bluuebunny/crossref_metadata_2025 huggingface dataset:
Complications of Aesthetic and Reconstructive Breast Implant Capsulectomy: An Analysis of 7486 Patients Using Nationwide Outcomes Data
Authors: Xu Hong Hao , Abi-Rafeh Jad , Davison Peter , Winocour Sebastian , Matros Evan , Vorstenbosch Joshua
Published: March 2024

Background

Despite increasing demand for breast capsular surgery to treat various benign and malignant implant-related pathologies, high-quality evidence elucidating complication profiles of capsulectomy and capsulotomy is lacking.

Objectives

The aim of this study was to provide the largest-scale analysis of associated outcomes and complications using the Tracking Operations and Outcomes for Plastic Surgeons (TOPS) database, and to investigate clinical scenarios that may subject patients to increased risks for complications, most notably extent of capsular surgery (complete vs partial) and index indication of implantation (aesthetic vs reconstructive).

Methods

An analysis of the TOPS database from 2008 to 2019 was performed. CPT codes were used to identify complete capsulectomy and partial capsulectomy/capsulotomy cases. Breast implant exchange procedures constituted procedural controls.

Results

In total, 7486 patients (10,703 breasts) undergoing capsulectomy or capsulotomy were assessed. Relative to controls, capsulectomy (4.40% vs 5.79%), but not capsulotomy (4.40% vs 4.50%), demonstrated higher overall complication rates. Both capsulectomies (0.83% vs 0.23%) and capsulotomies (0.56% vs 0.23%) also had greater rates of seroma relative to controls. Subgroup analyses demonstrated that reconstructive patients, relative to aesthetic patients, experienced greater overall complications (6.76% vs 4.34%), and increased risks for seroma (1.06% vs 0.47%), dehiscence (0.46% vs 0.14%), surgical site infections (1.03% vs 0.23%), and implant loss (0.52% vs 0.23%). A detailed synthesis of 30-day outcomes, including all patient- and breast-specific complications, for both capsulectomy and capsulotomy, stratified according to all potential confounders, is presented herein.

Conclusions

Surgeries on the breast capsule are safe overall, although complete capsulectomies and reconstructive patients are associated with significantly increased operative risks. The present findings will enhance patient selection, counseling, and informed consent.

Level of Evidence: 3
DDK-Linker: a network-based strategy identifies disease signals by linking high-throughput omics datasets to disease knowledge
Authors: Kong Xiangren , Diao Lihong , Jiang Peng , Nie Shiyan , Guo Shuzhen , Li Dong
Published: March 2024

The high-throughput genomic and proteomic scanning approaches allow investigators to measure the quantification of genome-wide genes (or gene products) for certain disease conditions, which plays an essential role in promoting the discovery of disease mechanisms. The high-throughput approaches often generate a large gene list of interest (GOIs), such as differentially expressed genes/proteins. However, researchers have to perform manual triage and validation to explore the most promising, biologically plausible linkages between the known disease genes and GOIs (disease signals) for further study. Here, to address this challenge, we proposed a network-based strategy DDK-Linker to facilitate the exploration of disease signals hidden in omics data by linking GOIs to disease knowns genes. Specifically, it reconstructed gene distances in the protein–protein interaction (PPI) network through six network methods (random walk with restart, Deepwalk, Node2Vec, LINE, HOPE, Laplacian) to discover disease signals in omics data that have shorter distances to disease genes. Furthermore, benefiting from the establishment of knowledge base we established, the abundant bioinformatics annotations were provided for each candidate disease signal. To assist in omics data interpretation and facilitate the usage, we have developed this strategy into an application that users can access through a website or download the R package. We believe DDK-Linker will accelerate the exploring of disease genes and drug targets in a variety of omics data, such as genomics, transcriptomics and proteomics data, and provide clues for complex disease mechanism and pharmacological research. DDK-Linker is freely accessible at http://ddklinker.ncpsb.org.cn/.
DEMO-EM2: assembling protein complex structures from cryo-EM maps through intertwined chain and domain fitting
Authors: Zhang Ziying , Cai Yaxian , Zhang Biao , Zheng Wei , Freddolino Lydia , Zhang Guijun , Zhou Xiaogen
Published: March 2024

The breakthrough in cryo-electron microscopy (cryo-EM) technology has led to an increasing number of density maps of biological macromolecules. However, constructing accurate protein complex atomic structures from cryo-EM maps remains a challenge. In this study, we extend our previously developed DEMO-EM to present DEMO-EM2, an automated method for constructing protein complex models from cryo-EM maps through an iterative assembly procedure intertwining chain- and domain-level matching and fitting for predicted chain models. The method was carefully evaluated on 27 cryo-electron tomography (cryo-ET) maps and 16 single-particle EM maps, where DEMO-EM2 models achieved an average TM-score of 0.92, outperforming those of state-of-the-art methods. The results demonstrate an efficient method that enables the rapid and reliable solution of challenging cryo-EM structure modeling problems.
Integrating physics in deep learning algorithms: a force field as a PyTorch module
Authors: Orlando Gabriele , Serrano Luis , Schymkowitz Joost , Rousseau Frederic
Published: March 2024

Motivation

Deep learning algorithms applied to structural biology often struggle to converge to meaningful solutions when limited data is available, since they are required to learn complex physical rules from examples. State-of-the-art force-fields, however, cannot interface with deep learning algorithms due to their implementation.

Results

We present MadraX, a forcefield implemented as a differentiable PyTorch module, able to interact with deep learning algorithms in an end-to-end fashion.

Availability and implementation

MadraX documentation, together with tutorials and installation guide, is available at madrax.readthedocs.io.
An independent origin of an annual life cycle in a North American killifish species
Authors: Domínguez-Castanedo Omar , Thompson Andrew W , Meredith Robert W , Furness Andrew I
Published: March 2024

An annual life cycle is characterized by short-lived adults that exploit seasonally productive but temporary habitats, paired with a hardy embryo stage that survives unfavourable environmental conditions, such as winter or the dry season. This life cycle is rare amongst vertebrates but has evolved independently several times in African and South American killifishes adapted to life in seasonally ephemeral aquatic pools. A single species of North American annual killifish, with a limited geographical distribution in Mexico, also exhibits this seasonal life cycle. This enigmatic species, Millerichthys robustus, is geographically separated from the nearest South American annual killifish species by >2000 km. Millerichthys robustus exhibits morphological features that have led to several competing phylogenetic hypotheses. To date, its phylogenetic relationships are unclear because no molecular data have been available. Here, we sequence the mitochondrial genome of Millerichthys robustus and generate a molecular phylogeny of killifishes that includes this species. Our results indicate that, rather than being most closely related to South American annual killifishes, this species is sister to two non-annual killifish species from Cuba (Rivulus cylindraceus and Rivulus berovidesi). Ancestral state reconstruction strongly supports an independent origin of an annual life cycle and embryonic diapause in Millerichthys robustus.
William Thompson and John Stuart Mill on co-operation and the rights of women
Authors: Prendergast Renee
Published: March 2024

William Thompson and, later, John Stuart Mill argued that women’s inferior position in society was a product of their environment and upbringing. As such, access to the franchise, and opportunities for education and employment would improve the welfare and position of women. Recognition of women’s reproductive roles led Thompson to argue that equality of outcome for women could not be achieved within the competitive framework and required a re-organisation of society into self-supporting co-operative communities in which women’s reproductive role would be valued and childcare and catering provided communally. While John Stuart Mill advocated access for women into all employments, he thought that a purely domestic role was consistent with women’s emancipation provided that role was freely chosen. Free choice was supported by better outside options but the bargaining power of women choosing the domestic route was not addressed by Mill. Mill supported co-operation but his favoured form involved co-operative ownership of firms operating within competitive markets. He believed that a society based on co-operation would foster favourable attitudes towards women’s emancipation and moral improvement more generally, but he saw no direct relationship between the development of co-operative enterprise and the status of women.
Brushing aside doubts: an evaluation of the beat-sheet brushing technique for detecting the Nearctic tree trunk sheetweaver (Araneae: Linyphiidae)
Authors: Forsythe Patrick S , Saxby Justice A , Fritsch Haillee R , Hoffmann Noah P , Ditzman Teona T , Suess Deakyn J , Radobicky Kelsey A , Schmitz Bennett A , Amasone Samantha D , Buchmann Charles K , Schultz Laken T , Clauer Addison L , Vista Allison S , Kienbaum April M , Ryan-Rabe Megan R , Monfils Brooklyn A M , Lara Bryan A , Draney Michael L
Published: March 2024

It is important to have reliable information on the presence/absence, population structure, and density of animals across their natural range. Detecting small organisms, however, such as the Nearctic tree trunk sheetweaver spider Drapetisca alteranda Chamberlin 1909 (Araneae: Linyphiidae), presents challenges due to its diminutive size and cryptic nature. We used a capture/recapture study to determine the detection and recapture probabilities of this spider using a standard beat sheet technique adopted for surveying tree trunks. Spiders were released on 3 different tree species that provided a range of microhabitats, including variable bark surface area and furrow depth/width. Microhabitat features played a small role in the timing of spider recapture (i.e., slower rate of recapture as furrowing increased). However, our results demonstrated 100% detection across replicate experiments and individual recapture probabilities exceeding 90% in most situations, with no significant differences in recapture observed among tree species and with respect to tree circumference. Furthermore, we show that most spiders could be recaptured within 2 sampling revolutions around the tree trunk, and there was no difference in the probability of collecting male and female spiders (although they differ markedly in size). Finally, we found no difference among brushers, supporting the idea that this method is replicable across collectors and studies. Collectively, we establish confidence in the ecological knowledge obtained with this technique and encourage its application with similar species and systems.
Top-Category Inflation in Ordered International Relations Outcomes
Authors: Bagozzi Benjamin E , Joo Minnie M , Mukherjee Bumba
Published: March 2024

Ordered dependent variables are widely employed in international relations (IR). These ordered dependent variables often suffer from inflated observations in their highest outcome category due to distinct processes. The application of standard ordered probit and ordered logit models to such ordinal measures will fail to capture these distinct processes, often producing biased inferences as a result. Yet IR researchers have thus far ignored the potential for top-category inflation in ordered outcome variables. We sensitize researchers to top-category inflation in ordered IR outcomes. We then intuitively extend the widely used zero-inflated ordered probit model to the top-category inflated setting, providing resources to facilitate the proper modeling of top-category inflation in ordered outcomes. Finally, we provide two applications to published IR research related to trade politics and political repression. Together, these applications illustrate the substantive and methodological potentials of our proposed tools for diagnosing and modeling top-category inflation in IR outcomes.
Characterization of the Pristionchus pacificus “epigenetic toolkit” reveals the evolutionary loss of the histone methyltransferase complex PRC2
Authors: Brown Audrey L , Meiborg Adriaan B , Franz-Wachtel Mirita , Macek Boris , Gordon Spencer , Rog Ofer , Weadick Cameron J , Werner Michael S
Published: March 2024

Comparative approaches have revealed both divergent and convergent paths to achieving shared developmental outcomes. Thus, only through assembling multiple case studies can we understand biological principles. Yet, despite appreciating the conservation—or lack thereof—of developmental networks, the conservation of epigenetic mechanisms regulating these networks is poorly understood. The nematode Pristionchus pacificus has emerged as a model system of plasticity and epigenetic regulation as it exhibits a bacterivorous or omnivorous morph depending on its environment. Here, we determined the “epigenetic toolkit” available to P. pacificus as a resource for future functional work on plasticity, and as a comparison with Caenorhabditis elegans to investigate the conservation of epigenetic mechanisms. Broadly, we observed a similar cast of genes with putative epigenetic function between C. elegans and P. pacificus. However, we also found striking differences. Most notably, the histone methyltransferase complex PRC2 appears to be missing in P. pacificus. We described the deletion/pseudogenization of the PRC2 genes mes-2 and mes-6 and concluded that both were lost in the last common ancestor of P. pacificus and a related species P. arcanus. Interestingly, we observed the enzymatic product of PRC2 (H3K27me3) by mass spectrometry and immunofluorescence, suggesting that a currently unknown methyltransferase has been co-opted for heterochromatin silencing. Altogether, we have provided an inventory of epigenetic genes in P. pacificus to compare with C. elegans. This inventory will enable reverse-genetic experiments related to plasticity and has revealed the first loss of PRC2 in a multicellular organism.
Expanding TheCellVision.org: a central repository for visualizing and mining high-content cell imaging projects
Authors: Masinas Myra Paz David , Litsios Athanasios , Razdaibiedina Anastasia , Usaj Matej , Boone Charles , Andrews Brenda J
Published: March 2024

We previously constructed TheCellVision.org, a central repository for visualizing and mining data from yeast high-content imaging projects. At its inception, TheCellVision.org housed two high-content screening (HCS) projects providing genome-scale protein abundance and localization information for the budding yeast Saccharomyces cerevisiae, as well as a comprehensive analysis of the morphology of its endocytic compartments upon systematic genetic perturbation of each yeast gene. Here, we report on the expansion of TheCellVision.org by the addition of two new HCS projects and the incorporation of new global functionalities. Specifically, TheCellVision.org now hosts images from the Cell Cycle Omics project, which describes genome-scale cell cycle-resolved dynamics in protein localization, protein concentration, gene expression, and translational efficiency in budding yeast. Moreover, it hosts PIFiA, a computational tool for image-based predictions of protein functional annotations. Across all its projects, TheCellVision.org now houses >800,000 microscopy images along with computational tools for exploring both the images and their associated datasets. Together with the newly added global functionalities, which include the ability to query genes in any of the hosted projects using either yeast or human gene names, TheCellVision.org provides an expanding resource for single-cell eukaryotic biology.
Exercise to Mitigate Cerebrovascular Aging: A Geroscience Perspective
Authors: Norling Amani M , Lipsitz Lewis A
Published: March 2024

Aging is characterized by a progressive loss of cellular functions that increase the risk of developing chronic diseases, vascular dysfunction, and neurodegenerative conditions. The field of geroscience has identified cellular and molecular hallmarks of aging that may serve as targets for future interventions to reduce the risk of age-related disease and disability. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Several studies show that exercise may favorably affect these processes and thereby have antiaging properties. The primary mechanisms through which exercise confers protective benefits in the brain are still incompletely understood. To better understand these effects and leverage them to help promote brain health, we present current findings supporting the notion that adaptive responses to exercise play a pivotal role in mitigating the hallmarks of aging and their effects on the aging cerebrovasculature, and ultimately contribute to the maintenance of brain function across the healthspan.
Quantifying the role of submesoscale Lagrangian transport features in the concentration of phytoplankton in a coastal system
Authors: Veatch Jacquelyn M , Kohut Josh T , Oliver Matthew J , Statscewich Hank , Fredj Erick
Published: March 2024

Food resources in the ocean are often found in low densities, and need to be concentrated for efficient consumption. This is done in part by oceanographic features transporting and locally concentrating plankton, creating a highly patchy resource. Lagrangian approaches applied to ocean dynamics can identify these transport features, linking Lagrangian transport and spatial ecology. However, little is known about how Lagrangian approaches perform in ageostrophic coastal flows. This study evaluates two Lagrangian Coherent Structure metrics against the distribution of phytoplankton; Finite Time Lyapunov Exponents (FTLE) and Relative Particle Density (RPD). FTLE and RPD are applied to High Frequency Radar (HFR) observed surface currents within a biological hotspot, Palmer Deep Canyon Antarctica. FTLE and RPD identify different transport patterns, with RPD mapping single particle trajectories and FTLE tracking relative motion of paired particles. Simultaneous measurements of circulation and phytoplankton were gathered through the integration of vessel and autonomous glider surveys within the HFR footprint. Results show FTLE better defined phytoplankton patches compared to RPD, with the strongest associations occurring in stratified conditions, suggesting that phytoplankton congregate along FTLE ridges in coastal flows. This quantified relationship between circulation and phytoplankton patches emphasizes the role of transport in the maintenance of coastal food webs.
(Political) political liberalism and the constitutional project
Authors: Kuo Ming-Sung
Published: March 2024

This review essay follows Alessandro Ferrara and Frank Michelman’s dialogic journey into the legitimation-by-constitution idea, which they submit as the institutional expression of political liberalism in Legitimation by Constitution: A Dialogue on Political Liberalism, to illustrate the challenges for contemporary philosophy of political liberalism in its transposition to the constitutional project. It argues that Ferrara and Michelman’s liberal endeavor to answer the fundamental questions surrounding political liberalism rests on a normative conception of identity, which eventually leads them to a dilemma: the project of constitutional democracy they defend and justify is sustained by a liberal ethos, while it is tasked to accommodate those who do not value the liberal form of life. Instead of choosing between the project of constitutional democracy and their liberal soul, Ferrara and Michelman eventually offer a thin constitutional account of political liberalism resembling the international legal order amidst the retrenchment of the liberal ethos. It contends that what liberal democracies need from political liberalism in battling antiliberal forces is not more political philosophy but rather something akin to what Jeremy Waldron calls “political political theory.” It is suggested that political liberalism take a political turn to confront antiliberal forces with an enriched rather than diluted constitutional project.
Metabolic syndrome burden, determinants and treatment status in an urban slum resettlement colony in Delhi, India
Authors: Rao Shivani , Basu Saurav , Nandi Kajal , Singh M M , Lalwani Heena , Maheshwari Vansh , Borle Amod , Sharma Nandini
Published: March 2024

Background

Metabolic syndrome (MetS) in low-resource settings contributes to accentuated risk of cardiovascular disease, including stroke. The study objective was to estimate the prevalence, determinants and treatment status of MetS in an urban slum resettlement population in Delhi, India.

Methods

This study was conducted from February to May 2023. Multiphase sampling was conducted with 1910 individuals screened for abdominal obesity (AO), with 996 detected as having AO, of which, 400 were selected by simple random sampling and further evaluated for triglycerides (TGs), high-density lipoprotein (HDL) and fasting glucose levels.

Results

Among the 400 participants detected as having AO, 211 had evidence of MetS (52.75% [95% confidence interval 47.83 to 57.62]). The most prevalent combination of MetS clustering was for all five components (AO, diabetes mellitus [DM], hypertension [HTN], low HDL and high TGs; 14.69%), followed by AO, DM and HTN (12.32%). On adjusted analysis, the odds of having MetS was found to be independently associated with increasing age (≥40 y) but not sex.

Conclusions

A high burden of MetS and suboptimal treatment status is prevalent in urban slum populations. Screening of individuals with AO, especially in those >40 y of age, can be an effective programmatic strategy for early diagnosis and management of MetS and its underlying components.
Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation
Authors: Fratoni Andrew J , Kois Abigail K , Gluck Jason A , Nicolau David P , Kuti Joseph L
Published: March 2024

Background

Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO.

Methods

Patients with infection supported on ECMO received 4–6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC–MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0–24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen.

Results

Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ± standard deviation parameters were: CL0, 15.21 ± 6.52 L/h; Vc, 10.13 ± 2.26 L; K12, 2.45 ± 1.16 h−1 and K21, 1.76 ± 0.49 h−1 for imipenem, and 6.95 ± 1.34 L/h, 9.81 ± 2.69 L, 2.43 ± 1.13 h−1 and 1.52 ± 0.67 h−1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L.

Conclusions

Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.
Experimental investigation of thawing behavior of saline soils using resistivity method
Authors: Chen Cihai , Yang Zhilong , Deng Yaping , Ma Haichun , Qian Jiazhong
Published: March 2024

Electrical resistivity method has been widely used to study permafrost and to monitor the process of freezing-thawing. However, a thorough understanding of the mechanism of electrical response during thawing is missing. In this study, we investigated the thawing behavior of saline soils in the temperature range from roughly −10 to 15°C considering the effects of soil type and salinity. A total of nine experiments were performed with three soil types (silica sand, sandy soil, and silt) and three salinities (0.01, 0.1, and 1 S m−1). The results show that resistivity variations with temperature can be divided into three stages. In Stage I, tortuosity and unfrozen water content play major roles in the decrease of resistivity. In Stage Ⅱ, which is an isothermal or near isothermal process, resistivity still decreases slightly due to the thawing of residual ice and pore water movement. In Stage III, ionic mobility plays an important impact on decreasing resistivity. In addition, the isothermal process is found to only occur in silica sand that can be explained by latent heat effect. Exponential and linear models linking temperature with resistivity are used to fit the experimental data in Stages I and III. The fitting parameter in different models shows great correlation with soil type and salinity. Furthermore, unfrozen water content below 0°C is also estimated and uncertainty of estimation is analyzed.
Endoplasmic reticulum stress drives macrophages to produce IL-33 to favor Th2 polarization in the airways
Authors: Xiao Yuan , Zhang Huangping , Liu Yu , Mo Lihua , Liao Yun , Huang Qinmiao , Yang Liteng , Zhou Caijie , Liu Jiangqi , Sun Xizhuo , Yu Haiqiong , Yang Pingchang
Published: March 2024

Interleukin (IL)-33 is a key driver of T helper 2 (Th2) cell polarization. Endoplasmic reticulum (ER) stress plays a role in the skewed T cell activation. The objective of this project is to elucidate the role of IL-33 derived from macrophages in inducing Th2 polarization in the airways. In this study, bronchoalveolar lavage fluids (BALF) were collected from patients with asthma and healthy control subjects. Macrophages were isolated from the BALF by flow cytometry cell sorting. An asthmatic mouse model was established using the ovalbumin/alum protocol. The results showed that increased IL33 gene activity and ER stress–related molecules in BALF-derived M2a macrophages was observed in asthmatic patients. Levels of IL33 gene activity in M2a cells were positively correlated with levels of asthma response in asthma patients. Sensitization exacerbated the ER stress in the airway macrophages, which increased the expression of IL-33 in macrophages of airway in sensitized mice. Conditional ablation of Il33 or Perk or Atf4 genes in macrophages prevented induction of airway allergy in mice. In conclusion, asthma airway macrophages express high levels of IL-33 and at high ER stress status. Inhibition of IL-33 or ER stress in macrophages can effectively alleviate experimental asthma.
Understanding health behaviors that modify the risk for obesity in ADHD
Authors: Roberts Delanie K , Sarver Dustin E , Cash Annah R , Walker Benjamin H , Lim Crystal S
Published: March 2024

Objective

Research provides support for the associated risk of inadequate sleep duration, limited physical activity, and excessive media use in attention-deficit/hyperactivity disorder (ADHD) and obesity. The present study aims to (1) examine the association between ADHD and overweight or obese status (OW/OB); (2) comprehensively examine sleep duration, physical activity, and media use as potential moderators of OW/OB; and (3) examine the moderating effects of these health behaviors cross-sectionally by comparing medicated youth with ADHD, unmedicated youth with ADHD, and youth without ADHD.

Methods

Data were acquired from the 2018 and 2019 National Survey of Children’s Health, a nationally representative survey of caregivers conducted across the United States. The current study used data for youth 11–17 years old with a final sample size of 26,644. Hours of sleep, physical activity, and media use per day were dichotomized based on national recommendation guidelines for each health behavior (i.e., either meeting or not meeting guidelines).

Results

The OW/OB prevalence rate was 7% greater among unmedicated youth with ADHD than among medicated youth with ADHD. Medicated youth with ADHD and peers without ADHD had similar OW/OB rates. Among medicated youth with ADHD, physical activity, sleep duration, and media use did not contribute to OW/OB risk after controlling for family poverty level. However, among unmedicated youth with ADHD, meeting sleep duration guidelines was linked to a lower OW/OB risk.

Conclusion

Overall, findings suggest that clinical providers and parents may wish to prioritize improved sleep duration in the management of OW/OB risk in youth with ADHD.
Integrating metabolomics and network pharmacology to assess the effects of Mahuang Xixin Fuzi decoction on migraine rats induced by nitroglycerin
Authors: Ge Fei , Zhang Yao , Luo Yamin , Wang Chunguo , Lu Yixing , Zhao Yafang , Zhang Di , Meng Fengxian , Zhang Dongmei , Chen Meng , Tao Xiaohua
Published: March 2024

Objectives

This study was designed to investigate the pharmacological activity and therapeutic mechanism of Mahuang Xixin Fuzi decoction (MXFD) on migraine.

Methods

Migraine model rats induced by nitroglycerin were established, and then orally administered with MXFD for 7 days. Blood and urine samples were collected to identify differential metabolites with metabolomics. To integrate the findings from network pharmacology and metabolomics analysis, the metabolites and targets related to MXFD therapy for migraine were filtered.

Key findings

MXFD was found to alleviate the symptoms of migraines in rats. After treatment with MXFD, nine metabolites were found to be regulated and returned to normal levels. MXFD acted directly on nine key targets including MAOB, MAOA, ADRB1, ADRB2, ADRB3, ADORA2A, ADORA2B, DRD5, and HTR4 and regulated two out of nine metabolites, namely deoxycholic acid and 5-methoxyindoleacetate.

Conclusions

The study found that MXFD can alleviate migraines through multitarget and multicomponent interaction networks.
Anticancer Drugs-Related Hypogonadism in Male Patients with Advanced Cancers on Active Treatment: A Systematic Review
Authors: Massa Giacomo , Zambelli Luca , Zecca Ernesto , Shkodra Morena , Tinè Gabriele , Caraceni Augusto
Published: March 2024

Background

In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy.

Methods

The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors.

Findings

Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies.

Conclusion

Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion.
Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins
Authors: Ma Ding , Xie An , Lv Jiahui , Min Xiaolin , Zhang Xinye , Zhou Qian , Gao Daxing , Wang Enyu , Gao Lei , Cheng Linzhao , Liu Senquan
Published: March 2024

Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely used strategy for cargo enrichment in EVs, which could compromise the stability and functionality of cargo. Herein, we report intracellular delivery via EV-based approach (IDEA) that efficiently packages and delivers native proteins both in vitro and in vivo without the use of a scaffold. As a proof-of-concept, we applied the IDEA to deliver cyclic GMP-AMP synthase (cGAS), an innate immune sensor. The results showed that cGAS-carrying EVs activated interferon signaling and elicited enhanced antitumor immunity in multiple syngeneic tumor models. Combining cGAS EVs with immune checkpoint inhibition further synergistically boosted antitumor efficacy in vivo. Mechanistically, scRNA-seq demonstrated that cGAS EVs mediated significant remodeling of intratumoral microenvironment, revealing a pivotal role of infiltrating neutrophils in the antitumor immune milieu. Collectively, IDEA, as a universal and facile strategy, can be applied to expand and advance the development of protein-based therapeutics.
Measuring the Size of the “Third Pillar”: A Global Dataset
Authors: Schiltz Fritz , MacKay Kelsey J , Vandekerckhove Philippe
Published: March 2024

Balancing the state and the market, the “third pillar” (i.e., any association of people that is neither public nor private) is a key sector in society. In contrast to the first two pillars (the public sector and the private sector), the third pillar has received very little attention in academic and policy debates. This paper aims to facilitate research on the third pillar's relevance by constructing the first global dataset on the size of the third pillar, including estimates for 120 countries. Results show that the size of the third pillar is substantial, both when measured as third pillar time (TPT) or third pillar participation (TPP). Global TPT is equivalent to 5.1 percent of total employment, more than half of the global agricultural sector. Moreover, findings indicate that TPP equals 13.4 percent, suggesting that more than one person in eight of the world's adult population is active as a volunteer in the third pillar.
Effectiveness of Lumbar Segmental Stabilization Exercises in Managing Disability and Pain Intensity Among Patients With Lumbar Spondylolysis and Spondylolisthesis
Authors: Lin Long-Huei , Lin Ting-Yu , Chang Ke-Vin , Wu Wei-Ting , Özçakar Levent
Published: March 2024

Study Design.

Systematic review and meta-analysis.

Objective.

This study aims to assess the effectiveness of lumbar segmental stabilization exercise (LSSE) in managing spondylolysis and spondylolisthesis.

Summary of Background Data.

Spondylolysis and spondylolisthesis are spinal disorders associated with lumbar segmental instability. LSSE has shown positive effects in treating these conditions; however, systematic reviews and meta-analyses are lacking.

Materials and Methods.

A systematic search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, including studies from the inception of the databases used up to January 2024, was conducted. Disability improvement and pain intensity change were the primary and secondary outcomes, respectively, standardized using Hedges g. Eligible articles underwent independent scrutiny by two authors, who also performed data extraction and quality assessment. Data pooling was accomplished using a random-effects model.

Results.

In total, five randomized controlled trials comprising 198 participants were included, revealing a trend effect toward disability improvement in the LSSE group (Hedges g=−0.598, 95% CI: −1.211 to 0.016, P=0.056, I
2=75.447%). When the LSSE was administered as a single treatment, disability improvement became significant (Hedge g=−1.325, 95% CI: −2.598 to −0.053, P=0.041, I
2=80.020%). No significant effect of LSSE on pain reduction was observed (Hedges g=−0.496, 95% CI: −1.082 to 0.090, P=0.097, I
2=73.935%).

Conclusions.

In summary, our meta-analysis suggests that LSSE can potentially improve disability, especially when used as a single treatment. LSSE appears more beneficial in reducing disability than alleviating pain. Future research on different patient groups is needed to understand comprehensively LSSE’s effects on other musculoskeletal disorders.
Fezolinetant treatment of moderate-to-severe vasomotor symptoms due to menopause: effect of intrinsic and extrinsic factors in two phase 3 studies (SKYLIGHT 1 and 2)
Authors: Santoro Nanette , Nappi Rossella E. , Neal-Perry Genevieve , English Marci , King Deanna D. , Yamaguchi Yusuke , Ottery Faith D.
Published: March 2024

Objective

This study aimed to assess the efficacy of the neurokinin 3 receptor antagonist, fezolinetant, according to several intrinsic (individual related) and extrinsic (external influence) factors that may influence the frequency and severity of moderate-to-severe vasomotor symptoms (VMS) using pooled 12-week data from SKYLIGHT 1 and 2.

Methods

SKYLIGHT 1 and 2 were two phase 3, randomized, double-blind studies conducted from July 2019 to August 2021 (SKYLIGHT 1) or April 2021 (SKYLIGHT 2). Participants were initially randomized to receive daily doses of placebo, fezolinetant 30 mg, or fezolinetant 45 mg. After 12 weeks, placebo participants were rerandomized to receive fezolinetant 30 mg or 45 mg, whereas those receiving fezolinetant continued on the same dose. Change in VMS frequency from baseline to week 12 was used to assess efficacy according to several intrinsic and extrinsic factors. Overall efficacy and safety were also investigated.

Results

Overall, 1,022 individuals were included. Fezolinetant was efficacious in reducing VMS frequency across all intrinsic and extrinsic factors. Efficacy was most notable for participants who self-identify as Black (least squares mean difference for fezolinetant 45 mg versus placebo, −3.67; 95% CI, −5.32 to −2.01), current smokers (−3.48; −5.19 to −1.77), and current alcohol users (−3.48; −4.42 to −2.54). Overall efficacy was −2.51 (95% CI, −3.20 to −1.82) for fezolinetant 45 mg versus placebo. Similar findings were observed for the fezolinetant 30 mg dose. Comparable incidences of treatment-emergent adverse events were observed for placebo (132 of 342 individuals [38.6%]), fezolinetant 30 mg (132 of 340 individuals [38.8%]), and fezolinetant 45 mg (135 of 340 individuals [39.7%]).

Conclusions

None of the intrinsic and extrinsic factors analyzed substantially reduced the efficacy response to fezolinetant in SKYLIGHT 1 and 2. These data provide additional confidence for using fezolinetant in a diverse population of individuals with VMS.
Velacur ACE outperforms FibroScan CAP for diagnosis of MASLD
Authors: Loomba Rohit , Ramji Alnoor , Hassanein Tarek , Yoshida Eric M. , Pang Emily , Schneider Caitlin , Curry Michael P. , Afdhal Nezam H.
Published: March 2024

Background:

As the prevalence of metabolic dysfunction-associated steatotic liver disease increases, it is imperative to have noninvasive alternatives to liver biopsy. Velacur offers a non-invasive, point-of-care ultrasound-based method for the assessment of liver stiffness and attenuation. The aim of this study was to perform a head-to-head comparison of liver stiffness and liver fat determined by Velacur and FibroScan using MRI-based measurements as the reference standard.

Methods:

This prospective cross-sectional study included 164 adult participants with well-characterized metabolic dysfunction-associated steatotic liver disease. Patients underwent a research exam including Velacur, FibroScan and contemporaneous magnetic resonance elastography, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) scans. The primary outcome was the presence of advanced fibrosis (>F2) as measured by magnetic resonance elastography and the presence of liver fat (>5%) as measured by MRI-PDFF.

Results:

The mean age and body mass index were 57±12 years and 30.6±4.8 kg/m2, respectively. The mean liver stiffness on magnetic resonance elastography was 3.22±1.39 kPa and the mean liver fat on MRI-PDFF was 14.2±8%. The liver stiffness assessments by Velacur and FibroScan were similar for the detection of advanced fibrosis (AUC 0.95 vs. 0.97) and were not statistically different (p=0.43). Velacur was significantly better than FibroScan (AUC 0.94 vs. 0.79, p=0.01), for the detection of MRI-PDFF >5% (diagnosis of metabolic dysfunction–associated liver disease).

Conclusions:

Velacur was superior to FibroScan for liver fat detection with MRI-PDFF as the reference. Velacur and FibroScan were not statistically different for liver stiffness assessment as defined by magnetic resonance elastography.
Impaired systemic proteostasis and peripheral immune cell dysfunction in kidney diseases
Authors: Desirée Bartolini , Anna Migni , Roberta Russo , Francesco Galli
Published: March 2024

Kidney diseases, encompassing a spectrum of either acute or chronic disorders, manifest complex systemic repercussions beyond renal dysfunction. These include a reduced efficacy of tissue proteostasis mechanisms to control protein synthesis, folding, and degradation in both the renal and extra-renal compartments. Emerging research has revealed a pivotal interplay between proteostasis and immune regulation in the pathogenesis of kidney diseases, along with their cardiovascular, immunometabolic, and organ dysfunction symptoms. This review outlines the multifaceted connections between proteostasis dysregulation and immune dysfunction in kidney disease onset and progression. The crosstalk between the proteostasis network and immune cells orchestrates a bidirectional communication that amplifies pathological cascades, exacerbating kidney injury and impairing organ resilience. Furthermore, the article focuses on the implications of systemic proteostasis defects in modulating immune responses in extra-renal tissues underscore the systemic nature of kidney diseases. The disruption of proteostasis mechanisms triggers the release of damage-associated molecular patterns (DAMPs) and inflammatory mediators, perpetuating a state of heightened immune activation, contributing to systemic complications in affected individuals. Understanding the intricate interaction between proteostasis and immune regulation in kidney diseases, including both chronic and acute forms, promises novel therapeutic interventions. Targeting proteostasis pathways to restore cellular homeostasis and modulating immune responses could offer innovative strategies to mitigate renal damage and ameliorate systemic complications associated with kidney diseases. Harnessing this knowledge may also pave the way for the development of more efficient dialysis therapies and interventions with sorbents and hemoperfusion methods, to improve the clinical outcome of the patients.
Psychedelic Therapy: A Primer for Primary Care Clinicians—3,4-Methylenedioxy-methamphetamine (MDMA)
Authors: Shinozuka Kenneth , Tabaac Burton J. , Arenas Alejandro , Beutler Bryce D. , Cherian Kirsten , Evans Viviana D. , Fasano Chelsey , Muir Owen S.
Published: March 2024

Background:

After becoming notorious for its use as a party drug in the 1980s, 3,4-methylenedioxy-methampetamine (MDMA), also known by its street names “molly” and “ecstasy,” has emerged as a powerful treatment for post-traumatic stress disorder (PTSD).

Areas of Uncertainty:

There are extensive data about the risk profile of MDMA. However, the literature is significantly biased. Animal models demonstrating neurotoxic or adverse effects used doses well beyond the range that would be expected in humans (up to 40 mg/kg in rats compared with roughly 1–2 mg/kg in humans). Furthermore, human samples often comprise recreational users who took other substances in addition to MDMA, in uncontrolled settings.

Therapeutic Advances:

Phase III clinical trials led by the Multidisciplinary Association for Psychedelic Studies (MAPS) have shown that MDMA-assisted psychotherapy has an effect size of d = 0.7–0.91, up to 2–3 times higher than the effect sizes of existing antidepressant treatments. 67%–71% of patients who undergo MDMA-assisted psychotherapy no longer meet the diagnostic criteria for PTSD within 18 weeks. We also describe other promising applications of MDMA-assisted psychotherapy for treating alcohol use disorder, social anxiety, and other psychiatric conditions.

Limitations:

Thus far, almost all clinical trials on MDMA have been sponsored by a single organization, MAPS. More work is needed to determine whether MDMA-assisted therapy is more effective than existing nonpharmacological treatments such as cognitive behavioral therapy.

Conclusions:

Phase III trials suggest that MDMA is superior to antidepressant medications for treating PTSD. Now that MAPS has officially requested the Food and Drug Administration to approve MDMA as a treatment for PTSD, legal MDMA-assisted therapy may become available as soon as 2024.