key member of the NuRD complex. We show thatCDK2AP1genetic ablation triggers a pro-inflammatory secretome encompassing several chemo- and cytokines thus promoting the recruitment of monocytes into the tumor microenvironment (TME). Furthermore,CDK2AP1deletion stimulates their differentiation into M2-like macrophages, as also validated on tumor microarrays from OSCC patient- derived tumor samples. Further analysis of the inverse correlation between CDK2AP1 expression and TME immune infiltration revealed specific downstream effects on CD68+macrophage abundance and localization. Our study sheds light on the role of chromatin remodeling complexes in OSCC locoregional invasion and points at the potential of CDK2AP1 and other members of the NuRD and SWI/SNF chromatin remodeling complexes as prognostic markers and therapeutic targets.