bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving symptom burden in adults with persistent post-concussive symptoms: a randomized aerobic exercise trial protocol
Authors: Mercier Leah J. , Fung Tak S. , Harris Ashley D. , Dukelow Sean P. , Debert Chantel T.
Published: February 2020

Background

Persistent post-concussive symptoms (PPCS) affect up to 30% of individuals following mild traumatic brain injury. PPCS frequently includes exercise intolerance. Sub-symptom threshold aerobic exercise has been proposed as a treatment option for symptom burden and exercise intolerance in this population. The primary aim of this study is to evaluate whether a progressive, sub-symptom threshold aerobic exercise program can alleviate symptom burden in adults with PPCS.

Methods

Fifty-six adults (18–65) with PPCS (>3mos-5 yrs) will be randomized into two groups: an immediate start 12-week aerobic exercise protocol (AEP) or delayed start 6-week placebo-like stretching protocol (SP), followed by AEP. Aerobic or stretching activities will be completed 5x/week for 30 mins during the intervention. Online daily activity logs will be submitted. Exercise prescriptions for the AEP will be 70–80% of heart rate at the point of symptom exacerbation achieved on a treadmill test with heart rate monitoring. Exercise prescription will be updated every 3-weeks with a repeat treadmill test. The Rivermead Post-concussion Symptom Questionnaire will be the primary outcome measure at 6 and 12-weeks of intervention. Secondary outcomes include assessments of specific symptoms (headache, quality of life, mood, anxiety, fatigue, dizziness, sleep parameters, daytime sleepiness) in addition to blood biomarkers and magnetic resonance imaging and spectroscopy data for quantification of brain metabolites including γ-aminobutyric acid (GABA), glutathione, glutamate and N-acetyl aspartate (NAA) all measured at 6 and 12-weeks of intervention.

Discussion

This trial will evaluate the use of aerobic exercise as an intervention for adults with PPCS, thus expanding our knowledge of this treatment option previously studied predominantly for adolescent sport-related concussion.

Trial registration

ClinicalTrials.gov -NCT03895450(registered 2019-Feb-11).
Predicting the response to neoadjuvant chemotherapy for breast cancer: wavelet transforming radiomics in MRI
Authors: Zhou Jiali , Lu Jinghui , Gao Chen , Zeng Jingjing , Zhou Changyu , Lai Xiaobo , Cai Wenli , Xu Maosheng
Published: February 2020

Background

The purpose of this study was to investigate the value of wavelet-transformed radiomic MRI in predicting the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) for patients with locally advanced breast cancer (LABC).

Methods

Fifty-five female patients with LABC who underwent contrast-enhanced MRI (CE-MRI) examination prior to NAC were collected for the retrospective study. According to the pathological assessment after NAC, patient responses to NAC were categorized into pCR and non-pCR. Three groups of radiomic textures were calculated in the segmented lesions, including (1) volumetric textures, (2) peripheral textures, and (3) wavelet-transformed textures. Six models for the prediction of pCR were Model I: group (1), Model II: group (1) + (2), Model III: group (3), Model IV: group (1) + (3), Model V: group (2) + (3), and Model VI: group (1) + (2) + (3). The performance of predicting models was compared using the area under the receiver operating characteristic (ROC) curves (AUC).

Results

The AUCs of the six models for the prediction of pCR were 0.816 ± 0.033 (Model I), 0.823 ± 0.020 (Model II), 0.888 ± 0.025 (Model III), 0.876 ± 0.015 (Model IV), 0.885 ± 0.030 (Model V), and 0.874 ± 0.019 (Model VI). The performance of four models with wavelet-transformed textures (Models III, IV, V, and VI) was significantly better than those without wavelet-transformed textures (Model I and II). In addition, the inclusion of volumetric textures or peripheral textures or both did not result in any improvements in performance.

Conclusions

Wavelet-transformed textures outperformed volumetric and/or peripheral textures in the radiomic MRI prediction of pCR to NAC for patients with LABC, which can potentially serve as a surrogate biomarker for the prediction of the response of LABC to NAC.
Coffee drinking and cancer risk: an umbrella review of meta-analyses of observational studies
Authors: Zhao Long-Gang , Li Zhuo-Ying , Feng Guo-Shan , Ji Xiao-Wei , Tan Yu-Ting , Li Hong-Lan , Gunter Marc J. , Xiang Yong-Bing
Published: February 2020

Background

Epidemiological studies on the association between coffee intake and cancer risk have yielded inconsistent results. To summarize and appraise the quality of the current evidence, we conducted an umbrella review of existing findings from meta-analyses of observational studies.

Methods

We searched PubMed, Embase, Web of Science and the Cochrane database to obtain systematic reviews and meta-analyses of associations between coffee intake and cancer incidence. For each association, we estimated the summary effect size using the fixed- and random-effects model, the 95% confidence interval, and the 95% prediction interval. We also assessed heterogeneity, evidence of small-study effects, and excess significance bias.

Results

Twenty-eight individual meta-analyses including 36 summary associations for 26 cancer sites were retrieved for this umbrella review. A total of 17 meta-analyses were significant at P ≤ 0.05 in the random-effects model. For the highest versus lowest categories, 4 of 26 associations had a more stringent P value (P ≤ 10− 6). Associations for five cancers were significant in dose-response analyses. Most studies (69%) showed low heterogeneity (I2 ≤ 50%). Three and six associations had evidence of excessive significance bias and publication bias, respectively. Coffee intake was inversely related to the risk of liver cancer and endometrial cancer and was characterized by dose-response relationships. There were no substantial changes when we restricted analyses to meta-analysis of cohort studies.

Conclusions

There is highly suggestive evidence for an inverse association between coffee intake and risk of liver and endometrial cancer. Further research is needed to provide more robust evidence for cancer at other sites.
Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors
Authors: Serrano César , Vivancos Ana , López-Pousa Antonio , Matito Judit , Mancuso Francesco M. , Valverde Claudia , Quiroga Sergi , Landolfi Stefania , Castro Sandra , Dopazo Cristina , Sebio Ana , Virgili Anna C. , Menso María M. , Martín-Broto Javier , Sansó Miriam , García-Valverde Alfonso , Rosell Jordi , Fletcher Jonathan A. , George Suzanne , Carles Joan , Arribas Joaquín
Published: February 2020

Background

Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients.

Methods

We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR).

Results

We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib.

Conclusions

ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
Comparison of antibiotic and acyclovir usage before and after the implementation of an on-site FilmArray meningitis/encephalitis panel in an academic tertiary pediatric hospital: a retrospective observational study
Authors: Hagen Alexandra , Eichinger Anna , Meyer-Buehn Melanie , Schober Tilmann , Huebner Johannes
Published: February 2020

Background

Prompt initiation of empiric therapy is common practice in case of suspected meningitis or encephalitis. However, in children the most common pathogens are viruses that usually do not require and are not covered by the applied anti-infective treatment. Novel multiplex PCR (mPCR) panels provide rapid on-site diagnostic testing for a variety of pathogens. This study compared empiric antibiotic and acyclovir usage before and after the introduction of an on-site FilmArray Meningitis/Encephalitis Panel (FA ME Panel).

Methods

We retrospectively compared data for empiric antibiotic and acyclovir usage between pediatric patients with suspected central nervous system (CNS) infection receiving mPCR testing and a matched historical control group. Patients were matched by age and suspected CNS infection. We included all patients for whom empiric antibiotics and/or acyclovir were prescribed.

Results

Each study group consisted of 46 patients with 29 (63.0%) infants and 17 (37.0%) older children. A viral pathogen was diagnosed in 5/46 (10.9%) patients in the control group (all enteroviruses) and in 14/46 (30.4%) patients in the mPCR group (enterovirus n = 9; human herpesvirus 6 (HHV-6) n = 5), (p = 0.038)). Length of Therapy (LoT) and Days of Therapy (DoT) for antibiotics were significantly lower for infants (4.0 vs. 3.0, p = 0.038 and 8.0 vs. 6.0, p = 0.015, respectively). Acyclovir therapy was significantly shorter for both, infants and older children (3.0 vs. 1.0 day, p < 0.001 for both age groups).

Conclusion

The findings of our study suggest that the introduction of a FA ME Panel into clinical routine procedures is associated with a significantly reduced LoT and DoT of empiric anti-infective treatment in children with suspected meningoencephalitis. The largest effect was observed in infants.
Challenges in measuring depression among Ugandan fisherfolk: a psychometric assessment of the Luganda version of the Center for Epidemiologic Studies Depression Scale (CES-D)
Authors: Miller Amanda P. , Kintu Michael , Kiene Susan M.
Published: February 2020

Background

Depression is a prevalent and serious mood disorder and a major source of disability adjusted life years (DALY) in Uganda. Furthermore, evidence from Uganda and other countries throughout sub-Saharan Africa suggests that nearly a third of persons living with human immunodeficiency virus (HIV) suffer from depression and it adversely affects healthcare seeking behavior. The high burden of disease attributable to depression makes data on the prevalence of depression in Uganda, a country with a generalized HIV epidemic, a public health priority. This paper describes the psychometric properties of the Center for Epidemiologic Studies-Depression (CES-D) measure when administered to men and women residing in three fishing communities along the shore of Lake Victoria.

Methods

We applied methods based on item response theory and classical test theory approaches to assess individual item characteristics, conducted exploratory factor analysis and assessed internal reliability, and construct and content validity of the measure. All analyses were performed in R Studio.

Results

The study sample consisted of 300 residents of fishing communities in Wakiso District, Uganda. Fifty-six percent of the sample was female and 19.7% reported being HIV positive. Seven items of the measure that did not perform well, either because they could not differentiate between levels of the latent trait or because they did not map onto the primary factor, were removed from the scale. A single factor structure best fit our final set of 13-items and we found an overall coefficient alpha of 0.89, indicating high internal consistency in this population.

Conclusions

Based on our findings, we recommend that future use of the CES-D in this population utilize our revised scale with the final set of 13-items. The addition of other measures that can improve the rigor of CES-D validation efforts, such as inclusion of a clinical depression measure and administration in both a clinical and a general population sample in this setting are needed.
Treatment recommendations made by a consultant psychiatrist to improve the quality of care in a collaborative mental health intervention in rural Nepal
Authors: Rimal Pragya , Maru Duncan , Chwastiak Lydia , Agrawal Pawan , Rao Deepa , Swar Sikhar , Citrin David , Acharya Bibhav
Published: February 2020

Background

The Collaborative Care Model (CoCM) for mental healthcare, where a consulting psychiatrist supports primary care and behavioral health workers, has the potential to address the large unmet burden of mental illness worldwide. A core component of this model is that the psychiatrist reviews treatment plans for a panel of patients and provides specific clinical recommendations to improve the quality of care. Very few studies have reported data on such recommendations. This study reviews and classifies the recommendations made by consulting psychiatrists in a rural primary care clinic in Nepal.

Methods

A chart review was conducted for all patients whose cases were reviewed by the treatment team from January to June 2017, after CoCM had been operational for 6 months. Free text of the recommendations were extracted and two coders analyzed the data using an inductive approach to group and categorize recommendations until the coders achieved consensus. Cumulative frequency of the recommendations are tabulated and discussed in the context of an adapted CoCM in rural Nepal.

Results

The clinical team discussed 1174 patient encounters (1162 unique patients) during panel reviews throughout the study period. The consultant psychiatrist made 214 recommendations for 192 (16%) patients. The most common recommendations were to revisit the primary mental health diagnosis (16%, n = 34), add or increase focus on counselling and psychosocial support (9%, n = 20), increase the antidepressant dose (9%, n = 20), and discontinue inappropriate medications (6%, n = 12).

Conclusions

In this CoCM study, the majority of treatment plans did not require significant change. The recommendations highlight the challenge that non-specialists face in making an accurate mental health diagnosis, the relative neglect of non-pharmacological interventions, and the risk of inappropriate medications. These results can inform interventions to better support non-specialists in rural areas
The youth concussion awareness network (You-CAN) - a school-based peer-led intervention to improve concussion reporting and social support: the protocol for a cluster randomized trial
Authors:   Youth Concussion Awareness Network (You-CAN) Team, Hickling Andrea , Mallory Kylie D. , Wilson Katherine E. , Del Fernandes Rosephine , Fuselli Pamela , Reed Nick
Published: February 2020

Background

Concussion prevalence is increasing in the pediatric population, and is a matter of public health concern. Concussion symptoms can be physical, cognitive, emotional and behavioural, and last longer in high school aged youth than adults. Concussions are underreported in youth due to their lack of knowledge, social environment, perceived outcomes of reporting, norms, and self-efficacy. The Youth Concussion Awareness Network (You-CAN) is a school-based peer-led program designed to increase high school students’ intent to report a concussion, and provide social support to a peer. This study aims to investigate whether participation in You-CAN, a program grounded in service learning principles, impacts concussion knowledge, attitudes, intent to report a suspected concussion to an adult, and intent to provide social support to a peer. Secondary aims include assessing the implementation fidelity and acceptability of the intervention.

Methods

This longitudinal study will use a cluster randomized trial design. Three high schools from six randomly selected Canadian school boards will participate and be randomized to three study arms: (1) You-CAN led by school staff; (2) You-CAN led by school staff and research team; and (3) untreated comparison group. Intervention arms 1 and 2 will deliver the You-CAN program and create a Concussion Council at their school. The Concussion Council will deliver a concussion awareness campaign and participate in an online showcase with other participating schools. In addition, arm 2 will have monthly video-calls with the research team. A survey based on the Theory of Planned Behaviour will be administered school-wide with all arms (1, 2, 3) at two time points (beginning {T0} and end {T1} of the school year). Exit interviews will be completed with the Concussion Councils and participating school staff.

Discussion

This study will provide evidence of the effectiveness of a school-based peer-led concussion program on increasing concussion knowledge, attitudes, subjective norms, perceived behavioural control, intent to report a concussion to an adult, and intent to provide social support to a peer amongst Canadian high school students. It will also provide important information about the implementation and acceptability of the You-CAN program for high school students and staff.

Trial registration

This trial is registered with the ISRCTN registry (ISRCTN64944275, 14/01/2020, retrospectively registered).
Dieting, body weight concerns and health: trends and associations in Swedish schoolchildren
Authors: Berg Christina , Larsson Christel
Published: February 2020

Background

Dieting is a risk factor of both eating disorders and obesity. The aim was to examine time trends of dieting in Swedish adolescents, and explore how dieting and body weight dissatisfaction are related to self-reported health, wellbeing and health behaviours.

Methods

Analyses of cross-sectional Swedish data from HBSC (Health Behaviour in School-aged Children) surveys 1994–2014. In total, about 30,000 girls and boys in the age of 11, 13 and 15 years participated. Data was collected by using classroom administered questionnaires in 5th, 7th and 9th grade. Logistic regressions was used to analyse secular trends of dieting, and how dieting and body dissatisfaction were associated with self-reported overall health, health behaviours, BMI and various physical, psychological and social aspects of health in 2014.

Results

Dieting increased from 1994 to 2014 in both girls and boys in all age groups, and in 2014, the prevalence was 14% in girls and 8% in boys. The prevalence of body satisfaction was 65% respectively 69%. Body weight dissatisfaction and dieting were present in all body weight classes and were associated with self-reported poor health and many other negative health aspects. In comparison with the participants that were satisfied with their body weight the odds ratio (95% CI) for self-reported poor health was 3.4 (2.6–4.4) in dieters, 4.9 (3.8–6.4) in participants who perceived a need to lose weight and 2.1 (1.5–2.8) in those who perceived a need to gain weight, when adjusting for age, sex and body weight class.

Conclusions

When promoting health among school age children body weight dissatisfaction and dieting ought to be considered. Furthermore, it is important to support girls and boys in all weight classes to reach and maintain a healthy body image and weight.
Chronic hypersensitivity pneumonitis in the southeastern United States: an assessment of how clinicians reached the diagnosis
Authors: Gu Jessie P. , Tsai Chen-Liang , Wysham Nicholas G. , Huang Yuh-Chin T.
Published: February 2020

Background

Chronic hypersensitivity pneumonitis (cHP) is a disease caused by exposure to inhaled environmental antigens. Diagnosis of cHP is influenced by the awareness of the disease prevalence, which varies significantly in different regions, and how clinicians utilize relevant clinical information. We conducted a retrospective study to evaluate how clinicians in the Southeast United States, where the climate is humid favoring mold growth, diagnosed cHP using items identified in the international modified Delphi survey of experts, i.e., environmental exposure, CT imaging and lung pathology,

Methods

We searched Duke University Medical Center database for patients over the age of 18 with a diagnosis of cHP (ICD-9 code: 495) between Jan. 1, 2008 to Dec. 31, 2013 using a query tool, Duke Enterprise Data Unified Content Explorer (DEDUCE).

Results

Five hundred patients were identified and 261 patients had cHP confirmed in clinic notes by a pulmonologist or an allergist. About half of the patients lived in the Research Triangle area where our medical center is located, giving an estimated prevalence rate of 6.5 per 100,000 persons. An exposure source was mentioned in 69.3% of the patient. The most common exposure sources were environmental molds (43.1%) and birds (26.0%). We used Venn diagram to evaluate how the patients met the three most common cHP diagnostic criteria: evidence of environmental exposures (history or precipitin) (E), chest CT imaging (C) and pathology from lung biopsies (P). Eighteen patients (6.9%) met none of three criteria. Of the remaining 243 patients, 135 patients (55.6%) had one (E 35.0%, C 3.3%, P 17.3%), 81 patients (33.3%) had two (E + C 12.3%, E + P 17.3%, C + P 4.9%), and 27 patients (11.1%) had all three criteria (E + C + P). Overall, 49.4% of patients had pathology from lung biopsy compared to 31.6% with CT scan.

Conclusions

Environmental mold was the most common exposure for cHP in the Southeast United States. Lung pathology was available in more than half of cHP cases in our tertiary care center, perhaps reflecting the complexity of referrals. Differences in exposure sources and referral patterns should be considered in devising future diagnostic pathways or guidelines for cHP.
Validity of computed tomographic measurements and morphological comparison of cubital tunnel in idiopathic cubital tunnel syndrome
Authors: Lee Sang Ki , Hwang Seok Young , Choy Won Sik
Published: February 2020

Background

Ulnar neuropathy is a common reason for referral to hand surgeons, and 10 to 30% of cubital tunnel syndrome (CuTS) is idiopathic. We hypothesized that the cause of idiopathic CuTS is in the bony structure.

Methods

We analyzed 79 elbows (39 idiopathic CuTS and 40 without CuTS symptom) using computed tomography and Materialize Mimics software to compare the differences between the two groups. We proposed a new bony cubital tunnel with a new boundary that could play a role in ulnar nerve compression symptom.

Results

The mean cubital tunnel volume was 1245.6 mm3 in all patients, 1180.6 mm3 in CuTS patients, and 1282.3 mm3 in the control group. A significant difference (p = 0.015) between two groups was found. Bony cubital tunnel cross-sectional area, cubital tunnel depth, and cubital tunnel angle also showed significant differences.

Conclusion

The shape of the bony cubital tunnel is an important cause of CuTS, and the normal variation of the volume and cross-sectional area of the cubital tunnel and cubital tunnel angle could influence the occurrence of idiopathic CuTS.
Evaluation of the hepatoprotective effect of Yigan mingmu oral liquid against acute alcohol-induced liver injury in rats
Authors: Mo Qigui , Zhou Gao , Xie Baibo , Ma Bingxin , Zang Xinyu , Chen Yuxin , Cheng Linyou , Zhou James Hua , Wang Youwei
Published: February 2020

Background

Yigan mingmu oral liquid (YGMM) is a herbal medicine based on a famous Chinese herbal formula that has been used for sore eyes for more than 400 years. Eye health is closely associated with the liver based on TCM. This study aimed to investigate the hepatoprotective effect of YGMM against acute liver injury induced by alcohol in rats.

Methods

Experimental rats were administered with silymarin and YGMM through the gastric gavage during the entire experiment. Starting from the 11th day, the rats were administered orally with 14 ml/kg Red Star Erguotou Liquor, a popular brand, at 4 h after the dose of silymarin (100 mg/kg) and YGMM (1, 2.5 and 5 ml/kg in low, middle and high dosage group, respectively) once a day for 4 weeks except for the rats in the normal group. Biochemical parameters, including ALT, AST, TB, TG, T-SOD, GSH, and MDA were detected to evaluate the protective effect of YGMM. Pathological changes were observed through histopathological examination.

Results

Treatment with YGMM exhibited a significant protective effect by reversing the biochemical parameters (ALT, AST, TB, TG, and GSH) and histopathological changes. Histopathological examination by Oil Red O Staining Solution showed that lipid droplets were significantly reduced in the silymarin and YGMM groups (p < 0.001) when compared to alcohol group.

Conclusions

YGMM exhibits a significant hepatoprotective activity against acute liver injury induced by alcohol in rats.
Study protocol for a randomized controlled trial: Qiliqiangxin in heart failUre: assESsment of reduction in morTality (QUEST)
Authors: Yao Wenming , Cheang Iokfai , Liao Shengen , Zhou Yanli , Zhou Fang , Xu Dongjie , Jia Zhenhua , Chang Liping , Zhang Haifeng , Li Xinli
Published: February 2020

Background

Qiliqiangxin (QLQX) capsule is a Traditional Chinese Medicine (TCM) that has been approved in China for the treatment of chronic heart failure (CHF). Our previous study showed with a background of standard HF treatment, QLQX capsules further reduced the levels of NT-proBNP and the incidence of composite cardiac events (CCEs) in CHF patients. This study aims to further assess the reduction in mortality when using QLQX compared with placebo for heart failure with reduced ejection fraction (HFrEF) patients.

Methods

This study is a randomized, double-blind, placebo-controlled, parallel-group, multi-center, event-driven clinical study of approximately 3080 patients for a targeted 620 events. Patients must have a diagnosis of heart failure for at least 3 months prior to screening. Patients will be randomized 1:1 to receive the placebo or QLQX in addition to their standard medications of CHF. The primary efficacy outcome event is a composite cardiovascular death and re-hospitalization due to the worsening of heart failure.

Discussion

The QUEST study is a randomized control study of TCM in chronic heart failure. It will determine the place of QLQX as an new treatment approach and provide additional and innovative information regarding TCM - and the specific used of QLQX in HFrEF.

Trial registration

The trial was registered at http://www.chictr.org.cn. ( Registration No.: ChiCTR1900021929); Date: 2019-03-16.
Structural modulation of gut microbiota during alleviation of non-alcoholic fatty liver disease with Gynostemma pentaphyllum in rats
Authors: Shen Shu-Hua , Zhong Ting-Yan , Peng Cui , Fang Jie , Lv Bin
Published: February 2020

Background

The current work aimed to assess whether Gynostemma pentaphyllum (GP), a Chinese herbal medicine, structurally modifies the gut microbiota in rats during non-alcoholic fatty liver disease (NAFLD) treatment.

Methods

High-fat diet (HFD)-induced NAFLD rats were orally administered water decoction of GP or equal amounts of distilled water per day for 4 weeks. Liver tissues were examined by histopathological observation, while intestinal tissues were examined by both histopathological and ultrastructural observations. The levels of fasting blood glucose (FBG), fasting serum insulin (FINS), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT) and aspartate transaminase (AST) were measured by enzymatic method. The levels of toll-like receptor 4 (TLR-4), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β) and interleukin-6 (IL-6) in both serum and hepatic tissues were measured by RT-qPCR. The protein expression level of TLR-4 in hepatic tissues was detected by western blot. The gut microbiota was assessed by 16S rRNA-based microbiota analysis.

Results

GP maintained intestinal integrity and reversed gut dysbiosis in high-fat diet (HFD)-induced NAFLD rats. This also reduced the ratio of Firmicutes to Bacteroidetes, enriching the abundance of beneficial bacteria (Lactococcus spp.) and inhibiting the abundance of pathogenic bacteria (Ruminococcus spp.) in the gut. The levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and the expression of TLR4 were downregulated (P < 0.05), while the insulin resistance index, HOMA-IR showed improvement by GP treatment (P < 0.05). Liver function indicators (ALT and AST) were remarkably decreased (P < 0.01). Besides, GP treatment reduced TG and LDL-C levels (P < 0.05), and increased HDL-C level (P < 0.05) compared with NAFLD group.

Conclusion

The structural alterations of gut microbiota induced by GP are associated with NAFLD alleviation.
Stakeholder views on the acceptability of human infection studies in Malawi
Authors: Kapumba Blessings M. , Jambo Kondwani , Rylance Jamie , Gmeiner Markus , Sambakunsi Rodrick , Parker Michael , Gordon Stephen B. , Gooding Kate
Published: February 2020

Background

Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMICs) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMICs.

Methods

We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members, and district health government officials.

Results

Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to the safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example, balancing equity, safety, and relevance in inclusion criteria.

Conclusions

Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out.
Use of smoking cessation pharmacotherapies during pregnancy is not associated with increased risk of adverse pregnancy outcomes: a population-based cohort study
Authors: Tran Duong Thuy , Preen David B. , Einarsdottir Kristjana , Kemp-Casey Anna , Randall Deborah , Jorm Louisa R. , Choi Stephanie K. Y. , Havard Alys
Published: February 2020

Background

Varenicline, bupropion and nicotine replacement therapy (NRT) are three effective pharmacotherapies for smoking cessation, but data about their safety in pregnancy are limited. We assessed the risk of adverse perinatal outcomes and major congenital anomalies associated with the use of these therapies in pregnancy in Australia.

Methods

Perinatal data for 1,017,731 deliveries (2004 to 2012) in New South Wales and Western Australia were linked to pharmaceutical dispensing, hospital admission and death records. We identified 97,875 women who smoked during pregnancy; of those, 233, 330 and 1057 were exposed to bupropion, NRT and varenicline in pregnancy, respectively. Propensity scores were used to match exposed women to those who were unexposed to any smoking therapy (1:10 ratio). Propensity scores and gestational age at exposure were used to match varenicline-exposed to NRT-exposed women (1:1 ratio). Time-dependent Cox proportional hazards models estimated hazard ratios (HR) with 95% confidence intervals (95% CI) for any adverse perinatal event (a composite of 10 unfavourable maternal and neonatal outcomes) and any major congenital anomaly.

Results

The risk of any adverse perinatal event was not significantly different between bupropion-exposed and unexposed women (39.2% versus 39.3%, HR 0.93, 95% CI 0.73–1.19) and between NRT-exposed and unexposed women (44.8% vs 46.3%, HR 1.02, 95% CI 0.84–1.23), but it was significantly lower in women exposed to varenicline (36.9% vs 40.1%, HR 0.86, 95% CI 0.77–0.97). Varenicline-exposed infants were less likely than unexposed infants to be born premature (6.5% vs 8.9%, HR 0.72, 95% CI 0.56–0.92), be small for gestational age (11.4% vs 15.4%, HR 0.68, 95% CI 0.56–0.83) and have severe neonatal complications (6.6% vs 8.2%, HR 0.74, 95% CI 0.57–0.96). Among infants exposed to varenicline in the first trimester, 2.9% had a major congenital anomaly (3.5% in unexposed infants, HR 0.91, 95% CI 0.72–1.15). Varenicline-exposed women were less likely than NRT-exposed women to have an adverse perinatal event (38.7% vs 51.4%, HR 0.58, 95% CI 0.33–1.05).

Conclusions

Pregnancy exposure to smoking cessation pharmacotherapies does not appear to be associated with an increased risk of adverse birth outcomes. Lower risk of adverse birth outcomes in varenicline-exposed pregnancies is inconsistent with recommendations that NRT be used in preference to varenicline.
Identification of a Yarrowia lipolytica acetamidase and its use as a yeast genetic marker
Authors: Hamilton Maureen , Consiglio Andrew L. , MacEwen Kyle , Shaw A. Joe , Tsakraklides Vasiliki
Published: February 2020

Background

Yarrowia lipolytica is an oleaginous yeast that can be genetically engineered to produce lipid and non-lipid biochemicals from a variety of feedstocks. Metabolic engineering of this organism usually requires genetic markers in order to select for modified cells. The potential to combine multiple genetic manipulations depends on the availability of multiple or recyclable selectable markers.

Results

We found that Y. lipolytica has the ability to utilize acetamide as the sole nitrogen source suggesting that the genome contains an acetamidase gene. Two potential Y. lipolytica acetamidase gene candidates were identified by homology to the A. nidulans acetamidase amdS. These genes were deleted in the wild-type Y. lipolytica strain YB-392, and deletion strains were evaluated for acetamide utilization. One deletion strain was unable to grow on acetamide and a putative acetamidase gene YlAMD1 was identified. Transformation of YlAMD1 followed by selection on acetamide media and counterselection on fluoroacetamide media showed that YlAMD1 can be used as a recyclable genetic marker in Saccharomyces cerevisiae and Ylamd1Δ Y. lipolytica.

Conclusions

These findings add to our understanding of Y. lipolytica nitrogen utilization and expand the set of genetic tools available for engineering this organism, as well as S. cerevisiae.
RETRACTED ARTICLE: Exosome-mediated lncRNA AFAP1-AS1 promotes trastuzumab resistance through binding with AUF1 and activating ERBB2 translation
Authors: Han Mingli , Gu Yuanting , Lu Pengwei , Li Jingyi , Cao Hui , Li Xiangke , Qian Xueke , Yu Chao , Yang Yunqing , Yang Xue , Han Na , Dou Dongwei , Hu Jianguo , Dong Huaying
Published: February 2020

Background

Although trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the emergence of resistance. Recent evidence suggests that long noncoding RNAs (lncRNAs) play important roles in tumorigenesis and chemoresistance. However, the regulatory mechanism of lncRNAs in trastuzumab resistance is not well established to date. In this research, we identified the differentially expressed lncRNA and investigated its regulatory role in trastuzumab resistance of breast cancer.

Methods

LncRNA microarray and qRT-PCR were performed to identify the dysregulated lncRNAs. Transmission electron microscopy, differential ultracentrifugation and qRT-PCR were used to verify the existence of exosomal AFAP1-AS1 (actin filament associated protein 1 antisense RNA 1). Bioinformatics prediction, RNA fluorescence in situ hybridization (RNA-FISH) and immunoprecipitation assays were performed to identify the direct interactions between AFAP1-AS1 and other associated targets, such as AU-binding factor 1 (AUF1) and ERBB2. Finally, a series gain- or loss-functional assays were done to prove the precise role of AFAP1-AS1 in trastuzumab resistance.

Results

AFAP1-AS1 was screened out due to its higher expression in trastuzumab-resistant cells compared to sensitive cells. Increased expression of AFAP1-AS1was associate with poorer response and shorter survival time of breast cancer patients. AFAP1-AS1 was upregulated by H3K27ac modification at promoter region, and knockdown of AFAP1-AS1 reversed trastuzumab resistance. Moreover, extracellular AFAP1-AS1 secreted from trastuzumab resistant cells was packaged into exosomes and then disseminated trastuzumab resistance of receipt cells. Mechanically, AFAP1-AS1 was associated with AUF1 protein, which further promoted the translation of ERBB2 without influencing the mRNA level.

Conclusion

Exosomal AFAP1-AS1 could induce trastuzumab resistance through associating with AUF1 and promoting ERBB2 translation. Therefore, AFAP1-AS1 level may be useful for prediction of trastuzumab resistance and breast cancer treatment.
Cut and paste: temperature-enhanced cotyledon micrografting for Arabidopsis thaliana seedlings
Authors: Bartusch Kai , Trenner Jana , Melnyk Charles W. , Quint Marcel
Published: February 2020

Background

Cotyledon micrografting represents a useful tool for studying the central role of cotyledons during early plant development, especially their interplay with other plant organs with regard to long distance transport. While hypocotyl micrografting methods are well-established, cotyledon micrografting is still inefficient. By optimizing cotyledon micrografting, we aim for higher success rates and increased throughput in the model speciesArabidopsis thaliana.

Results

We established a cut and paste cotyledon surgery procedure on a flat and solid but moist surface which improved handling of small seedlings. By applying a specific cutting and joining pattern, throughput was increased up to 40 seedlings per hour. The combination of short-day photoperiods and low light intensities for germination and long days plus high light intensities, elevated temperature and vertical plate positioning after grafting significantly increased ‘ligation’ efficiency. In particular high temperatures affected success rates favorably. Altogether, we achieved up to 92% grafting success inA. thaliana. Reconnection of vasculature was demonstrated by transport of a vasculature-specific dye across the grafting site. Phloem and xylem reconnection were completed 3–4 and 4–6 days after grafting, respectively, in a temperature-dependent manner. We observed that plants with grafted cotyledons match plants with intact cotyledons in biomass production and rosette development.

Conclusions

This cut and paste cotyledon-to-petiole micrografting protocol simplifies the handling of plant seedlings in surgery, increases the number of grafted plants per hour and greatly improves success rates forA. thalianaseedlings. The developed cotyledon micrografting method is also suitable for other plant species of comparable size.
Non-invasive prenatal test to screen common trisomies in twin pregnancies
Authors: Motevasselian Mahtab , Saleh Gargari Soraya , Younesi Sarang , Pooransari Parichehr , Saadati Pourandokht , Mirzamoradi Masoomeh , Savad Shahram , Taheri Amin Mohammad Mahdi , Modarresi Mohammad-Hossein , Afrakhteh Maryam , Ghafouri-Fard Soudeh
Published: February 2020

Objectives

Recent years have witnessed a shift from invasive methods of prenatal screening to non-invasive strategies. Accordingly, non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has gained a considerable deal of interest from both geneticists and obstetricians. Efficacy of this method in identification of common aneuploidies has been extensively assessed in singleton pregnancies. However, a limited number of studies have addressed the twin pregnancies. In this context, the present study is aimed at identification of the efficacy of NIPT in twin pregnancies.

Methods

NIPT was performed on twin pregnancies to screen trisomies 13, 18 and 21. Pregnant women referring to Nilou Clinical Laboratory between March 2016 and December 2018 were included in this research.

Results

In the current study, a total 356 twin pregnancies were screened in search for trisomies 13, 18 and 21. 6 cases exhibited positive NIPT results in which the presence of trisomies 13, 18 and 21 was confirmed by fetal karyotype in 1, 2 and 2 cases, respectively. One twin pregnancy showed normal karyotype. The combined false-positive rate for these trisomies was 0.28%. No false negative case was observed. The combined sensitivity and specificity of NIPT in twin pregnancies were 100 and 99.7%, respectively.

Conclusion

The results of the current study verify the feasibility, sensitivity and specificity of NIPT in twin pregnancies.
CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma
Authors: Ma Xiao-Lu , Hu Bo , Tang Wei-Guo , Xie Su-Hong , Ren Ning , Guo Lin , Lu Ren-Quan
Published: February 2020

Background

Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110β cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC.

Methods

CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation.

Results

We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73– counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3β. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis.

Conclusions

Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.
Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis is required for PD-L1 expression in drug-resistant cancer cells
Authors: Wang Haifang , Fu Chen , Du Jun , Wang Hongsheng , He Rui , Yin Xiaofeng , Li Haixia , Li Xin , Wang Hongxia , Li Kui , Zheng Lei , Liu Zongcai , Qiu Yurong
Published: February 2020

Background

Drug resistance is a major obstacle to treating cancers because it desensitizes cancer cells to chemotherapy. Recently, attention has been focused on changes in the tumor immune landscape after the acquisition of drug resistance. Programmed death-ligand-1 (PD-L1) is an immune suppressor that inhibits T cell-based immunity. Evidence has shown that acquired chemoresistance is associated with increased PD-L1 expression in cancer cells. However, the underlying mechanism is still largely unknown.

Methods

PD-L1 expression in three drug-resistant A549/CDDP, MCF7/ADR and HepG2/ADR cell lines was detected by qRT-PCR, western blotting and flow cytometry, and a T cell proliferation assay was performed to test its functional significance. Then, the potential roles of JNK/c-Jun, histone H3 acetylation, histone deacetylase 3 (HDAC3) and the E3 ligase COP1 in the PD-L1 increase were explored through ChIP assays and gain- and loss-of-function gene studies. Furthermore, murine xenograft tumor models were used to verify the role of JNK/c-Jun and HDAC3 in PD-L1 expression in A549/CDDP cells in vivo. Finally, the correlations of PD-L1, c-Jun and HDAC3 expression in clinical cisplatin-sensitive and cisplatin-resistant non-small cell lung cancer (NSCLC) tissues were analyzed by immunohistochemistry and Pearson’s correlation coefficient.

Results

PD-L1 expression was significantly increased in A549/CDDP, MCF7/ADR and HepG2/ADR cells and was attributed mainly to enhanced JNK/c-Jun signaling activation. Mechanistically, decreased COP1 increased c-Jun accumulation, which subsequently inhibited HDAC3 expression and thereby enhanced histone H3 acetylation of the PD-L1 promoter. Furthermore, PD-L1 expression could be inhibited by JNK/c-Jun inhibition or HDAC3 overexpression in vivo, which could largely reverse inhibited CD3+ T cell proliferation in vitro. PD-L1 expression was significantly increased in the cisplatin-resistant clinical NSCLC samples and positively correlated with c-Jun expression but negatively correlated with HDAC3 expression.

Conclusions

Enhanced histone H3 acetylation of the PD-L1 promoter via the COP1/c-Jun/HDAC3 axis was crucial for the PD-L1 increase in drug-resistant cancer cells. Our study reveals a novel regulatory network for the PD-L1 increase in drug-resistant cancer cells and that combined PD-L1-targeting strategies could improve T cell-based immunity in drug-resistant cancers.