bluuebunny/crossref_metadata_2025_split huggingface dataset:
Catastrophic pharmaceutical expenditure in patients with type 2 diabetes in Iran
Authors: Zarei Leila , Moradi Najmeh , Peiravian Farzad , Hatami-Mazinani Nazafarin , Mahi-Birjand Motahareh , Arabloo Jalal , Babar Zaheer-Ud-Din 
Published: December 2022

Abstract
Objectives
This study aimed to assess the financial burden of out-of-pocket (OOP) payments to purchase antidiabetic medicines for type 2 patients in Iran.

Method
The “budget share” and “capacity to pay” approaches were employed to assess the catastrophic pharmaceutical expenditures of antidiabetic medication therapies. The catastrophic thresholds were adjusted for pharmaceutical sectors. The data was 2019 monthly household expenditures in rural and urban areas, insurance coverages of antidiabetic medicines and patients' out-of-pocket (OOP) payments in 30-day treatment schedules.

Results
The results show that expenditure on diabetes medication therapies in the form of mono-dual therapy and some cases triple oral therapies were not catastrophic even for rural households. Insulin puts patients at risk of catastrophic pharmaceutical expenditures when added to the treatment schedules, and lack of financial protection intensifies it. In general, the poorer households and those resistant to first-line treatments were at increased risk of catastrophic pharmaceutical expenditures. The number of treatments that put patients at risk of catastrophic pharmaceutical expenditure in "budget share" was higher than the "capacity to pay" approach.

Conclusions
Assessing medication treatment affordability instead of a single medicine assessment is needed. Assessment could be done by utilizing a macro-level data approach and applying adjusted pharmaceutical sector threshold values. Considering the variation between treatment schedules that put patients at risk of catastrophic pharmaceutical expenditures, targeted pharmaceutical policies and reimbursement decisions are recommended to promote Universal Health Coverage (UHC) and to protect vulnerable populations from hardship.
Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study
Authors: Michael Tal , Kohn Elkana , Daniel Sharon , Hazan Ariela , Berkovitch Matitiahu , Brik Anna , Hochwald Ori , Borenstein-Levin Liron , Betser Moshe , Moskovich Miki , Livne Ayelet , Keidar Rimona , Rorman Efrat , Groisman Luda , Weiner Zeev , Rabin Adi Malkoff , Solt Ido , Levy Amalia 
Published: December 2022

Abstract
Background
Numerous studies have suggested significant associations between prenatal exposure to heavy metals and newborn anthropometric measures. However, little is known about the effect of various heavy metal mixtures at relatively low concentrations. Hence, this study aimed to investigate associations between prenatal exposures to a wide range of individual heavy metals and heavy metal mixtures with anthropometric measures of newborns.

Methods
We recruited 975 mother–term infant pairs from two major hospitals in Israel. Associations between eight heavy metals (arsenic, cadmium, chromium, mercury, nickel, lead, selenium, and thallium) detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using linear and Bayesian kernel machine regression (BKMR) models.

Results
Most heavy metals examined in our study were observed in lower concentrations than in other studies, except for selenium. In the linear as well as the BKMR models, birth weight and length were negatively associated with levels of chromium. Birth weight was found to be negatively associated with thallium and positively associated with nickel.

Conclusion
By using a large sample size and advanced statistical models, we could examine the association between prenatal exposure to metals in relatively low concentrations and anthropometric measures of newborns. Chromium was suggested to be the most influential metal in the mixture, and its associations with birth weight and length were found negative. Head circumference was neither associated with any of the metals, yet the levels of metals detected in our sample were relatively low. The suggested associations should be further investigated and could shed light on complex biochemical processes involved in intrauterine fetal development.
Responses of the tree peony (Paeonia suffruticosa, Paeoniaceae) cultivar ‘Yu Hong’ to heat stress revealed by iTRAQ-based quantitative proteomics
Authors: Ma Jin , Wang Qun , Wei Ling-Ling , Zhao Yu , Zhang Guo-Zhe , Wang Jie , Gu Cui-Hua 
Published: December 2022

AbstractHorticulture productivity has been increasingly restricted by heat stress from growing global warming, making it far below the optimum production capacity. As a popular ornamental cultivar of tree peony, Paeonia suffruticosa ‘Yu Hong’ has also been suffering from heat stress not suitable for its optimal growth. To better understand the response mechanisms against heat stress of tree peony, investigations of phenotypic changes, physiological responses, and quantitative proteomics were conducted. Phenotypic and physiological changes indicated that 24 h of exposure to heat stress (40 °C) was the critical duration of heat stress in tree peony. The proteomic analyses revealed a total of 100 heat-responsive proteins (HRPs). According to bioinformatic analysis of HRPs, the heat tolerance of tree peony might be related to signal transduction, synthesis/degradation, heat kinetic proteins, antioxidants, photosynthesis, energy conversion, and metabolism. Our research will provide some new insights into the molecular mechanism under the response against the heat stress of tree peony, which will benefit the future breeding of heat-resistant ornamental plants.
Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials
Authors: Bellerba Federica , Chatziioannou Anastasia Chrysovalantou , Jasbi Paniz , Robinot Nivonirina , Keski-Rahkonen Pekka , Trolat Amarine , Vozar Béatrice , Hartman Sheri J. , Scalbert Augustin , Bonanni Bernardo , Johansson Harriet , Sears Dorothy D. , Gandini Sara 
Published: December 2022

AbstractBackgroundObesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment.MethodsFasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment.ResultsParticipants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism.ConclusionsOur results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies.Trial registrationClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.
Interleukin-3 is associated with sTREM2 and mediates the correlation between amyloid-β and tau pathology in Alzheimer’s disease
Authors: Wang Zhi-Bo , Ma Ya-Hui , Sun Yan , Tan Lan , Wang Hui-Fu , Yu Jin-Tai ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundDysfunction of glial cell communication is involved in Alzheimer’s disease (AD) pathogenesis, and the recent study reported that astrocytic secreted interleukin-3 (IL-3) participated in astrocyte–microglia crosstalk and restricted AD pathology in mice, but the effect of IL-3 on the pathological progression of AD in human is still unclear.MethodsA total of 311 participants with cerebrospinal fluid (CSF) IL-3, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and AD biomarkers were included from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We assessed the associations of IL-3 with sTREM2 and AD biomarkers at baseline, and with cognitive change in longitudinal study. The mediation models were used to explore the potential mechanism of how IL-3 affects AD pathology.ResultsWe found that CSF IL-3 was significantly associated with CSF sTREM2 and CSF AD core biomarkers (Aβ42, p-tau, and t-tau) at baseline, and was also markedly related to cognitive decline in longitudinal analysis. Moreover, mediation analysis revealed that CSF IL-3 modulated the level of CSF sTREM2 and contributed to tau pathology (as measured by CSF p-tau/t-tau) and subsequent cognitive decline. In addition, Aβ pathology (as measured by CSF Aβ42) affected the development of tau pathology partly by modifying the levels of CSF IL-3 and CSF sTREM2. Furthermore, the effect of Aβ pathology on cognitive decline was partially mediated by the pathway from CSF IL-3 and CSF sTREM2 to tau pathology.ConclusionsOur findings provide evidence to suggest that IL-3 is linked to sTREM2 and mediates the correlation between Aβ pathology to tau pathology. It indicates that IL-3 may be a major factor in the spreading from Aβ pathology to tau pathology to cognitive impairment.
Immune checkpoint blockade PD-1 therapy for primary liver cancer: incidence and influencing factors of thyroid dysfunction
Authors: Wu Huili , Xiong Fang , Bao Xuli , Lu Jun 
Published: December 2022

Abstract
Objectives
To investigate the incidence and influencing factors of thyroid dysfunction (TD) in patients with primary liver cancer (PLC) induced by PD-1 monoclonal antibodies.

Methods
Clinical data were collected from 195 PLC patients treated with PD-1. They were divided into TD group and normal thyroid function (NTF) group, and further divided into TD subgroups, the differences between groups and subgroups were analyzed.

Results
A total of 113 of 195 (57.9%) PLC patients developed TD. The positive rate of thyroid antibody (20.6% vs. 0%, P = 0.041) and the median value of TSH (6.20 vs. 2.16 mU/L, P = 0.000) in TD group were higher than those in NTF group. Ten patients (8.8%) had the CTCAE grade of TD above grade 3, of which 2 patients died of liver failure. There were 20 patients (17.7%) in hyperthyroidism group and 93 patients (82.3%) in hypothyroidism group. The decompensated cirrhosis in hyperthyroidism group was lower than that in hypothyroidism group (33.3% vs. 65.6%, P = 0.010), and the proportion of patients who had previously received surgical treatment was higher than that in hypothyroidism group (35.0% vs. 9.7%, P = 0.003); The proportion of clinical hyperthyroidism was higher than that of clinical hypothyroidism (70.0% vs. 31.2%, P = 0.001), the proportion of decompensated liver cirrhosis in clinical hyperthyroidism group was lower than that in clinical hypothyroidism group (23.1% vs. 68.0%, P = 0.022), and the proportion of previous or combined surgical resection was much higher than that in clinical hypothyroidism group (42.9% vs. 7.1%, P = 0.018); The proportion of decompensated cirrhosis in primary TD group was lower than that in secondary TD group (36.5% vs. 83.3%, P = 0.002), and the proportion of patients using antitumor targeted drugs was higher than that in secondary TD group (73.1% vs. 45.0%, P = 0.014).

Conclusion
Patients with PLC had high incidence of TD after receiving PD-1 treatment, primary or subclinical hypothyroidism was the main manifestation type, which was related to the degree of disease and treatment.
Correlation between intracranial pressure monitoring for severe traumatic brain injury with hospital length of stay and discharge disposition: a retrospective observational cohort study
Authors: Foote Christopher W. , Jarvis Stephanie , Doan Xuan-Lan , Guice Jordan , Cruz Bianca , Vanier Cheryl , Betancourt Alejandro , Bar-Or David , Palacio Carlos H. 
Published: December 2022

Abstract
Objectives
Intracranial pressure (ICP) monitoring is recommended for severe traumatic brain injuries (TBI) but some data suggests it may not improve outcomes. The objective was to investigate the effect of ICP monitoring among TBI.

Methods
This retrospective observational cohort study (1/1/2015–6/1/2020) included severe TBI patients. Outcomes [discharge destination, length of stay (LOS)] were compared by ICP monitoring and were stratified by GCS (3 vs. 4–8), α < 0.05.

Results
Of the123 patients who met inclusion criteria, 47% received ICP monitoring. There were baseline differences in the two groups characteristics, ICP monitored patients were younger (p = 0.02), had a subarachnoid hemorrhage less often (p = 0.04), and a subdural hematoma more often (p = 0.04) than those without ICP monitors. ICP monitored patients had a significantly longer median LOS (12 vs. 3, p < 0.01) than patients without monitoring. There was a trend towards more ICP monitored patients discharged home (40% vs. 23%, p = 0.06). Among patients with GCS = 3, ICP monitored patients had a longer LOS (p < 0.01) with no significant differences in discharge destinations. For those with a GCS of 4–8, ICP monitoring was associated with a longer LOS (p = 0.01), but fewer were discharged to a skilled nursing facility or long-term care (p = 0.01).

Conclusions
For TBI patients, ICP monitoring was associated with an increased LOS, with no significant differences in discharge destinations when compared to those without ICP monitoring. However, among only those with a GCS of 4–8, ICP monitoring was associated with a decreased proportion of patients discharged to a skilled nursing facility or long-term acute care .
Sushi domain-containing protein 4 binds to epithelial growth factor receptor and initiates autophagy in an EGFR phosphorylation independent manner
Authors: Papadakos Konstantinos S. , Ekström Alexander , Slipek Piotr , Skourti Eleni , Reid Steven , Pietras Kristian , Blom Anna M. 
Published: December 2022

Abstract
Background
Sushi domain-containing protein 4 (SUSD4) is a recently discovered protein with unknown cellular functions. We previously revealed that SUSD4 can act as complement inhibitor and as a potential tumor suppressor.

Methods
In a syngeneic mouse model of breast cancer, tumors expressing SUSD4 had a smaller volume compared with the corresponding mock control tumors. Additionally, data from three different expression databases and online analysis tools confirm that for breast cancer patients, high mRNA expression of SUSD4 in the tumor tissue correlates with a better prognosis. In vitro experiments utilized triple-negative breast cancer cell lines (BT-20 and MDA-MB-468) stably expressing SUSD4. Moreover, we established a cell line based on BT-20 in which the gene for EGFR was knocked out with the CRISPR-Cas9 method.

Results
We discovered that the Epithelial Growth Factor Receptor (EGFR) interacts with SUSD4. Furthermore, triple-negative breast cancer cell lines stably expressing SUSD4 had higher autophagic flux. The initiation of autophagy required the expression of EGFR but not phosphorylation of the receptor. Expression of SUSD4 in the breast cancer cells led to activation of the tumor suppressor LKB1 and consequently to the activation of AMPKα1. Finally, autophagy was initiated after stimulation of the ULK1, Atg14 and Beclin-1 axis in SUSD4 expressing cells.

Conclusions
In this study we provide novel insight into the molecular mechanism of action whereby SUSD4 acts as an EGFR inhibitor without affecting the phosphorylation of the receptor and may potentially influence the recycling of EGFR to the plasma membrane.
Second generation Pichia pastoris strain and bioprocess designs
Authors: Ergün Burcu Gündüz , Laçın Kübra , Çaloğlu Buse , Binay Barış 
Published: December 2022

AbstractYeast was the first microorganism used by mankind for biotransformation processes that laid the foundations of industrial biotechnology. In the last decade,Pichia pastorishas become the leading eukaryotic host organism for bioproduct generation. Most of theP. pastorisbioprocess operations has been relying on toxic methanol and glucose feed. In the actual bioeconomy era, for sustainable value-added bioproduct generation, non-conventional yeastP. pastorisbioprocess operations should be extended to low-cost and renewable substrates for large volume bio-based commodity productions. In this review, we evaluated the potential ofP. pastorisfor the establishment of circular bioeconomy due to its potential to generate industrially relevant bioproducts from renewable sources and waste streams in a cost-effective and environmentally friendly manner. Furthermore, we discussed challenges with the second generationP. pastorisplatforms and propose novel insights for future perspectives. In this regard, potential of low cost substrate candidates, i.e., lignocellulosic biomass components, cereal by-products, sugar industry by-products molasses and sugarcane bagasse, high fructose syrup by-products, biodiesel industry by-product crude glycerol, kitchen waste and other agri-food industry by products were evaluated forP. pastoriscell growth promoting effects and recombinant protein production. Further metabolic pathway engineering ofP. pastoristo construct renewable and low cost substrate utilization pathways was discussed. Although, second generationP. pastorisbioprocess operations for valorisation of wastes and by-products still in its infancy, rapidly emerging synthetic biology tools and metabolic engineering ofP. pastoriswill pave the way for more sustainable environment and bioeconomy. From environmental point of view, second generation bioprocess development is also important for waste recycling otherwise disposal of carbon-rich effluents creates environmental concerns.P. pastorishigh tolerance to toxic contaminants found in lignocellulosic biomass hydrolysate and industrial waste effluent crude glycerol provides the yeast with advantages to extend its applications toward second generationP. pastorisstrain design and bioprocess engineering, in the years to come.Graphical Abstract
Improving the productivity of malic acid by alleviating oxidative stress during Aspergillus niger fermentation
Authors: Wu Na , Xing Mingyan , Chen Yaru , Zhang Chi , Li Yingfeng , Song Ping , Xu Qing , Liu Hao , Huang He 
Published: December 2022

Abstract
Background
As an attractive platform chemical, malic acid has been commonly used in the food, feed and pharmaceutical field. Microbial fermentation of biobased sources to produce malic acid has attracted great attention because it is sustainable and environment-friendly. However, most studies mainly focus on improving yield and ignore shortening fermentation time. A long fermentation period means high cost, and hinders the industrial applications of microbial fermentation. Stresses, especially oxidative stress generated during fermentation, inhibit microbial growth and production, and prolong fermentation period. Previous studies have shown that polypeptides could effectively relieve stresses, but the underlying mechanisms were poorly understood.

Results
In this study, polypeptides (especially elastin peptide) addition improves the productivity of malic acid in A. niger, resulting in shortening of fermentation time from 120 to 108 h. Transcriptome and biochemical analyses demonstrated that both antioxidant enzyme-mediated oxidative stress defense system, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), and nonenzymatic antioxidant system, such as glutathione, were enhanced in the presence of elastin peptide, suggesting elastin peptide relieving oxidative stresses is involved in many pathways. In order to further investigate the relationship between oxidative stress defense and malic acid productivity, we overexpressed three enzymes (Sod1, CAT, Tps1) related to oxidation resistance in A. niger, respectively, and these resulting strains display varying degree of improvement in malic acid productivity. Especially, the strain overexpressing the Sod1 gene achieved a malate titer of 91.85 ± 2.58 g/L in 96 h, corresponding to a productivity of 0.96 g/L/h, which performs better than elastin peptide addition.

Conclusions
Our investigation provides an excellent reference for alleviating the stress of the fungal fermentation process and improving fermentation efficiency.