bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of an automated smartphone-based smoking cessation intervention versus standard quitline-delivered treatment among underserved smokers: protocol for a randomized controlled trial
Authors: Vidrine Jennifer I. , Shih Ya-Chen Tina , Businelle Michael S. , Sutton Steven K. , Hoover Diana Stewart , Cottrell-Daniels Cherell , Fennell Bethany Shorey , Bowles Kristina E. , Vidrine Damon J.
Published: March 2022

Background

Smoking is the leading cause of preventable morbidity and mortality in the United States. Individuals with low socioeconomic status have disproportionately high smoking rates and greater difficulty quitting smoking. Efficiently connecting underserved smokers to effective tobacco cessation programs is crucial for disease prevention and the elimination of health disparities. Smartphone-based interventions have the potential to enhance the reach and efficacy of smoking cessation treatments targeting underserved smokers, but there is little efficacy data for these interventions. In this study, we will partner with a large, local hunger-relief organization to evaluate the efficacy and economic impact of a theoretically-based, fully-automated, and interactive smartphone-based smoking cessation intervention.

Methods

This study will consist of a 2-group randomized controlled trial. Participants (N = 500) will be recruited from a network of food distribution centers in West Central Florida and randomized to receive either Standard Treatment (ST,n = 250) or Automated Treatment (AT,n = 250). ST participants will be connected to the Florida Quitline for telephone-based treatment and will receive a 10-week supply of nicotine replacement therapy (NRT; transdermal patches and lozenges). AT participants will receive 10 weeks of NRT and a fully-automated smartphone-based intervention consisting of interactive messaging, images, and audiovisual clips. The AT intervention period will span 26 weeks, with 12 weeks of proactive content and 26 weeks of on-demand access. ST and AT participants will complete weekly 4-item assessments for 26 weeks and 3-, 6-, and 12-month follow-up assessments. Our primary aim is to evaluate the efficacy of AT in facilitating smoking abstinence. As secondary aims, we will explore potential mediators and conduct economic evaluations to assess the cost and/or cost-effectiveness of ST vs. AT.

Discussion

The overall goal of this project is to determine if AT is better at facilitating long-term smoking abstinence than ST, the more resource-intensive approach. If efficacy is established, the AT approach will be relatively easy to disseminate and for community-based organizations to scale and implement, thus helping to reduce tobacco-related health disparities.

Trial registration

Clinical Trials RegistryNCT05004662. Registered August 13, 2021.
Association of long-term exposure to PM2.5 with hypertension and diabetes among the middle-aged and elderly people in Chinese mainland: a spatial study
Authors: Ye Zirong , Li Xueru , Han Yaofeng , Wu Yafei , Fang Ya
Published: March 2022

Background

Epidemiological evidence has shown an association between long-term exposure to fine particulate matter (PM2.5) and hypertension and diabetes, but few studies have considered the spatial properties of the samples. This study aimed to investigate the long-term effect of PM2.5exposure on hypertension and diabetes among middle-aged and elderly people in China based on a spatial study.

Methods

We conducted a national cross-sectional study of the most recently launched wave 4 2018 data of the China Health and Retirement Longitudinal Study (CHARLS) to calculate the prevalence of hypertension and diabetes. The exposure data of annual average PM2.5concentrations were estimated combined with satellite observations, chemical transport modeling, and ground-based monitoring. A shared component model (SCM) was used to explore the association of PM2.5with hypertension and diabetes, in which these two diseases borrowed information on spatial variations from each other. Then, we evaluated the effect variations in PM2.5in different periods and smoking status on changes in outcomes.

Results

The prevalence of hypertension and diabetes was 44.27% and 18.44%, respectively, among 19,529 participants. The annual average PM2.5concentration in 31 provinces ranged from 4.4 μg/m3to 51.3 μg/m3with an average of 27.86 μg/m3in 2018. Spatial auto-correlations of the prevalence of hypertension and diabetes and PM2.5concentrations were seen (Moran’sI = 0.336,p = 0.01; Moran’sI = 0.288,p = 0.03; Moran’sI = 0.490,p = 0.01). An interquartile range (IQR: 16.2 μg/m3) increase in PM2.5concentrations was significantly associated with a higher prevalence of hypertension and diabetes with odds ratios (ORs) of 1.070 [95% credible interval (95% CrI): 1.034, 1.108] and 1.149 (95% CrI: 1.100, 1.200), respectively. Notably, the effect of PM2.5on both hypertension and diabetes was relatively stronger among non-smokers than smokers.

Conclusion

Our nationwide study demonstrated that long-term exposure to PM2.5might increase the risk of hypertension and diabetes, and could provide guidance to public policymakers to prevent and control hypertension and diabetes according to the spatial distribution patterns of the above effects in China.
Prevalence and correlates of perceived age-related discrimination among older adults in India
Authors: Maurya Priya , Sharma Palak , Muhammad T.
Published: March 2022

Background

Age is one of the predominant reasons for perceived discrimination in developing world where older people are considered a non-contributing burden. The present study explores the prevalence and correlates of perceived age discrimination among older Indian adults.

Methods

A cross-sectional study was conducted using a large representative survey data from the Longitudinal Ageing Study in India conducted during 2017–18. Participants included 31,464 older adults aged 60 years and above. Multivariable logistic regression analysis was used to test the associations between selected background characteristics and perceived age discrimination.

Results

The analysis revealed that 10.33 percent of older adults perceived their age as the main reason for discrimination, which was 11.86% among the oldest-old. Older adults with more than 10 years of schooling were 32% [adjusted odds ratio (AOR): 0.68; confidence interval (CI): 0.51—0.89] less likely to perceive age discrimination compared to their uneducated counterparts. The odds of perceived age discrimination were higher among older adults who earlier worked [AOR: 1.73; CI: 1.46—2.05] and currently working [AOR: 1.61; CI: 1.31—1.96] as compared to those who never worked. Further, having difficulty in instrumental activities of daily living (IADL) [AOR: 1.43; CI: 1.25 -1.65] and having one chronic condition [AOR: 1.16; CI: 1.02 -1.34] were associated with increased odds of perceived age discrimination among older adults.

Conclusion

Older adults with lower socioeconomic status, currently working, having more chronic conditions, difficulty in IADL and belonging to rural areas were found to perceive higher age discrimination than their counterparts. The findings of the study have important implications for policy makers with respect to strategies such as making the vulnerable populations aware of their legal rights that help in the prevention of age-based discrimination in the country.
Minimally invasive separation surgery for the treatment of spinal metastases with small incision and freehand pedicle screw fixation: the surgical learning curve
Authors: Lin Jiaming , Zhu Xiaojun , Tang Qinglian , Lu Jinchang , Xu Huaiyuan , Song Guohui , Deng Chuangzhong , Wu Hao , Huang Yufeng , Huang Anfei , Xu Yanyang , Chen Hongmin , Wang Jin
Published: March 2022

Background

Minimally invasive separation surgery (MISS) is a safe and effective surgical technique, the current optimal treatment for spinal metastases. However, the learning curve for this technique has not been analyzed. This study aimed to define and analyze the surgical learning curve of MISS for the treatment of spinal metastases with small incision and freehand pedicle screw fixation.

Methods

A continuous series of 62 patients with spinal metastases who underwent MISS were included. Each patient's operative data were accurately counted. The improvement of the patients' neurological function was followed up after surgery to evaluate the surgical treatment effect. Logarithmic curve-fit regression was used to analyze the surgical learning curve of MISS. The number of cases needed to achieve proficiency was analyzed. Based on this cut-off point, this series of cases was divided into the early phase and later phase groups. The influence of the time sequence of MISS on surgical data and surgical efficacy was analyzed.

Results

The operative time decreased gradually with the number of surgical cases increasing and stabilized after the 20th patient. There was no statistical difference in demographic characteristics and preoperative characteristics between the two groups. The mean operative time in the later phase group was about 39 min shorter than that in the early phase group (mean 227.95 vs. 189.02 min, P = 0.027). However, it did not affect other operative data or the surgical treatment effect.

Conclusion

The learning curve of MISS for spinal metastases is not steep. With the increase of surgeons' experience, the operative time drops rapidly and stabilizes within a certain range. MISS can be safely and effectively performed at the beginning of a surgeon's caree.
Promoting self-management behaviors in adolescents with type 1 diabetes, using digital storytelling: a pilot randomized controlled trial
Authors: Zarifsaniey Nahid , Shirazi Masoomeh Otrodi , Mehrabi Manoosh , Bagheri Zahra
Published: March 2022

Background

This study aimed to assess the effects of digital storytelling on the self-management behavior of adolescents with type 1 diabetes (TID).

Methods

In this pilot randomized controlled clinical trial, 60 adolescents with TID were randomly allocated into two parallel groups: intervention (training with digital storytelling method, n = 33) or control (training with a conventional method, n = 33). The primary outcome was assessing the Self-Management behavior of adolescents with TID (SMOD-A) at baseline and three months after the intervention.

Results

The results revealed that digital storytelling could significantly improve self-management behaviors amongst adolescents with TID (P = 0.005). In contrast, in the control group, no significant changes were observed (P > 0.05). Furthermore, the mean score of Collaboration with Parents subscale was significantly higher in the digital storytelling group than in the control group after the intervention (p = 0.022). The results also showed that the level of Collaboration With Parents' subscale scores had a meaningful reverse relationship with the adolescent age after digital storytelling (p = 0.048). Repeated measures ANOVAs showed that there were significant main effects of time and group on collaboration with parents(p = 0.002) and goal subscales (p = 0.035). With respect to HbA1c levels, significant changes were not observed in any of the groups (P > 0.05).

Conclusions

Digital storytelling is practicable and a potentially beneficial training modality for adolescents with TID.

Trial registration

This trial was respectively registered.

ClinicalTrials.gov Identifier: IRCT20191220045828N1.

Date of registration: Oct 29. 2020.
Virtual consultations for oral surgery patients
Authors: Crummey Aoife , Graham Abigail , Besi Eleni
Published: March 2022

Background

Following Covid-19, many departments have incorporated teledentistry into practice. As new consultation methods are introduced, it’s imperative that patients have as similar an experience with virtual consultations to ensure informed decision-making. This project evaluated patients' perceptions of video consultations and determined if patients seen virtually received the same standard of information by auditing compliance with sending patient information leaflets (PILs) following video consultation.

Method

The department’s PILs were used to create an inclusion list for patients requiring a PIL. A retrospective audit assessed the notes of 100 video consultations for records of if PILs were sent and by what method. The department’s PILs were digitalised and a clinical mailbox introduced enabling clinicians to email patients a PIL hyperlink. The audit was repeated for 88 video consultations. Patient and staff feedback was gathered via online surveys.

Results

Initially, 51% of cases met the criteria requiring a PIL and 16% of patients were sent PILs. Following mailbox introduction, 53% of cases met the criteria and 94% were sent PILs, 100% via email. Patient and staff feedback was positive regarding video consultations and digital PILS. Technical difficulties were reported in 44% of cases.

Conclusions

Patients perceive virtual consultations to be a positive change and the introduction of a mailbox enhances video consultations in an efficient and cost-effective manner. Patient information can be standardised, via digital PILs, regardless of consultation type. As departments implement post-pandemic changes, utilisation of a mailbox can provide multiple improvements to care.
Bioethics curriculum in medical schools in Portuguese-speaking countries
Authors: de Lemos Tavares Ana Carolina Alvares Lavigne , Travassos Ana Gabriela Alvares , Rego Francisca , Nunes Rui
Published: March 2022

Background

A curriculum is a fundamental tool for educators, and teaching bioethics is fundamental to good medical practice. Studies report a lack of consensus on the teaching of bioethics in undergraduate medicine, and a critical issue is that there remain no minimum curricular parameters. This study performed an analysis between the bioethics curricula of the medical schools of Brazil and Portugal and UNESCO’s Core Curriculum, in addition to proposing key criteria for designing a core bioethics curriculum.

Methods

This is a cross-sectional, descriptive study that analyzes the bioethics curricula of the medical schools in Brazil and in Portugal. The design of the study includes a qualitative summative content analysis-based approach and a quantitative analysis by means of descriptive statistics.

Results

Bioethics is taught in both Brazil and Portugal in a diversified way. The results showed that 65.5% of the medical schools analyzed provided at least the 30-h minimum workload recommended by the UNESCO Core Curriculum. Furthermore, bioethics sporadically offered at the end of the medical program in the vast majority of schools studied.

Conclusions

The most important points to take away from this study are the diversity of the curricular structure of bioethics courses and the lack of formalization of bioethics in the curricula of medical schools in Brazil and Portugal. Given the value of bioethics in clinical practice, we propose that medical schools in Portugal and Brazil update their curricula to encompass minimum criteria, which should be similar to one another and based on common sources, but which should also be tailored to each culture.
Exploration of changes in pharmacy students’ perceptions of and attitudes towards professionalism: outcome of a community pharmacy experiential learning programme in Taiwan
Authors: Huang Yen-Ming , Chan Hsun-Yu , Lee Ping-Ing , Tang Yun-Wen , Chiou Ta-Wei , Liu Karin C.S. Chen , Ho Yunn-Fang
Published: March 2022

Background

A powerful way to nurture and strengthen professionalism is by accruing practice-based experiences. However, few studies in Taiwan have evaluated the impacts of experiential learning programmes on pharmacy students’ views on professionalism − the core of quality healthcare practices and services. This study aimed to measure changes in perceptions of and attitudes towards professionalism among third-year pharmacy students following an introductory-intermediate experiential learning course.

Methods

A single-group pre- and postcourse comparative study using a self-administered survey was conducted in 2017. Pharmacy students in their third year of a six-year programme were eligible to participate in this study. We used a 28-item questionnaire with a 10-point Likert-type scale to assess students’ professionalism. Among them, 10 items were employed to assess students’ perceived importance of professionalism in pharmacy practice, and another 18 items adapted from the Pharmacy Professionalism Instrument were used to evaluate students’ attitudes towards pharmacy professionalism. An independent t test was performed to compare the differences in students’ anonymous survey responses before and after the course, with an a priori level of statistical significance of 0.05.

Results

Fifty-two pharmacy students participated in the study. They showed significant improvement in three tenets of professionalism, namely, altruism (p = 0.035), accountability (p = 0.026), and duty (p = 0.002), after completing the 5-week experiential course.

Conclusions

Pharmacy students’ attitudes towards professionalism were modifiable by purposely designed experiential learning programme in the community setting. Such experiences may help socialize students with positive attitudes towards altruism, accountability, and duty.
Perceived team roles of medical students: a five year cross-sectional study
Authors: Boone Anke , Roelants Mathieu , Hoppenbrouwers Karel , Vandermeulen Corinne , Du Bois Marc , Godderis Lode
Published: March 2022

Introduction

Despite the increasing importance of teamwork in healthcare, medical education still puts great emphasis on individual achievements. The purpose of this study is to examine medical students’ team role preferences, including the association with gender and specialty; and to provide implications for policy makers and medical educators.

Methods

We used an exploratory methodology, following a cross-sectional design. Data was collected from first year master students in medicine (n = 2293) during five consecutive years (2016–2020). The Belbin Team Role Self Perception Inventory (BTRSPI) was used to measure medical students’ self-perceptions of their team role.

Results

The Team Worker was the most preferred team role among medical students (35.8%), regardless of gender or specialty. Female and male students had similar team role patterns, although female students scored higher on Team Worker (40.4% vs. 29.1%, P < .001) and Completer-Finisher (14.0% vs. 8.0%, P < .001). With regard to specialties, the Team Worker role was more often chosen by general practitioners than by person-centered and technique-oriented specialties (47.1% vs. 41.8% vs. 29.1%, P < .001).

Conclusions

Our findings contribute to an increased scientific understanding of how medical students perceive their own team role, and how this is related to gender and specialty. This is valuable due to the increased importance of interdisciplinary teamwork in healthcare. Medical schools should prioritize stimulating teamwork skills through the implementation of different interventions at all stages (i.e. from the admission process to curricula to residency) and all levels (i.e. explicit and implicit curricula).
Cost analysis of employing general practitioners within residential aged care facilities based on a prospective, stepped-wedge, cluster randomised trial
Authors: Si Lei , Robinson Andrew , Haines Terry P. , Tierney Petra , Palmer Andrew J.
Published: March 2022

Objective

To assess the impacts of changing a model of care and employing general practitioners (GPs) within residential aged care facilities (RACFs) on costs to the aged care provider (ACP) and state and federal governments of Australia.

Methods

This study was a cost analysis of a prospective, stepped-wedge, cluster randomised trial. All financial data from the ACP for every RACF involved, before and after implementation of the new model were obtained. Costs of hospital transfers, admissions, ambulance usage and GP consultations were calculated. Costs of new infrastructure, recruiting and training new staff were accounted for. Costs were standardised to 2019 Australian Dollars per occupied bed day (OBD).

Results

Implementation of the new model of care resulted in overall cost savings of $9.7 per OBD to the ACP, with increased salary costs offset by increased federal government subsidies and Medicare claims income. Costs to the federal government increased by $19.6 per OBD, driven by increases in subsides. Costs savings of $3.0 per OBD to state governments were seen, driven by decreased costs of hospital transfers.

Conclusions

Implementation of a model of care including GPs employed at RACFs had a mixed impact on costs depending on perspective, with overall savings to the ACP and state government perspective.
A chemical probe inhibitor targeting STAT1 restricts cancer stem cell traits and angiogenesis in colorectal cancer
Authors: Chou Pei-Hsuan , Luo Cong-Kai , Wali Niaz , Lin Wen-Yen , Ng Shang-Kok , Wang Chun-Hao , Zhao Mingtao , Lin Sheng-Wei , Yang Pei-Ming , Liu Pin-Jung , Shie Jiun-Jie , Wei Tzu-Tang
Published: March 2022

Background

Colorectal cancer (CRC) is a worldwide cancer with rising annual incidence. New medications for patients with CRC are still needed. Recently, fluorescent chemical probes have been developed for cancer imaging and therapy. Signal transducer and activator of transcription 1 (STAT1) has complex functions in tumorigenesis and its role in CRC still needs further investigation.

Methods

RNA sequencing datasets in the NCBI GEO repository were analyzed to investigate the expression of STAT1 in patients with CRC. Xenograft mouse models, tail vein injection mouse models, and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were generated to study the roles of STAT1 in CRC. A ligand-based high-throughput virtual screening approach combined with SWEETLEAD chemical database analysis was used to discover new STAT1 inhibitors. A newly designed and synthesized fluorescently labeled 4’,5,7-trihydroxyisoflavone (THIF) probe (BODIPY-THIF) elucidated the mechanistic actions of STAT1 and THIF in vitro and in vivo. Colonosphere formation assay and chick chorioallantoic membrane assay were used to evaluate stemness and angiogenesis, respectively.

Results

Upregulation of STAT1 was observed in patients with CRC and in mouse models of AOM/DSS-induced CRC and metastatic CRC. Knockout of STAT1 in CRC cells reduced tumor growth in vivo. We then combined a high-throughput virtual screening approach and analysis of the SWEETLEAD chemical database and found that THIF, a flavonoid abundant in soybeans, was a novel STAT1 inhibitor. THIF inhibited STAT1 phosphorylation and might bind to the STAT1 SH2 domain, leading to blockade of STAT1-STAT1 dimerization. The results of in vitro and in vivo binding studies of THIF and STAT1 were validated. The pharmacological treatment with BODIPY-THIF or ablation of STAT1 via a CRISPR/Cas9-based strategy abolished stemness and angiogenesis in CRC. Oral administration of BODIPY-THIF attenuated colitis symptoms and tumor growth in the mouse model of AOM/DSS-induced CRC.

Conclusions

This study demonstrates that STAT1 plays an oncogenic role in CRC. BODIPY-THIF is a new chemical probe inhibitor of STAT1 that reduces stemness and angiogenesis in CRC. BODIPY-THIF can be a potential tool for CRC therapy as well as cancer cell imaging.
Factors regulating cellulolytic gene expression in filamentous fungi: an overview
Authors: Mattam Anu Jose , Chaudhari Yogesh Babasaheb , Velankar Harshad Ravindra
Published: March 2022

The growing demand for biofuels such as bioethanol has led to the need for identifying alternative feedstock instead of conventional substrates like molasses, etc. Lignocellulosic biomass is a relatively inexpensive feedstock that is available in abundance, however, its conversion to bioethanol involves a multistep process with different unit operations such as size reduction, pretreatment, saccharification, fermentation, distillation, etc. The saccharification or enzymatic hydrolysis of cellulose to glucose involves a complex family of enzymes called cellulases that are usually fungal in origin. Cellulose hydrolysis requires the synergistic action of several classes of enzymes, and achieving the optimum secretion of these simultaneously remains a challenge. The expression of fungal cellulases is controlled by an intricate network of transcription factors and sugar transporters. Several genetic engineering efforts have been undertaken to modulate the expression of cellulolytic genes, as well as their regulators. This review, therefore, focuses on the molecular mechanism of action of these transcription factors and their effect on the expression of cellulases and hemicellulases.
Do socio-demographic factors modify the effect of weather on malaria in Kanungu District, Uganda?
Authors: Ost Katarina , Berrang-Ford Lea , Bishop-Williams Katherine , Charette Margot , Harper Sherilee L. , Lwasa Shuaib , Namanya Didacus B. , Huang Yi , Katz Aaron B. ,   Bwindi Community Hospital,   IHACC Research Team, Ebi Kristie
Published: March 2022

Background

There is concern in the international community regarding the influence of climate change on weather variables and seasonality that, in part, determine the rates of malaria. This study examined the role of sociodemographic variables in modifying the association between temperature and malaria in Kanungu District (Southwest Uganda).

Methods

Hospital admissions data from Bwindi Community Hospital were combined with meteorological satellite data from 2011 to 2014. Descriptive statistics were used to describe the distribution of malaria admissions by age, sex, and ethnicity (i.e. Bakiga and Indigenous Batwa). To examine how sociodemographic variables modified the association between temperature and malaria admissions, this study used negative binomial regression stratified by age, sex, and ethnicity, and negative binomial regression models that examined interactions between temperature and age, sex, and ethnicity.

Results

Malaria admission incidence was 1.99 times greater among Batwa than Bakiga in hot temperature quartiles compared to cooler temperature quartiles, and that 6–12 year old children had a higher magnitude of association of malaria admissions with temperature compared to the reference category of 0–5 years old (IRR = 2.07 (1.40, 3.07)).

Discussion

Results indicate that socio-demographic variables may modify the association between temperature and malaria. In some cases, such as age, the weather-malaria association in sub-populations with the highest incidence of malaria in standard models differed from those most sensitive to temperature as found in these stratified models.

Conclusion

The effect modification approach used herein can be used to improve understanding of how changes in weather resulting from climate change might shift social gradients in health.
Role of D-mannose in urinary tract infections – a narrative review
Authors: Ala-Jaakkola Reeta , Laitila Arja , Ouwehand Arthur C. , Lehtoranta Liisa
Published: March 2022

Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of antibiotics targeted against UTI, the recurrence rates remain significant among the patients. Furthermore, the development of antibiotic resistance is a major concern and creates a demand for alternative treatment options. D-mannose, a monosaccharide naturally found in fruits, is commonly marketed as a dietary supplement for reducing the risk for UTIs. Research suggests that supplemented D-mannose could be a promising alternative or complementary remedy especially as a prophylaxis for recurrent UTIs. When excreted in urine, D-mannose potentially inhibits Escherichia coli, the main causative organism of UTIs, from attaching to urothelium and causing infection. In this review, we provide an overview of UTIs, E. coli pathogenesis and D-mannose and outline the existing clinical evidence of D-mannose in reducing the risk of UTI and its recurrence. Furthermore, we discuss the potential effect mechanisms of D-mannose against uropathogenic E.coli.
A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer
Authors: Fletcher C. E. , Deng L. , Orafidiya F. , Yuan W. , Lorentzen M. P. G. S. , Cyran O. W. , Varela-Carver A. , Constantin T. A. , Leach D. A. , Dobbs F. M. , Figueiredo I. , Gurel B. , Parkes E. , Bogdan D. , Pereira R. R. , Zhao S. G. , Neeb A. , Issa F. , Hester J. , Kudo H. , Liu Y. , Philippou Y. , Bristow R. , Knudsen K. , Bryant R. J. , Feng F. Y. , Reed S. H. , Mills I. G. , de Bono J. , Bevan C. L.
Published: March 2022

Background

miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent.

Methods

RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq).

Results

miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival.

INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes.

NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy.

Conclusions

A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.
Intended preoperative trans-arterial embolization for large hepatocellular carcinoma: a retrospective cohort study
Authors: Saito Ryo , Amemiya Hidetake , Hosomura Naohiro , Kawaida Hiromichi , Shoda Katsutoshi , Furuya Shinji , Akaike Hidenori , Kawaguchi Yoshihiko , Inoue Shingo , Kono Hiroshi , Ichikawa Daisuke
Published: March 2022

Background

Generally, a large tumor size of hepatocellular carcinoma (HCC) is associated with poor visibility and uncertainty in the surgical field which results in increased surgical difficulty as well as unfavorable postoperative outcomes. We performed intended preoperative trans-arterial embolization (TAE) in patients with a large HCC. In this study, we investigated the oncological significance of intended preoperative TAE for a large HCC, using a comparison between patients with and without TAE, and detailed analyses for pre- and post-TAE status.

Methods

A total of 411 patients who underwent hepatectomy for primary HCC at the University of Yamanashi Hospital between January 2007 and December 2018 were included in this study. The patients were divided into two groups: patients with larger HCCs (≥50 mm, n=51) and those with smaller HCC (<50 mm, n=360) according to the size of their HCCs. Comparison of clinicopathological features between these groups and clinical outcomes between the TAE and non-TAE groups were compared. In addition, a detailed analysis of each case in the TAE group was conducted, comparing clinicopathological factors between pre- and post-TAE status.

Results

The clinical unfavorable short- and long-term outcomes of patients with large HCCs (≥50 mm) were revealed compared to those with small HCCs (<50 mm). The prognostic analyses showed that a large tumor size and increased tumor markers, multiple tumor numbers, and others were adverse prognostic factors, and vascular invasions and residual tumors were included in the multivariate analysis.

Further detailed analyses revealed that the average rates of change in tumor size and tumor shrinkage after TAE were − 48.6±35.6 mm and − 30.7±17.0%, respectively. Pathological high necrotic changes in the tumor, after multiple-times TAE aiming to a better effect, were related to a better prognosis in patients with large HCC. Poor prognostic factors became less common in patients who underwent intended preoperative TAE, and these patients had better prognoses.

Conclusions

The large tumor size of HCC is associated with unfavorable outcomes; the intended preoperative TAE for large HCC patients performed multiple times aiming to affect the tumor as much as possible might improve their prognoses.
Role of Chemerin/ChemR23 axis as an emerging therapeutic perspective on obesity-related vascular dysfunction
Authors: Xie Yingying , Liu Ling
Published: March 2022

Sufficient epidemiological investigations demonstrate that there is a close correlation between obesity and vascular dysfunction. Nevertheless, specific mechanisms underlying this link remain currently unclear. Given the crucial and decisive role of vascular dysfunction in multitudinous diseases, various hypotheses had been proposed and numerous experiments were being carried out. One recognized view is that increased adipokine secretion following the expanded mass of white adipose tissue due to obesity contributes to the regulation of vascular function. Chemerin, as a neo-adipokine, whose systemic level is elevated in obesity, is believed as a regulator of adipogenesis, inflammation, and vascular dysfunction via binding its cell surface receptor, chemR23. Hence, this review aims to focus on the up-to-date proof on chemerin/chemR23 axis-relevant signaling pathways, emphasize the multifarious impacts of chemerin/chemR23 axis on vascular function regulation, raise certain unsettled questions to inspire further investigations, and explore the therapeutic possibilities targeting chemerin/chemR23.
CircESRP1 enhances metastasis and epithelial–mesenchymal transition in endometrial cancer via the miR-874-3p/CPEB4 axis
Authors: Shi Rui , Zhang Wei , Zhang Jun , Yu Zhicheng , An Lanfen , Zhao Rong , Zhou Xing , Wang Ziwei , Wei Sitian , Wang Hongbo
Published: March 2022

Background

Metastasis is critical for endometrial cancer (EC) progression and prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) can operate as independent functional entities. However, the functional regulatory mechanisms of circRNAs in EC remain unclear.

Methods

The levels of circESRP1, miR-874-3p, and CPEB4 mRNA in EC tissues and cells were determined by qRT-PCR. Sanger sequencing, PCR with divergent primers, an actinomycin D assay, and RNase R treatment were applied to verify the circular properties. Fluorescence in situ hybridization (FISH) and nuclear-cytoplasmic fractionation were used to determine the localization of circESRP1. CCK-8, EdU incorporation, colony formation, Transwell, and wound healing assays were applied to assess the effects of circESRP1 on cell proliferation, migration, and invasion. The mutual regulatory mechanism of ceRNAs was investigated using dual-luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP), and Western blot assays. The biological effects were further validated in vivo in nude mouse xenograft models.

Results

circESRP1 was highly expressed in EC tissues and cells and was mainly localized in the cytoplasm. Silencing circESRP1 inhibited the proliferation, migration, and invasion of EC cells in vitro and in vivo; however, overexpression of circESRP1 had the opposite effects. Mechanistically, circESRP1 sponged miR-874-3p to upregulate CPEB4 expression and ultimately contribute to EC cell proliferation and metastasis. Furthermore, circESRP1 regulated tumour growth in xenograft models.

Conclusions

CircESRP1 can interact with miR-874-3p to regulate EMT in endometrial cancer via the miR-874-3p/CPEB4 axis. CircESRP1 may serve as a promising therapeutic target for endometrial cancer.
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)
Authors: Haffke Milan , Freitag Helma , Rudolf Gordon , Seifert Martina , Doehner Wolfram , Scherbakov Nadja , Hanitsch Leif , Wittke Kirsten , Bauer Sandra , Konietschke Frank , Paul Friedemann , Bellmann-Strobl Judith , Kedor Claudia , Scheibenbogen Carmen , Sotzny Franziska
Published: March 2022

Background

Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.

Methods

We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.

Results

Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.

Conclusion

A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.
Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response
Authors: Ashrafizadeh Milad , Paskeh Mahshid Deldar Abad , Mirzaei Sepideh , Gholami Mohammad Hossein , Zarrabi Ali , Hashemi Farid , Hushmandi Kiavash , Hashemi Mehrdad , Nabavi Noushin , Crea Francesco , Ren Jun , Klionsky Daniel J. , Kumar Alan Prem , Wang Yuzhuo
Published: March 2022

Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a “self-degradation” mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients.

Graphical abstract
Aquatain® causes anti-oviposition, egg retention and oocyte melanization and triggers female death in Aedes aegypti
Authors: Dieng Hamady , McLean Storm , Stradling Holly , Morgan Cole , Gordon Malik , Ebanks Whitney , Ebanks Zoila , Wheeler Alan
Published: March 2022

Background

In arboviral disease systems where the virus can be transmitted from male to female vectors and from one generation to the next, targeting the female (especially when she is gravid) can help alter the persistence of the virus in nature and its transmission. A typical example is Aedes aegypti, which has become unmanageable due to the development of insecticide resistance. Despite evidence that monomolecular surface films prevent the selection of genetic resistance, their potential in Aedes vector control remains largely unexplored.

Methods

We examined the oviposition, egg retention, oocyte melanization, and female mortality of the Cayman Islands strain of Ae. aegypti, using choice (balanced and unbalanced) and no-choice bioassays involving Aquatain® Mosquito Formulation (AMF; Aquatain Products Pty Ltd.), a polydimethylsiloxane–based liquid used for mosquito control.

Results

When presented with similar opportunities to oviposit in two sites treated with AMF and two other sites with untreated water (control), egg deposition rates were significantly higher in the untreated water sites than in the AMF-treated sites (P < 0.05). We also observed a matching pattern of egg deposition preference in environments with more options in terms of AMF-treated sites. Females laid significantly more eggs when water was the only available medium than when all sites were treated with AMF (P < 0.05). Also, significantly more mature eggs were withheld in the AMF no-choice environment than in the no-choice test involving only water (P < 0.05). Internal oocyte melanization was not observed in females from the oviposition arenas with the lowest AMF presence (equal-choice and water-based no-choice); in contrast, this physiological response intensified as the number of AMF-treated sites increased. Female death occurred at high rates in AMF-treated environments, and this response increased with the increasing presence of such egg deposition sites.

Conclusions

This study demonstrated that AMF acted as a deterrent signal to ovipositing Ae. aegypti and as an indirect adulticide. These results suggest that AMF may be a promising control tool against the dengue vector, and this warrants further evaluation under field settings.

Graphical Abstract
Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer
Authors: Dong Qian , Song Nan , Qin Na , Chen Cheng , Li Zhenghong , Sun Xiaojun , Easton John , Mulder Heather , Plyler Emily , Neale Geoffrey , Walker Emily , Li Qian , Ma Xiaotu , Chen Xiang , Huang I-Chan , Yasui Yutaka , Ness Kirsten K. , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Wang Zhaoming
Published: March 2022

Background

Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.

Methods

Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.

Results

For EAA-Horvath, a genome-wide significant association was mapped to theSELPgene with the strongest SNP rs732314 (meta-GWAS:β=0.57,P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS:β=0.97 vs. 0.51,I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31,I2=66.3%). For EAA-Hannum, an association was mapped to theHLAlocus with the strongest SNP rs28366133 (meta-GWAS:β=0.78,P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09,P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21,P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.

Conclusions

We identified novel genetic variants in theSELPgene andHLAregion associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.
The association of sleep patterns and depressive symptoms in medical students: a cross-sectional study
Authors: Dudo Katrin , Ehring Emilia , Fuchs Stephan , Herget Sabine , Watzke Stefan , Unverzagt Susanne , Frese Thomas
Published: March 2022

Objective

Mental health is a fundamental aspect in ensuring the stable and successful professional life of future physicians. Depressive symptoms can negatively affect the work-life-balance and efficiency at work of medical students.

To date, there have been very few studies involving medical students that examine the association between single sleep characteristics and the outcome of the Beck Depression Inventory-II score. Therefore, the aim of the present study is to investigate this possible association. A classroom survey using socio-demographic characteristics, the Beck Depression Inventory-II, and the Pittsburgh Sleep Quality Index was conducted amongst students at a German medical school from December 2017 to September 2018. Data analysis was performed with descriptive statistics and binary logistic regression.

Results

Of the students surveyed, 19% showed depressive symptoms with a Beck Depression Inventory-II score over 13 and 42% of these cases were moderate or severe. The occurrence of relevant depressive symptoms was associated with lower sleep quality, higher sleep latency, and the consumption of sleeping pills. In general, female students and students from abroad had a higher risk of depressive symptoms. Addressing these relevant findings in medical school can increase awareness of mental health.