bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of ultrasonography screening for breast cancer: a systematic review and meta-analysis
Authors: Yang Lei , Wang Shengfeng , Zhang Liwen , Sheng Chao , Song Fengju , Wang Ping , Huang Yubei
Published: June 2020

Background

To investigate the performance of primary ultrasound (P-US) screening for breast cancer, and that of supplemental ultrasound (S-US) screening for breast cancer after negative mammography (MAM).

Methods

Electronic databases (PubMed, Scopus, Web of Science, and Embase) were systematically searched to identify relevant studies published between January 2003 and May 2018. Only high-quality or fair-quality studies reporting any of the following performance values for P-US or S-US screening were included: sensitivity, specificity, cancer detected rate (CDR), recall rate (RR), biopsy rate (BR), proportion of invasive cancers among screening-detected cancers (ProIC), and proportion of node-negative cancers among screening-detected invasive cancers (ProNNIC).

Results

Twenty-three studies were included, including 12 studies in which S-US screening was used after negative MAM and 11 joint screening studies in which both primary MAM (P-MAM) and P-US were used. Meta-analyses revealed that S-US screening could detect 96% [95% confidential intervals (CIs): 82 to 99%] of occult breast cancers missed by MAM and identify 93% (95% CIs: 89 to 96%) of healthy women, with a CDR of 3.0/1000 (95% CIs: 1.8/1000 to 4.6/1000), RR of 8.8% (95% CIs: 5.0 to 13.4%), BR of 3.9% (95% CIs: 2.7 to 5.4%), ProIC of 73.9% (95% CIs: 49.0 to 93.7%), and ProNNIC of 70.9% (95% CIs: 46.0 to 91.6%). Compared with P-MAM screening, P-US screening led to the recall of significantly more women with positive screening results [1.5% (95% CIs:0.6 to 2.3%),P = 0.001] and detected significantly more invasive cancers [16.3% (95% CIs: 10.6 to 22.1%),P < 0.001]. However, there were no significant differences for other performance measures between the two screening methods, including sensitivity, specificity, CDR, BR, and ProNNIC.

Conclusions

Current evidence suggests that S-US screening could detect occult breast cancers missed by MAM. P-US screening has shown to be comparable to P-MAM screening in women with dense breasts in terms of sensitivity, specificity, cancer detection rate, and biopsy rate, but with higher recall rates and higher detection rates for invasive cancers.
Next-generation sequencing-based clinical diagnosis of choroideremia and comprehensive mutational and clinical analyses
Authors: Gao Feng-Juan , Tian Guo-Hong , Hu Fang-Yuan , Wang Dan-Dan , Li Jian-Kang , Chang Qing , Chen Fang , Xu Ge-Zhi , Liu Wei , Wu Ji-Hong
Published: June 2020

Background

To report the clinical and genetic findings from seven Chinese patients with choroideremia.

Methods

Five hundred seventy-eight patients with a clinically suspected diagnosis of retinitis pigmentosa (RP) underwent comprehensive ophthalmic examinations. Next-generation sequencing (NGS) was performed on samples from all patients. Detailed clinical characteristics of the patients with choroideremia identified in this study were assessed using multimodal imaging.

Results

Seven patients with choroideremia were identified, and six novel variants in CHM (c.1960 T > C p.Ter654Gln, c.1257del p.Ile420*fs1, c.1103_1121delATGGCAACACTCCATTTTT p.Tyr368Cysfs35, c.1414-2A > T, and c.1213C > T p.Gln405Ter, c.117-1G > A) were revealed. All variants were deleterious mutations: two were frameshifts, two were nonsense mutations, two were splicing mutations, and one was a readthrough mutation. The clinical phenotypes of these patients were markedly heterogeneous, and they shared many common clinical features with RP, including night blindness, constriction of the visual field and gradually reduced visual acuity. However, patients with choroideremia showed pigment hypertrophy and clumping, and chorioretinal atrophy, and a majority of patients with choroideremia presented with retinal tubulations in the outer layer of the retina.

Conclusions

We provide a detailed description of the genotypes and phenotypes of seven patients with choroideremia who were accurately diagnosed using NGS. These findings provide a better understanding of the genetics and phenotypes of choroideremia.
A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol
Authors: Phillips Jennifer L. , Jaworska Natalia , Kamler Elizabeth , Bhat Venkat , Blier Jean , Foster Jane A. , Hassel Stefanie , Ho Keith , McMurray Lisa , Milev Roumen , Moazamigoudarzi Zahra , Placenza Franca M. , Richard-Devantoy Stéphane , Rotzinger Susan , Turecki Gustavo , Vazquez Gustavo H. , Kennedy Sidney H. , Blier Pierre ,   on behalf of the CAN-BIND Investigator Team
Published: June 2020

Background

Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes.

Methods

Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality.

Discussion

This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery.

Trial registration

ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.
Workplace experiences of mental health consumer peer workers in New South Wales, Australia: a survey study exploring job satisfaction, burnout and turnover intention
Authors: Scanlan Justin Newton , Still Megan , Radican Jae , Henkel Daya , Heffernan Tim , Farrugia Peter , Isbester Jemima , English Jessica
Published: June 2020

Background

Consumer peer workers are individuals with lived experience of mental health issues and recovery who are employed to use their lived experience to support others. The consumer peer workforce has expanded substantially in recent years. While some research has explored the workplace experiences of peer workers, no previous studies have explored job satisfaction, burnout or turnover intention for this workforce.

Methods

Consumer peer workers in New South Wales, Australia were invited to complete a survey designed to explore their workplace experiences. The survey included measures of job satisfaction, burnout, turnover intention, job demands and job resources, and satisfaction with supervision, professional development and opportunities for career progression. Questions also explored positive and negative aspects of positions. Analyses included exploration of the relationships between of job satisfaction, burnout, turnover intention, job demands and job resources as well as tabulation of common positive and negative aspects of positions. Results were also compared with findings from a previous study exploring workplace experiences of other mental health workers.

Results

A total of 67 peer workers participated in the study. Overall job satisfaction, burnout (disengagement and exhaustion) and turnover intention for peer workers was not significantly different to other mental health workers. Job satisfaction, disengagement, exhaustion and turnover intention were all significantly inter-related. Job resources of social support, job control, feedback, and rewards and recognition were associated with positive workplace experiences and the job demand of “physical environment” was most substantially associated with poorer workplace experiences. The most common positive aspect of positions was “connecting with consumers” and the most common negative aspect of positions was “attitudes of clinicians / workplace culture”. Access to supervision from a senior peer worker was associated with more positive workplace experiences.

Conclusions

This research demonstrates that while consumer peer workers do not appear to experience poorer job satisfaction or higher levels of burnout or turnover intention than other mental health workers, a range of challenges do exist. Efforts to further expand the peer workforce (especially senior peer worker roles) and to promote more positive attitudes and workplace cultures are likely to promote better workplace experiences for peer workers.
Effects of an mHealth voice message service (mMitra) on maternal health knowledge and practices of low-income women in India: findings from a pseudo-randomized controlled trial
Authors: Murthy Nirmala , Chandrasekharan Subhashini , Prakash Muthu Perumal , Ganju Aakash , Peter Joanne , Kaonga Nadi , Mechael Patricia
Published: June 2020

Background

Mobile Health (mHealth) is becoming an important tool to improve health outcomes in maternal, newborn and child health (MNCH). Studies of mHealth interventions, have demonstrated their effectiveness in improving uptake of recommended maternal services such as antenatal visits. However, evidence of impact on maternal health outcomes is still limited.

Methods

A pseudo-randomized controlled trial (single blind) was conducted to assess the impact of a voice-message based maternal intervention on maternal health knowledge, attitudes, practices and outcomes over time: Pregnancy (baseline/Time 1); Post-partum (Time 2) and when the infant turned one year old (Time 3). Women assigned to the mMitra intervention arm received gestational age- and stage-based educational voice messages via mobile phone in Hindi and Marathi, while those assigned to the control group did not. Both groups received standard care.

Results

Two thousand sixteen women were enrolled. Interviews were conducted with 1516 women in the intervention group and 500 women in the control group at baseline and post-partum. The intervention group performed significantly better than controls on four maternal health practice indicators: receiving the tetanus toxoid injection (OR: 1.6, 95% Confidence Interval (CI): 1.05–2.4, p = 0.028), consulting a doctor if spotting or bleeding (OR: 1.72, 95%CI: 1.07–2.75, p = 0.025), saving money for delivery expenses (OR: 1.79, 95%CI: 1.38–2.33, p = 0.0001), and delivering in hospital (OR: 2.5, 95%CI: 1.49–4.35, p = 0.001). The control group performed significantly better than the intervention group on two practice indicators: resting regularly during pregnancy (OR: 0.7, 95%CI: 0.54–0.88, p = 0.002) and having at-home deliveries attended by a skilled birth attendant (OR: 0.46, 95%CI: 0.23–0.91, p = 0.027). Both groups’ knowledge improved from Time 1 to Time 2. Only one knowledge indicator, on seeking medical care during pregnancy, was statistically increased in the intervention group compared to controls. Anemia status at or near the time of delivery was unable to be assessed due to missing data from maternal health cards.

Conclusions

This study provides evidence that in low-resource settings, mobile voice messages providing tailored and timed information about pregnancy can positively impact maternal health care practices proven to improve maternal health outcomes. Additional research is needed to assess whether voice messaging can motivate behavior change better than text messaging, particularly in low literacy settings.

Trial registration

The mMitra impact evaluation is registered with ISRCTN under Registration # 88968111, assigned on 6 September 2018 (See https://www.isrctn.com/ISRCTN88968111).
Reevaluation of risk factors for time to subsequent events after first stroke occurrence using a new weighted all-cause effect measure
Authors: Ozga Ann-Kathrin , Rauch Bernhard , Palm Frederick , Urbanek Christian , Grau Armin , Becher Heiko , Rauch Geraldine
Published: June 2020

Background

Risk diseases and risk factors for stroke include atrial fibrillation, hypertension, diabetes mellitus, smoking, and elevated LDL-cholesterol. Due to modern treatment options, the impact of these risk diseases on subsequent cardiovascular events or death after a first stroke is less clear and needs to be elucidated. We therefore aimed to get insights into the persistence of adverse prognostic effects of these risk diseases and risk factors on subsequent stroke or death events 1 year after the first stroke by using the new weighted all-cause hazard ratio.

Methods

This study evaluates the 1 year follow-up of 470 first ever stroke cases identified in the area of Ludwigshafen, Germany, with 23 deaths and 34 subsequent stroke events. For this purpose, the recently introduced “weighted all-cause hazard ratio” was used, which allows a weighting of the competing endpoints within a composite endpoint. Moreover, we extended this approach to allow an adjustment for covariates.

Results

None of these risk factors and risk diseases, most probably being treated after the first stroke, remained to be associated with a subsequent death or stroke [weighted hazard ratios (95% confidence interval) for diabetes mellitus, atrial fibrillation, high cholesterol, hypertension, and smoking are 0.4 (0.2–0.9), 0.8 (0.4–2.2), 1.3 (0.5–2.5), 1.2 (0.3–2.7), 1.6 (0.8–3.6), respectively]. However, when analyzed separately in terms of death and stroke, the risk factors and risk diseases under investigation affect the subsequent event rate to a variable degree.

Conclusions

Using the new weighted hazard ratio, established risk factors and risk diseases for the occurrence of a first stroke do not remain to be significant predictors for subsequent events like death or recurrent stroke. It has been demonstrated that the new weighted hazard ratio can be used for a more adequate analysis of cardiovascular risk and disease progress. The results have to be confirmed within a larger study with more events.
The metabolic role of PFKFB4 in androgen-independent growth in vitro and PFKFB4 expression in human prostate cancer tissue
Authors: Li Ximing , Chen Zhi , Li Zuan , Huang Guihai , Lin Junhao , Wei Qiang , Liang Jianbo , Li Wei
Published: June 2020

Background

It is well known that androgen-deprivation therapy (ADT) can inevitably drive prostate cancer (PCa) cells into a castration-resistant state. According to the “Warburg effect”, the metabolism of aggressive tumor cells increases significantly. The growth of cancer cells depends on glycolysis, which may be a potential target for cancer control. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) plays key roles in the proliferation and metastasis of PCa cells. However, there is very limited knowledge on the role of PFKFB4 in the conversion to castration resistance. The present study aimed to determine the changes in glucose consumption and PFKFB4 expression in LNCaP cells and androgen-independent LNCaP (LNCaP-AI) cells during the whole process of androgen-independent growth. Additionally, PFKFB4 expression in human PCa tissues was evaluated.

Methods

We established an androgen-independent LNCaP-AI cell line derived from LNCaP cells to mimic the traits of castration resistance in vitro. LNCaP-AI and LNCaP cells were cultured in the corresponding medium containing the same amount of glucose. At the end of experiments, the medium supernatant and blank medium were collected, and absorbance was measured. LNCaP-AI and LNCaP cells were harvested to detect PFKFB4 expression by Western blotting. Prostate tissue samples including PCa tissue, carcinoma-adjacent tissue and benign prostatic hyperplasia (BPH) tissue specimens were evaluated for PFKFB4 expression using immunohistochemistry.

Results

In 18 h supernatant samples, the glucose consumption and lactate secretion of LNCaP-AI cells were higher than those of LNCaP cells. The Western blot results indicated that PFKFB4 expression was increased in LNCaP-AI cells compared with LNCaP cells. Immunohistochemistry revealed that the expression of PFKFB4 in PCa tissue specimens was higher than that in BPH and adjacent tissue specimens. However, the differences in PCa tissue before and after ADT were not statistically significant.

Conclusion

PFKFB4 may be associated with enhanced glycolysis during the androgen-independent growth of PCa cells in vitro. PFKFB4 may be a marker of PCa progression. Our results provide a rationale for further clinical investigation of PCa treatment focused on controlling PFKFB4 expression.
Colorectal cysts as a validating tool for CAR therapy
Authors: Dillard Pierre , Lie Maren , Baken Elizabeth , Lobert Viola Hélène , Benard Emmanuelle , Köksal Hakan , Inderberg Else Marit , Wälchli Sébastien
Published: June 2020

Background

Treatment of cancers has largely benefited from the development of immunotherapy. In particular, Chimeric Antigen Receptor (CAR) redirected T cells have demonstrated impressive efficacy against B-cell malignancies and continuous efforts are made to adapt this new therapy to solid tumors, where the immunosuppressive tumor microenvironment is a barrier for delivery. CAR T-cell validation relies on in vitro functional assays using monolayer or suspension cells and in vivo xenograft models in immunodeficient animals. However, the efficacy of CAR therapies remains difficult to predict with these systems, in particular when challenged against 3D organized solid tumors with highly intricate microenvironment. An increasing number of reports have now included an additional step in the development process in which redirected T cells are tested against tumor spheres.

Results

Here, we report a method to produce 3D structures, or cysts, out of a colorectal cancer cell line, Caco-2, which has the ability to form polarized spheroids as a validation tool for adoptive cell therapy in general. We used CD19CAR T cells to explore this method and we show that it can be adapted to various platforms including high resolution microscopy, bioluminescence assays and high-throughput live cell imaging systems.

Conclusion

We developed an affordable, reliable and practical method to produce cysts to validate therapeutic CAR T cells. The integration of this additional layer between in vitro and in vivo studies could be an important tool in the pre-clinical workflow of cell-based immunotherapy.
Gender awareness among medical students in a Swiss University
Authors: Rrustemi Ilire , Locatelli Isabella , Schwarz Joëlle , Lagro-Janssen Toine , Fauvel Aude , Clair Carole
Published: June 2020

Background

Gender is an important social determinant, that influences healthcare. The lack of awareness on how gender influences health might lead to gender bias and can contribute to substandard patient care. Our objectives were to assess gender sensitivity and the presence of gender stereotypes among swiss medical students.

Methods

A validated scale (N-GAMS – Nijmegen Gender Awareness in Medicine Scale), with 3 subscores assessing gender sensitivity (GS) and gender stereotypes toward patients (GRIP) and doctors (GRID) (ranging from 1 to 5), was translated into French and was distributed to all medical students registered at the University of Lausanne, Switzerland in April–May 2017. Reliability of the three subscales was assessed calculating the alpha Cronbach coefficient. Mean subscales were calculated for male and female students and compared using two sample t-tests. A linear model was built with each subscale as a dependent variable and students’ sex and age as covariables.

Results

In total, 396 students answered the N-GAMS questionnaire, their mean age was 22 years old, 62.6% of them were women. GS and GRID sub-scores were not significantly different between female and male students (GS 3.62 for women, 3.70 for men, p = 0.27, GRID 2.10 for women, 2.13 for men, p = 0.76). A statistically significant difference was found in the GRIP subscale, with a mean score of 1.83 for women and 2.07 for men (p < 0.001), which suggests a more gender stereotyped opinion toward patients among male students. A trend was observed with age, gender sensibility increased (p < 0.001) and stereotypes decreased (GRIP p = 0.04, GRID p = 0.02) with students getting older.

Conclusion

Medical students’ gender sensitivity seems to improve throughout the medical curriculum, and women students have less stereotypes towards patients than men do. The implementation of a gender-sensitive teaching in the medical curriculum could improve students’ knowledge, limit gender bias and improve patients’ care.
Differences in factors influencing the use of eRehabilitation after stroke; a cross-sectional comparison between Brazilian and Dutch healthcare professionals
Authors: Brouns Berber , van Bodegom-Vos Leti , de Kloet Arend J. , Vliet Vlieland Thea P. M. , Gil Ingrid L. C. , Souza Lígia M. N. , Braga Lucia W. , Meesters Jorit J. L.
Published: June 2020

Background

To improve the use of eRehabilitation after stroke, the identification of barriers and facilitators influencing this use in different healthcare contexts around the world is needed. Therefore, this study aims to investigate differences and similarities in factors influencing the use of eRehabilitation after stroke among Brazilian Healthcare Professionals (BHP) and Dutch Healthcare Professionals (DHP).

Method

A cross-sectional survey study including 88 statements about factors related to the use of eRehabilitation (4-point Likert scale; 1–4; unimportant-important/disagree-agree). The survey was conducted among BHP and DHP (physical therapists, rehabilitating physicians and psychologists). Descriptive statistics were used to analyse differences and similarities in factors influencing the use of eRehabilitation.

Results

ninety-nine (response rate 30%) BHP and 105 (response rate 37%) DHP participated. Differences were found in the top-10 most influencing statements between BHP and DHP BHP rated the following factors as most important: sufficient support from the organisation (e.g. the rehabilitation centre) concerning resources and time, and potential benefits of the use of eRehabilitation for the patient. DHP rated the feasibility of the use of eRehabilitation for the patient (e.g. a helpdesk and good instructions) as most important for effective uptake. Top-10 least important statements were mostly similar; both BHP and DHP rated problems caused by stroke (e.g. aphasia or cognitive problems) or problems with resources (e.g. hardware and software) as least important for the uptake of eRehabilitation.

Conclusion

The results indicate that the use of eRehabilitation after stroke by BHP and DHP is influenced by different factors. A tailored implementation strategy for both countries needs to be developed.
Setting up a nurse-led model of care for management of hypertension and diabetes mellitus in a high HIV prevalence context in rural Zimbabwe: a descriptive study
Authors: Frieden Marthe , Zamba Blessing , Mukumbi Nisbert , Mafaune Patron T. , Makumbe Brian , Irungu Elizabeth , Moneti Virginia , Isaakidis Petros , Garone Daniela , Prasai Madhu
Published: June 2020

Background

In the light of the increasing burden of non-communicable diseases (NCDs) on health systems in low- and middle-income countries, particularly in Sub-Saharan Africa, context-adapted, cost-effective service delivery models are now required as a matter of urgency. We describe the experience of setting up and organising a nurse-led Diabetes Mellitus (DM) and Hypertension (HTN) model of care in rural Zimbabwe, a low-income country with unique socio-economic challenges and a dual disease burden of HIV and NCDs.

Methods

Mirroring the HIV experience, we designed a conceptual framework with 9 key enablers: decentralization of services, integration of care, simplification of management guidelines, mentoring and task-sharing, provision of affordable medicines, quality assured laboratory support, patient empowerment, a dedicated monitoring and evaluation system, and a robust referral system. We selected 9 primary health care clinics (PHC) and two hospitals in Chipinge district and integrated DM and HTN either into the general out-patient department, pre-existing HIV clinics, or an integrated chronic care clinic (ICCC). We provided structured intensive mentoring for staff, using simplified protocols, and disease-specific education for patients. Free medication with differentiated periodic refills and regular monitoring with point of care (POC) glycosylated haemoglobin (HbA1c) were provided.

Results

Nurses in 7 PHC facilities and one hospital developed sufficient knowledge and skills to diagnose, initiate treatment and monitor DM and HTN patients, and 3094 patients were registered in the programme (188 with DM only, 2473 with HTN only, 433 with both DM and HTN). Major lessons learned from our experience include: the value of POC devices in the management of diabetes; the pressure on services of the added caseload, exacerbated by the availability of free medications in supported health facilities; and the importance of leadership in the successful implementation of care in health facilities.

Conclusion

Our experience demonstrates a model for nurse-led decentralized integrated DM and HTN care in a high HIV prevalence rural, low-income context. Developing a context-adapted efficient model of care is a dynamic process. We present our lessons learned with the intention of sharing experience which may be of value to other public health programme managers.
Coiled-coil inspired functional inclusion bodies
Authors: Gil-Garcia Marcos , Navarro Susanna , Ventura Salvador
Published: June 2020

Background

Recombinant protein expression in bacteria often leads to the formation of intracellular insoluble protein deposits, a major bottleneck for the production of soluble and active products. However, in recent years, these bacterial protein aggregates, commonly known as inclusion bodies (IBs), have been shown to be a source of stable and active protein for biotechnological and biomedical applications. The formation of these functional IBs is usually facilitated by the fusion of aggregation-prone peptides or proteins to the protein of interest, leading to the formation of amyloid-like nanostructures, where the functional protein is embedded.

Results

In order to offer an alternative to the classical amyloid-like IBs, here we develop functional IBs exploiting the coiled-coil fold. An in silico analysis of coiled-coil and aggregation propensities, net charge, and hydropathicity of different potential tags identified the natural homo-dimeric and anti-parallel coiled-coil ZapB bacterial protein as an optimal candidate to form assemblies in which the native state of the fused protein is preserved. The protein itself forms supramolecular fibrillar networks exhibiting only α-helix secondary structure. This non-amyloid self-assembly propensity allows generating innocuous IBs in which the recombinant protein of interest remains folded and functional, as demonstrated using two different fluorescent proteins.

Conclusions

Here, we present a proof of concept for the use of a natural coiled-coil domain as a versatile tool for the production of functional IBs in bacteria. This α-helix-based strategy excludes any potential toxicity drawback that might arise from the amyloid nature of β-sheet-based IBs and renders highly active and homogeneous submicrometric particles.
Optimization of hydrogenobyrinic acid biosynthesis in Escherichia coli using multi-level metabolic engineering strategies
Authors: Jiang Pingtao , Fang Huan , Zhao Jing , Dong Huina , Jin Zhaoxia , Zhang Dawei
Published: June 2020

Background

Hydrogenobyrinic acid is a key intermediate of the de-novo aerobic biosynthesis pathway of vitamin B12. The introduction of a heterologous de novo vitamin B12 biosynthesis pathway in Escherichia coli offers an alternative approach for its production. Although E. coli avoids major limitations that currently faced by industrial producers of vitamin B12, such as long growth cycles, the insufficient supply of hydrogenobyrinic acid restricts industrial vitamin B12 production.

Results

By designing combinatorial ribosomal binding site libraries of the hemABCD genes in vivo, we found that their optimal relative translational initiation rates are 10:1:1:5. The transcriptional coordination of the uroporphyrinogen III biosynthetic module was realized by promoter engineering of the hemABCD operon. Knockdown of competitive heme and siroheme biosynthesis pathways by RBS engineering enhanced the hydrogenobyrinic acid titer to 20.54 and 15.85 mg L−1, respectively. Combined fine-tuning of the heme and siroheme biosynthetic pathways enhanced the hydrogenobyrinic acid titer to 22.57 mg L−1, representing a remarkable increase of 1356.13% compared with the original strain FH215-HBA.

Conclusions

Through multi-level metabolic engineering strategies, we achieved the metabolic balance of the uroporphyrinogen III biosynthesis pathway, eliminated toxicity due to by-product accumulation, and finally achieved a high HBA titer of 22.57 mg L−1 in E. coli. This lays the foundation for high-yield production of vitamin B12 in E. coli and will hopefully accelerate its industrial production.
The efficacy of surgery in advanced hepatocellular carcinoma: a cohort study
Authors: Chen Lei , Sun Tao , Chen Shi , Ren Yanqiao , Yang Fan , Zheng Chuansheng
Published: June 2020

Background

It is still controversial whether hepatocellular carcinoma (HCC) patients with lymph node invasion should receive surgery treatment. This study aimed to evaluate the efficacy of surgery (liver resection and local tumor destruction treatments) in HCC patients with regional lymph node metastasis.

Methods

The study utilized data from the Surveillance, Epidemiology, and End Results-18 (SEER-18) cancer registry. Patients for whom the treatment type was not clear or those with distant metastasis or without regional lymph nodule invasion were excluded. For survival analysis, patients with the survival months coded as 0 and 999 were excluded. All 1434 patients were included in the analysis. Among them, 168 patients were treated surgically and the other 1266 received non-surgery therapy. Propensity score matching (PSM) model was used to reduce selection bias.

Results

Before PSM, the median overall survival (mOS) and median cancer-specific survival (mCSS) of patients treated surgically were longer than that of receiving non-surgery treatment (mOS 20 months, 95% CI 15.3–24.7 vs. 7 months, 95% CI 6.4–7.6, P < 0.001; mCSS 21 months, 95% CI 115.5–26.5 vs. 6 months, 95% CI 5.3–6.7, P < 0.001). Subgroup analysis found no significant differences in mOS and mCSS between liver resection and non-liver resection surgery cohorts (P = 0.886 and P = 0.813, respectively). Similar results were obtained in the PSM analysis. The mOS and mCSS in the surgery group were longer than those in the non-surgery group (mOS 20 months vs. 7 months, P < 0.001; mCSS 20 months vs. 6 months, P < 0.001). The multivariate analysis documented that surgery was an independent predictor for OS and CSS before and after PSM.

Conclusions

HCC patients with invasion of regional lymph nodules may get more survival benefit from surgery than other types of treatment.
Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1
Authors: Okła Karolina , Rajtak Alicja , Czerwonka Arkadiusz , Bobiński Marcin , Wawruszak Anna , Tarkowski Rafał , Bednarek Wiesława , Szumiło Justyna , Kotarski Jan
Published: June 2020

Background

Previous studies have shown clinical relevance of programmed death-ligand 1 (PD-L1) and soluble PD-L1 (sPD-L1) in human cancers. However, still contradictory results exist. Our aim was evaluation of PD-L1-expressing monocytic myeloid-derived suppressor cells (M-MDSCs), monocytes/macrophages (MO/MA), tumour cells (TC) and immune/inflammatory cells (IC) as well as investigation of the sPD-L1 in ovarian cancer (OC) patients.

Methods

The group of 74 pretreatment women were enrollment to the study. The expression of PD-L1 on M-MDSCS and MO/MA was assessed by flow cytometry. The profile of sPD-L1 was examined with ELISA. The expression of PD-L1 in mononuclear cells (MCs) was analyzed using real time PCR. PD-L1 immunohistochemical analysis was prepared on TC and IC. An in silico validation of prognostic significance of PD-L1 mRNA expression was performed based microarray datasets.

Results

OC patients had significantly higher frequency of MO/MA versus M-MDSC in the blood, ascites and tumour (each p < 0.0001). In contrast, PD-L1 expression was higher on M-MDSCs versus MO/MA in the blood and ascites (each p < 0.0001), but not in the tumour (p > 0.05). Significantly higher accumulation of blood-circulating M-MDSC, MO/MA, PD-L1+M-MDSC, PD-L1+MO/MA and sPD-L1 was observed in patients versus control (p < 0.001, p < 0.05, p < 0.001, p < 0.001 and p < 0.0001, respectively). Accumulation of these factors was clinicopathologic-independent (p > 0.05). The expression of PD-L1 was significantly higher on IC versus TC (p < 0.0001) and was clinicopathologic-independent (p > 0.05) except higher level of PD-L1+TC in the endometrioid versus mucinous tumours. Interestingly, blood-circulating sPD-L1 positively correlated with PD-L1+M-MDSCs (p = 0.03) and PD-L1+MO/MA (p = 0.02) in the blood but not with these cells in the ascites and tumours nor with PD-L1+TC/IC (each p > 0.05). PD-L1 and sPD-L1 were not predictors of overall survival (OS; each p > 0.05). Further validation revealed no association between PD-L1 mRNA expression and OS in large independent OC patient cohort (n = 655, p > 0.05).

Conclusions

Although PD-L1 may not be a prognostic factor for OC, our study demonstrated impaired immunity manifested by up-regulation of PD-L1/sPD-L1. Furthermore, there was a positive association between PD-L1+myeloid cells and sPD-L1 in the blood, suggesting that sPD-L1 may be a noninvasive surrogate marker for PD-L1+myeloid cells immunomonitoring in OC. Overall, these data should be under consideration during future clinical studies/trials.
Women’s, partners’ and healthcare providers’ views and experiences of assisted vaginal birth: a systematic mixed methods review
Authors: Crossland Nicola , Kingdon Carol , Balaam Marie-Clare , Betrán Ana Pilar , Downe Soo
Published: June 2020

Background

When certain complications arise during the second stage of labour, assisted vaginal delivery (AVD), a vaginal birth with forceps or vacuum extractor, can effectively improve outcomes by ending prolonged labour or by ensuring rapid birth in response to maternal or fetal compromise. In recent decades, the use of AVD has decreased in many settings in favour of caesarean section (CS). This review aimed to improve understanding of experiences, barriers and facilitators for AVD use.

Methods

Systematic searches of eight databases using predefined search terms to identify studies reporting views and experiences of maternity service users, their partners, health care providers, policymakers, and funders in relation to AVD. Relevant studies were assessed for methodological quality. Qualitative findings were synthesised using a meta-ethnographic approach. Confidence in review findings was assessed using GRADE CERQual. Findings from quantitative studies were synthesised narratively and assessed using an adaptation of CERQual. Qualitative and quantitative review findings were triangulated using a convergence coding matrix.

Results

Forty-two studies (published 1985–2019) were included: six qualitative, one mixed-method and 35 quantitative. Thirty-five were from high-income countries, and seven from LMIC settings. Confidence in the findings was moderate or low. Spontaneous vaginal birth was most likely to be associated with positive short and long-term outcomes, and emergency CS least likely. Views and experiences of AVD tended to fall somewhere between these two extremes. Where indicated, AVD can be an effective, acceptable alternative to caesarean section. There was agreement or partial agreement across qualitative studies and surveys that the experience of AVD is impacted by the unexpected nature of events and, particularly in high-income settings, unmet expectations. Positive relationships, good communication, involvement in decision-making, and (believing in) the reason for intervention were important mediators of birth experience. Professional attitudes and skills (development) were simultaneously barriers and facilitators of AVD in quantitative studies.

Conclusions

Information, positive interaction and communication with providers and respectful care are facilitators for acceptance of AVD. Barriers include lack of training and skills for decision-making and use of instruments.
Achieving SDG related sexual and reproductive health targets in China: what are appropriate indicators and how we interpret them?
Authors: Fang Jing , Tang Shenglan , Tan Xiaoping , Tolhurst Rachel
Published: June 2020

Background

Sexual and Reproductive Health (SRH) targets have been included as part of the United Nations Sustainable Development Goals and indictors are important to monitor progress towards these targets. SRH indicators are recommended for setting norms and measuring progress globally. However, given the diverse political, socioeconomic and cultural contexts in different countries, and lack of global agreement on broad indicators, it is important to select appropriate indicators for specific countries. Based on internationally recommended indicators and data availability in China, this paper selected four indictors to reflect SRH in China and interpreted these indictors by analyzing the underlying factors.

Methods

We employed secondary data analysis and key informant interviews. Secondary data were obtained from the China Health Statistical Yearbook (2005–2017), China Statistical Yearbook (2005–2017), and the sub-national estimates of the Global Burden Diseases Study 2016. We interviewed 36 key informants at national and sub-national levels.

Results

The four selected SRH indicators are contraceptive prevalence rate (CPR), adolescent birth rate, abortion rate, and availability of school sex education. CPR of married women has remained above 75% over the last three decades, indicating a high level of access to family planning (FP) services; however, unmarried but sexually active women have significant unmet needs for FP services. Although adolescent birth rates in China remain low, the abortion rate, abortion numbers, and the ratio of abortions to births increased from 2014 to 2016 while FP policy was relaxed. This suggests that abortion among unmarried women is a significant contributor to overall figures. Qualitative analysis of the availability of school sex education, reveals an absence of policy due to conservative attitudes of key stakeholders.

Conclusion

Since SRH challenges vary significantly between contexts, indicators for measuring progress towards SRH targets should be selected based on country context. The CPR and abortion rate are currently available and important indicators to monitor the most basic part of SRH in China, but require modification to ensure they reflect universal access to quality reproductive healthcare by all reproductive age women, regardless of their marriage status. Policy and indicators on sex education need to be carefully developed to fit the context in China.
Perception and practices of menstruation restrictions among urban adolescent girls and women in Nepal: a cross-sectional survey
Authors: Mukherjee Amrita , Lama Mingma , Khakurel Uddhav , Jha Alok Nath , Ajose Fatima , Acharya Sanjeev , Tymes-Wilbekin Kristina , Sommer Marni , Jolly Pauline E. , Lhaki Pema , Shrestha Sadeep
Published: June 2020

Background

Menstruation, a natural biologic process is associated with restrictions and superstitious beliefs in Nepal. However, factual data on women’s perspectives on menstrual practices and restrictions are scarce. This study aimed to assess socio-cultural perceptions of menstrual restrictions among urban Nepalese women in the Kathmandu valley.

Methods

Using a clustered random sampling, 1342 adolescent girls and women of menstruating age (≥15 years) from three urban districts in the Kathmandu valley completed a survey related to menstrual practices and restriction. This was a cross-sectional survey study using a customized program allowing pull-down, multiple choice and open-ended questions in the Nepali language. The self-administered questionnaire consisted of 13 demographic questions and 22 questions related to menstruation, menstrual hygiene, socio-cultural taboos, beliefs and practices. Univariate descriptive statistics were reported. Unadjusted associations of socio-cultural practices with ethnicity, education, four major social classes, three major religions, marital status and family type were assessed using logistic regression models.

Results

More than half (59%) of the participants were aged between 15- < 25 years. The majority were Hindus (84.5%), reported not praying during menstruation (83.1%) and were encouraged by their mothers (72.1%) to practice a range of menstrual restrictions. Purifying either the kitchen, bed, bedsheets or other household things on the fourth day of menstruation was reported by 66.1% of the participants, and 45.4% saw menstruation as a “bother” or “curse.” There were differences among social classes, where participants of the Janajati caste, an indigenous group, were more likely to enter places of worship [OR (95%CI): 1.74 (1.06–2.86)] and pray [OR (95%CI): 1.79 (1.18–2.71)] while menstruating, compared to the Brahmins. Participants with a master’s degree were more likely to pray while menstruating, compared to participants with less than a high school education [OR (95%CI): 2.83 (1.61–4.96)].

Conclusion

This study throws light on existing social discriminations, deep-rooted cultural and religious superstitions among women, and gender inequalities in the urban areas of Kathmandu valley in Nepal. Targeted education and awareness are needed to make changes and balance between cultural and social practices during menstruation.
Development of a human in vitro blood–brain tumor barrier model of diffuse intrinsic pontine glioma to better understand the chemoresistance
Authors: Deligne Clémence , Hachani Johan , Duban-Deweer Sophie , Meignan Samuel , Leblond Pierre , Carcaboso Angel M. , Sano Yasuteru , Shimizu Fumitaka , Kanda Takashi , Gosselet Fabien , Dehouck Marie-Pierre , Mysiorek Caroline
Published: June 2020

Background

Pediatric diffuse intrinsic pontine glioma (DIPG) represents one of the most devastating and lethal brain tumors in children with a median survival of 12 months. The high mortality rate can be explained by the ineligibility of patients to surgical resection due to the diffuse growth pattern and midline localization of the tumor. While the therapeutic strategies are unfortunately palliative, the blood–brain barrier (BBB) is suspected to be responsible for the treatment inefficiency. Located at the brain capillary endothelial cells (ECs), the BBB has specific properties to tightly control and restrict the access of molecules to the brain parenchyma including chemotherapeutic compounds. However, these BBB specific properties can be modified in a pathological environment, thus modulating brain exposure to therapeutic drugs. Hence, this study aimed at developing a syngeneic human blood–brain tumor barrier model to understand how the presence of DIPG impacts the structure and function of brain capillary ECs.

Methods

A human syngeneic in vitro BBB model consisting of a triple culture of human (ECs) (differentiated from CD34+-stem cells), pericytes and astrocytes was developed. Once validated in terms of BBB phenotype, this model was adapted to develop a blood–brain tumor barrier (BBTB) model specific to pediatric DIPG by replacing the astrocytes by DIPG-007, -013 and -014 cells. The physical and metabolic properties of the BBTB ECs were analyzed and compared to the BBB ECs. The permeability of both models to chemotherapeutic compounds was evaluated.

Results

In line with clinical observation, the integrity of the BBTB ECs remained intact until 7 days of incubation. Both transcriptional expression and activity of efflux transporters were not strongly modified by the presence of DIPG. The permeability of ECs to the chemotherapeutic drugs temozolomide and panobinostat was not affected by the DIPG environment.

Conclusions

This original human BBTB model allows a better understanding of the influence of DIPG on the BBTB ECs phenotype. Our data reveal that the chemoresistance described for DIPG does not come from the development of a “super BBB”. These results, validated by the absence of modification of drug transport through the BBTB ECs, point out the importance of understanding the implication of the different protagonists in the pathology to have a chance to significantly improve treatment efficiency.
An efficient method to reduce grain angle influence on NIR spectra for predicting extractives content from heartwood stem cores of Toona. sinensis
Authors: Li Yanjie , Dong Xin , Sun Yang , Liu Jun , Jiang Jingmin
Published: June 2020

Background

A fast, reliable and non-destructive method is needed to qualify the extractives content (EC) in heartwood of T. sinensis cores in the breeding program for studying the genetic effect on EC. However, the influence of grain angle on near infrared (NIR) spectra prediction model for EC is unclear. In this study, NIR spectra were collected from both cross section and radial section of wood core samples in order to predict the EC in heartwood.

Results

The effect of grain angle on calibration EC model was studied. Several different spectra pre-processing methods were implemented for calibration. It was found that standard normal variation (SNV) followed by 1st derivative yielded the best calibration result for T. sinensis EC. Grain angle had a significant influence on the predicted model for EC when using the whole NIR spectra. However, after testing a certain point of the prior variables for EC that were selected by the significant multivariate correlation (sMC), the influence of grain angle was significantly eliminated.

Conclusions

It is suggested that NIR spectroscopy is a promising method to predict EC in the solid wood without effecting grain angle.