bluuebunny/crossref_metadata_2025 huggingface dataset:
Welcome back! The impact of ‘return initiatives’ on return migration to rural regions
Authors: Meister Moritz , Peters Jan Cornelius , Rossen Anja
Published: August 2024

This article studies the effect of return initiatives in rural regions of Germany on interregional return migration. The initiatives aim to increase return migration by, amongst other things, providing information on local employment opportunities and personal support to workers interested in returning to find a job in the former rural region of residence. Analysing administrative data on individual labour market trajectories through survival analysis and difference-in-differences estimation, we find that return initiatives, on average, promote interregional return migration. Among the considered workers, particularly those in the middle and at the top of the wage distribution are more likely to return.
Role of lipids in the organization of tight junction
Authors: Ikenouchi Junichi , Shigetomi Kenta
Published: August 2024

Cell membrane structures are supramolecular complexes that require the ordered assembly of membrane proteins and lipids. The morphology of various cell adhesion structures in multicellular organisms, such as those between epithelial cells, neural synapses and immune synapses, was initially described through electron microscopic analyses. Subsequent studies aimed to catalog their constituent proteins, which encompass transmembrane cell adhesion molecules, cytoskeletal proteins and scaffolding proteins that bind the two components. However, the diversity of plasma membrane lipids and their significance in the organization of cell adhesion structures were underappreciated until recently. It is now understood that phase separation of lipids and liquid–liquid phase separation of proteins are important driving forces for such self-assembly. In this review, we summarized recent findings on the role of lipids as scaffolds for supramolecular complexes using tight junctions in epithelial cells as an example.
Executive and attentional functioning interventions in preterm children: a systematic review
Authors: Maalouf Yara , Provost Sarah , Gaudet Isabelle , Dodin Philippe , Paquette Natacha , Gallagher Anne
Published: August 2024

Objective

This systematic review, performed in accordance with the PRISMA guidelines, seeks to summarize the interventions that have been developed in order to improve executive functioning and attention in children born prematurely.

Methods

The PICOS framework helped guide the structure and relevant terms selected for the study. Electronic systematic searches of the databases PubMed (NLM), Ovid Medline, Ovid All EBM Reviews, Ovid Embase, and Ovid PsycINFO were completed in March 2022. This review focuses on interventions that target attention and executive functioning in prematurely born children between birth and 12 years old, with outcome measures assessed between 3 and 12 years old, even if the age range in the study can exceed our own parameters. Data extraction included sample characteristics, country of recruitment, type of intervention, description of the intervention group and control group, outcome measures, and overall results. An assessment of the quality of methodology of studies was performed through an adaptation of the Downs and Black checklist for both randomized and nonrandomized studies in healthcare interventions. An assessment of the risk of bias was also presented using the Cochrane risk of bias tool for randomized trials 2.0.

Results

A total of 517 premature children received an intervention at some point between birth and early adolescence. Eleven different interventions were assessed in 17 studies, with rating of the quality of methodology and outcomes ranging from lower quality studies (44% quality rating) to robust studies (96% quality rating) in terms of reporting standards, external and internal validity, and power. Five of those studies focused on interventions administered in the neonatal intensive care unit or shortly postdischarge (e.g., the Mother–Infant Transaction Program and the Newborn Individualized Developmental Care and Assessment Program, documented in two articles each [11%] or the Infant Behavioral Assessment and Intervention Program assessed in one study [about 5%]), while 12 articles reported on interventions administered between the ages of 1.5–12 years old [mostly computerized cognitive training programs such as Cogmed (23%) and BrainGame Brian (17%)]. Of the 17 articles examined, 12 (70%) showed positive short-term outcomes postintervention and 3 (17%) demonstrated positive long-term results with small to large effect sizes (0.23–2.3). Among included studies, 50% showed an overall high risk of bias, 21.4% showed some concerns, and 28.6% were low risk of bias.

Conclusions

Due to the heterogeneity of the programs reviewed, the presented findings should be interpreted as descriptive results. A careful and individualized selection from the various available interventions should be made based on the target population (i.e., age at intervention administration and outcome testing) before implementing these program protocols in clinical settings.
Exploration of the potential mechanism of aqueous extract of Artemisia capillaris for the treatment of non-alcoholic fatty liver disease based on network pharmacology and experimental verification
Authors: Liang Meng , Dong Siyu , Guo Yi , Zhang Yuyi , Xiao Xiao , Ma Jun , Jiang Xiaowen , Yu Wenhui
Published: August 2024

Objectives

Non-alcoholic fatty liver disease (NAFLD) is a nutritional and metabolic disease with a high prevalence today. Artemisia capillaris has anti-inflammatory, antioxidant, and other effects. However, the mechanism of A. capillaris in treating NAFLD is still poorly understood.

Methods

This study explored the mechanism of A. capillaris in the treatment of NAFLD through network pharmacology and molecular docking, and verified the results through in vivo experiments using a high-fat diet-induced mouse model and in vitro experiments using an oleic acid-induced HepG2 cell model.

Key findings

Aqueous extract of A. capillaris (AEAC) can reduce blood lipids, reduce liver lipid accumulation and liver inflammation in NAFLD mice, and improve NAFLD. Network pharmacology analysis revealed that 51 drug ingredients in A. capillaris correspond to 370 targets that act on NAFLD. GEO data mining obtained 93 liver differentially expressed genes related to NAFLD. In the UHPLC-MS detection results, 36 components were characterized and molecular docked with JNK. Verified in vitro and in vivo, the results show that JNK and the phosphorylation levels of IL-6, IL-1β, c-Jun, c-Fos, and CCL2 are key targets and pathways.

Conclusions

This study confirmed that AEAC reduces lipid accumulation and inflammation in the liver of NAFLD mice by inhibiting the JNK/AP-1 pathway.
First Case of HIV Seroconversion With Integrase Resistance Mutations on Long-Acting Cabotegravir for Prevention in Routine Care
Authors: Koss Catherine A , Gandhi Monica , Halvas Elias K , Okochi Hideaki , Chu Carolyn , Glidden David V , Georgetti Gomez Lisa , Heaps Amy L , Conroy Amy A , Tran Michael , Shetler Cory , Hoeth Dianna , Kuncze Karen , Louie Alexander , Rivera Garza Hana , Wafula Mugoma Erick , Penrose Kerri J , Chohan Bhavna H , Ayieko James O , Mills Anthony , Patel Rupa R , Mellors John W , Parikh Urvi M
Published: August 2024

Background

Long-acting cabotegravir (CAB-LA) is highly effective for HIV prevention, but delayed HIV diagnoses and integrase strand transfer inhibitor (INSTI) resistance were observed in trials. We report the first case in routine clinical care of HIV infection on CAB-LA with INSTI resistance.

Methods

The SeroPrEP study enrolls individuals in the United States who acquire HIV on pre-exposure prophylaxis modalities to assess diagnostics, antiretroviral (ARV) drug levels, resistance, and treatment outcomes. Resistance mutations in full-length HIV-1 integrase were identified by single-genome sequencing (SGS). Cabotegravir concentrations in plasma and hair segments were measured by liquid chromatography–tandem mass spectrometry.

Results

A 23-year-old gender-nonbinary person, male at birth, restarted CAB-LA 6 months after discontinuation due to losing insurance. Prior to restart, HIV-1 RNA was not detected, but 20 days elapsed before CAB-LA injection. After the second CAB-LA injection, HIV antigen/antibody returned reactive (HIV-1 RNA 451 copies/mL). SGS of plasma HIV-1 RNA identified INSTI mutation Q148R in 2/24 sequences 2 days postdiagnosis; commercial genotype failed amplification. Cabotegravir hair concentration was 0.190 ng/mg 2 weeks prediagnosis; plasma cabotegravir was high (3.37 μg/mL; ∼20× PA-IC90) 14 days postdiagnosis. Viral suppression was maintained for 6 months on darunavir/cobicistat/emtricitabine/tenofovir alafenamide, then switched to doravirine + emtricitabine/tenofovir alafenamide due to nausea.

Conclusions

In this first case of HIV infection on CAB-LA with INSTI resistance in routine care, cabotegravir resistance was detected only with a sensitive research assay. Accelerated pathways to minimize time between HIV testing and CAB-LA initiation are needed to optimize acute HIV detection and mitigate resistance risk. Sustained product access regardless of insurance is imperative to reduce HIV infections on CAB-LA.
Associations of Early Prolonged Secondary Amenorrhea in Women With and Without HIV
Authors: Swann Shayda A , King Elizabeth M , Pang Davi , Silva Marcela A P , Campbell Amber R , Prior Jerilynn C , Loutfy Mona , Kaida Angela , Côté Hélène C F , Murray Melanie C M
Published: August 2024

Background

The menstrual cycle is a critical indicator of women's health. Early prolonged secondary amenorrhea increases risks for morbidity and mortality. Menstrual cycle research in women with HIV is inconsistent and often lacks an adequate comparison sample. We aimed to determine whether women with HIV have a higher lifetime prevalence of amenorrhea and whether this is independently associated with HIV and/or other biopsychosocial variables.

Methods

With data from 2 established HIV cohorts, participants assigned female at birth were eligible if aged ≥16 years, not pregnant/lactating, and without anorexia/bulimia nervosa history. Amenorrhea was defined by self-reported history of (1) no menstrual flow for ≥12 months postmenarche not due to pregnancy/lactation, medications, or surgery or (2) early menopause or premature ovarian insufficiency. Multivariable logistic regression models explored biopsychosocial covariates of amenorrhea.

Results

Overall, 317 women with HIV (median age, 47.5 years [IQR, 39.2–56.4]) and 420 women without HIV (46.2 [32.6–57.2]) were included. Lifetime amenorrhea was significantly more prevalent among women with HIV than women without HIV (24.0% vs 13.3%). In the multivariable analysis, independent covariates of amenorrhea included HIV (adjusted odds ratio, 1.70 [95% CI, 1.10–2.64]), older age (1.01 [1.00–1.04]), White ethnicity (1.92 [1.24–3.03]), substance use history (6.41 [3.75–11.1]), and current food insecurity (2.03 [1.13–3.61]).

Conclusions

Nearly one-quarter of women with HIV have experienced amenorrhea, and this is associated with modifiable risk factors, including substance use and food insecurity. Care providers should regularly assess women's menstrual health and advocate for actionable sociostructural change to mitigate risks.
Nutrient Requirements Shape the Preferential Habitat of Allorhizobium vitis VAR03-1, a Commensal Bacterium, in the Rhizosphere of Arabidopsis thaliana
Authors: Hemelda Niarsi Merry , Bao Jiyuan , Watanabe Megumi , Matsui Hidenori , Toyoda Kazuhiro , Ichinose Yuki , Noutoshi Yoshiteru
Published: August 2024

A diverse range of commensal bacteria inhabit the rhizosphere, influencing host plant growth and responses to biotic and abiotic stresses. While root-released nutrients can define soil microbial habitats, the bacterial factors involved in plant–microbe interactions are not well characterized. In this study, we investigated the colonization patterns of two plant disease biocontrol agents, Allorhizobium vitis VAR03-1 and Pseudomonas protegens Cab57, in the rhizosphere of Arabidopsis thaliana using Murashige and Skoog (MS) agar medium. VAR03-1 formed colonies even at a distance from the roots, preferentially in the upper part, while Cab57 colonized only the root surface. The addition of sucrose to the agar medium resulted in excessive proliferation of VAR03-1, similar to its pattern without sucrose, whereas Cab57 formed colonies only near the root surface. Overgrowth of both bacterial strains upon nutrient supplementation inhibited host growth, independent of plant immune responses. This inhibition was reduced in the VAR03-1 ΔrecA mutant, which exhibited increased biofilm formation, suggesting that some activities associated with the free-living lifestyle rather than the sessile lifestyle may be detrimental to host growth. VAR03-1 grew in liquid MS medium with sucrose alone, while Cab57 required both sucrose and organic acids. Supplementation of sugars and organic acids allowed both bacterial strains to grow near and away from Arabidopsis roots in MS agar. These results suggest that nutrient requirements for bacterial growth may determine their growth habitats in the rhizosphere, with nutrients released in root exudates potentially acting as a limiting factor in harnessing microbiota.
Barking up the wrong tree? Voter bias and female underrepresentation in Japanese politics
Authors: Lim Sijeong , Tanaka Seiki
Published: August 2024

Previous studies on gender bias in the evaluation of politicians by voters have reported mixed results. We seek to understand these mixed findings by focusing on Japan, where female political representation is the lowest among advanced democracies and gender stereotypes are prevalent. We consider that gender stereotypes and the dearth of women in politics affect the evaluation of politicians via two distinct mechanisms: biased beliefs and weak priors. The two mechanisms are assumed to run counter to each other, thus leading to the null or mixed findings for gendered evaluation reported by previous studies. To test our argument, we conduct a series of survey experiments in Japan. Our findings conform to neither of the two mechanisms. Even in a society with low female political representation, we find no evidence of the gendered evaluation of candidates by voters. We suggest that rather than biasing voters’ evaluation of candidates, gender stereotypes dissuade women from aspiring to a political career and elite electoral gatekeepers from selecting female candidates.
Sexual behaviors and HIV-related knowledge among GBMSM: evidence from 2011 to 2021 in Hangzhou, China
Authors: Jiang Jiahan , Zhang Xingliang , Juma Omar , Xu Ke , Xu Junfang
Published: August 2024

Introduction

Considering that many new HIV infections are transmitted by homosexual behaviors, gay, bisexual, and other men who have sex with men (GBMSM) are more likely to be infected with HIV than other groups due to the higher risk associated with unprotected anal intercourse. It is important to explore the changes in sexual behaviors and HIV-related knowledge among GBMSM in the last 10 years, which could provide evidence for improving public health interventions to reduce HIV infections.

Objectives

The study sought to explore the changes of 3 sexual behaviors and HIV knowledge among men who have sex with men from 2011 to 2021.

Methods

Data were collected from national HIV sentinel surveillance among GBMSM in Hangzhou conducted between 2011 and 2021. Univariate and multivariate logistic regression were used to analyze the associated factors of sexual behaviors. The variation trend of variables was evaluated based on the linear trend test in the regression model.

Results

A total of 5111 GBMSM with an average age of 32.00 years were incorporated in the analysis. From 2011 to 2021, the HIV-related knowledge score of GBMSM ranged from 6 to 7.5, and it increased significantly (P trend < .001). The rate of homosexual sex in the past 6 months remained at a high level (75.06%-82.75%). Homosexual behavior was associated with a higher HIV-related knowledge score (P = .004). Heterosexual sex was associated with an increase in the old age, married persons, and domicile outside the province (P < .05). Commercial sex was associated with an increase in drug users (P <.001).

Conclusions

In the past 10 years, HIV-related knowledge of GBMSM increased and the rate of unprotected sex was at a high level among GBMSM, especially in heterosexual behaviors. Moreover, the likelihood of having homosexual behaviors is raised with the increasing HIV-related knowledge. Conducting precise behavioral interventions for GBMSM are crucial for preventing HIV infection.
The effect of live body condition score of beef cows on carcass characteristics, carcass-cutting yields, processor profitability, and tenderness in the longissimus lumborum and psoas major muscles
Authors: Scott Kayla G , Wang Yifei , Bohrer Benjamin M , Garcia Lyda G
Published: August 2024

The objective of this study was to investigate the effects of body condition score (BCS) of cull cows on carcass characteristics, carcass-cutting yields, profitability, and tenderness development for the longissimus lumborum and psoas major muscles. During a 5-wk period (May–June 2023), 10 boner cull cows (BCS 4 to 6) and 10 leaner cull cows (BCS 1 to 3) were purchased at a commercial auction market. Live conformation, carcass characteristics, weights of fabricated cuts, tenderness, pH decline, and temperature decline were recorded following slaughter. Carcasses were fabricated into the following cuts: knuckle, inside round, outside round, eye of round, strip loin, top sirloin, bottom sirloin flap, tenderloin, flank, ribeye roll, chuck tender, and brisket, whereas lean was separated into lean and fat components. Beef processor returns for boner cows were calculated as the sum of USDA Carlot Report values for the subprimal cuts, trim, bone, and drop value subtracted by actual live costs at the auction market whereas beef processor returns for leaner cows were calculated as the sum of USDA Carlot Report values for the trim, bone, and drop value subtracted by actual live costs at the auction market. Carcass and merchandizing value parameters were analyzed using a completely randomized design with a fixed effect of classification (leaner or boner) and a random effect of slaughter day. Live weight was used as a covariant for all carcass and merchandizing value parameters due to the pronounced effect of live weight for most parameters. Temperature decline, pH decline, shear force, and cooking loss parameters were analyzed using a completely randomized design with a fixed effect of classification (leaner or boner) and a random effect of slaughter day. Boner cows were found to be heavier for both live and carcass weights when compared with leaner cows. In addition, backfat thickness was 0.39 cm greater (P = 0.03), and ribeye area was 9.17 cm2 (P = 0.05) greater for boner cows compared with leaner cows. This resulted in boner cows yielding larger subprimal cuts and a greater amount of lean trim, which in turn generated more beef processor revenue. However, specific consideration should be provided for profitability as the ability to market subprimal cuts is highly dependent on muscle size, fat deposition, meat quality, and market prices for both boner and leaner cows.
Expanding Child Health Screenings Through School–Community Partnerships
Authors: McCabe Ellen M. , Best Nakia C. , Bennett Sheryl , Johnson Emma , Jameson Beth E.
Published: August 2024

Child health screenings are a critical, but often overlooked, aspect of children's medical care. School–community partnerships to conduct screenings and ensure that diagnostic follow-up and treatment occur can help achieve optimal child health outcomes. Such partnerships also serve to mitigate the impact of social determinants of health on children's well-being, address health disparities, and promote health equity. This article reviews four essential childhood health screenings—vision, hearing, dental, and mental health—and discusses how schools and community partners can collaborate to offer these screenings.
Crossing the Cervicothoracic Junction
Authors: McDonald Christopher L. , Badida Rohit , Alsoof Daniel , Daher Mohammad , Homer Alex , Crisco Joseph J. , Wronski Peter T. , Diebo Bassel G. , Daniels Alan H. , Kuris Eren O.
Published: August 2024

Study Design.

A biomechanical study.

Objective.

This study aims to evaluate the biomechanical adjacent segment effects of multilevel posterior cervical fusion constructs that terminate at C7 compared with those that terminate at T1 in cadaveric specimens.

Background.

The cervicothoracic junction poses unique challenges for spine surgeons. Deciding to terminate multilevel posterior cervical fusion constructs at C7 or extend them across the cervicothoracic junction remains a controversial issue.

Methods.

Six cadaveric specimens underwent biomechanical testing in the intact state and after instrumentation with constructs from C3 and terminating at either C7 or T1. Range of motion (ROM) was assessed in flexion-extension, lateral bending, and axial rotation globally and at cranial and caudal adjacent segments.

Results.

There was a significant decrease in overall flexion/extension by both C7 (−35.5°, P=0.002) and T1 (−39.8°, P=0.002) instrumentation compared with the intact spine. T1 instrumentation had significantly lower (−4.3°, P=0.008) flexion/extension ROM compared with C7 instrumentation. There were significant decreases in axial rotation by both C7 (−31.4°, P=0.009) and T1 (−36.8°, P=0.009) instrumentation compared with the intact spine, but no significant differences were observed between the 2. There were also significant decreases in lateral bending by both C7 (−27.9°, P=0.022) and T1 (−33.7°, P=0.022) instrumentation compared with the intact spine, but no significant differences were observed between the 2. No significant differences were observed in ROM at cranial or caudal adjacent segments between constructs terminating at C7 and those extending to T1.

Conclusion.

This biomechanical investigation demonstrates that constructs that cross the cervicothoracic junction experience less overall spinal motion in flexion-extension compared with those that terminate at C7. However, contrary to prior studies, there is no difference in cranial and caudal adjacent segment motion. Surgeons should make clinical decisions regarding the caudal extent of fusion in multilevel posterior cervical fusions without major concerns about adjacent segment motion.
Clinical Features, Treatment, and Outcomes of Nivolumab-Induced Hemophagocytic Lymphohistiocytosis
Authors: Sun Jichun , Luo Panpan , Guo Yuge , He Yang , Wang Chunjiang
Published: August 2024

Haemophagocytic lymphohistiocytosis (HLH) is a rare and fatal immune-related event of nivolumab. The clinical features of nivolumab-induced HLH are unclear. The aim of this study was to investigate the clinical features, treatment, and outcome of nivolumab-induced HLH to provide information for prevention and treatment. We collected nivolumab-induced HLH-related case reports for retrospective analysis by searching the Chinese and English databases from inception to March 31, 2024. HLH developed in 24 patients, with a median age of 57 years (range: 26, 86). The onset of HLH symptoms ranged from 3 days to 68 weeks after administration, with a median time of 5.5 weeks. Fever (87.5%) was the most common symptom and could be accompanied by splenomegaly (66.7%) and hepatomegaly (20.8%). Laboratory tests revealed hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, increased sCD25, and decreased natural killer cell activity. Bone marrow biopsy showed hemophagocytosis (62.5%). After discontinuing nivolumab, HLH patients receiving systemic steroids, tocilizumab, and anakinra showed positive results. As a rare adverse reaction of nivolumab, HLH requires rapid diagnosis and appropriate treatment based on clinical symptoms and laboratory tests. Tocilizumab and anakinra can be used as an effective treatment against the steroid HLH.
How to ventilate critically ill children with cancer?: a narrative review
Authors: Domínguez-Rojas Jesús , Torres Godoy Silvio Fabio , Mora Robles Lupe Nataly , Méndez Aceituno Alejandra
Published: August 2024

The management of respiratory failure and hypoxemia in children with cancer presents a critical challenge. Choosing between invasive and noninvasive mechanical ventilation can profoundly impact mortality rates, especially in resource-limited settings. Choosing between invasive and noninvasive mechanical ventilation can impact mortality rates, particularly in resource-limited settings. Extensive clinical studies are imperative to thoroughly evaluate the efficacy of invasive mechanical ventilation (IMV) and noninvasive ventilation (NIV) during the early stages of treatment. Further research is crucial to determine the most optimal therapeutic approach. Early implementation of IMV or NIV could significantly reduce mortality rates in these patients.[

1

] Additionally, this article examines the admission of children with terminal cancer, evaluating their use of invasive and noninvasive ventilatory support versus palliative care. The interdisciplinary medical team, in collaboration with the family, must carefully consider the benefits and risks of these interventions, whether in the early or terminal stages of the disease. Furthermore, the article delves into the controversies surrounding the utilization of ventilation in critically ill children with cancer.
Sex- and age-associated factors drive the pathophysiology of MASLD
Authors: Yadav Ajay K. , MacNeill Justin J. , Krylov Aleksei , Ashrafi Nadia , Mimi Romana Ashrafi , Saxena Romil , Liu Sheng , Graham Stewart F. , Wan Jun , Morral Núria
Published: August 2024

Background:

Metabolic dysfunction–associated steatotic liver disease (MASLD) is strongly associated with obesity. Sex and age affect MASLD prevalence and pathophysiology. The use of animal models fed Western-style diets is vital for investigating the molecular mechanisms contributing to metabolic dysregulation and for facilitating novel drug target identification. However, the sex-associated and age-associated mechanisms underlying the pathophysiology remain poorly understood. This knowledge gap limits the development of personalized sex-specific and age-specific drug treatments.

Methods:

Young (7 wk) and aged (52 wk) male and female mice were fed a high-fat diet (HFD) or low-fat diet. Liver metabolome (>600 molecules) and transcriptome profiles were analyzed.

Results:

Male and female mice fed an HFD developed obesity, glucose intolerance, and hepatic steatosis. However, fasting blood glucose, insulin, and serum alanine aminotransferase levels were higher in males fed an HFD, indicating a more severe metabolic disease. In addition, males showed significant increases in liver diacylglycerides and glycosylceramides (known mediators of insulin resistance and fibrosis), and more changes in the transcriptome: extracellular matrix organization and proinflammatory genes were elevated only in males. In contrast, no major increase in damaging lipid classes was observed in females fed an HFD. However, aging affected the liver to a greater extent in females. Acylcarnitine levels were significantly reduced, suggestive of changes in fatty acid oxidation, and broad changes in the transcriptome were observed, including reduced oxidative stress response gene expression and alterations in lipid partitioning genes.

Conclusions:

Here, we show distinct responses to an HFD between males and females. Our study underscores the need for using both sexes in drug target identification studies, and characterizing the molecular mechanisms contributing to the MASLD pathophysiology in aging animals.
Cholangiocyte ciliary defects induce sustained epidermal growth factor receptor signaling
Authors: Pant Kishor , Richard Seth , Peixoto Estanislao , Baral Subheksha , Yang Rendong , Ren Yanan , Masyuk Tatyana V. , LaRusso Nicholas F. , Gradilone Sergio A.
Published: August 2024

Background and Aims:

The primary cilium, an organelle that protrudes from cell surfaces, is essential for sensing extracellular signals. With disturbed cellular communication and chronic liver pathologies, this organelle’s dysfunctions have been linked to disorders, including polycystic liver disease and cholangiocarcinoma. The goal of this study was to elucidate the relationship between primary cilia and the crucial regulator of cellular proliferation, the epidermal growth factor receptor (EGFR) signaling pathway, which has been associated with various clinical conditions.

Approach and Results:

The study identified aberrant EGFR signaling pathways in cholangiocytes lacking functional primary cilia using liver-specific intraflagellar transport 88 knockout mice, a Pkhd1 mutant rat model, and human cell lines that did not have functional cilia. Cilia-deficient cholangiocytes showed persistent EGFR activation because of impaired receptor degradation, in contrast to their normal counterparts, where EGFR localization to the cilia promotes appropriate signaling. Using histone deacetylase 6 inhibitors to restore primary cilia accelerates EGFR degradation, thereby reducing maladaptive signaling. Importantly, experimental intervention with the histone deacetylase 6 inhibitor tubastatin A in an orthotopic rat model moved EGFR to cilia and reduced ERK phosphorylation. Concurrent administration of EGFR and histone deacetylase 6 inhibitors in cholangiocarcinoma and polycystic liver disease cells demonstrated synergistic antiproliferative effects, which were associated with the restoration of functioning primary cilia.

Conclusions:

This study’s findings shed light on ciliary function and robust EGFR signaling with slower receptor turnover. We could use therapies that restore the function of primary cilia to treat EGFR-driven diseases in polycystic liver disease and cholangiocarcinoma.
Colorectal cancer mortality trend analysis in Montenegro from 1990 to 2018
Authors: Vuković Mirjana Nedović , Jakšić Marina , Smolović Brigita , Golubović Mileta , Laušević Dragan
Published: August 2024

Colorectal cancer (CRC) is the second leading cause of cancer-related death in Europe. This study aimed to investigate CRC mortality trends in Montenegro from 1990 to 2018 and critically review the impact of preventive activities on cancer suppression in this country. We used the national CRC mortality data categorized by sex and age. Mortality rates were age-standardized according to the World Standard Population. The trends were described using regression techniques. In the period from 1990 to 2018, there was a significant increase in CRC mortality (P < .05). The death rates and the number of deaths from CRC were constantly increasing for both the overall level and gender, with the mean annual percentage change for the rates respectively average annual percent change (95% confidence interval—CI): 2.6% (1.9–3.2), 2.6% (1.8–3.5); 2.3% (1.3–3.3), and for the number of cases, respectively: 4.2% (3.5–4.9), 4.3% (3.3–5.3), 4.3% (3.2–5.5). The most affected age groups were 65 to 74 years (33%), followed by those aged 75 to 84 years (25%) and the age group 55 to 64 (22%). In Montenegro, CRC mortality trends are increasing among both men and women over the age of 45. Additional research on the risk factors and mechanisms that contribute to the unfavorable trends in CRC mortality in Montenegro is necessary.
Smoking behaviors, physical activities, pulmonary diseases and COVID-19 severity: A Mendelian randomization study
Authors: Zheng Xuwen , Chen Maobing , Zhuang Yi , Xu Jin , Zhao Liang , Qian Yongjun , Shen Wenming
Published: August 2024

Smoking behaviors, physical activities, and pulmonary diseases have been revealed to be associated with COVID-19 severity through observational research. The possible causative effect remains undetermined. To investigate this, we thus carried out a Mendelian randomization (MR) analysis. We chose genetic variants from genome-wide association studies that are strongly linked to 5 exposures related to smoking, 1 exposure related to drinking, 3 levels of physical activity, and 3 pulmonary diseases. The COVID-19 Host Genetics Initiative provided summary-level data for severe COVID-19 (13,769 cases and 1,072,442 noncases), hospitalized COVID-19 (32,519 cases and 2,062,805 noncases), and COVID-19 susceptibility (122,616 cases and 2,475,240 noncases). Univariate and multivariate MR analyses were carried out. Significant associations were found between severe COVID-19 and cigarette smoking per day (OR = 1.357, 95% CI: 1.087–1.694), lifetime smoking index (OR = 2.277, 95% CI: 1.602–3.325), and interstitial lung disease (OR = 1.23, 95% CI: 1.112–1.362), hospitalized COVID-19 and lifetime smoking index (OR = 2.199, 95% CI: 1.738–2.781), smoking initiation (OR = 1.419, 95% CI: 1.230–1.637), and interstitial lung disease (OR = 1.146, 95% CI: 1.082–1.214), as well as COVID-19 susceptibility and lifetime smoking index (OR = 1.39, 95% CI: 1.252–1.543), smoking initiation (OR = 1.235, 95% CI: 1.163–1.311), and duration of vigorous activity per day (OR = 0.733, 95% CI: 0.574–0.935). Duration of vigorous activity per day was suggestively inversely linked to hospitalized COVID-19 (OR = 0.434, 95% CI: 0.221–0.853) and severe COVID-19 (OR = 0.323, 95% CI: 0.123–0.850). The association for lifetime smoking index remained consistent with severe COVID-19, hospitalized COVID-19, and COVID-19 susceptibility in multivariable MR analysis. Genetic liability to lifetime smoking index mediated the interstitial lung disease effects on severe COVID-19 risk (21.0%) and hospitalized COVID-19 risk (14.4%). This study identified several smoking behaviors, duration of vigorous activity per day, and interstitial lung disease that may be causally related to COVID-19 severity.
Preconceptional thyroid-stimulating hormone affects antral follicle count rather than pregnancy outcomes in patients with first in vitro fertilization/intracytoplasmic sperm injection cycle
Authors: Cai Jie , Li Huan-Huan , Tian Xiang-Ming , Yang Li , Sun Jun-Jian , Zhou Wen-Hui
Published: August 2024

Objective:

To study the effects of preconceptional thyroid-stimulating hormone (TSH) levels on antral follicle count (AFC) and pregnancy outcomes in a first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle.

Methods:

A retrospective cohort study was conducted to explore the effects of preconceptional TSH levels on AFC and pregnancy outcomes in 1340 patients. The patients were divided into three groups: group 1, 0.55≤ TSH <2.5 uIU/mL (n = 868); group 2, 2.5≤ TSH <4.0 uIU/mL (n = 334); and group 3, TSH ≥4.0 uIU/mL (n = 138).

Results:

There were significant differences in AFC (P = 0.002), number of zygotes (P = 0.008), and fertilization rate (P = 0.015) among the three groups. Among the three groups, there were no obvious differences in live birth (P = 0.559), high-quality embryo (P = 0.108), or clinical pregnancy (P = 0.939) rates. Binary logistics regression analysis showed that TSH correlated with AFC when TSH was ≥4 uIU/mL (P = 0.033); however, TSH levels had no effect on live birth or clinical pregnancy rate.

Conclusions:

Although the preconceptional TSH level negatively related with AFC, number of zygotes, and fertility rate, especially when TSH was >4 uIU/mL, TSH was not an independent factor on the live birth rate among fertile women undergoing their first IVF/ICSI-embryo transfer treatment. The effect of TSH levels on couples undergoing assisted reproductive technology requires further investigation.
Transition to Adult Care in Autoinflammatory Diseases
Authors: Elhani Inès , Hentgen Véronique , Quartier Pierre , Bader-Meunier Brigitte , Kone-Paut Isabelle , Neven Bénédicte , Rossi Linda , Faye Albert , Meinzer Ulrich , Melki Isabelle , Grateau Gilles , Savey Léa , Georgin-Lavialle Sophie
Published: August 2024

Background

Transitioning from pediatric to adult care is a critical step for individuals with autoinflammatory diseases, requiring effective programs to ensure continuity of care and disease management. Despite various recommendations, the effectiveness of transition programs, particularly in monogenic autoinflammatory diseases, remains understudied.

Methods

A single-center medical records review study was conducted at the French National Reference Center for Adult Autoinflammatory Diseases in Tenon Hospital from 2017 to 2023. All patients who had consulted for the first time between the ages of 15 and 30 years and had received care for an autoinflammatory disease during childhood were included. The patients were classified according to whether they had undergone a transition, defined as either no transition, simple transition (referral letter), or joint transition (pediatrician and adult physician consultation).

Results

One hundred eleven patients (median age, 18 years) were included. Patients who consulted without transition started adult follow-up and were followed up less regularly than those who underwent the transition process (p < 0.001 and p = 0.028). In patients with familial Mediterranean fever, the absence of a formal transition was associated with poorer disease control at baseline (p = 0.019). The type of transition did not impact disease control during follow-up.

Conclusions

Participation in a transition program is associated with earlier and more regular follow-up in adulthood. Although transition type did not significantly impact disease control during follow-up in familial Mediterranean fever, the potential benefit of joint consultation extends beyond consultation frequency and disease outcomes, encompassing patient perspectives and self-management abilities. This study highlights the significance of collaborative transition programs in AIDs.
Nonvisualized Ovaries on Ultrasound
Authors: Alhamshari Ahmad , Krigman Hannah R. , Siegel Cary L. , Zhu Quing , Itani Malak
Published: August 2024

The risk of malignancy in nonvisualized ovaries on pelvic ultrasound is presumed to be close to zero per imaging correlation; the goal of this manuscript is to define the risk of malignancy in nonvisualized ovaries on pelvic ultrasound as defined by surgical pathology. Records for patients with pelvic ultrasound and surgical pathology containing the word “ovary” or “ovaries” performed at our institution between 10/1/2015 and 9/30/2021 were reviewed. Data for ovarian visualization were extracted from the radiology report and correlated with surgical pathology results within each ovary. Eighty-seven ovaries in 71 patients out of 422 ovaries (20.6%) in 215 eligible patients were not visualized on ultrasound. Twenty ovaries were excluded because imaging showed large pelvic mass, and 19 ovaries were excluded because surgical pathology for the ovary of interest was not available. A total of 48 ovaries in 37 patients were nonvisualized and had available surgical pathology. Out of 48 nonvisualized ovaries, 31 were normal on surgical pathology and 17 had abnormalities, with 15 benign lesions (12 of which were ≤1 cm in size). Two ovaries in 1 patient contained malignant lesions; although the ovaries were not visualized on ultrasound, the scan demonstrated peritoneal carcinomatosis. In conclusion, a high proportion of ovaries (20.6%, 87/422) are not visualized on pelvic ultrasound, and surgical pathology reveals ovarian lesions in 35.4% (17/48) of nonvisualized ovaries on pelvic ultrasound, with the majority being subcentimeter benign lesions. In the absence of peritoneal carcinomatosis, nonvisualized ovaries had no malignant lesions.
BURN INJURY RESULTS IN MYELOID PRIMING DURING EMERGENCY HEMATOPOIESIS
Authors: Johnson Ryan M. , Galicia Kevin E. , Wang Huashan , Gonzalez Richard , Choudhry Mashkoor , Kubasiak John C.
Published: August 2024

Introduction: Hematopoiesis proceeds in a tiered pattern of differentiation, beginning with hematopoietic stem cells (HSC) and culminating in erythroid, myeloid, and lymphoid lineages. Pathologically altered lineage commitment can result in inadequate leukocyte production or dysfunctional cell lines. Drivers of emergency hematopoiesis after burn injury are inadequately defined. Burn injury induces a myeloid predominance associated with infection that worsens outcomes. This study aims to further profile bone marrow HSCs following burn injury in a murine model. Methods: C57BL/6 mice received burn or sham injury with ~12% total body surface area scald burn on the dorsal surface with subsequent sacrifice at 1, 2, 3, 7, and 10 days postinjury. Bone marrow from hindlimbs was analyzed for HSC populations via flow cytometry and analyzed using FlowJo Software (version 10.6). Event counts and frequencies were analyzed with multiple unpaired t tests and linear mixed-effect regression. Real-time polymerase chain reaction performed on isolated lineage-negative bone marrow cell RNA targeted PU.1, GATA-1, and GATA-3 with subsequent analysis conducted with QuantStudio 3 software. Statistical analysis and representation were performed on GraphPad software (Prism). Results: Flow cytometry revealed significantly elevated proportions of long-term HSCs at 3 days post-injury (P < 0.05) and short-term HSCs at days 2, 3, and 10 (all P < 0.05) in burn-injured mice. There was a sustained, but not significant, increase in proportions in the multipotent progenitor (MPP) 2 and 3 subpopulations in the burn cohort compared to sham controls. The common myeloid progenitor (CMP) proportion was significantly higher on days 3 and 10 (both P < 0.01), whereas the granulocyte-macrophage progenitor (GMP) proportion increased on days 1, 2, and 10 (P < 0.05, P < 0.01, P < 0.01, respectively). Although the megakaryocyte-erythrocyte progenitor (MEP) proportion appeared consistently lower in the burn cohort, this did not reach significance. mRNA analysis resulted in a downregulation of PU.1 on day 1 (P = 0.0002) with an upregulation by day 7 (P < 0.01). GATA-1 downregulation occurred by day 7 (P < 0.05), and GATA3 showed downregulation on days 3 and 7 (P < 0.05). Discussion: Full-thickness burn results in an emergency hematopoiesis via proportional increase of long-term HSC and short-term HSC/MPP1 subpopulations beginning in the early postinjury period. Subsequent lineage commitment displays a myeloid predominance with a shift toward myeloid progenitors with mRNA analysis corroborating this finding with associated upregulation of PU.1 and downregulation of GATA-1 and GATA-3. Further studies are needed to understand how burn-induced emergency hematopoiesis may predispose to infection by pathologic lineage selection.
Computational Models of High-Definition Electroconvulsive Therapy for Focal or Multitargeting Treatment
Authors: Khadka Niranjan , Deng Zhi-De , Lisanby Sarah H. , Bikson Marom , Camprodon Joan A.
Published: August 2024

Attempts to dissociate electroconvulsive therapy (ECT) therapeutic efficacy from cognitive side effects of ECT include modifying electrode placement, but traditional electrode placements employing 2 large electrodes are inherently nonfocal, limiting the ability to selectively engage targets associated with clinical benefit while avoiding nontargets associated with adverse side effects. Limited focality represents a technical limitation of conventional ECT, and there is growing evidence that the spatial distribution of the ECT electric fields induced in the brain drives efficacy and side effects. Computational models can be used to predict brain current flow patterns for existing and novel ECT montages. Using finite element method simulations (under quasi-static, nonadaptive assumptions, 800-mA total current), the electric fields generated in the superficial cortex and subcortical structures were predicted for the following traditional ECT montages (bilateral temporal, bifrontal, right unilateral) and experimental montages (focal electrically administered seizure therapy, lateralized high-definition [HD]-ECT, unilateral 4 × 1-ring HD-ECT, bilateral 4 × 1-ring HD-ECT, and a multipolar HD-ECT). Peak brain current density in regions of interest was quantified. Conventional montages (bilateral bifrontal, right unilateral) each produce distinct but diffuse and deep current flow. Focal electrically administered seizure therapy and lateralized HD-ECT produce unique, lateralized current flow, also impacting specific deep regions. A 4 × 1-ring HD-ECT restricts current flow to 1 (unilateral) or 2 (bilateral) cortical regions. Multipolar HD-ECT shows optimization to a specific target set. Future clinical trials are needed to determine whether enhanced control over current distribution is achieved with these experimental montages, and the resultant seizures, improve the risk/benefit ratio of ECT.
The Spherical Tokamak for Energy Production (STEP) in context: UK public sector approach to fusion energy
Authors: Baker Adam
Published: August 2024

The UK’s fusion energy approach has developed over the past 5 years to include government policy initiatives and a range of public sector investments designed to be delivered in partnership with the private sector. These have aimed to create an environment that stimulates innovation and investment to deliver economic as well as scientific and environmental benefits throughout the lifetime of the public sector fusion energy programme. The Spherical Tokamak for Energy Production acts as a focus and anchor for both public and private sector efforts to develop fusion energy, developing the supply chain and potential for Intellectual Property development and export opportunities well ahead of the anticipated STEP completion date of 2040. This is maximized by the UK’s approach to a holistic research and innovation programme backed up by a regulatory and skills programme.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Safety: a proportionate approach in an uncertain application
Authors: Afify Omar
Published: August 2024

Fusion is inherently safer than fission due to the absence of nuclear chain reactions. However, operating fusion power plants will not be risk free. There will still be numerous hazards that will need careful management in order to safely build, operate and ultimately decommission a fusion power plant. Ensuring a robust safety demonstration that covers all radiological and non-radiological hazards is therefore vitally important for the future permissioning and consenting of fusion power plants. The safety case for the STEP prototype plant will be developed in line with a set of safety philosophies, safety functional requirements and design safety principles to ensure that the safety case production process is consistent and robust.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
The Spherical Tokamak for Energy Production: theme issue introduction
Authors: Chapman I. T. , Cowley S. C. , Wilson H. R.
Published: August 2024

This theme issue collects together papers summarising the conceptual design of the Spherical Tokamak for Energy Production (STEP). In 2019, the UK government funded the first design stages of a prototype fusion powerplant based on a compact toroidal geometry, called STEP. The primary technical aims of STEP are to produce net energy, to be self-sufficient in tritium fuel and to demonstrate a maintenance regime that would extrapolate to appropriate availability for commercial powerplants. After 5 years and over 1000 person-years of detailed scientific and engineering conceptual design, this theme issue acts as a compendium of the current design basis for STEP, noting that this is a snapshot in time and that the design will continue to evolve.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.