bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors
Authors: Kennedy Susan A. , Morrissey Maria E. , Dunne Margaret R. , O’Connell Fiona , Butler Clare T. , Cathcart Mary-Clare , Buckley Amy M. , Mehigan Brian J. , Larkin John O. , McCormick Paul , Kennedy Breandán N. , O’Sullivan Jacintha
Published: October 2020

Background

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication.

Method

Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry.

Results

Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers.

Conclusion

Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.
A 38-gene model comprised of key TET2-associated genes shows additive utility to high-risk prostate cancer cases in the prognostication of biochemical recurrence
Authors: Kamdar Shivani , Fleshner Neil E. , Bapat Bharati
Published: October 2020

Background

Early treatment of patients at risk for developing aggressive prostate cancer is able to delay metastasis and reduce mortality; as such, up-front identification of these patients is critical. Several risk classification systems, including CAPRA-S, are currently used for disease prognostication. However, high-risk patients identified by these systems can still exhibit wide-ranging disease outcomes, leading to overtreatment of some patients in this group.

Methods

The master methylation regulator TET2 is downregulated in prostate cancer, where its loss is linked to aggressive disease and poor outcome. Using a random forest strategy, we developed a model based on the expression of 38 genes associated with TET2 utilizing 100 radical prostatectomy samples (training cohort) with a 49% biochemical recurrence rate. This 38-gene model was comprised of both upregulated and downregulated TET2-associated genes with a binary outcome, and was further assessed in an independent validation (n = 423) dataset for association with biochemical recurrence.

Results

38-gene model status was able to correctly identify patients exhibiting recurrence with 81.4% sensitivity in the validation cohort, and added significant prognostic utility to the high-risk CAPRA-S classification group. Patients considered high-risk by CAPRA-S with negative 38-gene model status exhibited no statistically significant difference in time to recurrence from low-risk CAPRA-S patients, indicating that the expression of TET2-associated genes is able to separate truly high-risk cases from those which have a more benign disease course.

Conclusions

The 38-gene model may hold potential in determining which patients would truly benefit from aggressive treatment course, demonstrating a novel role for genes linked to TET2 in the prognostication of PCa and indicating the importance of TET2 dysregulation among high-risk patient groups.
Assessment of online patient education materials designed for people with age-related macular degeneration
Authors: Fortuna Jennifer , Riddering Anne , Shuster Linda , Lopez-Jeng Cassie
Published: October 2020

Background

Age-related macular degeneration (AMD) is a chronic eye condition that leads to permanent vision loss in the central visual field. AMD makes reading challenging and inefficient. People with AMD often find it difficult to access, process and understand written patient education materials (PEMs). To promote health literacy, the demands of written PEMs must match the literacy capacities of the target audience. This study aims to evaluate the readability (grade level) and suitability (appropriateness) of online PEMs designed for people with AMD.

Methods

Online PEMs were sourced from websites of national organizations providing patient education materials designed for people with AMD. The Flesch-Kincaid Grade Level formula and the Suitability Assessment of Materials instrument were used to assess the readability and suitability of PEMs. Descriptive statistics were used to compare online PEMs by organization based on national guidelines for readability level (≤ sixth grade) and the recommended suitability score (≥ 70%) for “superior” material.

Results

One hundred online PEMs were evaluated from websites of 16 professional organizations. The mean readability level was 9.3 (range 5.0–16.6). The mean suitability score was 53% (range 18–78%). Only six (6%) of PEMs achieved the recommended guidelines for readability level and suitability score.

Conclusion

The majority of online PEMs designed for people with AMD were written above the recommended readability level, and below the suggested suitability score. To promote health literacy, the demands of written health information must match the reading capacities of the target audience. Heeding to evidence-based guidelines for providing written information to patients with low health literacy and low vision is beneficial for both patients and health care providers. Future research is warranted.
Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study
Authors: Iwanami Akira , Saito Kazuhiko , Fujiwara Masakazu , Okutsu Daiki , Ichikawa Hironobu
Published: October 2020

Background

To assess the safety and efficacy of long-term administration of guanfacine extended-release (GXR) in adults with attention-deficit/hyperactivity disorder (ADHD).

Methods

In this open-label, long-term, phase 3 extension study in Japan, 150 patients transitioned from a double-blind trial, and 41 newly enrolled patients received once daily GXR (starting dose 2 mg/day, maintenance dose 4–6 mg/day) for 50 weeks. Primary outcome measures were the frequency and nature of treatment-emergent adverse events (TEAEs); secondary outcome measures included the change from week 0 in ADHD Rating Scale IV with Adult Prompts (ADHD-RS-IV; Japanese version) total and subscale scores, Conners’ Adult ADHD Rating Scales (CAARS), Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression-Improvement (PGI-I) scales, and quality of life (QoL) and executive functioning measures.

Results

Of all patients, 94.2% (180/191) reported ≥1 TEAE and 19.9% (38/191) discontinued because of a TEAE. Most TEAEs were mild to moderate in severity; there were two serious TEAEs and no deaths. Commonly reported TEAEs (≥10% of patients) were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia, malaise, constipation, and dizziness. Mean changes from week 0 in ADHD-RS-IV total and subscale scores and CAARS subscale scores were significantly improved in former placebo or GXR patients and new patients at last observation (p < .0001), and the percentage of patients with very much or much improved CGI-I and PGI-I scores increased.

Conclusions

There were no major safety concerns during long-term GXR administration in adults with ADHD. After long-term treatment, patients had significant improvements from baseline in ADHD symptoms, QoL, and executive functioning.

Trial registration

Japan Primary Registries Network (https://rctportal.niph.go.jp/en/): JapicCTI-163232, registered 04/21/2016.
“A loving man has a very huge responsibility”: A mixed methods study of Malawian men’s knowledge and beliefs about cervical cancer
Authors: Lewis Samuel , Moucheraud Corrina , Schechinger Devon , Mphande Misheck , Banda Ben Allan , Sigauke Hitler , Kawale Paul , Dovel Kathryn , Hoffman Risa M.
Published: October 2020

Background

In Malawi, numerous barriers may prevent women from accessing cervical cancer screening services — including social factors such as male partner involvement. We conducted surveys that included open- and closed-ended questions with married Malawian men to evaluate their knowledge and beliefs about cervical cancer.

Methods

HIV-positive adult (≥18 years) men (married or in a stable relationship) were recruited from an antiretroviral therapy clinic in Lilongwe, Malawi. Men were asked a series of survey questions to assess their knowledge about cervical cancer, experience with cervical cancer, their female partner’s screening history, and their beliefs about gender norms and household decision-making. Following the survey, participants responded to a set of open-ended interview questions about cervical cancer screening, and men’s role in prevention.

Results

One hundred-twenty men were enrolled with average age 44 years and 55% having completed secondary school or higher education. Despite only moderate knowledge about cervical cancer and screening (average assessment score of 62% correct), all men expressed support of cervical cancer screening, and most (86%) believed they should be involved in their female partner’s decision to be screened. Over half (61%) of men said their female partner had previously been screened for cervical cancer, and this was positively correlated with the male respondent having more progressive gender norms around sexual practices. Some men expressed concerns about the screening process, namely the propriety of vaginal exams when performed by male clinicians, and whether the procedure was painful.

Conclusions

Male partners in Malawi want to be involved in decisions about cervical cancer screening, but have limited knowledge about screening, and hold rigid beliefs about gender norms that may affect their support for screening. Messaging campaigns addressing men’s concerns may be instrumental in improving women’s adoption of cervical cancer screening services in Malawi and similar settings.
Health status of female Moldovan migrants to Italy by health literacy level and age group: a descriptive study
Authors: Vianello Francesca Alice , Zaccagnini Federica , Pinato Carlo , Maculan Pietro , Buja Alessandra
Published: October 2020

Background

Migration flows from Eastern Europe to Italy have been large and continue to grow. The purpose of this study was to examine the health status of a population of Moldovan migrant women, and their access to health care services in northern Italy, by age group and health literacy level.

Methods

We administered an ad-hoc questionnaire to adult Moldovan women. A bivariate analysis was conducted to test the association between health literacy and age groups with other variables (lifestyles, symptoms and diseases, access to health services). A stepwise logistic regression analysis was run to test the association between access to primary care and health literacy. Moreover, the study compare Moldovan women data with a sample of Italian women of the same age range living in North-Eastern region.

Results

Our sample included 170 Moldovan women (aged 46.5 ± 12.3) in five occupational categories: home care workers (28.2%); cleaners (27.1%); health care workers (5.9%); other occupations (28.8%); and unemployed (10%). Active smokers were twice as prevalent among the women with a low health literacy. Health literacy level also determined access to primary healthcare services. For all age groups, the Moldovan sample reported a higher prevalence of allergies, lumbar disorders and depression than the Italian controls.

Conclusions

The reported prevalence of some diseases was higher among Moldovan migrant women than among Italian resident women. Health literacy was associated with the migrant women’s lifestyle and the use of primary health care services, as previously seen for the autochthonous population.
Uptake of routine vitamin A supplementation for children in Humbo district, southern Ethiopia: community-based cross-sectional study
Authors: Kassa Getnet , Mesfin Addisalem , Gebremedhin Samson
Published: October 2020

Background

In low- and middle-income countries routine vitamin A supplementation (VAS) is a key strategy for reducing vitamin A deficiency and mortality and morbidity of preschool children. However, in Ethiopia, there is paucity of evidence regarding the level and determinants of the uptake of the supplement. This study was designed to assess the coverage and predictors of VAS among preschool children in Humbo district, Southern Ethiopia.

Methods

A cross-sectional study was conducted in April 2016. A total of 840 mothers/caregivers having children 6–59 months of age were selected using multistage cluster sampling technique from six rural villages implementing routine VAS program. Data were collected using interviewer administered questionnaire. Possible predictors considered in the study include distance from the nearby health facility, household socio-economic status, type of the household (model vs non-model), maternal access to health education on VAS, and knowledge on vitamin A and VAS. Multivariable logistic regression analysis was performed to identify predictors of uptake of VAS. The outputs are presented using adjusted odds ratio (AOR) with the respective 95% confidence interval (CI).

Results

The coverage of VAS was 75.0% (95% CI: 72.1–77.9). Better knowledge of mothers about the importance of the supplement (AOR: 1.49, 1.02–2.17), obtaining VAS related information from frontline community health workers (AOR: 1.51, 1.34–2.72) than health professionals and being from households in the “rich” wealth tertile (AOR: 1.80, 95% CI: 1.07–3.03) were positively associated with uptake VAS.

Conclusion

The VAS coverage of the area was approaching the expected national target of 80%. However, the uptake can be enhanced though awareness creation and improving socio-economic status of the community.
Clinical significance of peripheral blood-derived inflammation markers in advanced gastric cancer after radical resection
Authors: Gu Lihu , Wang Mian , Cui Xuena , Mo Jiahang , Yuan Lingling , Mao Feiyan , Zhang Kang , Ng Derry Minyao , Chen Ping , Wang Dongjie
Published: October 2020

Background

The prognostic significance of peripheral blood-derived inflammation markers in patients with gastric cancer (GC) has not been elucidated. This study aimed to investigate the relationship between systemic inflammatory markers and GC prognosis.

Methods

A prospective observational cohort study involving 598 patients was conducted to analyze the prognosis of GC based on systemic inflammatory markers. The following peripheral blood-derived inflammation markers were evaluated: the neutrophil-lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), systemic immune-inflammation index (SII), C-reactive protein/albumin (CRP/Alb) ratio, Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), prognostic nutrition index (PNI), and prognostic index (PI). The receiver operating characteristics (ROC) curve and the Youden index were used to determine the optimal cutoff values. Univariate and multivariate analysis of prognostic factors was conducted accordingly.

Results

The optimal cutoff values of the PNI, fibrinogen, NLR, PLR, SII, and CRP/Alb were 49.5, 397 ng/dl, 2.5, 154, 556, and 0.05, respectively. Multivariate analysis showed that age, PLR, TNM stage, and chemotherapy were the independent prognostic factors for advanced gastric cancer (AGC). Adjuvant chemotherapy improved the long-term prognosis of patients with PLR ≥154, but chemotherapy had no significant effect on the survival of patients with PLR < 154.

Conclusions

Our findings show that higher PLR (≥154) is an independent risk factor for poor prognosis in GC patients. Besides, PLR can predict adjuvant chemotherapy (oxaliplatin/5-fluorouracil combination) response in patients with GC after surgery.
A novel structure for online surgical undergraduate teaching during the COVID-19 pandemic
Authors: Chandrasinghe P. C. , Siriwardana R. C. , Kumarage S. K. , Munasinghe B.N.L , Weerasuriya A. , Tillakaratne S. , Pinto D. , Gunathilake B. , Fernando F. R.
Published: October 2020

Background

The Covid-19 pandemic necessitated the delivery of online higher education. Online learning is a novel experience for medical education in Sri Lanka. A novel approach to undergraduate surgical learning was taken up in an attempt to improve the interest amongst the students in clinical practice while maximizing the limited contact time.

Method

Online learning activity was designed involving medical students from all stages and multi consultant panel discussions. The discussions were designed to cover each topic from basic sciences to high-level clinical management in an attempt to stimulate the student interest in clinical medicine. Online meeting platform with free to use basic plan and a social media platform were used in combination to communicate with the students. The student feedback was periodically assessed for individual topics as well as for general outcome. Lickert scales and numeric scales were used to acquire student agreement on the desired learning outcomes.

Results

A total of 1047 student responses for 7 questionnaires were analysed. During a 6-week period, 24 surgical topics were discussed with 51 contact hours. Eighty-seven per cent definitely agreed (highest agreement) with the statement ‘students benefitted from the discussions’. Over 95% have either participated for all or most sessions. A majority of the respondents (83.4%) ‘definitely agreed’ that the discussions helped to improve their clinical sense. Of the total respondents, 79.3% definitely agreed that the discussions helped to build an interest in clinical medicine. Around 90% agreed that both exam-oriented and clinical practice-oriented topics were highly important and relevant. Most widely raised concerns were the poor Internet connectivity and limitation of access to the meeting platform.

Conclusion

Online teaching with a novel structure is feasible and effective in a resource-limited setting. Students agree that it could improve clinical interest while meeting the expected learning outcomes.
Validation of the French translation of the Dutch residency educational climate test
Authors: Majbar Mohamed Anass , Majbar Yassin , Benkabbou Amine , Amrani Laila , Bougtab Abdeslam , Mohsine Raouf , Souadka Amine
Published: October 2020

Background

The learning environment is one of the most influential factors in training of medical residents. The Dutch Residency Educational Climate Test (D-RECT) is one of the strongest instruments for measuring the learning environment. However, it has not been translated in French. The objective of this study is the psychometric validation of the DRECT French version.

Material and methods

After translation of the D-RECT questionnaire into French, residents of five Moroccan hospitals were invited to complete the questionnaire between July and September 2018. Confirmatory factor analysis was used to evaluate the validity of the construct using the standardized root mean square residual (SRMR), the root mean square error approximation (RMSEA), the Comparative Fit Index (CFI) and the Tucker- Lewis Index (TLI). Reliability analysis was analysed using Internal consistency and Test-retest.

Results

During the study period, 211 residents completed the questionnaire. Confirmatory factor analysis showed an adequate model fit with the following indicators: SRMR = 0.058 / RMSEA = 0.07 / CFI = 0.88 / TLI = 0.87. The French translation had a good internal consistency (Cronbach alpha score >  0.7 for all subscales) and a good temporal stability (correlation score between two measurements = 0.89).

Conclusion

This French version has an acceptable validity of the construct, a good internal consistency and good temporal reliability, and may be used to evaluate the learning climate. Additional research is necessary in other French-speaking contexts, in order to confirm these results.
Distance learning in clinical medical education amid COVID-19 pandemic in Jordan: current situation, challenges, and perspectives
Authors: Al-Balas Mahmoud , Al-Balas Hasan Ibrahim , Jaber Hatim M. , Obeidat Khaled , Al-Balas Hamzeh , Aborajooh Emad A. , Al-Taher Raed , Al-Balas Bayan
Published: October 2020

Background

As COVID-19 has been declared as a pandemic disease by the WHO on March 11th, 2020, the global incidence of COVID-19 disease increased dramatically. In response to the COVID-19 situation, Jordan announced the emergency state on the 19th of March, followed by the curfew on 21 March. All educational institutions have been closed as well as educational activities including clinical medical education have been suspended on the 15th of March. As a result, Distance E-learning emerged as a new method of teaching to maintain the continuity of medical education during the COVID-19 pandemic related closure of educational institutions. Distance E-Learning is defined as using computer technology to deliver training, including technology-supported learning either online, offline, or both. Before this period, distance learning was not considered in Jordanian universities as a modality for education. This study aims to explore the situation of distance E-learning among medical students during their clinical years and to identify possible challenges, limitations, satisfaction as well as perspectives for this approach to learning.

Methods

This cross-sectional study is based on a questionnaire that was designed and delivered to medical students in their clinical years. For this study, the estimated sample size (n = 588) is derived from the online Raosoft sample size calculator.

Results

A total of 652 students have completed the questionnaire, among them, 538 students (82.5%) have participated in distance learning in their medical schools amid COVID-19 pandemic. The overall satisfaction rate in medical distance learning was 26.8%, and it was significantly higher in students with previous experience in distance learning in their medical schools as well as when instructors were actively participating in learning sessions, using multimedia and devoting adequate time for their sessions. The delivery of educational material using synchronous live streaming sessions represented the major modality of teaching and Internet streaming quality and coverage was the main challenge that was reported by 69.1% of students.

Conclusion

With advances in technologies and social media, distance learning is a new and rapidly growing approach for undergraduate, postgraduate, and health care providers. It may represent an optimal solution to maintain learning processes in exceptional and emergency situations such as COVID-19 pandemic. Technical and infrastructural resources reported as a major challenge for implementing distance learning, so understanding technological, financial, institutional, educators, and student barriers are essential for the successful implementation of distance learning in medical education.
Researchers’ views on, and experiences with, the requirement to obtain informed consent in research involving human participants: a qualitative study
Authors: Xu Antonia , Baysari Melissa Therese , Stocker Sophie Lena , Leow Liang Joo , Day Richard Osborne , Carland Jane Ellen
Published: October 2020

Background

Informed consent is often cited as the “cornerstone” of research ethics. Its intent is that participants enter research voluntarily, with an understanding of what their participation entails. Despite agreement on the necessity to obtain informed consent in research, opinions vary on the threshold of disclosure necessary and the best method to obtain consent. We aimed to investigate Australian researchers’ views on, and their experiences with, obtaining informed consent.

Methods

Semi-structured interviews were conducted with 23 researchers from NSW institutions, working in various fields of research. Interviews were analysed and coded to identify themes.

Results

Researchers reported that consent involved information disclosure, understanding and a voluntary decision. They emphasised the variability of consent interactions, which were dependent on potential participants’ abilities and interests, study complexity and context. All researchers reported providing written information to potential participants, yet questioned the readability and utility of this information. The majority reported using signed consent forms to ‘operationalise’ consent and reported little awareness of, and lack of support in implementing more dynamic informed consent procedures, such as verbal informed consent, that was fit for the purposes of their studies. Views on Human Research Ethics Committees (HRECs) varied. Some reported inconsistent, arduous inputs on the information form and consent process. Others expressed reliance on HRECs for guidance, viewing them as institutional safeguards.

Conclusions

This study highlights the importance of transparent relationships, both between researchers and participants, and between researchers and HRECs. Where the relationship with study participants was reported as more robust, researchers felt that they were better able to ensure participants made better, more informed decisions. Where the relationship with HRECs was reported as more robust, researchers were more likely to view them as institutional safeguards, rather than as bureaucratic hindrances. Conscientious and mindful researchers are paramount to ensuring the procedure accommodates individual requirements. This study advocates that when designing ethical informed consent practices, researchers should be integrated as autonomous players with a positive input on the process, rather than, in the worst case, predatory recruiters to be curtailed by information forms and oversight.
Ada-WHIPS: explaining AdaBoost classification with applications in the health sciences
Authors: Hatwell Julian , Gaber Mohamed Medhat , Atif Azad R. Muhammad
Published: October 2020

Background

Computer Aided Diagnostics (CAD) can support medical practitioners to make critical decisions about their patients’ disease conditions. Practitioners require access to the chain of reasoning behind CAD to build trust in the CAD advice and to supplement their own expertise. Yet, CAD systems might be based on black box machine learning models and high dimensional data sources such as electronic health records, magnetic resonance imaging scans, cardiotocograms, etc. These foundations make interpretation and explanation of the CAD advice very challenging. This challenge is recognised throughout the machine learning research community. eXplainable Artificial Intelligence (XAI) is emerging as one of the most important research areas of recent years because it addresses the interpretability and trust concerns of critical decision makers, including those in clinical and medical practice.

Methods

In this work, we focus on AdaBoost, a black box model that has been widely adopted in the CAD literature. We address the challenge – to explain AdaBoost classification – with a novel algorithm that extracts simple, logical rules from AdaBoost models. Our algorithm,Adaptive-Weighted High Importance Path Snippets(Ada-WHIPS), makes use of AdaBoost’s adaptive classifier weights. Using a novel formulation, Ada-WHIPS uniquely redistributes the weights among individual decision nodes of the internal decision trees of the AdaBoost model. Then, a simple heuristic search of the weighted nodes finds a single rule that dominated the model’s decision. We compare the explanations generated by our novel approach with the state of the art in an experimental study. We evaluate the derived explanations with simple statistical tests of well-known quality measures, precision and coverage, and a novel measurestabilitythat is better suited to the XAI setting.

Results

Experiments on 9 CAD-related data sets showed that Ada-WHIPS explanations consistently generalise better (mean coverage 15%-68%) than the state of the art while remaining competitive for specificity (mean precision 80%-99%). A very small trade-off in specificity is shown to guard against over-fitting which is a known problem in the state of the art methods.

Conclusions

The experimental results demonstrate the benefits of using our novel algorithm for explaining CAD AdaBoost classifiers widely found in the literature. Our tightly coupled, AdaBoost-specific approach outperforms model-agnostic explanation methods and should be considered by practitioners looking for an XAI solution for this class of models.
Endothelin receptor antagonist improves donor lung function in an ex vivo perfusion system
Authors: Walweel K. , Skeggs K. , Boon A. C. , See Hoe L. E. , Bouquet M. , Obonyo N. G. , Pedersen S. E. , Diab S. D. , Passmore M. R. , Hyslop K. , Wood E. S. , Reid J. , Colombo S. M. , Bartnikowski N. J. , Wells M. A. , Black D. , Pimenta L. P. , Stevenson A. K. , Bisht K. , Marshall L. , Prabhu D. A. , James L. , Platts D. G. , Macdonald P. S. , McGiffin D. C. , Suen J. Y. , Fraser J. F.
Published: October 2020

Background

A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD).

Methods

After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema).

Results

Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control.

Conclusions

These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.
Quantitative CT-based image registration metrics provide different ventilation and lung motion patterns in prone and supine positions in healthy subjects
Authors: Shin Kyung Min , Choi Jiwoong , Chae Kum Ju , Jin Gong Yong , Eskandari Ali , Hoffman Eric A. , Hall Chase , Castro Mario , Lee Chang Hyun
Published: October 2020

Background

Previous studies suggested that the prone position (PP) improves oxygenation and reduces mortality among patients with acute respiratory distress syndrome (ARDS). However, the mechanism of this clinical benefit of PP is not completely understood. The aim of the present study was to quantitatively compare regional characteristics of lung functions in the PP with those in the supine position (SP) using inspiratory and expiratory computed tomography (CT) scans.

Methods

Ninety subjects with normal pulmonary function and inspiration and expiration CT images were included in the study. Thirty-four subjects were scanned in PP, and 56 subjects were scanned in SP. Non-rigid image registration-based inspiratory-expiratory image matching assessment was used for regional lung function analysis. Tissue fractions (TF) were computed based on the CT density and compared on a lobar basis. Three registration-derived functional variables, relative regional air volume change (RRAVC), volumetric expansion ratio (J), and three-dimensional relative regional displacement (s*) were used to evaluate regional ventilation and deformation characteristics.

Results

J was greater in PP than in SP in the right middle lobe (P = 0 .025), and RRAVC was increased in the upper and right middle lobes (P < 0.001). The ratio of the TF on inspiratory and expiratory scans, J, and RRAVC at the upper lobes to those at the middle and lower lobes and that ratio at the upper and middle lobes to those at the lower lobes of were all near unity in PP, and significantly higher than those in SP (0.98–1.06 vs 0.61–0.94, P < 0.001).

Conclusion

We visually and quantitatively observed that PP not only induced more uniform contributions of regional lung ventilation along the ventral-dorsal axis but also minimized the lobar differences of lung functions in comparison with SP. This may help in the clinician’s search for an understanding of the benefits of the application of PP to the patients with ARDS or other gravitationally dependent pathologic lung diseases.

Trial registration

Retrospectively registered.
MsrR is a thiol-based oxidation-sensing regulator of the XRE family that modulates C. glutamicum oxidative stress resistance
Authors: Si Meiru , Chen Can , Zhong Jingyi , Li Xiaona , Liu Yang , Su Tao , Yang Ge
Published: October 2020

Background

Corynebacterium glutamicum thrives under oxidative stress caused by the inevitably extreme environment during fermentation as it harbors antioxidative stress genes. Antioxidant genes are controlled by pathway-specific sensors that act in response to growth conditions. Although many families of oxidation-sensing regulators in C. glutamicum have been well described, members of the xenobiotic-response element (XRE) family, involved in oxidative stress, remain elusive.

Results

In this study, we report a novel redox-sensitive member of the XER family, MsrR (multiple stress resistance regulator). MsrR is encoded as part of the msrR-3-mst (3-mercaptopyruvate sulfurtransferase) operon; msrR-3-mst is divergent from multidrug efflux protein MFS. MsrR was demonstrated to bind to the intergenic region between msrR-3-mst and mfs. This binding was prevented by an MsrR oxidation-mediated increase in MsrR dimerization. MsrR was shown to use Cys62 oxidation to sense oxidative stress, resulting in its dissociation from the promoter. Elevated expression of msrR-3-mst and mfs was observed under stress. Furthermore, a ΔmsrR mutant strain displayed significantly enhanced growth, while the growth of strains lacking either 3-mst or mfs was significantly inhibited under stress.

Conclusion

This report is the first to demonstrate the critical role of MsrR-3-MST-MFS in bacterial stress resistance.
Overexpression of microRNA-367 inhibits angiogenesis in ovarian cancer by downregulating the expression of LPA1
Authors: Zheng Qingling , Dai Xin , Fang Wei , Zheng Yan , Zhang Jin , Liu Yanxiang , Gu Donghua
Published: October 2020

Background

Compelling evidences reported the role of microRNAs (miRNAs) in ovarian cancer. However, little was known regarding the molecular mechanism of miR-367 in ovarian cancer. This study intended to investigate the role and regulatory mechanism of miR-367 in ovarian cancer involving lysophosphatidic acid receptor-1 (LPA1).

Methods

Potentially regulatory miRNAs in ovarian cancer were obtained from bioinformatics analysis. RT-qPCR was used to detect miR-367 expression in both ovarian cancer tissues and relevant adjacent normal tissues. Relationship between miR-367 and LPA1 was predicted by miRNA database and further verified using dual luciferase reporter gene assay and RIP. EdU and Transwell assay were used to measure the proliferation and invasion ability of cells. Moreover, tube formation and chick chorioallantois membrane (CAM) assay were performed to determine angiogenesis of human umbilical vein endothelial cells (HUVECs). Finally, the roles of LPA1 in tumor growth was also studied using nude mice xenograft assay.

Results

High expression of LPA1 and low expression of miR-367 were observed in ovarian cancer tissues and cells. Overexpressed miR-367 downregulated LPA1 expression to inhibit proliferation, invasion, and angiogenesis of cancer cells. Low expression of LPA1 suppressed tumor formation and repressed angiogenesis in ovarian in vivo.

Conclusion

All in all, overexpression of miR-367 downregulated LPA1 expression to inhibit ovarian cancer progression, which provided a target for the cancer treatment.
Evaluation of the potential role of long non-coding RNA LINC00961 in luminal breast cancer: a case–control and systems biology study
Authors: Mehrpour Layeghi Sepideh , Arabpour Maedeh , Esmaeili Rezvan , Naghizadeh Mohammad Mehdi , Tavakkoly Bazzaz Javad , Shakoori Abbas
Published: October 2020

Background

Luminal subtype is the most common subgroup of breast cancer (BC), accounting for more than 70% of this cancer. Long non-coding RNAs (lncRNAs) are a group of RNAs which play critical roles in diverse cellular processes. It is proved that dysregulation of them can contribute to the development of various cancers, including BC. LINC00961 was reported to be downregulated in several cancers, however, its expression level in BC remains largely unknown. The purpose of the present study was to investigate the possible role of LINC00961 in luminal A and B subtypes of BC.

Methods

To obtain novel lncRNAs associated with different cancers and differentially expressed lncRNAs (DElncRNAs) between BC tumor and normal tissues, Lnc2Cancer and GDC databases were used, respectively. After performing literature review, the expression level of the selected lncRNA (LINC00961) was evaluated in 79 luminal A and B BC specimens and adjacent non-cancerous tissues by Quantitative Reverse Transcription PCR (qRT-PCR). LINC00961 expression was also evaluated in two luminal A BC cell lines, compared to a normal breast cell line. The comparison of the differences between tumor and adjacent non-tumor samples was performed by paired sample t-test. Moreover, correlation analysis between LINC00961 expression and clinicopathological features was performed using the chi-square, fisher exact, and independent t-test. In order to investigate the possible roles of LINC00961 in luminal A and B BC, different bioinformatics analyses such as functional annotation of the LINC00961 co-expressed genes and protein–protein interaction (PPI) networks construction were also performed.

Results

LINC00961 was selected as a significant DElncRNA which had not been studied in BC. According to q-RT PCR assay, LINC00961 was downregulated in luminal BC tissues and cell lines. Its expression was correlated with smoking status and the age of menarche in luminal BC patients. Also, the results of the bioinformatics analysis were consistent with the data obtained from q-RT PCR assay. The final results indicated that LINC00961 might be involved in multiple cancer-associated pathways such as chemokine, Ras and PI3K–Akt signaling pathways, GPCR ligand binding, and signal transduction in luminal subtypes of BC. CDH5, GNG11, GNG8, SELL, S1PR1, CCL19, FYN, ACAN, CD3E, ACVRL1, CAV1, and PPARGC1A were identified as the top hub genes of the PPI networks across luminal subgroup.

Conclusion

Our findings suggested that LINC00961 was significantly downregulated in luminal A and B subtypes of BC. Moreover, bioinformatics analysis provided a basis for better identification of the potential role of LINC00961 in luminal subtype of BC.
Micelles self-assembled by 3-O-β-d-glucopyranosyl latycodigenin enhance cell membrane permeability, promote antibiotic pulmonary targeting and improve anti-infective efficacy
Authors: Zhang Man , Ye Lili , Huang Hao , Cheng Dandan , Liu Kaixin , Wu Wenbo , Shen Fukui , Jiang Zhihong , Hou Yuanyuan , Bai Gang
Published: October 2020

Background

Nanoparticle-based pulmonary drug delivery systems are commonly developed and applied for drug-targeted delivery. They exhibit significant advantages compared to traditional pulmonary drug delivery systems. However, developing the formulation of each drug is a time-consuming and laborious task.

Results

In this study, a universal lung-targeting nanoparticle was designed and constructed. The self-assembled micelles were composed of a platycodon secondary saponin, 3-O-β-d-glucopyranosyl platycodigenin 682 (GP-682), based on its specific amphiphilic structure. The GP-682 micelles exhibited a relatively stable zeta potential with a particle size between 60 and 90 nm, and the critical micelle concentration (CMC) value was approximately 42.3 μg/mL. Preincubation of GP-682 micelles markedly enhanced their cell membrane permeability and improved drug uptake in vitro. The results were visualized using fluorescent dye tracing, transmission electron microscopy (TEM) observations and the lactate dehydrogenase (LDH) release assay. The obtained benefits enhanced the distribution of levofloxacin (Lev) in mouse lung tissue and reduced antibiotics overdosing. The acute lung injury mouse model induced by the Pseudomonas aeruginosa PA 14 strain demonstrated that preinjection of GP-682 micelles before antibiotic administration resulted in a higher survival rate and anti-infective efficacy in vivo. It also caused reductions in pulmonary injury, bacterial invasion and cytokine expression compared with treatment with Lev alone.

Conclusions

GP-682 micelles are another nanoparticle-based pulmonary drug delivery system and provide a new lung-targeting therapy option.
Cross-cultural adaptation and validation of the Amsterdam Instrumental Activities of Daily Living questionnaire short version German for Switzerland
Authors: Bruderer-Hofstetter Marina , Dubbelman Mark A. , Meichtry André , Koehn Florian , Münzer Thomas , Jutten Roos J. , Scheltens Philip , Sikkes Sietske A. M. , Niedermann Karin
Published: October 2020

Background

Instrumental Activities of Daily Living (IADL) limitations are associated with reduced health-related quality of life for people with mild cognitive impairment (MCI). For these people, the assessment of IADL is crucial to the diagnostic process, as well as for the evaluation of new interventions addressing MCI. The Amsterdam IADL Questionnaire Short Version (A-IADL-Q-SV) is an established assessment tool with good psychometric properties that has been shown to be robust to cultural differences in Western countries. The aims of this study were to: (1) cross-culturally adapt and validate the A-IADL-Q-SV for the German-speaking population of Switzerland; (2) investigate its cultural comparability; and (3) evaluate further psychometric properties.

Methods

The A-IADL-Q-SV German was pretested on clinicians and participants in a memory clinic setting. The psychometric properties and cultural comparability of the questionnaire were investigated in memory clinic settings including participants with MCI or mild dementia, as well as participants with normal cognition recruited from the community. Item response theory (IRT) was applied to investigate measurement invariance by means of differential item functioning to assess item bias. Additionally, the test–retest reliability on scale level, the construct validity through hypothesis testing and the discriminant validity of the A-IADL-Q-SV German were evaluated.

Results

Ninety-six informants of participants with normal cognition, MCI or mild dementia completed the A-IADL-Q-SV German. The basic assumptions for IRT scoring were met. No meaningful differential item functioning for culture was detected between the Swiss and Dutch reference samples. High test–retest reliability on scale level (ICC 0.93; 95% CI 0.9–0.96) was found. More than 75% of the observed correlations between the A-IADL-Q-SV German and clinical measures of cognition and functional status were found to be in the direction and of the magnitude hypothesized. The A-IADL-Q-SV German was shown to be able to discriminate between participants with normal cognition and MCI, as well as MCI and mild dementia.

Conclusions

The A-IADL-Q-SV German is a psychometrically robust measurement tool for a Swiss population with normal cognition, MCI and mild dementia. Thus, it provides a valuable tool to assess IADL functioning in clinical practices and research settings in Switzerland.

Trial registration This study was registered retrospectively in July 2019 on ClinicalTrials.gov (NCT04012398).
Associations between gut microbiota and Alzheimer’s disease, major depressive disorder, and schizophrenia
Authors: Zhuang Zhenhuang , Yang Ruotong , Wang Wenxiu , Qi Lu , Huang Tao
Published: October 2020

Background

Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer’s disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ).

Methods

A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively.

Results

We found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79–0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92–1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00–1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83–0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00–1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02–1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition.

Conclusions

These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.