bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of Kami-guibi-tang for mild cognitive impairment: a pilot, randomized, double-blind, placebo-controlled trial
Authors: Shin Hee-Yeon , Kim Ha-Ri , Jahng Geon-Ho , Jin Chul , Kwon Seungwon , Cho Seung-Yeon , Park Seong-Uk , Jung Woo-Sang , Moon Sang-Kwan , Ko Chang-Nam , Park Jung-Mi 
Published: October 2021

AbstractBackgroundMild cognitive impairment (MCI) is considered an intermediate phase between normal aging and dementia. As the majority of cases of amnestic MCI (aMCI) progress to Alzheimer’s disease (AD), it is considered the prodromal stage of AD, and a treatment target for prevention of further cognitive decline. However, no medications have been shown to have symptomatic or preventive benefits in MCI. Kami-guibi-tang (KGT) is a traditional herbal formula used in Korean medicine to treat amnesia, which is reported to increase acetylcholine levels via activation of choline acetyltransferase. The objective of this study was to evaluate the efficacy and safety of KGT in patients with aMCI.MethodsThis study was designed as a single-center, randomized, double-blind, placebo-controlled pilot study. Participants diagnosed with aMCI were randomized to receive either KGT or placebo granules for 24 weeks. The efficacy measure was a change in the Seoul Neuropsychological Screening Battery (SNSB) score. The safety measures included the occurrence of adverse events and abnormalities in vital signs and blood chemistry, electrocardiogram (ECG), and brain magnetic resonance imaging (MRI) findings.ResultsA total of 16 patients in the KGT group and 14 patients in the placebo group were investigated in the study. The mean score of Clinical Dementia Rating-Sum of Boxes (CDR-SB) significantly improved from 1.53 (0.64) points to 1.13 (0.62) points in the KGT group (p = 0.010), whereas it worsened from 1.61 (0.88) points to 1.75 (0.94) points in the placebo group. There was a significant difference in the CDR-SB scores between the two groups after the intervention (p = 0.045). The total SNSB-D scores and the scores in the memory domain after the treatment were significantly higher than the baseline values in the KGT group, but not in the placebo group. The frequency of adverse events was not significantly different between the two groups, and there were no abnormalities in vital signs or blood test, ECG, and brain MRI findings after the intervention.ConclusionsKGT may provide a safe and effective treatment option for patients with aMCI. Further studies with a larger sample size are needed to validate the findings.Trial registrationKorean Clinical Trial Registry, ID: KCT0002407; Registered on March 30, 2017,http://cris.nih.go.kr/
When do physicians perceive the success of a new care model differently?
Authors: Richter Simone , Demirer Ibrahim , Nocon Maya , Pfaff Holger , Karbach Ute 
Published: October 2021

Abstract
Background
The health care innovation “MamBo – people with multimorbidity in outpatient care: patient-focused and needs-oriented healthcare management” aims to improve the efficiency and quality of care for multimorbid patients by delegating tasks (e.g. taking over house calls or coordinating specialist appointments) to a monitoring and coordination assistant (MoniKa). Participating physicians are very important for the success of the health care innovation due to their direct involvement as practitioners and their task of enrolling patients. The aim of this part of the evaluation study is therefore to identify the physicians’ personal values, which influence the individual perception of the project’s advantages and thus possibly the acceptance and sustainable implementation of new care structures.

Methods
Two Focus groups (n = 4; n = 6) and three individual interviews with general practitioners and specialists who decided to implement the health care innovation within the first year were conducted. The semi-structured guidelines were developed by the research team. The interviews were analysed according to the content analysis by Mayring. We used the learning model of operant conditioning to place our study results in a theoretical context.

Result
Two central personal values of the participants, which determine the desired advantages of the health care innovation were identified: More patient-oriented and more economic-oriented values. Participants with more patient-oriented values quickly perceived advantages, which seems to be beneficial for the acceptance of the new care structures. Economic-oriented participants tended to be more critical. The benefits of the health care innovation, which was expressed, for example, in an improvement of the practice routine, has not yet been perceived by this group, or only to a limited extent.

Conclusions
The results suggest that the respective values of the participants define the individual perceived advantages and thus, the assessment of the success of the health care innovation in general. These findings could be used in the implementation process by increasing the motivation of the project participants through typified supervision.

Trial registration
The study has been registered in the German Clinical Trials Register (DRKS00014047).
Whole-genome sequencing reveals high genetic diversity of Streptococcus uberis isolated from cows with mastitis
Authors: Silva Nathália Cristina Cirone , Yang Yongqiang , Rodrigues Marjory Xavier , Tomazi Tiago , Bicalho Rodrigo Carvalho 
Published: October 2021

Abstract
Background
Bovine mastitis is an important cause of economic loss in dairy farms. Streptococcus uberis is among the most frequently isolated bacterial species isolated from cows with mastitis. The aim of this study was to perform an in-depth genetic assessment of S. uberis strains isolated from bovine clinical mastitis (CM) and to perform a phylogenetic analysis to represent the evolutionary relationship among S. uberis sequences.

Results
A total of 159 isolates was genetically characterized using whole genome sequencing. According to the virulence determinants, all strains harbored the hasC, leuS, perR, purH, and purN virulence genes. Thirty-four resistance genes were identified in at least one strain. In terms of acquired genes, we observed that 152 (95.6 %) strains had a resistance gene to lincosamine (lnuD), 48 (30.2 %) to tetracycline (tetM), 4 (2.51 %) to tobramicine (ant6), and 1 to lincosamide (lsa(E)). MLST detected the Sequence Type (ST)797 (n = 23), while 85.5 % of the strains did not match to known STs.

Conclusions
Then, eleven distinct ST were identified after we submitted the new alleles to assign new STs. The other prevalent STs observed were ST1215 (n = 58), ST1219 (n = 35), and ST1213 (n = 15). And it was not possible to identify the MLST of four strains. Phylogenetic lineages indicated a high genomic diversity of S. uberis in our collection, confirming that most strains isolated from bovine mastitis have different reservoirs, typical of environmental pathogens.
Genetic and epigenetic associations of ANRIL with coronary artery disease and risk factors
Authors: Xu Bayi , Xu Zhixia , Chen Yequn , Lu Nan , Shu Zhouwu , Tan Xuerui 
Published: October 2021

Abstract
Background
Both DNA genotype and methylation of antisense non-coding RNA in the INK4 locus (ANRIL) have been robustly associated with coronary artery disease (CAD), but the interdependent mechanisms of genotype and methylation remain unclear.

Methods
Eighteen tag single nucleotide polymorphisms (SNPs) of ANRIL were genotyped in a matched case–control study (cases 503 and controls 503). DNA methylation of ANRIL and the INK4/ARF locus (p14ARF, p15INK4b and p16INK4a) was measured using pyrosequencing in the same set of samples (cases 100 and controls 100).

Results
Polymorphisms of ANRIL (rs1004638, rs1333048 and rs1333050) were significantly associated with CAD (p < 0.05). The incidence of CAD, multi-vessel disease, and modified Gensini scores demonstrated a strong, direct association with ANRIL gene dosage (p < 0.05). There was no significant association between ANRIL polymorphisms and myocardial infarction/acute coronary syndrome (MI/ACS) (p > 0.05). Methylation levels of ANRIL were similar between the two studied groups (p > 0.05), but were different in the rs1004638 genotype, with AA and AT genotype having a higher level of ANRIL methylation (pos4, p = 0.006; pos8, p = 0.019). Further Spearman analyses indicated that methylation levels of ANRIL were positively associated with systolic blood pressure (pos6, r = 0.248, p = 0.013), diastolic blood pressure (pos3, r = 0.213, p = 0.034; pos6, r = 0.220, p = 0.028), and triglyceride (pos4, r = 0.253, p = 0.013), and negatively associated with high-density lipoprotein cholesterol (pos2, r = − 0.243, p = 0.017). Additionally, we identified 12 transcription factor binding sites (TFBS) within the methylated ANRIL region, and functional annotation indicated these TFBS were associated with basal transcription. Methylation at the INK4/ARF locus was not associated with ANRIL genotype.

Conclusions
These results indicate that ANRIL genotype (tag SNPs rs1004638, rs1333048 and rs1333050) mainly affects coronary atherosclerosis, but not MI/ACS. There may be allele-related DNA methylation and allele-related binding of transcription factors within the ANRIL promoter.
Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study
Authors: Lin Fang-Ju , Wang Chi-Chuan , Hsu Chien-Ning , Yang Chen-Yi , Wang Chih-Yuan , Ou Huang-Tz 
Published: October 2021

Abstract
Background
To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2).

Methods
Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics.

Results
There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37–0.69), 0.51 (0.37–0.70), and 0.47 (0.31–0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups.

Conclusions
This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.
The effect of short term exposure to outdoor air pollution on fertility
Authors: González-Comadran Mireia , Jacquemin Bénédicte , Cirach Marta , Lafuente Rafael , Cole-Hunter Thomas , Nieuwenhuijsen Mark , Brassesco Mario , Coroleu Buenaventura , Checa Miguel Angel 
Published: October 2021

AbstractBackgroundThere is evidence to suggest that long term exposure to air pollution could be associated with decreased levels of fertility, although there is controversy as to how short term exposure may compromise fertility in IVF patients and what windows of exposure during the IVF process patients could be most vulnerable.MethodsThis prospective cohort study aimed to evaluate the impact of acute exposure that air pollution have on reproductive outcomes in different moments of the IVF process. Women undergoing IVF living in Barcelona were recruited. Individual air pollution exposures were modelled at their home address 15 and 3 days before embryo transfer (15D and 3D, respectively), the same day of transfer (D0), and 7 days after (D7). The pollutants modelled were: PM2.5[particulate matter (PM) ≤2.5 μm], PMcoarse(PM between 2.5 and 10μm), PM10(PM≤10 μm), PM2.5abs, and NO2and NOx. Outcomes were analyzed using multi-level regression models, with adjustment for co-pollutants and confouding factors. Two sensitivity analyses were performed. First, the model was adjusted for subacute exposure (received 15 days before ET). The second analysis was based on the first transfer performed on each patient aiming to exclude patients who failed previous transfers.ResultsOne hundred ninety-four women were recruited, contributing with data for 486 embryo transfers.Acute and subacute exposure to PMs showed a tendency in increasing miscarriage rate and reducing clinical pregnancy rate, although results were not statistically significant. The first sensitivity analysis, showed a significant risk of miscarriage for PM2.5exposure on 3D after adjusting for subacute exposure, and an increased risk of achieving no pregnancy for PM2.5, PMcoarseand PM10on 3D.The second sensitivity analysis showed a significant risk of miscarriage for PM2.5exposure on 3D, and a significant risk of achieving no pregnancy for PM2.5, PMcoarseand PM10 particularly on 3D. No association was observed for nitrogen dioxides on reproductive outcomes.ConclusionsExposure to particulate matter has a negative impact on reproductive outcomes in IVF patients. Subacute exposure seems to increase the harmful effect of the acute exposure on miscarriage and pregnancy rates. Nitrogen dioxides do not modify significantly the reproductive success.
Niraparib exhibits a synergistic anti-tumor effect with PD-L1 blockade by inducing an immune response in ovarian cancer
Authors: Meng Jinyu , Peng Jin , Feng Jie , Maurer Jochen , Li Xiao , Li Yan , Yao Shu , Chu Ran , Pan Xiyu , Li Junting , Zhang Ting , Liu Lu , Zhang Qing , Yuan Zeng , Bu Hualei , Song Kun , Kong Beihua 
Published: October 2021

Abstract
Background
Immune checkpoint blockades (ICBs) therapy showed limited efficacy in ovarian cancer management. Increasing evidence indicated that conventional and targeted therapies could affect tumor-associated immune responses and increase the effectiveness of immunotherapy. However, the effects of Niraparib, one of the poly (ADP) ribose polymerase (PARP) inhibitors, on the immune response remains unclear. Delineating the crosstalk between cytotoxic anticancer agents and cancer-associated immunity may lead to more efficient combinatorial strategies.

Methods
Programmed death ligand 1 (PD-L1) expression in human ovarian cancer cells after PARP inhibitors treatment was examined by western blotting (WB) and flow cytometry. The expression of poly ADP-ribose polymerase (PARP1), PD-L1, and CD8 in human ovarian cancer tissues was detected by immunohistochemistry(IHC). The effect of Niraparib and PD-L1 blockade in ovarian cancer progression was investigated in vivo. The changes of immune cells and cytokines in vitro and in vivo were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Changes of cGAS/STING signal pathway after Niraparib treatment were determined by WB, ELISA.

Results
Niraparib upregulated membrane PD-L1 and total PD-L1 expression in ovarian cancer cells and had a synergistic effect with PD-L1 blockade in vivo. In clinical patient samples, Niraparib augmented cytotoxic CD8+T cell proportion and function. In vivo and vitro, Niraparib can also increase the proportion of T cells and combined with PD-L1 blockade could further enhance the effect. Besides, Niraparib activated the cGAS-STING pathway, increasing the levels of cytokines such as CCL5 and CXCL10, which played a vital role in augmenting the infiltration and activation of cytotoxic T cells.

Conclusions
Niraparib could modulate the immune response via the activation of the cGAS/STING pathway, and combination with PD-L1 blockade could further enhance the effect. These results provide a sound theoretical basis for clinical treatment.
Improving mental health literacy among young people aged 11–15 years in Java, Indonesia: the co-development of a culturally-appropriate, user-centred resource (The IMPeTUs Intervention)
Authors: Brooks Helen , Syarif Armaji Kamaludi , Pedley Rebecca , Irmansyah Irman , Prawira Benny , Lovell Karina , Opitasari Cicih , Ardisasmita Adam , Tanjung Ira Savitri , Renwick Laoise , Salim Soraya , Bee Penny 
Published: October 2021

Abstract
Background
Many mental health problems emerge in late childhood and contribute significantly to the global burden of disease. Adverse outcomes can extend into adulthood if left untreated. This impact is exacerbated in low- and middle-income countries where significant treatment gaps persist. Improving mental health literacy may offer an effective strategy for early intervention but remains underexplored in these contexts.

Methods
An intervention was co-developed with children and young people (CYP) by undertaking a needs analysis combined with stakeholder consensus activities. A systematic review of mental health literacy interventions in South-East Asia was undertaken in addition to semi-structured interviews with 43 children and young people (19 with and 24 without experience of anxiety and depression), 19 parents of children with experience of mental health problems and 25 education and health professionals. A focus group was also held with 8 key stakeholders immersed nationally in policy and practice. Interview schedules explored participants’ experiences of mental health, unmet needs and priorities for intervention. Data were synthesised and presented at a 3-day co-production workshop. Attendees included 13 CYP, 6 parents/guardians, 2 teachers, 8 health professionals, 2 academics and 3 game designers. Consensus exercises were utilised to identify the preferred format, content and delivery of the intervention. A smaller group of patient and public involvement contributors worked with designers to further iterate the intervention.

Results
An immersive storyline digital application was co-developed for young people aged 11–15 with the primary aim of improving mental health literacy and self-management. The intervention comprises two chapters; one depression focussed, and the other anxiety focussed. The storyline format is interspersed with interactive games and exercises to promote engagement and encourage self-management. CYP also take part in group sessions delivered by trained facilitators before and after intervention use to discuss outcomes of and issues raised during the game.

Conclusion
The IMPeTUs intervention has been co-designed for CYP aged 11–15 to improve mental health literacy and enhance self-management abilities. To the best of our knowledge, this is the first Indonesian digital intervention to improve mental health literacy and self-management for this population. Implementation, acceptability, and impact are currently being explored in a multi-site case study evaluation.
Prevalence and risk factors for trypanosome infection in cattle from communities surrounding the Murchison Falls National Park, Uganda
Authors: Kizza Daniel , Ocaido Michael , Mugisha Anthony , Azuba Rose , Nalule Sarah , Onyuth Howard , Musinguzi Simon Peter , Okwasiimire Rodney , Waiswa Charles 
Published: October 2021

Abstract
Background
Bovine trypanosomosis transmitted by tsetse flies is a major constraint to cattle health and productivity in all sub-Saharan countries, including Uganda. The objectives of this study were to determine the prevalence of bovine trypanosomosis and identify its associated risk factors and the species of trypanosomes associated with the disease.

Methodology
A cross-sectional study was conducted around Murchison Falls National Park, Uganda from January 2020 to April 2020. Trypanosomes were detected in blood samples by PCR analysis targeting the internal transcribed spacer 1 (ITS-PCR assays), and trypanosomes in positive blood samples were sequenced.

Results
Of 460 blood samples collected and tested, 136 (29.6%) were positive for trypanosome infections and 324 (70.4%) were negative. The overall trypanosome prevalence was 29.6% (95% confidence interval 25.4–33.8%), attributed to three trypanosome species. Of these three species, Trypanosoma vivax was the most prevalent (n = 130, 28.3%) while the others were detected as mixed infections: T. vivax + Trypanosomacongolense (n = 2, 0.4%) and T. vivax + Trypanosomaevansi (n = 1, 0.2%). There were significant differences in trypanosome prevalence according to sex (χ2 = 62, df = 1, P < 0.05), age (χ2 = 6.28, df = 2, P = 0.0043) and cattle breed (χ2 = 10.61, df = 1, P = 0.001).

Conclusions
Trypanosomosis remains a major limitation to cattle production around Murchison Falls National Park and interventions are urgently needed. In our study, the prevalence of trypanosome infections was high, with T. vivax identified as the most prevalent species. Age, sex and breed of cattle were risk factors for trypanosome infection.

Graphical Abstract
Rapamycin-induced hyperglycemia is associated with exacerbated age-related osteoarthritis
Authors: Minton Dennis M. , Elliehausen Christian J. , Javors Martin A. , Santangelo Kelly S. , Konopka Adam R. 
Published: October 2021

Abstract
Background
The objective of this study was to determine if mechanistic target of rapamycin (mTOR) inhibition with or without AMP-activated protein kinase (AMPK) activation can protect against primary, age-related OA.

Design
Dunkin-Hartley guinea pigs develop mild primary OA pathology by 5 months of age that progresses to moderate OA by 8 months of age. At 5 months, guinea pigs served as young control (n = 3) or were fed either a control diet (n = 8), a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14 ppm, n = 8), or Rap with the AMPK-activator metformin (Rap+Met, 1000 ppm, n = 8) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting.

Results
Rap- and Rap+Met-treated guinea pigs displayed lower body weight than control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap- and Rap+Met-treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with proteoglycan loss, suggesting hyperglycemic stress after Rap treatment was related to worsened OA.

Conclusions
This is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap and Rap+Met did not appear to protect against primary OA during the prevailing hyperglycemia.