bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose Range-Finding Toxicity Study in Rats With Recombinant Human Lactoferrin Produced in Komagataella phaffii
Authors: Peterson Ross , Crawford Robert B. , Blevins Lance K. , Kaminski Norbert E. , Sass June S. , Ferraro Bryce , Vishwanath-Deutsch Roma , Clark Anthony J. , Malinczak Carrie-Anne 
Published: April 2024

The oral toxicity of recombinant human lactoferrin (rhLF, Helaina rhLF, Effera™) produced in Komagataella phaffii was investigated in adult Sprague Dawley rats by once daily oral gavage for 14 consecutive days. The study used groups of 3–6 rats/sex/dose. The vehicle control group received sodium citrate buffer, and the test groups received daily doses of 200, 1000, and 2000 mg of rhLF in sodium citrate buffer per kg body weight. Bovine LF at 2000 mg/kg body weight per day was used as a comparative control. Clinical observations, body weight, hematology, clinical chemistry, iron parameters, immunophenotyping, and gross examination at necropsy were used as criteria for detecting the effects of treatment in all groups and to help select dose levels for future toxicology studies. Quantitative LF levels were also analyzed as an indication of bioavailability. Overall, administration of Helaina rhLF by once daily oral gavage for 14 days was well tolerated in rats at levels up to 2000 mg/kg/day, or 57 × Helaina’s intended commercial use in adults, and indicating that a high dose of 2000 mg/kg/day is appropriate for future definitive toxicology studies.
Luteolin Inhibits Lung Cancer Cell Migration by Negatively Regulating TWIST1 and MMP2 Through Upregulation of miR-106a-5p
Authors: Wang Qiang , Chen Mengyuan , Tang Xiaofang 
Published: April 2024

Background: Luteolin, a common dietary flavonoid found in plants, has been shown to have anti-cancer properties. However, its exact mechanisms of action in non-small cell lung cancer (NSCLC) are still not fully understood, particularly its role in regulating broader genomic networks and specific gene targets. In this study, we aimed to elucidate the role of microRNAs (miRNAs) in NSCLC treated with luteolin, using A549 cells as a model system. Materials and Methods: miRNA profiling was conducted on luteolin-treated A549 cells using Exiqon microarrays, with validation of selected miRNAs by qRT-PCR. Bioinformatic analysis identified the regulatory roles of miRNAs in biological processes and pathways following luteolin treatment. Computational algorithms were employed to identify potential target genes. A549 cells were transfected with miR-106a-5p mimic and inhibitor or their corresponding controls. The expression levels of 2 genes, twist basic helix-loop-helix transcription factor 1 (TWIST1) and matrix metallopeptidase 2 (MMP2), and cell migration were assessed. Results: miRNA profiling identified 341 miRNAs, with 18 exhibiting significantly altered expression ( P < 0.05). Subsequent qRT-PCR analysis confirmed altered expression of 6 selected miRNAs. KEGG and GO analyses revealed significant alterations in pathways and biological processes crucial for tumor biology. TWIST1 and MMP2, which both contain conserved miR-106a-5p binding sites, exhibited an inverse correlation with the expression levels of miR-106a-5p. Dual-luciferase reporter assays confirmed TWIST1 and MMP2 as direct targets of miR-106a-5p. Luteolin treatment led to a reduction in A549 cell migration, and this reduction was further amplified by the overexpression of miR-106a-5p. Conclusion: Luteolin inhibits A549 cell migration by modulating the miRNA landscape, shedding light on its mechanisms and laying the foundation for miRNA-based therapeutic approaches for NSCLC.
Long-term real-world data of ustekinumab in Crohn’s disease: the Stockholm ustekinumab study
Authors: Bello Francesca , Muhsen Samer , Sabhan Haider , Borin Alexandra , Johansson Fredrik , Höög Charlotte , Forsberg Ole , Wennerström Christina , Söderman Charlotte , Lördal Mikael , Almer Sven 
Published: April 2024

Background: Ustekinumab is used to treat inflammatory bowel disease mainly in patients failing anti-tumour necrosis factor (TNF)-agents. Objectives: To provide real-world data in unselected patients with Crohn’s disease (CD), treated with ustekinumab. Design: Longitudinal retrospective study at four hospitals in Stockholm, Sweden. Methods: Disease activity (Harvey–Bradshaw index and physician global assessment), laboratory parameters, endoscopic findings and drug persistence were assessed. Follow-up data were obtained in patients that stopped ustekinumab. Results: In total, 322 patients (median age 38 years, 48% women) were included. All had luminal disease and 22% also fistulizing disease. A total of 271 (84%) had failed ⩾1 and 148 (46%) ⩾2 anti-TNF drugs; 34% failed vedolizumab. At inclusion, 93% had active disease; 28% were on oral corticosteroids and 18% on thiopurines. The median follow-up on treatment was 13.5 months; overall 67% were followed at least 24 months. By intention to treat analysis, response rate at 3 and 12 months was 43% and 42%, respectively. Among patients with ongoing ustekinumab, 19% were in steroid-free remission at 3 months and 64% at 12 months. The median faecal calprotectin level decreased from 460 µg/g at baseline to 156 µg/g at 3 months and was 182 µg/g at 12 months. C-reactive protein remained stable at 4 mg/L whereas serum albumin increased slightly. About 31% of patients were withdrawn during the first 12 months, mainly due to persisting disease activity 21%, adverse events 5%, bowel surgery 0.6% or malignancy 0.3%. The overall persistence on ustekinumab was 88%, 51%, 34% and 20% at 3, 12, 24 and 36 months, respectively. Within 12 months following withdrawal of ustekinumab in 121 patients, 64% had active disease most of the time, 68% needed another biologic and 24% underwent surgery. Conclusion: Among difficult-to-treat patients with CD, ustekinumab was effective in the majority, with high drug persistence at 12 and 24 months in combination with a favourable safety profile.
mTOR signaling pathway regulation HIF-1 α effects on LPS induced intestinal mucosal epithelial model damage
Authors: Huang Zeyong , Teng Wenbin , Yao Liuxu , Xie Kai , Hang Suqin , He Rui , Li Yuhong 
Published: April 2024

Abstract
Background
Sepsis-induced small-intestinal injury is associated with increased morbidity and mortality. Our previous study and other papers have shown that HIF-1α has a protective effect on intestinal mucosal injury in septic rats. The purpose of this study is to further verify the protective effect of HIF-1α on intestinal mucosa and its molecular mechanism in vitro experiments.

Methods
Caco-2 cells were selected and experiment was divided into 2 parts. Part I: HIF-1α activator and inhibitor were used to treat lipopolysacchrides (LPS)-stimulated Caco-2 cells respectively, to explore the effect of HIF-1α on LPS induced Caco-2 cell epithelial model; Part II: mTOR activator or inhibitor combined with or without HIF-1α activator, inhibitor to treat LPS-stimulated Caco-2 cells respectively, and then the molecular mechanism of HIF-1α reducing LPS induced Caco-2 cell epithelial model damage was detected.

Results
The results showed that HIF-1α activator decreased the permeability and up regulated tight junction (TJ) expression, while HIF-1α inhibitor had the opposite effect with the HIF-1α activator. mTOR activation increased, while mTOR inhibition decreased HIF-1α protein and expression of its downstream target molecules, which can be attenuated by HIF-1α activator or inhibitor.

Conclusion
This study once again confirmed that HIF-1α alleviates LPS-induced mucosal epithelial model damage through P70S6K signalling pathway. It is of great value to explore whether HIF-2α plays crucial roles in the regulation of mucosal epithelial model functions in the future.
Conserved DNA sequence analysis reveals the phylogeography and evolutionary events of Akebia trifoliata in the region across the eastern edge of the Tibetan Plateau and subtropical China
Authors: Dong Qing , Zhang Yongle , Zhong Shengfu , Zhang Qiuyi , Yang Hao , Yang Huai , Yi Xiaoxiao , Tan Feiquan , Chen Chen , Luo Peigao 
Published: April 2024

Abstract
Background
The eastern edge of the Qinghai‒Tibet Plateau (QTP) and subtropical China have various regions where plant species originate and thrive, but these regions have been the focus of very few integrative studies. Here, we elucidated the phylogeographic structure of a continuous and widespread Akebia trifoliata population across these two regions.

Results
Sixty-one populations consisting of 391 genotypes were examined to assess population diversity and structure via network distribution analysis, maximum likelihood phylogenetic tree reconstruction, divergence time estimation, demographic history inference, and ancestral area reconstruction of both conserved internal transcribed spacer (ITS) and chloroplast (rps16) DNA sequences. The results showed that the ITS region was more variable than the rps16 region and could be suitable for studying intraspecific phylogeography. The A. trifoliata population displayed high genetic diversity, genetic differentiation and obvious phylogeographical structure, possibly originating on the eastern QTP, expanding during the last glacial-interglacial cycle, diverging in the early Pleistocene and middle Pleistocene, and extensively migrating thereafter. The migration route from west to east along rivers could be largely responsible for the long-distance dispersal of this species, while three main refuges (Qinba Mountains, Nanling Mountains and Yunnan-Guizhou Plateau) with multiple ice shelters facilitated its wide distribution.

Conclusions
Our results suggested that the from west to east long migration accompanying with the minor short reciprocal migration in the south-north direction, and the three main refuges (the Qinba Mountains, Nanling Mountains and Yunnan-Guizhou Plateau) contributed to the extant geographical distribution of A. trifoliata. In addition, this finding also strongly reduced the discrepancy between glacial contraction and postglacial expansion and the in situ survival hypothesis by simultaneously considering the existence of many similar climate-related ecological niches and migration influences.
Optimizing nicardipine dosage for effective control of pituitrin-induced hypertension in laparoscopic myomectomy undergoing total intravenous anesthesia
Authors: Wang Chen , Zhao Xiaoli , Chen Yunyun , Xia Jianhua , Zhang Xixue , Wang Tingting 
Published: April 2024

Abstract
Background
This study aimed to determine the median effective dose (ED50) and 95% effective dose (ED95) of nicardipine for treating pituitrin-induced hypertension during laparoscopic myomectomy, providing guidance for the management of intraoperative blood pressure in such patients.

Methods
Among the initial 40 participants assessed, 24 underwent elective laparoscopic myomectomy. A sequential up-and-down method was employed to ascertain the ED50 of nicardipine based on its antihypertensive efficacy. Nicardipine was initially administered at 6 µg/kg following the diagnosis of pituitrin-induced hypertension in the first patient. Dosing adjustments were made to achieve the desired antihypertensive effect, restoring systolic blood pressure and heart rate to within ± 20% of baseline within 120 s. The dosing increment or reduction was set at 0.5 µg/kg for effective or ineffective responses, respectively. The ED50 and ED95 of nicardipine were calculated using Probit regression by Maximum Likelihood Estimation (MLE) to establish dose-response curves and confidence intervals.

Results
24 patients were included for analysis finally. The ED50 and ED95 of nicardipine for blood pressure control after pituitrin injection were determined. The study found that the ED50 of nicardipine for treating pituitrin-induced hypertension was 4.839 µg/kg (95% CI: 4.569–5.099 µg/kg), and the ED95 was estimated at 5.308 µg/kg (95% CI: 5.065–6.496 µg/kg). Nicardipine effectively mitigated the hypertensive response caused by pituitrin without inducing significant tachycardia or hypotension.

Conclusions
Nicardipine effectively controlled blood pressure after pituitrin injection during laparoscopic myomectomy, with ED50 and ED95 values established. This research highlights the potential utility of nicardipine in addressing hypertensive responses induced by pituitrin, particularly in clinical settings where pituitrin is routinely administered.
“They are saying it’s high, but I think it’s quite low”: exploring cardiovascular disease risk communication in NHS health checks through video-stimulated recall interviews with patients – a qualitative study
Authors: Cowap Lisa , Riley Victoria , Grogan Sarah , Ellis Naomi J. , Crone Diane , Cottrell Elizabeth , Chambers Ruth , Clark-Carter David , Gidlow Christopher J. 
Published: April 2024

Abstract
Background
NHS Health Check (NHSHC) is a national cardiovascular disease (CVD) risk identification and management programme. However, evidence suggests a limited understanding of the most used metric to communicate CVD risk with patients (10-year percentage risk). This study used novel application of video-stimulated recall interviews to understand patient perceptions and understanding of CVD risk following an NHSHC that used one of two different CVD risk calculators.

Methods
Qualitative, semi-structured video-stimulated recall interviews were conducted with patients (n = 40) who had attended an NHSHC using either the QRISK2 10-year risk calculator (n = 19) or JBS3 lifetime CVD risk calculator (n = 21). Interviews were transcribed and analysed using reflexive thematic analysis.

Results
Analysis resulted in the development of four themes: variability in understanding, relief about personal risk, perceived changeability of CVD risk, and positive impact of visual displays. The first three themes were evident across the two patient groups, regardless of risk calculator; the latter related to JBS3 only. Patients felt relieved about their CVD risk, yet there were differences in understanding between calculators. Heart age within JBS3 prompted more accessible risk appraisal, yet mixed understanding was evident for both calculators. Event-free survival age also resulted in misunderstanding. QRISK2 patients tended to question the ability for CVD risk to change, while risk manipulation through JBS3 facilitated this understanding. Displaying information visually also appeared to enhance understanding.

Conclusions
Effective communication of CVD risk within NHSHC remains challenging, and lifetime risk metrics still lead to mixed levels of understanding in patients. However, visual presentation of information, alongside risk manipulation during NHSHCs can help to increase understanding and prompt risk-reducing lifestyle changes.

Trial registration
ISRCTN10443908. Registered 7th February 2017.
Understanding suboptimal insulin use in type 1 and 2 diabetes: a cross-sectional survey of healthcare providers who treat people with diabetes
Authors: Newson Rachel S. , Spaepen Erik , Liao Birong , Bower Julie , Bhattacharya Indranil , Artime Esther , Polonsky William 
Published: April 2024

Abstract
Background
The purpose of this study was to understand the healthcare provider (HCP) perspective on the extent of suboptimal insulin dosing in people with diabetes (PwD), as well as specific challenges and solutions to insulin management.

Methods
An online survey of general practitioners and specialists (N = 640) who treat PwD in Germany, Spain, the United Kingdom, and the United States was conducted. Responses regarding HCP background and their patients, HCP perceptions of suboptimal insulin use, and challenges associated with optimal insulin use were collected. Categorical summary statistics were presented.

Results
Overall, for type 1 diabetes (T1D) and type 2 diabetes (T2D), most physicians indicated < 30% of PwD missed or skipped a bolus insulin dose in the last 30 days (T1D: 83.0%; T2D: 74.1%). The top 3 reasons (other than skipping a meal) HCPs believed caused the PwD to miss or skip insulin doses included they “forgot,” (bolus: 75.0%; basal: 67.5%) “were too busy/distracted,” (bolus: 58.8%; basal: 48.3%), and “were out of their normal routine” (bolus: 57.8%; basal: 48.6%). HCPs reported similar reasons that they believed caused PwD to mistime insulin doses. Digital technology and improved HCP-PwD communication were potential solutions identified by HCPs to optimize insulin dosing in PwD.

Conclusions
Other studies have shown that PwD frequently experience suboptimal insulin dosing. Conversely, results from this study showed that HCPs believe suboptimal insulin dosing among PwD is limited in frequency. While no direct comparisons were made in this study, this apparent discrepancy could lead to difficulties in HCPs giving PwD the best advice on optimal insulin management. Approaches such as improving the objectivity of dose measurements for both PwD and HCPs may improve associated communications and help reduce suboptimal insulin dosing, thus enhancing treatment outcomes.
Socioeconomic status, loneliness, and depression among older adults: a cross-sectional study in Spain
Authors: Sánchez-Moreno Esteban , Gallardo-Peralta Lorena , Barrón López de Roda Ana , Rivera Álvarez Joaquín M. 
Published: April 2024

Abstract
Background
The association between socioeconomic status and depression is weaker in older adults than in younger populations. Loneliness may play a significant role in this relationship, explaining (at least partially) the attenuation of the social gradient in depression. The current study examined the relationship between socioeconomic status and depression and whether the association was affected by loneliness.

Methods
A cross-sectional design involving dwelling and nursing homes residents was used. A total of 887 Spanish residents aged over 64 years took part in the study. Measures of Depression (GDS-5 Scale), Loneliness (De Jong-Gierveld Loneliness Scale), Socioeconomic Status (Education and Economic Hardship), and sociodemographic parameters were used. The study employed bivariate association tests (chi-square and Pearson’s r) and logistic regression analyses.

Results
The percentage of participants at risk of suffering depression was significantly higher among those who had not completed primary education (45.5%) and significantly lower among those with university qualifications (16.4%) (X2 = 40.25;p <.001), and respondents who could not make ends meet in financial terms faced a higher risk of depression (X2 = 23.62;p <.001). In terms of the respondents who experienced loneliness, 57.5% were at risk of depression, compared to 19% of those who did not report loneliness (X2 = 120.04;p <.001). The logistic regression analyses showed that having university qualifications meant a 47% reduction in the risk of depression. This risk was 86% higher among respondents experiencing financial difficulties. However, when scores for the loneliness measure were incorporated, the coefficients relating to education and economic hardships ceased to be significant or were significantly reduced.

Conclusion
Loneliness can contribute to explaining the role played by socioeconomic inequalities in depression among older adults.
The clinical utility of cystatin C based eGFR in assessing renal function among HIV/AIDs patients on ART at Mildmay Uganda
Authors: Wekiya Enock , Mujuzi Godfrey P. , Nakiyingi Jane , Sanya Juliet , Matovu Moses , Guido Ocung , Nakaweesi Jane , Karamagi Charles , Nakayaga Joan K. , Mutebi Edrisa I. , Nakanjako Damalie 
Published: April 2024

Abstract
Background
In clinical practice, Measurement of estimated glomerular filtration rates (eGFR) is the gold standard assessing renal function the glomerular filtration rate often estimated from plasma creatinine. Several studies have shown Cystatin C based eGFR (Cys C) to be a better parameter for the diagnosis of impaired renal function. Cystatin C based eGFR has been proposed as a potential renal function marker but its use in HIV&AIDS patients has not been well evaluated.

Methods
A cross sectional study was carried out on 914 HIV&AIDS patients on antiretroviral therapy (ART) attending Mildmay Uganda for care and treatment between January to March 2015. Serum Cystatin C based eGFR was measured using the particle enhanced immunoturbidimetric assay. Creatinine was analyzed using enzymatic Creatinine PAP method and creatinine clearance was calculated according to C&G.

Results
The sensitivity of Cystatin C based eGFR was 15.1% (95% CI = 8.4, 24) with specificity 99.3% (95% CI = 98- 99.7). The positive and negative predictive values were 70.0% (95% CI 45.7–88.1) and 91.2% (95% CI 98.11–92.94) respectively. The positive likelihood ratio was 18.81 and negative likelihood ratio was 0.85. Cystatin C based eGFR had diagnostic accuracy of 90.7 and area under curve was 0.768.

Conclusion
Cystatin C based eGFR exhibited a high specificity and a high positive likelihood ratio in diagnosis of kidney disease among HIV&AIDS patients. Cystatin C based eGFR can be used as a confirmatory test.
Pre-pregnancy body mass index and caesarean section in Andean women in Peru: a prospective cohort study
Authors: Sanchez-Samaniego Giuliana , Mäusezahl Daniel , Hartinger-Peña Stella Maria , Hattendorf Jan , Verastegui Hector , Fink Günther , Probst-Hensch Nicole 
Published: April 2024

Abstract
Background
During the last two decades, Caesarean section rates (C-sections), overweight and obesity rates increased in rural Peru. We examined the association between pre-pregnancy body mass index (BMI) and C-section in the province of San Marcos, Northern Andes-Peru.

Methods
This is a prospective cohort study. Participants were women receiving antenatal care in public health establishments from February 2020 to January 2022, who were recruited and interviewed during pregnancy or shortly after childbirth. They answered a questionnaire, underwent a physical examination and gave access to their antenatal care card information. BMI was calculated using maternal height, measured by the study team and self-reported pre-pregnancy weight measured at the first antenatal care visit. For 348/965 (36%) women, weight information was completed using self-reported data collected during the cohort baseline. Information about birth was obtained from the health centre’s pregnancy surveillance system. Regression models were used to assess associations between C-section and BMI. Covariates that changed BMI estimates by at least 5% were included in the multivariable model.

Results
This study found that 121/965 (12.5%) women gave birth by C-section. Out of 495 women with pre-pregnancy normal weight, 46 (9.3%) had C-sections. Among the 335 women with pre-pregnancy overweight, 53 (15.5%) underwent C-sections, while 23 (18.5%) of the 124 with pre-pregnancy obesity had C-sections. After adjusting for age, parity, altitude, food and participation in a cash transfer programme pre-pregnancy overweight and obesity increased the odds of C-section by more than 80% (aOR 1.82; 95% CI 1.16–2.87 and aOR 1.85; 95% CI 1.02–3.38) compared to women with a normal BMI.

Conclusions
High pre-pregnancy BMI is associated with an increased odds of having a C-section. Furthermore, our results suggest that high BMI is a major risk factor for C-section in this population. The effect of obesity on C-section was partially mediated by the development of preeclampsia, suggesting that C-sections are being performed due to medical reasons.