bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic review and meta-analysis of the diagnostic accuracy of prostate-specific antigen (PSA) for the detection of prostate cancer in symptomatic patients
Authors: Merriel Samuel W. D. , Pocock Lucy , Gilbert Emma , Creavin Sam , Walter Fiona M. , Spencer Anne , Hamilton Willie 
Published: February 2022

AbstractBackgroundProstate-specific antigen (PSA) is a commonly used test to detect prostate cancer. Attention has mostly focused on the use of PSA in screening asymptomatic patients, but the diagnostic accuracy of PSA for prostate cancer in patients with symptoms is less well understood.MethodsA systematic database search was conducted of Medline, EMBASE, Web of Science, and the Cochrane library. Studies reporting the diagnostic accuracy of PSA for prostate cancer in patients with symptoms were included. Two investigators independently assessed the titles and abstracts of all database search hits and full texts of potentially relevant studies against the inclusion criteria, and data extracted into a proforma. Study quality was assessed using the QUADAS-2 tool by two investigators independently. Summary estimates of diagnostic accuracy were calculated with meta-analysis using bivariate mixed effects regression.ResultsFive hundred sixty-three search hits were assessed by title and abstract after de-duplication, with 75 full text papers reviewed. Nineteen studies met the inclusion criteria, 18 of which were conducted in secondary care settings with one from a screening study cohort. All studies used histology obtained by transrectal ultrasound-guided biopsy (TRUS) as a reference test; usually only for patients with elevated PSA or abnormal prostate examination. Pooled data from 14,489 patients found estimated sensitivity of PSA for prostate cancer was 0.93 (95% CI 0.88, 0.96) and specificity was 0.20 (95% CI 0.12, 0.33). The area under the hierarchical summary receiver operator characteristic curve was 0.72 (95% CI 0.68, 0.76). All studies were assessed as having a high risk of bias in at least one QUADAS-2 domain.ConclusionsCurrently available evidence suggests PSA is highly sensitive but poorly specific for prostate cancer detection in symptomatic patients. However, significant limitations in study design and reference test reduces the certainty of this estimate. There is very limited evidence for the performance of PSA in primary care, the healthcare setting where most PSA testing is performed.
Estimating the effect of non-pharmaceutical interventions to mitigate COVID-19 spread in Saudi Arabia
Authors: Bisanzio Donal , Reithinger Richard , Alqunaibet Ada , Almudarra Sami , Alsukait Reem F. , Dong Di , Zhang Yi , El-Saharty Sameh , Herbst Christopher H. 
Published: February 2022

Abstract
Background
The Kingdom of Saudi Arabia (KSA) quickly controlled the spread of SARS-CoV-2 by implementing several non-pharmaceutical interventions (NPIs), including suspension of international and national travel, local curfews, closing public spaces (i.e., schools and universities, malls and shops), and limiting religious gatherings. The KSA also mandated all citizens to respect physical distancing and to wear face masks. However, after relaxing some restrictions during June 2020, the KSA is now planning a strategy that could allow resuming in-person education and international travel. The aim of our study was to evaluate the effect of NPIs on the spread of the COVID-19 and test strategies to open schools and resume international travel.

Methods
We built a spatial-explicit individual-based model to represent the whole KSA population (IBM-KSA). The IBM-KSA was parameterized using country demographic, remote sensing, and epidemiological data. A social network was created to represent contact heterogeneity and interaction among age groups of the population. The IBM-KSA also simulated the movement of people across the country based on a gravity model. We used the IBM-KSA to evaluate the effect of different NPIs adopted by the KSA (physical distancing, mask-wearing, and contact tracing) and to forecast the impact of strategies to open schools and resume international travels.

Results
The IBM-KSA results scenarios showed the high effectiveness of mask-wearing, physical distancing, and contact tracing in controlling the spread of the disease. Without NPIs, the KSA could have reported 4,824,065 (95% CI: 3,673,775–6,335,423) cases by June 2021. The IBM-KSA showed that mandatory mask-wearing and physical distancing saved 39,452 lives (95% CI: 26,641–44,494). In-person education without personal protection during teaching would have resulted in a high surge of COVID-19 cases. Compared to scenarios with no personal protection, enforcing mask-wearing and physical distancing in schools reduced cases, hospitalizations, and deaths by 25% and 50%, when adherence to these NPIs was set to 50% and 70%, respectively. The IBM-KSA also showed that a quarantine imposed on international travelers reduced the probability of outbreaks in the country.

Conclusions
This study showed that the interventions adopted by the KSA were able to control the spread of SARS-CoV-2 in the absence of a vaccine. In-person education should be resumed only if NPIs could be applied in schools and universities. International travel can be resumed but with strict quarantine rules. The KSA needs to keep strict NPIs in place until a high fraction of the population is vaccinated in order to reduce hospitalizations and deaths.
Identification of targetable kinases in idiopathic pulmonary fibrosis
Authors: Higo Hisao , Ohashi Kadoaki , Tomida Shuta , Okawa Sachi , Yamamoto Hiromasa , Sugimoto Seiichiro , Senoo Satoru , Makimoto Go , Ninomiya Kiichiro , Nakasuka Takamasa , Nishii Kazuya , Taniguchi Akihiko , Kubo Toshio , Ichihara Eiki , Hotta Katsuyuki , Miyahara Nobuaki , Maeda Yoshinobu , Toyooka Shinichi , Kiura Katsuyuki 
Published: February 2022

Abstract
Background
Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF).

Methods
Thirteen samples from five patients with IPF (Cases 1–5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC).

Results
Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions.

Conclusions
We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.
Plasma apolipoprotein concentrations and incident diabetes in subjects with prediabetes
Authors: Croyal Mikaël , Wargny Matthieu , Chemello Kevin , Chevalier Chloé , Blanchard Valentin , Bigot-Corbel Edith , Lambert Gilles , Le May Cédric , Hadjadj Samy , Cariou Bertrand 
Published: February 2022

Abstract
Background
The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up.

Methods
In the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110–125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman’s coefficients. Kaplan–Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models.

Results
During a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA1c, and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan–Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds.

Conclusions
The plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations.
Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509
Dual CRISPR interference and activation for targeted reactivation of X-linked endogenous FOXP3 in human breast cancer cells
Authors: Cui Xuelian , Zhang Chao , Xu Zhifang , Wang Shuaibin , Li Xin , Stringer-Reasor Erica , Bae Sejong , Zeng Leiping , Zhao Dehua , Liu Runhua , Qi Lei S. , Wang Lizhong 
Published: February 2022

Abstract
Background
Unlike autosomal tumor suppressors, X-linked tumor suppressors can be inactivated by a single hit due to X-chromosome inactivation (XCI). Here, we argue that targeted reactivation of the non-mutated allele from XCI offers a potential therapy for female breast cancers.

Methods
Towards this goal, we developed a dual CRISPR interference and activation (CRISPRi/a) approach for simultaneously silencing and reactivating multiple X-linked genes using two orthogonal, nuclease-deficient CRISPR/Cas9 (dCas9) proteins.

Results
Using Streptococcus pyogenes dCas9-KRAB for silencing XIST and Staphylococcus aureus dCas9-VPR for activating FOXP3, we achieved CRISPR activation of FOXP3 in various cell lines of human female breast cancers. In human breast cancer HCC202 cells, which express a synonymous heterozygous mutation in the coding region of FOXP3, simultaneous silencing of XIST from XCI led to enhanced and prolonged FOXP3 activation. Also, reactivation of endogenous FOXP3 in breast cancer cells by CRISPRi/a inhibited tumor growth in vitro and in vivo. We further optimized CRISPRa by fusing dCas9 to the demethylase TET1 and observed enhanced FOXP3 activation. Analysis of the conserved CpG-rich region of FOXP3 intron 1 confirmed that CRISPRi/a-mediated simultaneous FOXP3 activation and XIST silencing were accompanied by elevated H4 acetylation, including H4K5ac, H4K8ac, and H4K16ac, and H3K4me3 and lower DNA methylation. This indicates that CRISPRi/a targeting to XIST and FOXP3 loci alters their transcription and their nearby epigenetic modifications.

Conclusions
The simultaneous activation and repression of the X-linked, endogenous FOXP3 and XIST from XCI offers a useful research tool and a potential therapeutic for female breast cancers.
Pregnancy, perinatal and childhood outcomes in women with and without polycystic ovary syndrome and metformin during pregnancy: a nationwide population-based study
Authors: Fornes Romina , Simin Johanna , Nguyen Minh Hanh , Cruz Gonzalo , Crisosto Nicolás , van der Schaaf Maartje , Engstrand Lars , Brusselaers Nele 
Published: February 2022

Abstract
Background
Polycystic Ovary Syndrome (PCOS) is an endocrine disorder that affects women in reproductive age and represents an unfavourable risk factor for several pregnancy and perinatal outcomes. Despite, no guidelines or pharmaceutical strategies for treating PCOS during pregnancy are available. The aim of this study is to determine the association between polycystic ovary syndrome with or without metformin and the pregnancy, perinatal outcomes as well as the risk of obesity in children born to these mothers.

Methods
In this nationwide population-based cohort study based in Swedish population, all singleton births (n = 1,016,805) from 686,847 women since 2006 up to 2016 were included. Multivariable logistic and Cox regression modelling with odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals were used to study the association between the exposure of maternal PCOS, metformin during pregnancy (or the combination of both) and: 1) Pregnancy outcomes: preeclampsia, gestational diabetes, caesarean section, and acute caesarean section, 2) Perinatal outcomes: preterm birth, stillbirth, low birth weight, macrosomia, Apgar < 7 at 5 min, small for gestational age and large for gestational age, and 3) Childhood Obesity.

Results
PCOS in women without metformin use during pregnancy was associated with higher risks of preeclampsia (OR = 1.09, 1.02–1.17), gestational diabetes (OR = 1.71, 1.53–1.91) and caesarean section (OR = 1.08, 1.04–1.12), preterm birth (OR = 1.30, 1.23–1.38), low birth weight (OR = 1.29, 1.20–1.38), low Apgar scores (OR = 1.17, 1.05–1.31) and large for gestational age (OR = 1.11, 1.03–1.20). Metformin use during pregnancy (in women without PCOS) was associated with a 29% lower risks of preeclampsia (OR = 0.71, 0.51–0.97), macrosomia and large for gestational age. Obesity was more common among children born to mothers with PCOS without metformin (HR = 1.61, 1.44–1.81); and those with metformin without PCOS (HR = 1.67, 1.05–2.65). PCOS with metformin was not associated with any adverse outcome.

Conclusion
PCOS was associated with increased risks of adverse pregnancy and perinatal outcomes and childhood obesity. Metformin appears to reduce these risks in mothers with polycystic ovary syndrome and their children; but may increase the risk of childhood-obesity in children form women without PCOS.
On-the-job vocational training of nonprofessional ethnic health workers of a primary health care team improves their sense of coherence
Authors: Katona Cintia , Bíró Éva , Vincze Szilvia , Kósa Karolina 
Published: February 2022

Abstract
Objectives
A Primary Care Model Programme had been implemented in Hungary between 2013 and 2017 in which group practices were established that employed—among others—nonprofessional health workers (health mediators, similar to community health workers) to facilitate access for the most disadvantaged population groups. The health of mediators, themselves mostly disadvantaged ethnic Roma, was monitored every odd year of the Programme.

Methods
A repeated cross-sectional health interview survey had been implemented inviting all health mediators who were employed at the time of the survey. The same questionnaire was used in all 3 surveys with items from the European Health Interview Survey 2009 and validated versions of other scales.

Results
Positive changes occurred in the health status of mediators during 5 years of follow-up. Significant improvement in mental health occurred among those who completed on-the-job vocational training. By 2017, significant increase in sense of coherence was observed among those who obtained vocational qualification as opposed to those who did not. The proportion of highly stressed mediators showed a significant increase among those with no vocational training. Improvement was detected in all mediators in health awareness, dysfunctional attitudes, psychological stress and smoking prevalence.

Conclusions
Significant improvement in mental status among those who obtained on-the-job vocational qualification were observed during follow-up of ethnic Roma health mediators in the programme in which they were equal members of the primary health care team. Employment of health mediators in primary care teams not only contributed to improving access to care for disadvantaged groups, but also improved the mental health of mediators themselves.
Mild-to-severe traumatic brain injury in children: altered cytokines reflect severity
Authors: Ryan Emer , Kelly Lynne , Stacey Catherine , Huggard Dean , Duff Eimear , McCollum Danielle , Leonard Ann , Boran Gerard , Doherty Dermot R. , Bolger Turlough , Molloy Eleanor J. 
Published: February 2022

Abstract
Background
Paediatric traumatic brain injury (TBI) is recognised to have significant longer-term neurocognitive effects. Childhood is a time of high risk for head injury. Functional recovery is variable with a combination of any or all of physical, cognitive and emotional impairment. Immune activation and alteration in cytokine levels are present following TBI which may differ from adults.

Methods
Pro- and anti-inflammatory cytokines including Interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-17A, Tumor Necrosis Factor (TNF)-α and Interferon (IFN)-γ were examined at baseline and following in vitro treatment with endotoxin of whole blood, in the following children: severe TBI (sTBI: initial Glasgow coma scale(GCS) ≤ 8), mild TBI (mTBI; GCS 14/15) at 0-4d and at 10-14d post-TBI and compared to healthy age-matched controls.

Results
The study enrolled 208 children, including 110 with TBI cohort (n = 104 mild; 6 severe) and controls (n = 98). At baseline all children with TBI had increased IL-6. The mTBI group had significantly increased IFN-γ versus controls. In sTBI at baseline, IFN-γ was decreased compared to controls. At baseline IL-8, IL-10, IL-17A, and TNF-α were decreased in mTBI compared to controls. This persisted at 2 week post-mTBI. The AUC for detecting mTBI was 0.801 CI (0.73–086) using IL6/IL10 ratio. mTBI showed a greater fold change in IL-8 and TNF-α in response to endotoxin stimulation, a response that persisted at 2 weeks. Children with sTBI did not have a significant IL-6 response to endotoxin, but did show an increase in IL-17A.

Conclusion
Children with all TBI including mTBI show altered cytokine profiles and altered endotoxin responses. Although cytokines increased in sTBI especially in response to endotoxin, suppressed responses were found in mTBI coupled with persistent immune dysfunction post-injury.
Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway
Authors: Dang Ruozhi , Wang Mingyang , Li Xinhui , Wang Haiyang , Liu Lanxiang , Wu Qingyuan , Zhao Jianting , Ji Ping , Zhong Lianmei , Licinio Julio , Xie Peng 
Published: February 2022

Abstract
Background
The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms.

Methods
A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement of MDA, SOD, GSH, GSH-PX, T-AOC and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)–EGFP infusion.

Results
The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. In addition, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage, energy metabolism and pro-inflammatory cytokines activation in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. EX527 abolished the antidepressant effect of EDA as well as the protein levels of Nrf2, HO-1 and Gpx4. Similarly, ML385 reversed the antidepressant and anxiolytic effects of EDA via decreased expressions of HO-1 and Gpx4. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors.

Conclusion
These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.