bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experience of early-life pain in premature infants is associated with atypical cerebellar development and later neurodevelopmental deficits
Authors: Cook Kevin M. , De Asis-Cruz Josepheen , Kim Jung-Hoon , Basu Sudeepta K. , Andescavage Nickie , Murnick Jonathan , Spoehr Emma , Liggett Melissa , du Plessis Adré J. , Limperopoulos Catherine 
Published: November 2023

AbstractBackgroundInfants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits.MethodsResting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment.ResultsWe observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months.ConclusionsThese results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later.
Is metabolic-healthy obesity associated with risk of dementia? An age-stratified analysis of the Whitehall II cohort study
Authors: Machado-Fragua Marcos D. , Sabia Séverine , Fayosse Aurore , Hassen Céline Ben , van der Heide Frank , Kivimaki Mika , Singh-Manoux Archana 
Published: November 2023

Abstract
Background
Metabolically healthy obesity is hypothesized to be a benign condition but whether this is the case for dementia remains debated. We examined the role of age at assessment of metabolic-obesity phenotypes in associations with incident dementia.

Methods
Obesity (body mass index ≥ 30 kg/m2) and poor metabolic health (≥ 2 of elevated serum triglycerides, low HDL-C, elevated blood pressure, and elevated serum fasting glucose) were used to define four metabolic-obesity phenotypes (metabolically healthy (MHNO) and unhealthy non-obesity (MUNO), metabolically healthy (MHO) and unhealthy obesity (MUO)) at < 60, 60 to < 70, and ≥ 70 years using 6 waves of data from the Whitehall II study and their associations with incident dementia was examined using Cox regression.

Results
Analyses with exposures measured < 60, 60 to < 70, and ≥ 70 years involved 410 (5.8%), 379 (5.6%), and 262 (7.4%) incident dementia cases over a median follow-up of 20.8, 10.3, and 4.2 years respectively. In analyses of individual components, obesity before 60 years (HR 1.41, 95% CI: [1.08, 1.85]) but not at older ages was associated with dementia; unhealthy metabolic status when present < 60 years (HR 1.33, 95% CI: [1.08, 1.62]) and 60 to < 70 years (HR 1.32, 95% CI: [1.07, 1.62]) was associated with dementia. Compared to the metabolically healthy non-obesity group, the risk of dementia was higher in those with metabolically healthy obesity before 60 years (1.69; 95% CI: [1.16, 2.45]); this was not the case when metabolic-obesity phenotype was present at 60 to < 70 years or ≥ 70 years. Analyses at older ages were on smaller numbers due to death and drop-out but inverse probability weighting to account for missing data yielded similar results.

Conclusions
Individuals with metabolically healthy obesity before age 60 had a higher risk of incident dementia over a 27-year follow-up; the excess risk dissipates when metabolic health and obesity are measured after 70 years.
Expression of PD-1/PD-L1 axis in mediastinal lymph nodes and lung tissue of human and experimental lung fibrosis indicates a potential therapeutic target for idiopathic pulmonary fibrosis
Authors: Karampitsakos Theodoros , Galaris Apostolos , Chrysikos Serafeim , Papaioannou Ourania , Vamvakaris Ioannis , Barbayianni Ilianna , Kanellopoulou Paraskevi , Grammenoudi Sofia , Anagnostopoulos Nektarios , Stratakos Grigoris , Katsaras Matthaios , Sampsonas Fotios , Dimakou Katerina , Manali Effrosyni D. , Papiris Spyridon , Tourki Bochra , Juan-Guardela Brenda M , Bakakos Petros , Bouros Demosthenes , Herazo-Maya Jose D , Aidinis Vassilis , Tzouvelekis Argyris 
Published: November 2023

Abstract
Background
Mediastinal lymph node enlargement is prevalent in patients with idiopathic pulmonary fibrosis (IPF). Studies investigating whether this phenomenon reflects specific immunologic activation are lacking.

Methods
Programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1) expression in mediastinal lymph nodes and lung tissues was analyzed. PD-1, PD-L1 mRNA expression was measured in tracheobronchial lymph nodes of mice following bleomycin-induced injury on day 14. Finally, the effect of the PD-1 inhibitor, pembrolizumab, in bleomycin-induced pulmonary fibrosis was investigated.

Results
We analyzed mediastinal lymph nodes of thirty-three patients (n = 33, IPF: n = 14, lung cancer: n = 10, concomitant IPF and lung cancer: n = 9) and lung tissues of two hundred nineteen patients (n = 219, IPF: 123, controls: 96). PD-1 expression was increased, while PD-L1 expression was decreased, in mediastinal lymph nodes of patients with IPF compared to lung cancer and in IPF lungs compared to control lungs. Tracheobronchial lymph nodes isolated on day 14 from bleomycin-treated mice exhibited increased size and higher PD-1, PD-L1 mRNA levels compared to saline-treated animals. Pembrolizumab blunted bleomycin-induced lung fibrosis, as indicated by reduction in Ashcroft score and improvement in respiratory mechanics.

Conclusions
Mediastinal lymph nodes of patients with IPF exhibit differential expression profiles than those of patients with lung cancer indicating distinct immune-mediated pathways regulating fibrogenesis and carcinogenesis. PD-1 expression in mediastinal lymph nodes is in line with lung tissue expression. Lower doses of pembrolizumab might exert antifibrotic effects. Clinical trials aiming to endotype patients based on mediastinal lymph node profiling and accordingly implement targeted therapies such as PD-1 inhibitors are greatly anticipated.
COVID-19 induces more pronounced extracellular matrix deposition than other causes of ARDS
Authors: de Souza Xavier Costa Natália , Ribeiro Júnior Gabriel , do Nascimento Ellen Caroline Toledo , de Brito Jôse Mara , Antonangelo Leila , Faria Caroline Silvério , Monteiro Jhonatas Sirino , Setubal João Carlos , Pinho João Renato Rebello , Pereira Roberta Verciano , Seelaender Marilia , de Castro Gabriela Salim , Lima Joanna D. C. C. , de Almeida Monteiro Renata Aparecida , Duarte-Neto Amaro Nunes , Saldiva Paulo Hilário Nascimento , Ferraz da Silva Luiz Fernando , Dolhnikoff Marisa , Mauad Thais 
Published: November 2023

Abstract
Background
Lung fibrosis is a major concern in severe COVID-19 patients undergoing mechanical ventilation (MV). Lung fibrosis frequency in post-COVID syndrome is highly variable and even if the risk is proportionally small, many patients could be affected. However, there is still no data on lung extracellular matrix (ECM) composition in severe COVID-19 and whether it is different from other aetiologies of ARDS.

Methods
We have quantified different ECM elements and TGF-β expression in lung tissue of 28 fatal COVID-19 cases and compared to 27 patients that died of other causes of ARDS, divided according to MV duration (up to six days or seven days or more). In COVID-19 cases, ECM elements were correlated with lung transcriptomics and cytokines profile.

Results
We observed that COVID-19 cases presented significant increased deposition of collagen, fibronectin, versican, and TGF-β, and decreased decorin density when compared to non-COVID-19 cases of similar MV duration. TGF-β was precociously increased in COVID-19 patients with MV duration up to six days. Lung collagen was higher in women with COVID-19, with a transition of upregulated genes related to fibrillogenesis to collagen production and ECM disassembly along the MV course.

Conclusions
Fatal COVID-19 is associated with an early TGF-β expression lung environment after the MV onset, followed by a disordered ECM assembly. This uncontrolled process resulted in a prominent collagen deposition when compared to other causes of ARDS. Our data provides pathological substrates to better understand the high prevalence of pulmonary abnormalities in patients surviving COVID-19.
Discovery and overproduction of novel highly bioactive pamamycins through transcriptional engineering of the biosynthetic gene cluster
Authors: Eckert Nikolas , Rebets Yuriy , Horbal Lilya , Zapp Josef , Herrmann Jennifer , Busche Tobias , Müller Rolf , Kalinowski Jörn , Luzhetskyy Andriy 
Published: November 2023

Abstract
Background
Pamamycins are a family of highly bioactive macrodiolide polyketides produced by Streptomyces alboniger as a complex mixture of derivatives with molecular weights ranging from 579 to 705 Daltons. The large derivatives are produced as a minor fraction, which has prevented their isolation and thus studies of chemical and biological properties.

Results
Herein, we describe the transcriptional engineering of the pamamycin biosynthetic gene cluster (pam BGC), which resulted in the shift in production profile toward high molecular weight derivatives. The pam BGC library was constructed by inserting randomized promoter sequences in front of key biosynthetic operons. The library was expressed in Streptomyces albus strain with improved resistance to pamamycins to overcome sensitivity-related host limitations. Clones with modified pamamycin profiles were selected and the properties of engineered pam BGC were studied in detail. The production level and composition of the mixture of pamamycins was found to depend on balance in expression of the corresponding biosynthetic genes. This approach enabled the isolation of known pamamycins and the discovery of three novel derivatives with molecular weights of 663 Da and higher. One of them, homopamamycin 677A, is the largest described representative of this family of natural products with an elucidated structure. The new pamamycin 663A shows extraordinary activity (IC50 2 nM) against hepatocyte cancer cells as well as strong activity (in the one-digit micromolar range) against a range of Gram-positive pathogenic bacteria.

Conclusion
By employing transcriptional gene cluster refactoring, we not only enhanced the production of known pamamycins but also discovered novel derivatives exhibiting promising biological activities. This approach has the potential for broader application in various biosynthetic gene clusters, creating a sustainable supply and discovery platform for bioactive natural products.
Role of lipins in cardiovascular diseases
Authors: Ding Zerui , Song Hongyu , Wang Fang 
Published: November 2023

AbstractLipin family members in mammals include lipins 1, 2, and 3. Lipin family proteins play a crucial role in lipid metabolism due to their bifunctionality as both transcriptional coregulators and phosphatidate phosphatase (PAP) enzymes. In this review, we discuss the structural features, expression patterns, and pathophysiologic functions of lipins, emphasizing their direct as well as indirect roles in cardiovascular diseases (CVDs). Elucidating the regulation of lipins facilitates a deeper understanding of the roles of lipins in the processes underlying CVDs. The activity of lipins is modulated at various levels, e.g., in the form of the transcription of genes, post-translational modifications, and subcellular protein localization. Because lipin characteristics are undergoing progressive clarification, further research is necessitated to then actuate the investigation of lipins as viable therapeutic targets in CVDs.
Genetically predicted triglycerides mediate the relationship between type 2 diabetes Mellitus and intervertebral disc degeneration
Authors: Chen Ding-Qiang , Xu Wen-Bin , Chen Xin , Xiao Ke-Yi , Que Zhi-Qiang , Sun Nai-Kun , Feng Jin-Yi , Rui Gang 
Published: November 2023

Abstract
Background
To validate the causal relationship between type 2 diabetes mellitus (T2DM) and intervertebral disc degeneration (IVDD) and to identify and quantify the role of triglycerides (TGs) as potential mediators.

Methods
A two-sample Mendelian randomization (MR) analyses of T2DM (61,714 cases and 1178 controls) and IVDD (20,001 cases and 164,682 controls) was performed using genome-wide association studies (GWAS). Moreover, two-step MR was employed to quantify the proportionate impact of TG-mediated T2DM on IVDD.

Results
MR analysis showed that T2DM increased IVDD risk (OR: 1.0466, 95% CI 1.0049–1.0899, P = 0.0278). Reverse MR analyses demonstrated that IVDD does not affect T2DM risk (P = 0.1393). The proportion of T2DM mediated through TG was 11.4% (95% CI 5.5%-17.4%).

Conclusion
This work further validates the causality between T2DM and IVDD, with a part of the effect mediated by TG, but the greatest impacts of T2DM on IVDD remain unknown. Further studies are needed to identify other potential mediators.
Six-month cost-effectiveness of adding motivational interviewing or a stratified vocational advice intervention to usual case management for workers with musculoskeletal disorders: the MI-NAV economic evaluation
Authors: Tingulstad Alexander , Maas Esther T. , Rysstad Tarjei , Øiestad Britt Elin , Aanesen Fiona , Pripp Are Hugo , Van Tulder Maurits W. , Grotle Margreth 
Published: November 2023

Abstract
Objectives
This study evaluates the six-month cost-effectiveness and cost-benefits of motivational interviewing (MI) or a stratified vocational advice intervention (SVAI) added to usual case management (UC) for workers on sick leave due to musculoskeletal disorders.

Methods
This study was conducted alongside a three-arm RCT including 514 employed workers on sick leave for at least 50% for ≥ 7 weeks. All participants received UC. The UC + MI group received two MI sessions, and the UC + SVAI group received 1–4 SVAI sessions. Sickness absence days, quality-adjusted life-years (QALYs), and societal costs were measured between baseline and six months.

Results
Adding MI to UC, resulted in incremental cost-reduction of -2580EUR (95%CI -5687;612), and a reduction in QALYs of -0.001 (95%CI -0.02;0.01). Secondly, adding MI to UC resulted in an incremental cost-reduction of -538EUR (95%CI -1358;352), and reduction of 5.08 (95%CI -3.3;13.5) sickness-absence days. Financial return estimates were positive, but not statistically significant. Adding SVAI to UC, resulted in an incremental cost-reduction of -2899 EUR (95% CI -5840;18), and a reduction in QALYs of 0.002 (95% CI -0.02;0.01). Secondly, adding SVAI to UC resulted in an statistically significant incremental cost-reduction of -695 EUR (95% CI -1459;-3), and a reduction of 7.9 (95% CI -0.04;15.9) sickness absence days. Financial return estimates were positive and statistically significant. The probabilities of cost-effectiveness for QALYs were high for adding MI or SVAI (ceiling ratio 0.90).

Conclusions
In comparison to UC only, adding MI to UC tends to be cost-effective. Adding SVAI to UC is cost-effective for workers on sick leave due to musculoskeletal disorders.

Trial registration
ClinicalTrials.gov (identifier: NCT03871712).
Giant benign intrathoracic schwannoma: a decade-long progression towards fatality
Authors: Miyawaki Michiyo , Karashima Takashi , Abe Miyuki , Takumi Yohei , Hashimoto Takafumi , Kamohara Ryotaro , Osoegawa Atsushi , Sugio Kenji 
Published: November 2023

Abstract
Background
Intrathoracic neurogenic tumors arise from sympathetic nerve trunks and intercostal nerves; more than 90% are benign. Schwannomas are the most common histological variety, but fatalities due to giant schwannomas are rare.

Case presentation
We report a case of a 65-year-old woman who presented with chest pain and cough. Computed tomography (CT) revealed a large left chest wall mass of 130-mm in size, and the patient was referred to our department. Tumor biopsy was performed under local anesthesia, and a diagnosis of schwannoma was made. Ten years previously, a 30-mm tumor had been noted in the left third intercostal space by a previous doctor, but follow-up had been interrupted owing to depressive disorder. Although we planned to perform intercostal artery embolization followed by chest wall tumor resection, the patient did not consent to surgery due to uncontrolled depression. After four months, she developed respiratory failure caused by compression due to an enlarged tumor and died. Autopsy also revealed a benign schwannoma with no malignant findings.

Conclusions
Although schwannomas are benign tumors, there are some very rare cases in which they can become huge and life-threatening. Therefore, a benign tumor should not be neglected, and if surgery is not possible at the time of diagnosis, a regular follow up is necessary, in order not to miss the right timing for surgery.
Intractable chylous leak after radical esophagectomy treated with radiotherapy
Authors: Ahn Seha , Lee Heejin , Kang Joon Kyu , Kim In Sub , Moon Youngkyu , Choi Jung Suk , Won Yoo Dong , Jeong Seong Cheol , Choi Si Young 
Published: November 2023

AbstractPostoperative chylous leak after esophagectomy is a rare but potentially life-threatening complication that results in hypovolemia, electrolyte imbalance, malnutrition, and immunologic deficiency. However, the management of postoperative chylous leak remains controversial. Following a diagnosis of esophageal cancer, a 64-year-old man was treated by video-assisted thoracoscopic esophagectomy, laparoscopic gastric tube formation, prophylactically thoracic duct ligation, and reconstruction with esophagogastrostomy at the neck level. Massive postoperative drainage from the thorax and abdomen did not initially meet the diagnostic criteria for chylothorax, which was ultimately diagnosed 3 weeks after the operation. Despite various treatments including total parenteral nutrition, octreotide and midodrine, reoperation (thoracic duct ligation and mechanical pleurodesis), and thoracic duct embolization, the chylous leak persisted. Finally, low-dose radiation therapy was administered with a daily dose of 2 Gy and completed at a total dose of 14 Gy. After this, the amount of pleural effusion gradually decreased over 2 weeks, and the last drainage tube was removed. The patient was alive and well at 60 months postoperatively. Herein, we describe a patient with intractable chylous leak after esophagectomy, which persisted despite conservative treatment, thoracic duct ligation, and embolization, but was finally successfully treated with radiotherapy.
Non-drug interventions of traditional Chinese medicine in preventing type 2 diabetes: a review
Authors: Liu Jingying , Yao Chun , Wang Yitao , Zhao Jinmin , Luo Hua 
Published: November 2023

AbstractTraditional Chinese medicine (TCM) is increasingly used to manage type 2 diabetes and its nonpharmacological interventions are showing potential for preventing type 2 diabetes. This study mainly reviews relevant research. The most mentioned non-drug treatments for preventing type 2 diabetes in TCM are healthy diet, physical activity, emotional therapy, and acupuncture. In most studies, blood glucose status in patients with prediabetes and type 2 diabetes was significantly improved after TCM non-drug interventions, and there was no significant difference between the adverse effect of TCM and control groups or other intervention groups, while the methodological quality of the clinical trials involving TCM generally kept a low level. The effectiveness of TCM in preventing type 2 diabetes has yet to be validated in large randomized controlled trials and the underlying mechanism also needs further exploration.
Optogenetic activation of dopamine D1 receptors in island cells of medial entorhinal cortex inhibits temporal association learning
Authors: Yokose Jun , Yamamoto Naoki , Ogawa Sachie K. , Kitamura Takashi 
Published: November 2023

AbstractA critical feature of episodic memory formation is to associate temporally segregated events as an episode, called temporal association learning. The medial entorhinal cortical-hippocampal (EC-HPC) networks is essential for temporal association learning. We have previously demonstrated that pyramidal cells in the medial EC (MEC) layer III project to the hippocampal CA1 pyramidal cells and are necessary for trace fear conditioning (TFC), which is an associative learning between tone and aversive shock with the temporal gap. On the other hand, Island cells in MECII, project to GABAergic neurons in hippocampal CA1, suppress the MECIII input into the CA1 pyramidal cells through the feed-forward inhibition, and inhibit TFC. However, it remains unknown about how Island cells activity is regulated during TFC. In this study, we report that dopamine D1 receptor is preferentially expressed in Island cells in the MEC. Optogenetic activation of dopamine D1 receptors in Island cells facilitate the Island cell activity and inhibited hippocampal CA1 pyramidal cell activity during TFC. The optogenetic activation caused the impairment of TFC memory recall without affecting contextual fear memory recall. These results suggest that dopamine D1 receptor in Island cells have a crucial role for the regulation of temporal association learning.