bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term safety and exploratory efficacy of fevipiprant in patients with inadequately controlled asthma: the SPIRIT randomised clinical trial
Authors: Maspero Jorge , Agache Ioana Octavia , Kamei Tadashi , Yoshida Makoto , Boone Bryan , Felser James M. , Kawakami Fernando , Knorr Barbara , Lawrence David , Lehmann Thomas , Wang Wei , Pedinoff Andrew J. 
Published: December 2021

Abstract
Background
The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites.

Methods
SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits.

Results
In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks’ treatment, while 163 received ≥ 104 weeks’ treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies.
In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor.

Conclusions
In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile.

Trial registration

Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517.
Crosstalk between autophagy and microbiota in cancer progression
Authors: Wang Yu , Du Jiang , Wu Xuemei , Abdelrehem Ahmed , Ren Yu , Liu Chao , Zhou Xuan , Wang Sinan 
Published: December 2021

AbstractAutophagy is a highly conserved catabolic process seen in eukaryotes and is essentially a lysosome-dependent protein degradation pathway. The dysregulation of autophagy is often associated with the pathogenesis of numerous types of cancers, and can not only promote the survival of cancer but also trigger the tumor cell death. During cancer development, the microbial community might predispose cells to tumorigenesis by promoting mucosal inflammation, causing systemic disorders, and may also regulate the immune response to cancer. The complex relationship between autophagy and microorganisms can protect the body by activating the immune system. In addition, autophagy and microorganisms can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses involved in cancer progression. Various molecular mechanisms, correlating the microbiota disorders and autophagy activation, control the outcomes of protumor or antitumor responses, which depend on the cancer type, tumor microenvironment and disease stage. In this review, we mainly emphasize the leading role of autophagy during the interaction between pathogenic microorganisms and human cancers and investigate the various molecular mechanisms by which autophagy modulates such complicated biological processes. Moreover, we also highlight the possibility of curing cancers with multiple molecular agents targeting the microbiota/autophagy axis. Finally, we summarize the emerging clinical trials investigating the therapeutic potential of targeting either autophagy or microbiota as anticancer strategies, although the crosstalk between them has not been explored thoroughly.
A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy
Authors: Li Jiali , Li Shichao , Li Yang , Yuan Guanjie , Shen Yaqi , Peng Yang , Kong Li , Yang Conglian , Zhang Zhiping , Li Zhen 
Published: December 2021

Abstract
Background
Immunochemotherapy is a potent anti-tumor strategy, however, how to select therapeutic drugs to enhance the combined therapeutic effect still needs to be explored.

Methods and results
Herein, a magnetic resonance nanoprobe (MnP@Lip) with STING (Stimulator of INterferon Genes) activation character was synthesized and co-administered with platinum-based chemotherapeutics for enhanced immunochemotherapy. MnP@Lip nanoparticles was prepared by simple fabrication process with good reproducibility, pH-sensitive drug release behavior and biocompatibility. In vitro experiments elucidated that Mn2+ can promote the polarization of M0 and/or M2 macrophages to M1 phenotype, and promote the maturation of BMDC cells. Upon Mn2+ treatment, the STING pathway was activated in tumor cells, mouse lung epithelial cells, and immune cells. More importantly, anti-tumor experiments in vivo proved that MnP@Lip combined with platinum-based chemotherapeutics increased T cells infiltration in the tumor microenvironment, and inhibited tumor growth in the orthotopic therapeutic and postoperative tumor models.

Conclusions
This kind of therapeutic strategy that combined MnP@Lip nanoparticles with platinum-based chemotherapeutics may provide a novel insight for immunochemotherapy.

Graphical Abstract
Sex-related differences of early cardiac functional and proteomic alterations in a rat model of myocardial ischemia
Authors: Barta Bálint András , Ruppert Mihály , Fröhlich Klemens Erwin , Cosenza-Contreras Miguel , Oláh Attila , Sayour Alex Ali , Kovács Krisztián , Karvaly Gellért Balázs , Biniossek Martin , Merkely Béla , Schilling Oliver , Radovits Tamás 
Published: December 2021

Abstract
Background
Reduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach.

Methods
Ischemia was induced in male (M-Isch) and female (F-Isch) rats with sc. injection of isoproterenol (85 mg/kg) daily for 2 days, while controls (M-Co, F-Co) received sc. saline solution. At 48 h after the first injection pressure–volume analysis was carried out to assess left ventricular function. FFPE tissue slides were scanned and analyzed digitally, while myocardial proteins were quantified by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using isobaric labeling. Concentrations of circulating steroid hormones were measured with LC–MS/MS. Feature selection (PLS and PLS-DA) was used to examine associations among functional, proteomic and hormonal datasets.

Results
Induction of ischemia resulted in 38% vs 17% mortality in M-Isch and F-Isch respectively. The extent of ischemic damage to surviving rats was comparable between the sexes. Systolic dysfunction was more pronounced in males, while females developed a more severe impairment of diastolic function. 2224 proteins were quantified, with 520 showing sex-specific differential regulation. Our analysis identified transcriptional, cytoskeletal, contractile, and mitochondrial proteins, molecular chaperones and the extracellular matrix as sources of disparity between the sexes. Bioinformatics highlighted possible associations of estrogens and their metabolites with early functional and proteomic alterations.

Conclusions
Our study has highlighted sex-specific alterations in systolic and diastolic function shortly after ischemia, and provided a comprehensive look at the underlying proteomic changes and the influence of estrogens and their metabolites. According to our bioinformatic analysis, inflammatory, mitochondrial, chaperone, cytoskeletal, extracellular and matricellular proteins are major sources of intersex disparity, and may be promising targets for early sex-specific pharmacologic interventions.

Graphical Abstract
Would you offer contraception to a 14-year-old girl? Perspectives of health students and professionals in Dar es Salaam, Tanzania
Authors: Mwakawanga Dorkasi L. , Mkonyi Ever , Mushy Stella E. , Trent Maria , Bonilla Zobeida , Massae Agnes F. , Lukumay Gift G. , Mgopa Lucy R. , Mohammed Inari , Wadley James , Ross Michael W. , Leshabari Sebalda , Rosser B. R. Simon 
Published: December 2021

Abstract
Background
Rates of unplanned adolescent pregnancy and unsafe induced abortions are very high in Sub-Saharan African countries including Tanzania. Despite their availability and accessibility, modern family planning methods are reported to be critically underutilized by adolescents. This study is part of a broader study that aims to develop a curriculum that will be used in training health professionals by investigating the sexual health training needs of health providers and students in Tanzania.

Aim
This study describes the perceptions of health professionals and students on the provision of contraceptives to adolescents.

Methods
Qualitative formative assessment type of research was conducted using 18 focus groups stratified among health professionals and students (midwives, nurses, and medical doctors). Study participants were presented with the theoretical scenario of a 14-year-old girl who sought contraceptive services at a family planning clinic. This theoretical scenario was used to determine how health professionals and students would handle the case. Thematic analysis guided the examination and determination of data results.

Results
Three main themes emerged from the data, including (1) knowledge about the provision of contraceptives to adolescents, (2) perception of the adolescents’ right to contraceptive use, and (3) barriers to the provision of contraceptives to adolescents. Participants stated that having a baseline knowledge of contraceptive services for adolescents and their rights to contraceptives would trigger their decision on offering the contraceptive. On the other hand, being unaware of the reproductive health rights for adolescents, judgmental behavior of providers, as well as religious and cultural dynamics were all found to be major barriers for providers to offer contraceptive services to the 14-year-old adolescent girl in the theoretical scenario.

Conclusion
These findings support the need for comprehensive sexual health education in Tanzanian health professional training programs.
HIV/AIDS late presentation and its associated factors in China from 2010 to 2020: a systematic review and meta-analysis
Authors: Sun Chengqing , Li Jianjun , Liu Xiaoyan , Zhang Zhi , Qiu Tao , Hu Haiyang , Wang You , Fu Gengfeng 
Published: December 2021

Abstract
Background
Late presentation to HIV/AIDS care presents serious health concerns, like increased transmission and high healthcare costs, increased mortality, early development of opportunistic infection, increased risk of antiretroviral therapy drug resistance. Despite the effort to contain the HIV/AIDS epidemic, LP has remained an impediment to individual immune reconstitution and public health.

Objective
This review aimed to estimate the prevalence and determine the factors associated with late presentation to HIV/AIDS care.

Methods
We searched PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Wanfang, and Weipu database for articles published from 2010 to 2020. We utilized I2 statistics and Q-test to estimate heterogeneity between studies. Random-effects meta-analysis models were used to calculate the aggregate odds ratio of late presentation to HIV/AIDS care.

Results
Of 9563 titles and abstracts retrieved, 189 were identified as potentially eligible and 39 fulfilled the inclusion criteria. The pooled prevalence of late presentation to HIV/AIDS care was 43.26%. The major risk factors were patients ≥ 50 years old (OR = 2.19, 95% CI: 1.85–2.58; I2 = 97.44%), married (OR = 1.50, 95% CI: 1.35–1.68; I2 = 96.58%), with heterosexual contact as risk factor for infection (OR = 1.91, 95% CI: 1.73–2.11; I2 = 90.74%) and diagnosed in medical institutions (OR = 2.35,95% CI: 2.11–2.62; I2 = 96.05%). In middle or low HIV prevalence areas, patients ≥ 50 years old (P = 0.01), married (P < 0.01) and diagnosed in medical institutions (P = 0.01) were more likely to be presented late than in high prevalence areas. From 2016–2020, the OR of patients who were married and diagnosed in medical facilities were significantly lower than before (P < 0.01).

Conclusion
Patients ≥ 50 years old, married, with heterosexual contact as risk factor for infection, and diagnosed in medical institutions were risk factors of LP. Gender had no significant relationship with LP. In middle or low prevalence areas, patients who were ≥ 50 years old, married, and diagnosed in medical institutions were more likely to be presented late than in other areas. Married patients and those diagnosed in medical institutions after 2015 have a lower risk of LP than before.
Success and complication rate of miniscrew assisted non-surgical palatal expansion in adults - a consecutive study using a novel force-controlled polycyclic activation protocol
Authors: Winsauer Heinz , Walter Andre , Katsaros Christos , Ploder Oliver 
Published: December 2021

Abstract
Introduction
Bone-borne miniscrew assisted palatal expansion (MAPE) is a common technique to improve maxillary transverse deficiency in young adolescents. Adult patients usually present a challenge, as they often require additional surgical assisted maxillary expansion (SARPE). There is still no clear statement about non-surgical expansion in adult patients using this technique. The aim of this study was to evaluate the success and complication rate of non-surgical palatal expansion in adults utilizing MAPE with a novel force-controlled polycyclic expansion protocol (FCPC).

Methods
This consecutive study consisted of 33 adult patients with an average age of 29.1 ± 10.2 years (min. 18 years, max. 58 years), including one dropout patient. First, four miniscrews were inserted and after 12-weeks latency, the expander was placed and the FCPC protocol was applied (MAPE group). In case of missing expansion, a SARPE was performed (SARPE group). After maximum expansion, a cone beam CT was made and widening of the midpalatal suture was measured. The outcome variables were successful non-surgical expansion and, with sample size power above 80%, the odds of failed non-surgical expansion and associated complications were evaluated. The primary predictor variable was age. Statistical analysis was performed using R (Version 3.1) to calculate power, to construct various models for measuring the odds of requiring surgical intervention/complications, and others.

Results
Successful non-surgical expansion was achieved in 27 patients (84.4%), ranging from 18 to 49 years. Mean age differed significantly between both groups (26.8 ± 8.2 years vs. 41.3 ± 9.9 years; p < 0.001). Mean expansion at the anterior and posterior palate for the MAPE group was 5.4 ± 1.5 mm and 2.5 ± 1.1 mm, respectively. Among these subjects’ complications were observed in 18.5%. Age significantly increased the odds of complications (p = 0.019).

Conclusions
1. The success rate of MAPE among individuals aged 18 to 49 years was 84.4%.
2. A V-shaped expansion pattern in the antero-posterior dimension was mostly observed.
3. Complications were significantly associated with age.
4. A careful expansion protocol seems to be beneficial to prevent unfavorable results in adult patients.

Trial registration
Consecutive cohort study, Review Board No. EK-2-2014/0016.
Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories
Authors: Bargar Connor , De Luca Chiara Maria Giulia , Devigili Grazia , Elia Antonio Emanuele , Cilia Roberto , Portaleone Sara Maria , Wang Wen , Tramacere Irene , Bistaffa Edoardo , Cazzaniga Federico Angelo , Felisati Giovanni , Legname Giuseppe , Di Fonzo Alessio , Xu Rong , Gunzler Steven Alexander , Giaccone Giorgio , Eleopra Roberto , Chen Shu Guang , Moda Fabio 
Published: December 2021

Abstract
Background
Detection of the pathological and disease-associated alpha-synuclein (αSynD) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson’s disease (PD). We recently showed that αSynD can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes.

Methods
OM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data.

Results
The αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83–1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability.

Conclusions
Our study provides evidence that OM-αSynD may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.
The effectiveness of a model-based health education program on genital warts preventive behaviors: a quasi-experimental study
Authors: Hosseini Zahra , Seyrafi Niloofar , Aghamolaei Teamur , Mohseni Shokrollah , Alavi Azin , Dadipoor Sakineh 
Published: December 2021

Abstract
Background
Genital warts (GWs) are highly prevalent among Iranian women. GWs are not only highly infectious but are also followed by severe adverse effects, including the development of cervical cancer. Therefore, the present study aimed to explore the effect of an educational intervention based on the health belief model (HBM) on the adoption of GWs preventive behaviors by married women in Bandar Abbas, a city in the south of Iran.

Methods
A quasi-experimental intervention was conducted between 2019 and 2020 among 150 women participants (75 as the intervention and 75 as the control group). The sampling method was multi-stage clustering. The required data was collected using a reliable and valid tripartite questionnaire which explored demographic information, awareness, and HBM constructs. A total number of 15 educational sessions were held, each 90 min long. The control group received only one 90-min session. The final follow-up was completed three months after the intervention in November 2020.

Results
The two research groups had no statistically significant differences in terms of awareness, perceived susceptibility, severity, benefits, barriers, and self-efficacy before the intervention (in the pre-test) (p > .05). After the educational intervention, the two groups showed statistically significant differences in all constructs except for the perceived benefits (p < .001). In the intervention group, in the pretest (before the intervention), the behavior score was 2.77 ± 2.59, which was increased to 3.73 ± .52 after the intervention (p < .001). In the control group, however, the difference was not statistically significant (p = 0.227).

Conclusion
The present findings showed that the educational intervention based on the HBM can improve the prevalence of GWs preventive behaviors in women. This education should be provided by experts at regular intervals in all healthcare centers.
Enhanced synchronization between prelimbic and infralimbic cortices during fear extinction learning
Authors: Watanabe Mayumi , Uematsu Akira , Johansen Joshua P. 
Published: December 2021

AbstractThe ability to extinguish aversive memories when they are no longer associated with danger is critical for balancing survival with competing adaptive demands. Previous studies demonstrated that the infralimbic cortex (IL) is essential for extinction of learned fear, while neural activity in the prelimbic cortex (PL) facilitates fear responding and is negatively correlated with the strength of extinction memories. Though these adjacent regions in the prefrontal cortex maintain mutual synaptic connectivity, it has been unclear whether PL and IL interact functionally with each other during fear extinction learning. Here we addressed this question by recording local field potentials (LFPs) simultaneously from PL and IL of awake behaving rats during extinction of auditory fear memories. We found that LFP power in the fast gamma frequency (100–200 Hz) in both PL and IL regions increased during extinction learning. In addition, coherency analysis showed that synchronization between PL and IL in the fast gamma frequency was enhanced over the course of extinction. These findings support the hypothesis that interregional interactions between PL and IL increase as animals extinguish aversive memories.