bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe α1-antitrypsin deficiency associated with lower blood pressure and reduced risk of ischemic heart disease: a cohort study of 91,540 individuals and a meta-analysis
Authors: Winther Sine Voss , Ahmed Dunia , Al-Shuweli Suzan , Landt Eskild Morten , Nordestgaard Børge Grønne , Seersholm Niels , Dahl Morten 
Published: March 2022

Abstract
Background
Increased elastase activity in α1-antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α1-antitrypsin deficiency is associated with reduced blood pressure and susceptibility to cardiovascular disease.

Methods
We genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish α1-Antitrypsin Deficiency Registry and recorded baseline blood pressure, baseline plasma lipids and cardiovascular events during follow-up. 185 participants carried the ZZ genotype, 207 carried the SZ genotype and 91,148 carried the MM genotype.

Results
α1-Antitrypsin deficiency was associated with decreases in blood pressure of up to 5 mmHg for systolic blood pressure and up to 2 mmHg for diastolic blood pressure, in ZZ vs SZ vs MM individuals (trend test, P’s ≤ 0.01). Plasma triglycerides and remnant cholesterol were reduced in ZZ individuals compared with MM individuals (t-test, P’s < 0.001). α1-Antitrypsin deficiency was associated with lower risk of myocardial infarction (trend test P = 0.03), but not with ischemic heart disease, ischemic cerebrovascular disease or hypertension (trend test, P’s ≥ 0.59). However, when results for ischemic heart disease were summarized in meta-analysis with results from four previous studies, individuals with versus without α1-antitrypsin deficiency had an odds ratio for ischemic heart disease of 0.66 (95% CI:0.53–0.84).

Conclusions
Individuals with severe α1-antitrypsin deficiency have lower systolic and diastolic blood pressure, lower plasma triglycerides and remnant cholesterol, reduced risk of myocardial infarction, and a 34% reduced risk of ischemic heart disease.
Citizens’ opinions and experiences related to costs and reimbursements for medications in times of retrenchment: cross-sectional population surveys in 2015 and 2017
Authors: Aaltonen Katri , Niemelä Mikko , Prix Irene 
Published: March 2022

AbstractBackgroundFinland has universal coverage for prescription medications under the National Health Insurance. Eligibility schemes target higher reimbursements to individuals with chronic illness. Nevertheless, co-payments always apply, and austerity reforms implemented in 2016 and 2017 led to further increases in co-payments. We examined the extent to which people with chronic illness experienced financial difficulties in purchasing medications, how perceptions of fairness regarding the national reimbursements differs by exposure to policies and medicine use, and in what way do these experiences and opinions vary between surveys collected before and after the reforms.MethodsWe used two waves of Medicines Barometer (2015 and 2017, pooledn = 10,801), a national, biennial, cross-sectional population survey. Logistic regression analyses were performed with experiences of financial difficulties and perceptions of fairness as dependent variables. We compared people with and without prescription medication use, eligibilities, and/or diabetes (exposure groups), controlling for age, gender, survey type and geographic area (NUTS2). To examine the modifying effect of study year, we fitted models with an interaction term between group and year.ResultsRespondents with diabetes or eligibility based on chronic illness had a notably higher risk than other respondents with at least some prescription medication use to have experienced financial difficulties in affording medications. The share of respondents experiencing difficulties increased the most among people with diabetes. Three-quarters of respondents were either critical or unsure of whether the reimbursements for medications were fair and just. People with recent prescription medication use tended to be more sceptical than people without. Overall, scepticism tended to be more prevalent in 2017 than in 2015.ConclusionsDespite the protective policies in place, individuals with chronic illness were disproportionately burdened by costs of medications already before the reforms. Among individuals with diabetes, financial difficulties were even more prevalent in 2017 than in 2015, which is likely attributed to the particularly high co-payment increases targeted to type 2 diabetes medicines. Perceived fairness of the processes and outcomes of policies and regulations is a key dimension of trust in public policy. Thus, increasing scepticism implies that retrenchment may also have implications in terms of public legitimacy.
Ceria-Zirconia nanoparticles reduce intracellular globotriaosylceramide accumulation and attenuate kidney injury by enhancing the autophagy flux in cellular and animal models of Fabry disease
Authors: An Jong Hun , Hong Sang-Eun , Yu Seong-Lan , Kang Jaeku , Park Chang Gyo , Lee Hoi Young , Lee Sung-Ki , Lee Dong Chul , Park Hwan-Woo , Hwang Won-Min , Yun Sung-Ro , Park Yohan , Park Moon Hyang , Yoon Kuk Ro , Yoon Se-Hee 
Published: March 2022

AbstractBackgroundFabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid–polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We analyzed whether they suppress globotriaosylceramide (Gb3) accumulation by enhancing autophagy flux and thereby attenuate kidney injury in both cellular and animal models of FD.ResultsGb3 was significantly increased in cultured human renal proximal tubular epithelial cells (HK-2) and human podocytes following the siRNA silencing of α galactosidase A (α-GLA). PEG-CZNPs effectively reduced the intracellular accumulation of Gb3 in both cell models of FD and improved both intracellular inflammation and apoptosis in the HK-2 cell model of FD. Moreover these particles attenuated pro fibrotic cytokines in the human podocyte model of FD. This effect was revealed through an improvement of the intracellular autophagy flux function and a reduction in reactive oxygen species (ROS). An FD animal model was generated in which 4-week-old maleB6;129-Glatm1Kul/J mice were treated for 8 weeks with 10 mg/kg of PEG-CZNPs (twice weekly via intraperitoneal injection). Gb3 levels were reduced in the kidney tissues of these animals, and their podocyte characteristics and autophagy flux functions were preserved.ConclusionsPEG-CZNPs alleviate FD associated kidney injury by enhancing autophagy function and thus provide a foundation for the development of new drugs to treat of storage disease.Graphical Abstract
RETRACTED ARTICLE: Artificial photoactive chlorophyll conjugated vanadium carbide nanostructure for synergistic photothermal/photodynamic therapy of cancer
Authors: Lu Huiting , Zada Shah , Tang Songsong , Yaru Cheng , Wei Wei , Yuchun Qiao , Yang Qiqi , Du Jinya , Fu Pengcheng , Dong Haifeng , Zhang Xueji 
Published: March 2022

AbstractOptically active nanostructures consisting of organic compounds and metallic support have shown great promise in phototherapy due to their increased light absorption capacity and high energy conversion. Herein, we conjugated chlorophyll (Chl) to vanadium carbide (V2C) nanosheets for combined photodynamic/photothermal therapy (PDT/PTT), which reserves the advantages of each modality while minimizing the side effects to achieve an improved therapeutic effect. In this system, the Chl from Leptolyngbya JSC-1 extracts acted as an efficient light-harvest antenna in a wide NIR range and photosensitizers (PSs) for oxygen self-generation hypoxia-relief PDT. The available large surface of two-dimensional (2D) V2C showed high Chl loading efficiency, and the interaction between organic Chl and metallic V2C led to energy conversion efficiency high to 78%. Thus, the Chl/ V2C nanostructure showed advanced performance in vitro cell line killing and completely ablated tumors in vivo with 100% survival rate under a single NIR irradiation. Our results suggest that the artificial optical Chl/V2C nanostructure will benefit photocatalytic tumor eradication clinic application.
Graphical Abstract
Visualization of the process of a nanocarrier-mediated gene delivery: stabilization, endocytosis and endosomal escape of genes for intracellular spreading
Authors: Ma Zhongzheng , Zheng Yang , Chao Zijian , Chen Hongtao , Zhang Yunhui , Yin Meizhen , Shen Jie , Yan Shuo 
Published: March 2022

AbstractNanoparticles have been widely applied as gene carrier for improving RNA interference (RNAi) efficiency in medical and agricultural fields. However, the mechanism and delivery process of nanoparticle-mediated RNAi is not directly visualized and elucidated. Here we synthesized a star polymer (SPc) consisted of a hydrophilic shell with positively-charged tertiary amine in the side chain, which was taken as an example to investigate the mechanism in gene delivery. The SPc could assemble with dsRNA spontaneously through electrostatic force, hydrogen bond and van der Waals force. Interestingly, the SPc could protect dsRNA from degradation by RNase A and insect hemolymph, thus remarkably increasing the stability of dsRNA. Meanwhile, the SPc could efficiently promote the cellular uptake and endosomal escape for intracellular spreading of dsRNA. Transcriptome analysis revealed that the SPc could up-regulate some key genes such asChc,AP2S1andArf1for activating clathrin-mediated endocytosis. Furthermore, the suppression of endocytosis hindered the cellular uptake of SPc-delivered dsRNA in vitro, and the subsequent RNAi effect was also disappeared in vivo.To our knowledge, our study is the first direct visualization of the detailed cellular delivery process and mechanism of nanocarrier-mediated gene delivery. Above mechanism supports the application of nanocarrier-based RNAi in gene therapy and pest management.Graphical Abstract
Integrative metabolomic profiling reveals aberrations in myometrium associated with adenomyosis: a pilot study
Authors: Song Wei , Zhang Zhibo , Jiang Ying , Cao Yang , Zhang Bo , Wang Yujie , Shi Honghui , Zhu Lan 
Published: March 2022

AbstractBackgroundUterine adenomyosis is a common gynecologic disease in premenopausal women, the pathological mechanism of which remains largely unknown. The aim of this study was to identify metabolic biomarkers significantly altered in the myometrium of adenomyosis patients.MethodsThe comprehensive metabolomic profiles of 17 myometrium specimens from adenomyosis patients and 25 control specimens were analyzed using untargeted approach by combination of gas chromatography–mass spectrometry and high performance liquid chromatography-mass spectrometry. Metabolic data were filtered using orthogonal partial least square-discriminant analysis and univariate statistics.ResultsWe firstly demonstrated that the myometrial metabolome of women with adenomyosis is distinct from that of women without adenomyosis. A total of 106 metabolites, mainly including nucleosides, lipids (including acylcarnitines), amino acids, organic acids and carbohydrates, were found to be differentially expressed in myometrium of uteri with adenomyosis compared to the control subjects. Functional inferences of these perturbed metabolites indicated that inflammation, oxidative stress, cell proliferation and apoptosis, and energy metabolism appeared to be involved in the progress of adenomyosis.ConclusionThis study firstly described the integrated metabolic signatures of the adenomyosis uterus, which provided novel insights for the pathogenesis study of this disease.
Changes in the intestinal expression of drug metabolism-related genes in a piglet model of parenteral nutrition
Authors: Dai Li-Na , Zhao Yu-Ling , Jiang Lu , Yan Jun-Kai 
Published: March 2022

Abstract
Background
Parenteral nutrition (PN) may serve as a nutritional supportive therapy accompanied by oral medication, but the effect of PN on intestinal expression of drug metabolism-related genes remains unknown.

Methods
Twelve Bama piglets receiving PN for 14 days were used as in vivo model. Changes in intestinal drug metabolism-related genes were examined by proteomic analysis. Serum levels of fibroblast growth factor 19 (FGF19) were determined by ELISA, and the effect of FGF19 on the expression of drug metabolism-related genes was examined using murine ileum organoids.

Results
A total of 1063 differentially expressed proteins were identified in PN group. Of note, two drug transporters (Abcb1 and Abcc2) were significantly decreased in PN group, along with two glutathione-related drug-metabolizing enzymes, glutathione peroxidase (Gpx2) and glutathione S-transferase (Gsta1). Serum FGF19 levels were dramatically reduced in PN group. Treatment with recombinant FGF19 in vitro dose-dependently up-regulated the expression of Abcb1, Abcc2, Gpx2 and Gsta1 in organoids.

Conclusion
Our data indicated that intestinal drug metabolism-related genes were significantly dysregulated under PN, and some of the changed genes were attributed to gut-derived FGF19.
Quantification of biological range uncertainties in patients treated at the Krakow proton therapy centre
Authors: Garbacz Magdalena , Gajewski Jan , Durante Marco , Kisielewicz Kamil , Krah Nils , Kopeć Renata , Olko Paweł , Patera Vincenzo , Rinaldi Ilaria , Rydygier Marzena , Schiavi Angelo , Scifoni Emanuele , Skóra Tomasz , Skrzypek Agata , Tommasino Francesco , Rucinski Antoni 
Published: March 2022

Abstract
Background
Variable relative biological effectiveness (vRBE) in proton therapy might significantly modify the prediction of RBE-weighted dose delivered to a patient during proton therapy. In this study we will present a method to quantify the biological range extension of the proton beam, which results from the application of vRBE approach in RBE-weighted dose calculation.

Methods and materials
The treatment plans of 95 patients (brain and skull base patients) were used for RBE-weighted dose calculation with constant and the McNamara RBE model. For this purpose the Monte Carlo tool FRED was used. The RBE-weighted dose distributions were analysed using indices from dose-volume histograms. We used the volumes receiving at least 95% of the prescribed dose (V95) to estimate the biological range extension resulting from vRBE approach.

Results
The vRBE model shows higher median value of relative deposited dose and D95 in the planning target volume by around 1% for brain patients and 4% for skull base patients. The maximum doses in organs at risk calculated with vRBE was up to 14 Gy above dose limit. The mean biological range extension was greater than 0.4 cm.

Discussion
Our method of estimation of biological range extension is insensitive for dose inhomogeneities and can be easily used for different proton plans with intensity-modulated proton therapy (IMPT) optimization. Using volumes instead of dose profiles, which is the common method, is more universal. However it was tested only for IMPT plans on fields arranged around the tumor area.

Conclusions
Adopting a vRBE model results in an increase in dose and an extension of the beam range, which is especially disadvantageous in cancers close to organs at risk. Our results support the need to re-optimization of proton treatment plans when considering vRBE.
Prevalence of bacterial species associated with ovine footrot and contagious ovine digital dermatitis in Swedish slaughter lambs
Authors: Rosander Anna , Albinsson Rebecka , König Ulrika , Nyman Ann , Frosth Sara 
Published: March 2022

Abstract
Background
Ovine footrot and contagious ovine digital dermatitis (CODD) are contagious mixed bacterial infections with major impacts on animal health and production. In Sweden, ovine footrot and CODD were first detected in 2004 and 2019, respectively. In 2009, a voluntary control programme for footrot was established, and a prevalence study in slaughter lambs was conducted, however, the distribution of footrot and CODD-associated bacteria is still unknown. This study examined the prevalence of Dichelobacter nodosus, Fusobacterium necrophorum and Treponema spp., as well as the current prevalence of footrot and CODD, in Swedish slaughter lambs.

Results
A total of 2048 feet, from 512 slaughter lambs, were collected from eight slaughterhouses throughout Sweden in autumn 2020. All feet were visually examined for lesions of footrot and CODD and sampled for subsequent real-time polymerase chain reaction (PCR) analysis. Nine lambs (1.8%) had at least one foot affected with footrot (footrot score ≥ 2). A CODD grade 1 lesion was detected in a single lamb (0.2%). The prevalence of D. nodosus, F. necrophorum and Treponema spp. was 6.1%, 7.6% and 90.6%, respectively. The D. nodosus detected were benign strains.

Conclusions
The prevalence of footrot in Swedish slaughter lambs has been significantly reduced, from 5.8 to 1.8%, during the past 11 years. This indicates that preventive measures, such as the national control programme and elimination of footrot from affected flocks, have been effective. A single lamb (0.2%) was found with a CODD lesion (grade 1). In Sweden, benign rather than virulent strains of D. nodosus seem to be the most common. Neither D. nodosus nor F. necrophorum were widespread among Swedish slaughter lambs, but both were more likely to be found in lambs with footrot. Treponema spp. was very commonly found in lambs with and without footrot, but there is a lack of information on the individual Treponema spp. present in Swedish slaughter lambs and their potential pathogenicity.
BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers
Authors: Khan Sajid , Wiegand Janet , Zhang Peiyi , Hu Wanyi , Thummuri Dinesh , Budamagunta Vivekananda , Hua Nan , Jin Lingtao , Allegra Carmen J. , Kopetz Scott E. , Zajac-Kaye Maria , Kaye Frederic J. , Zheng Guangrong , Zhou Daohong 
Published: March 2022

AbstractKRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRASG12C inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-XL proteolysis targeting chimera [PROTAC]) on KRASG12C-mutated NSCLC, CRC and pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced BCL-XL/BIM interaction leading to enhanced apoptosis in KRASG12C tumor cell lines. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.
Italian intersociety consensus on management of long covid in children
Authors: Esposito Susanna , Principi Nicola , Azzari Chiara , Cardinale Fabio , Di Mauro Giuseppe , Galli Luisa , Gattinara Guido Castelli , Fainardi Valentina , Guarino Alfredo , Lancella Laura , Licari Amelia , Mancino Enrica , Marseglia Gian Luigi , Leonardi Salvatore , Nenna Raffaella , Zampogna Stefania , Zona Stefano , Staiano Annamaria , Midulla Fabio 
Published: March 2022

AbstractBackgroundTwo sequelae of pediatric COVID-19 have been identified, the multisystem inflammatory syndrome in children (MIS-C) and the long COVID. Long COVID is much less precisely defined and includes all the persistent or new clinical manifestations evidenced in subjects previously infected by SARS-CoV-2 beyond the period of the acute infection and that cannot be explained by an alternative diagnosis. In this Intersociety Consensus, present knowledge on pediatric long COVID as well as how to identify and manage children with long COVID are discussed.Main findingsAlthough the true prevalence of long COVID in pediatrics is not exactly determined, it seems appropriate to recommend evaluating the presence of symptoms suggestive of long COVID near the end of the acute phase of the disease, between 4 and 12 weeks from this. Long COVID in children and adolescents should be suspected in presence of persistent headache and fatigue, sleep disturbance, difficulty in concentrating, abdominal pain, myalgia or arthralgia. Persistent chest pain, stomach pain, diarrhea, heart palpitations, and skin lesions should be considered as possible symptoms of long COVID. It is recommended that the primary care pediatrician visits all subjects with a suspected or a proven diagnosis of SARS-CoV-2 infection after 4 weeks to check for the presence of symptoms of previously unknown disease. In any case, a further check-up by the primary care pediatrician should be scheduled 3 months after the diagnosis of SARS-CoV-2 infection to confirm normality or to address emerging problems. The subjects who present symptoms of any organic problem must undergo a thorough evaluation of the same, with a possible request for clinical, laboratory and / or radiological in-depth analysis in case of need. Children and adolescents with clear symptoms of mental stress will need to be followed up by existing local services for problems of this type.ConclusionsPediatric long COVID is a relevant problem that involve a considerable proportion of children and adolescents. Prognosis of these cases is generally good as in most of them symptoms disappear spontaneously. The few children with significant medical problems should be early identified after the acute phase of the infection and adequately managed to assure complete resolution. A relevant psychological support for all the children during COVID-19 pandemic must be organized by health authorities and government that have to treat this as a public health issue.